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The Role of Ligands in the Chemical Synthesis and Applications of Inorganic Nanoparticles

The Role of Ligands in the Chemical Synthesis and Applications of Inorganic Nanoparticles This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. Review pubs.acs.org/CR Cite This: Chem. Rev. 2019, 119, 4819−4880 The Role of Ligands in the Chemical Synthesis and Applications of Inorganic Nanoparticles †,◇ ‡,⊥ ■ § ∥,⊥ Amelie Heuer-Jungemann, Neus Feliu, Ioanna Bakaimi, Majd Hamaly, Alaaldin Alkilany, ⊥ + #,^ ∇ ○,◆ Indranath Chakraborty, Atif Masood, Maria F. Casula, Athanasia Kostopoulou, Eunkeu Oh, ○,◆ ◆ ¶ ∇ Kimihiro Susumu, Michael H. Stewart, Igor L. Medintz, Emmanuel Stratakis, ⊥ ,† Wolfgang J. Parak, and Antonios G. Kanaras* School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO17 1BJ, U.K. Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm 171 77, Sweden King Hussein Cancer Center, P. O. Box 1269, Al-Jubeiha, Amman 11941, Jordan Department of Pharmaceutics & Pharmaceutical Technology, School of Pharmacy, The University of Jordan, Amman 11942, Jordan Fachbereich Physik, CHyN, Universitaẗ Hamburg, 22607 Hamburg, Germany INSTM and Department of Chemical and Geological Sciences, University of Cagliari, 09042 Monserrato, Cagliari, Italy Institute of Electronic Structure and Laser, Foundation for Research and TechnologyHellas, Heraklion, 71110 Crete, Greece KeyW Corporation, Hanover, Maryland 21076, United States Optical Sciences Division, Code 5600, U.S. Naval Research Laboratory, Washington, D.C. 20375, United States Center for Bio/Molecular Science and Engineering, Code 6900, U.S. Naval Research Laboratory, Washington, D.C. 20375, United States Fachbereich Physik, Philipps Universitaẗ Marburg, 30357 Marburg, Germany School of Chemistry, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO171BJ, U.K. Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy ABSTRACT: The design of nanoparticles is critical for their efficient use in many applications ranging from biomedicine to sensing and energy. While shape and size are responsible for the properties of the inorganic nanoparticle core, the choice of ligands is of utmost importance for the colloidal stability and function of the nanoparticles. Moreover, the selection of ligands employed in nanoparticle synthesis can determine their final size and shape. Ligands added after nanoparticle synthesis infer both new properties as well as provide enhanced colloidal stability. In this article, we provide a comprehensive review on the role of the ligands with respect to the nanoparticle morphology, stability, and function. We analyze the interaction of nanoparticle surface and ligands with different chemical groups, the types of bonding, the final dispersibility of ligand-coated nanoparticles in complex media, their reactivity, and their performance in biomedicine, photodetectors, photovoltaic devices, light-emitting devices, sensors, memory devices, thermoelectric applications, and catalysis. 2.2.2. Magnetic Nanoparticles 4833 CONTENTS 2.2.3. Luminescent Nanoparticles 4834 1. Introduction 4820 2.2.4. Other Nanoparticles 4838 2. Surface Stabilization of Colloidal Nanoparticles 4822 3. Ligand Modification for Well-Dispersed and 2.1. Ligand Coating on Inorganic Nanoparticles Functional Nanoparticles in Complex Media 4839 Synthesized in Aqueous Media 4822 3.1. Ligand Coating of Nanoparticles for Bio- 2.1.1. Plasmonic Nanoparticles 4822 medical Applications 4840 2.1.2. Magnetic Nanoparticles 4828 3.1.1. Ethylene Glycol Containing Ligands 4840 2.1.3. Luminescent Nanoparticles 4829 2.2. Ligand Coating on Nanoparticles Synthe- sized in Organic Media 4832 Received: December 3, 2018 2.2.1. Plasmonic Nanoparticles 4832 Published: March 28, 2019 © 2019 American Chemical Society 4819 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Downloaded via 78.15.220.100 on May 5, 2019 at 17:49:23 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Chemical Reviews Review 3.1.2. Silanes 4842 manner. For example, NPs can be equipped with targeting and 3.1.3. Oligonucleotides 4845 cargo delivery abilities, engineered to be biocompatible or 15−23 3.1.4. Small Peptides 4847 designed to assemble in an ordered manner. The ability to 3.1.5. Proteins 4848 attach a large number of various types of ligands to the surface 3.1.6. Carbohydrates 4849 of a single NP offers additional benefits such as higher 3.2. Ligand Coating of Nanoparticles for Other reactivity at the local microenvironment around the NP core Applications 4850 and multitasking performance. Therefore, the appropriate 3.2.1. Photodetectors 4851 choice of ligands plays a critical role in the structure, colloidal 3.2.2. Photovoltaic Devices 4852 stability, and function of NPs. Appropriate protocols to coat 3.2.3. Light-Emitting Devices 4854 the NP surface with ligands or perform secondary conjugation 3.2.4. Sensors 4855 ligand reactions define the quality of NPs. To choose suitable 3.2.5. Memory Devices 4856 ligands for either direct synthesis of NPs or postsynthetic 3.2.6. Thermoelectric Applications 4857 modification of a NP surface, there are many important 3.2.7. Catalysis 4859 parameters to consider which will directly affect intended 4. Conclusions and Future Perspectives 4860 application. These include: (1) The chemical composition of the 4.1. Stability of NPs 4861 NP surface: The nature and strength of bonding between the 4.2. Density and Steric Configuration of Surface ligand and NP surface is strongly correlated to the individual Ligands 4861 characteristics of each NP type. For example, carboxyl and Author Information 4861 hydroxyl groups have a strong binding affinity for iron oxide Corresponding Author 4861 NPs, whereas thiols have high affinity to gold surfaces. The ORCID 4861 strength of ligand binding is critical to the long-term colloidal Present Address 4861 stability of NPs, and when they are coated with weak affinity Notes 4861 ligands they must be stored either as powders or in an excess Biographies 4861 amount of free ligand in solution to retain sufficient ligand Acknowledgments 4863 coverage. The use of multidentate anchoring groups on ligands Abbreviations Used 4863 can additionally aid in increasing binding strength and hence References 4864 colloidal particle stability. Table 1 shows an overview of some Table 1. Different NPs and Common Anchoring Groups 1. INTRODUCTION Used for Ligand Conjugation Nanoparticles (NPs) have attracted great research interest due common anchoring group for ligand to their unique properties, which derive from a combination of NP composition conjugation their intrinsic characteristics such as chemical composition, noble metal thiol (−SH) size, shape, and the type of molecules employed to coat their amine (−NH ) surface. Owing to the inorganic core composition, metallic carboxyl (−COOH) NPs (especially gold and silver) can exhibit strong optical phosphine (−PR ) 1−4 absorption and scattering, while semiconductor quantum dots (e.g., cadmium selenide (CdSe) or cadmium telluride semiconducting quantum dot phosphine oxide (O = PR ) (CdTe), lead sulfide (PbS), and perovskite NPs (e.g., thiol (−SH) methylammonium or cesium lead halides) can be highly phosphonyl (−PO(OR) ) 5−7 fluorescent as a result of their electronic band structure. On carboxyl (−COOH) the other hand, NPs synthesized from magnetic materials (e.g., iron oxide or cobalt) can exhibit unique magnetic phenomena transition metal oxide carboxyl (−COOH) such as superparamagnetism, which are not encountered in the hydroxyl (−OH) 8,9 corresponding bulk counterparts. These properties have phosphonyl (−PO(OH) ) rendered NPs highly interesting candidates for a vast variety of amine (−NH ) 6,10−13 applications. One of the key parameters to synthesize robust and well crystalline NPs of defined morphologies and function is the choice of surface ligands. Ligands play multiple of the NPs discussed in this review as well as common roles ranging from the regulation of the solubility and anchoring groups for ligand attachment. Figure 1 shows an availability of active components during NP synthesis to the example of the variety of different ligands and anchoring post synthetic minimization of surface energy of NPs (required groups available for NP functionalization, illustrated here for for their colloidal stability) as well as the encoding of NP the case of colloidal quantum dots (QDs). This figure functionality. The type of ligands employed to fulfill these epitomizes the diversity of NP ligand chemistry using the roles include small organic compounds with redox properties example of QDs and surface ligand strategies applied for or ability to complexate with active components (e.g., biological applications. First it highlights how different trisodium citrate, oleic acid, etc.), large polymers (e.g., strategies can be utilized to attach a ligand to the QD surface polyethylene glycols) with tunable polarity to preferentially by direct coordination or hydrophilic interdigitating of ligands bind crystallographic domains on the NP surface, or other to the native moiety present on the as-synthesized QD. A functional biomolecules (such as peptides, proteins, and variety of different mechanisms can be utilized to stabilize QDs oligonucleotides), which enrich NPs with additional proper- such as charge or the hydrophilicity of ethylene glycol repeats. ties. An additional feature of surface ligands is the option to The different sizes of ligands, impact the overall hydrodynamic offer multiple functionalities, which can act in a synergistic radius of the nanoparticles, and any downstream utility 4820 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 1. (A) Ligand binding at the QD surface. (B) Association of an amphipol (blue) with the native QD ligands (red). (C) Ligand chemistries (i) thioalkyl acids, (ii) PEGylated ligands, (iii) zwitterionic ligands, (iv) dihydrolipoic acid ligands and (v) PEGylated, (vi) zwitterionic and (vii) modular derivatives thereof, (viii) multidentate charged, and (ix) multidentate PEGylated ligands. (D) Amphipol coatings (i) phospholipid micelles, (ii) hydrophilic polymer backbones grafted with alkyl chains, (iii) triblock copolymers, and (iv) alternating copolymers that hydrolyzeto acids or (v) are grafted with PEG chains. (E) Copolymers with pendant PEG oligomers and (i) dithiol or (ii) imidazole groups. Discrete moieties for (a) QD binding, (b) solubility, and (c) bioconjugation are identified where applicable (green). The arrows illustrate a conceptual progression and not synthetic pathways or chronological development. Reprinted with permission from ref 27. Copyright 2011 American Chemical Society. especially in a biological context. The end groups displayed on range of different pH values, buffers, and biological or organic the ligands are also important for bioconjugation of functional media. For example, intracellular applications will limit the molecules to the QD. (2) The environment the particles are choice of ligands to the ones that are biocompatible and can designed for: The appropriate selection of a ligand to coat NPs ideally protect the particles from nonspecific binding of is directly correlated to the actual environment that the biomolecules (e.g., proteins) and will also require ligands particles will be utilized in. NPs may need to be dispersed in a that bind strongly to the NPs surface and remain bound in 4821 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review complex biological media and buffers. (3) The desired NP ligands retain their colloidal stability via repulsion forces, while morphology: Ligands will have different binding energies, ligands that occupy significant space stabilize the NPs via steric diffusion rates, and packing characteristics near the NP surface, effects. The surface stabilizing ligands can be present during which, in turn, influences the final morphology imparted to the the nucleation and growth of the NPs (surface passivation NPs during synthesis. For example, the presence of thiols during synthesis), or they can be added post synthetically to during the reduction of gold salts to form gold NPs (Au NPs) exchange ligands to the NPs’ surface. In the following section, usually favors the growth of smaller size particles ranging from we focus on the synthesis of NPs in the presence of the surface 1 to 10 nm. On the other hand, the use of weakly interacting stabilizing ligands. This route represents the most straightfor- ligands (such as citrate ions, which bind electrostatically to Au ward approach to introduce surface functionalization on the NPs) allows the growth of colloidal particles ranging from 2 NP surface and provides a significant example on the nm up to 100 nm and beyond. Other types of ligands, such multifaceted and powerful role of ligands. as the amphiphilic cetyltrimethylammonium bromide (CTAB), 2.1.1. Plasmonic Nanoparticles. Surface Passivation act as a stabilizing agent and shape directing agent due to its during Synthesis. One of the first chemical syntheses of gold differential adsorption to gold facets and thus driving the NPs (Au NPs) was reported by Michael Faraday in 1857. growth not only of spherical but also anisotropic nanomaterials Gold hydrosols were prepared by the reduction of an aqueous such as gold nanorods (Au NRs), cubes, and stars. (4) The solution of chloroaurate and phosphorus (or hydrogen) need for secondary chemical modification of the ligand shell: For dissolved in carbon disulfide. Later, Turkevich published an secondary modification of NPs with biomolecules or other alternative chemical method to synthesize spherical gold desired polymers, specific functional groups are needed to NPs, which involved the thermal reduction of gold ions in an provide a chemical handles for subsequent coupling chemistry. aqueous trisodium citrate solution. When the trisodium citrate In many cases, these groups are placed at a ligand’s termini or was added to the boiling aqueous solution of gold salt under periphery. However, these functional groups can limit the vigorous stirring, a color change from purple to ruby-red could choice of a ligand due to potential additional unwanted be observed, indicating the formation of spherical Au NPs. The interactions with the NP surface. The number and availability method was further developed by G. Frens to enable control of these groups are important factors in any subsequent over the Au NP size by varying the ratio of gold salt to sodium chemistry as is their propensity for cross-linking. In other cases, citrate. Since then, numerous modifications and detailed biomolecules can be attached directly to a NP surface but this kinetic studies of the Turkevich process have been may be at the cost of displacing some of the stabilizing ligands 32−37 reported. It was also found that sodium citrate plays or even losing biological activity of the biomolecules due to multiple roles during the reaction. Besides reducing the gold their interactions with the NP surface. Clearly, the salt and stabilizing the NP surface via electrostatic repulsion, experimental protocols for ligand conjugation to NPs must citrate also plays a crucial role in determining the reaction pH, be customized to the various types of ligands available in which in turn is correlated with the final size and dispersity of conjunction with what is desired in the final application. the resulting NPs. Citrate adsorbs onto the gold surface Fortunately, the depth and diversity of this field continues to through its carboxyl groups with different possible binding grow at an astounding rate and this serves to provide a strong modes. It was shown that changes in pH drastically alter its literature resource from which to draw. This review will focus affinity to gold. While at neutral pH, only the central on the role of the ligands in determining the formation, carboxylate group is adsorbed on the surface, at pH ≥ 11 all functionalities, and applications of NPs. Various postsynthetic of the carboxyl and hydroxyl groups are adsorbed. The strategies to functionalize and stabilize NPs of different negative charge of citrate provides colloidal stability through chemical composition (metal, metal oxide, semiconductor, electrostatic repulsion and electrostatically coated colloids are organic) and morphologies dispersed in aqueous or organic well-dispersed in water. However, a disadvantage of the media are discussed. As extensive research in the field of NPs’ electrostatic stabilization is the inherent susceptibility of the design has demonstrated that the use of ligands during NPs to irreversible aggregation induced by high salt synthesis has a dramatic effect on the resulting size, shape, concentrations and pH changes. On the other hand, the crystal structure, dispersion, and colloidal stability, the ligands weak binding of citrate can also be of benefit when a employed to assist NPs synthesis in aqueous or organic media postsynthetic ligand exchange is required. Post ligand will also be reviewed. Furthermore, commonly chosen ligands exchange is highly feasible for citrate protected Au NPs by to coat various types of NPs for specific biomedical or energy applications will be discussed. Representative examples of considering the weak binding of citrate to the Au NPs (6.7 kJ/ ligands and their utility from the literature are employed to mol). Ligand exchange with numerous other ligands of 42−45 accentuate this discussion and highlight key approaches along different anchoring groups such as thiolates and 43,46,47 with many of the remaining issues. Clearly, the vastness of this amines have been reported, which also enhance their 44,48,49 field precludes us from doing a comprehensive review of every colloidal stabilities and biocompatibilities. Among these, example and our apologies are extended for any and all thiol exchange has been found more effective and extensively omissions. used because thiol interacts strongly with the gold surface 50,51 (126−167 kJ/mol). Although citrate is often utilized as a capping agent for Au NPs, other types of metal NPs made from 2. SURFACE STABILIZATION OF COLLOIDAL NANOPARTICLES Ag, Pt, Pd, or Cu have also been synthesized using sodium citrate. For example, it was shown that triangular core−shell 2.1. Ligand Coating on Inorganic Nanoparticles gold−silver nanoprisms with a citrate coating could be grown Synthesized in Aqueous Media from citrate Au NPs used as seeds, by irradiating at the Ligands enable the colloidal stability of NPs via electrostatic plasmon frequency. In a systematic study, Zhang et al. and/or steric interactions. NPs stabilized with highly charged similarly described how to obtain different sizes/shapes of Ag 4822 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 2. Synthetic scheme and corresponding TEM images of Au@citrate NP synthesis of tunable size. In the first step, NP seeds of 3.6 nm are formed. Subsequent injection steps yield larger NPs with excellent size monodispersity. Reprinted with permission from ref 55. Copyright 2016 American Chemical Society. nanoplates by using a combination of citrate, PVP, polyol (EG, Although often used in conjunction with sodium citrate, tannic acid has also been employed on its own for the synthesis PEG, TEG, DEG), and hydrogen peroxide. of Ag NPs with sizes ranging from 3.3 to 22.1 nm. Besides Sodium citrate has also been used in conjunction with tannic citrate and tannic acid, sodium acrylate has also been reported acid to produce highly monodisperse Au NPs with sizes 54,55 for the synthesis of highly monodisperse Au NPs (2% ranging from 3.6 to 200 nm. The method included a polydispersity index) with sizes ranging from 10 to 100 nm. multistep seed-mediated growth reaction as shown in Figure 55 Here, repetitive additions of the Au−ligand complex were used 2. In another report, sodium citrate has also been used in to control the resulting particle size. Both tannic acid and conjunction with hydroquinone to prepare monodispersed Au sodium acrylate follow similar mechanisms for NP formation NPs at room temperature. as in the case of citrate, acting both as reducing agents and A similar synthetic route employing sodium citrate and stabilizing the NPs through carboxylate groups. tannic acid was also reported for the formation of highly Surfactants as Capping Agents. Cetyltrimethylammonium monodisperse silver NPs (Ag NPs) with sizes ranging from 14 bromide (CTAB) has been widely utilized in the synthesis of to 200 nm. Following on the early work of Henglein et al., both spherical and anisotropic NPs such as gold nanorods (Au the uniformity, final size, and crystallinity of Ag NPs could be NRs). Murphy and co-workers as well as other groups carried changed as a function of the concentration of citrate because out comprehensive studies to prepare high quality Au these NPs coalesce at lower citrate concentrations. nanorods (Au NRs) employing a seed-mediated wet chemistry 4823 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 3. Schematic illustration of the synthesis of a β-cyclodextrin-functionalized Au NP, which can be loaded via a host−guest interaction with an adamantane−Pt(IV) complex. Reprinted with permission from ref 87. Copyright 2013 American Chemical Society. protocol, in which CTAB was used as a stabilizing and shape Unlike citrate, alkyl ammonium halide ligands provide the directing ligand (promoting the formation of rod shaped NP with a net positive charge. Similar to citrate, alkyl 61−64 particles). Although the exact mechanism for the ammonium halides bind weakly to the NP surface, allowing for facile ligand exchange reactions with stronger binding formation of Au NRs still remains somewhat unclear, it is ligands (e.g., thiol containing compounds), which can render evident that CTAB binds preferentially to the (100) crystal the NPs appropriate for biomedical applications. plane on the side of the NR promoting an anisotropic crystal Thiol Containing Ligands on NPs. Because of the strong growth (unidirectionally) on the (111) facets at the tips. On −1 Au−thiol interaction (bond strength of 40−50 kcal mol ), the another example, branched Au NPs with different degrees of synthesis of Au NPs with thiolated ligands results in NPs which branching were prepared in the presence of CTAB, ascorbic typically have excellent colloidal stability. The most acid, and silver. The degree of NP branching and size were also commonly accepted model for thiol−Au interaction is the tuned by regulating the amounts of the reducing agent ascorbic binding of the deprotonated sulfhydryl group (forming a thiyl acid and inducing preferential binding of CTAB and silver. radical) to Au. In its protonated form, SH is only able to bind The use of surfactant mixture such as sodium oleate combined to gold through the lone pair electrons on the sulfur, forming with CTAB was shown to be a successful strategy to obtain Au coordination-type bonds. For example, it was shown that the NRs with superior quality (percentage of rod-shape particles), small thiol-containing biomolecule glutathione (GSH), a dimensional tunabiltity and even stability under oxidizing 67 common antioxidant, could be used to produce ultrasmall conditions. Furthermore, the inclusion of aromatic additives Au NPs (0.9 nm) in a methanol−water mixture (2:3). Some during CTAB-mediated Au NR growth can narrow the size other examples of thiols used to produce ultrasmall Au NPs distribution of the resulting NRs. The aromatic additives can be found in ref 76. On the other hand, slightly larger Au intercalate in the CTAB micelle altering its micelle behavior. NPs with diameters ranging from 2.3 to 10 nm could be The micellar packing can be tuned according to the type of prepared by mixing an aqueous solution of gold salt with additive used to derive monodisperse micelles. The use of mercaptopropionate and citrate under reflux. Dithiol other additional cosurfactants such as cetyltrimethylammo- containing compounds such dihydrolipoic acid (DHLA) have nium chloride (CTAC) and decyltrimethylammonium bro- also shown great promise for the synthesis of Au NPs. While mide (DTAB) was shown to result in shorter aspect ratio rods the thiol−gold bond provides strong ligand binding, the but with a poorer yield of Au NRs. These observations were terminal carboxylate moiety provides the particles with attributed to the direct influence of chlorine counterions and electrostatic stabilization and further offers a site for additional DTAB to the CTAB micelles. CTAC has further been used postsynthetic modification. In addition, it was found that the in the synthesis of triangular Au nanoplatelets in combination displacement of the DHLA ligands was more difficult with iodine ions. The gold nanoplatelets’ growth is promoted compared to other thiol-containing ligands, which was by the preferential binding of I− ions to the Au (111) facet as attributed to the dithiol binding versus monothiol binding. well as through oxidative etching, removing less stable nuclei. Another very popular coating for NPs are (thiolated) ethylene 79,80 Tetradecyltrimethylammonium bromide (TTAB) is another glycols and their derivatives. Alkyl-thiol containing ligands micelle-forming ligand, which has been employed to synthesize such as thioalkylated tetraethylene glycol (TTG) have also cubic and cuboctahedra shape of platinum NPs (Pt NPs) been used to stabilize Au NPs. This ligand was superior as during a borohydride reduction. opposed to traditional PEG coatings due to its dual functional 4824 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review properties. While its hydrophobic part could firmly assemble and pack to a monolayer around the hydrophobic Au core, the hydrophilic part (ethylene glycol) rendered the particles very stable in water and challenging biological environments. A one- pot synthesis of Au NPs by using bidentate thiolated PEG (M : 550−750 Da), via room temperature Au reduction with sodium borohydride (for 1−16 nm Au NPs), and a seeded growth method in boiling water (for 10−130 nm) was also reported by Oh et al.. The thiolated PEG ligands allowed for the functionalization of Au NPs with various biomolecules through amide bond formation (amine-PEG-Au NPs, carboxyl- 82−84 PEG-Au NPs) and click chemistry (azide-PEG-Au NPs). Furthermore, the thiolated PEG ligands provided enhanced colloidal stability to Au NPs under a wide range of conditions with respect to their monothiolated counterparts. Thio- sulfates (Bunte salts) have also been used as ligand precursors to synthesize Au NPs (1.5−20 nm) stabilized with mercaptoethoxyethoxyethanol, 9-mercaptononanoic acid, and mercaptopentyl(trimethylammonium) chloride. Beyond these types of thiols, cage-like molecules such as β- cyclodextrin have also been used as ligands for Au NPs. Si et al. reported a per-6-thio-β-cyclodextrin protected Au NP of size Figure 4. Structure of the BSPP ligand (a). TEM image (b) and 4.7 ± 1.1 nm (Figure 3), which can be used as a cargo for the HRTEM image (c) of BSPP-stabilized Au NPs prepared in aqueous delivery of a cisplatin prodrug (oxoplatin−adamentane solvent at room temperature. Adapted with permission from ref 88. Copyright 2011 Elsevier. conjugate). This binding is due to the well-known strong host−guest interaction between adamantane and β-cyclo- dextrin. presence of sodium polyacrylate, where the concentration ratio Phosphines as Ligands. Triphenyl phosphine (TPP) and of polyacrylate to Pt determined whether cubic, tetrahedral, its derivatives have been widely used as ligands to synthesize or icosahedral, cuboctahedral, or irregular-prismatic NPs were 91−93 coat Au NPs. While TPP is soluble in organic solvents, many formed. Another interesting study revealed that poly(vinyl of its derivatives, such as as bis(p-sulfonatophenyl)phenyl) pyrrolidone) (PVP)-stabilized Au NPs showed changes in their phosphine dehydrate (BSPP), are soluble in aqueous solvent. optical properties due to energy transfer between the PVP and Zhong et al. synthesized monodisperse Au NPs using BSPP as Au NP core. In hot water, dispersed PVP molecules served the ligand (figure 2.3 ). The particle size could be adjusted by not only as a surface ligand but also governed clustering and controlling the pH of the solution. Synthesis at higher pH growth of polygonal Au NPs (25−50 nm in diameter) using (using NaOH, pH ∼ 12) yielded ultrasmall sized nanoclusters small polymer templates. PVP was also used to synthesize 4−8 (NCs), whereas synthesis at neutral pH yielded 4 nm Au NPs nm cuboctahedral Pd NPs by a polyol reduction method using as presented in Figure 4. ethylene glycol. A good summary of the roles of PVP in the BSPP and other related derivatives introduced by Schmid et synthesis of colloidal NPs can be found in this perspective al., have been used extensively for the stabilization of Au article: Similar to PVP, poly(vinyl alcohol) (PVA) has also 89,90 nanospheres among other materials. Unlike thiols, been shown as a suitable ligand for NP synthesis. Copper NPs phosphines bind to Au via the phosphorus’ lone electron (Cu NPs) could be formed by reduction with citrate in the pair. This type of bond is stronger than the electrostatic presence of sodium formaldehyde sulfoxylate (SFS) and interactions between citrate or alkyl halides and Au, but still PVA. PEG was also tested for stabilizing the Cu NPs during not as strong as the sulfur−Au bond, thus allowing for facile reduction with borohydride/ascorbic acid, and the size (4−28 ligand exchange. The mechanism by which NPs are stabilized nm) was controlled by changing the amount of PEG with by phosphines is believed to arise from both charge and steric concomitant plasmon band shifts observed near 560−570 interactions owing to the bulky aromatic rings on TPP nm. Near-monodisperse 1.4−4 nm Au NPs were synthesized derivatives. Additionally, an advantage of using charged in an aqueous solution of alkyl thioether end-functionalized phosphines such as BSPP as a capping agent is the ability to poly(methacrylic acid), where the desired product size again redisperse aggregated NPs previously precipitated by the depended on the ratio of polymer to Au. Various sizes of addition of salt. This allows for the concentration of AuNP polyelectrolyte-protected Au NPs have been obtained directly solutions by centrifugation, which is an important preparatory by heating AuCl in an aqueous solution of amine-containing step for many subsequent applications. On the other hand, polyelectrolytes such as poly(ethylenimine) and poly- citrate capped particles can display irreversible aggregation (allylamine hydrochloride). Wang et al. reported a one- behavior due to the weak binding to the Au surface. step aqueous preparation of highly monodisperse Au NPs with Polymers and Plasmonic NPs. Polymers can sterically and diameters below 5 nm using thioether- and thiol-functionalized electrostatically stabilize NPs by physisorption or chemisorp- polymer ligands: dodecanethiol (DDT)-poly(acrylic acid), tion to the NP surface. During NP synthesis, polymers can DDT-poly(methacrylic acid), DDT-poly(vinylsulfonic acid), bind preferentially to specific crystallographic planes of the NP DDT-poly(vinylpyrrolidone), DDT-poly (hydroxyethyl acryl- surface and promote preferential anisotropic crystal growth or ate), and DDT-poly(ethyleneglycol methacrylate). Here act as a matrix for nanocrystal growth. For example, the shape particle uniformity and colloidal stability as a function of of colloidal platinum NPs (Pt NPs) could be controlled in the changes in ionic strength and pH were strongly dependent on 4825 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 2. Metal NPs Synthesized in Aqueous Media material reducing agent ligand/surfactant size (nm) shape other comments Au sodium citrate sodium citrate 20 sphere (sp) thermal single phase Au reduction Au sodium citrate sodium citrate 16−149 sp thermal single phase Au reduction Au sodium citrate sodium citrate 20−100 sp RT seed-growth Ag sodium citrate sodium citrate 5−30 sp RT reduction/coalescence Ag sodium citrate sodium citrate, tannic 14−200 sp thermal seed-growth acid Au citrate, ascorbic acid sodium citrate 9−120 sp thermal/UV reduction Au pottasium citrate sodium citrate 18−100 sp/polygon thermal single phase Au reduction with pH variation c 59 Au/Ag tannic acid tannic acid 2−10/3.3-21.1 sp pH adjusted RT Au:Ag sodium citrate sodium citrate 32−172 sp thermal seed-growth Ag borohydride sodium citrate/PVP, ∼50 nanoplate, wire H O 2 2 EG, TEG, PEG Au phosphorus carbon sulfide sp Au H carbon sulfide Rod Au hydroxylamine hydroxylamine 20−119 sp RT seed-growth hydrochloride Au hydroxylamine hydroxylamine 12.7 × 11.7−116 × 112, 13.7 × sp/rod iterative RT seed-growth 11.2−233.6 × 74.2 Au borohydride alkyl thiosulfates 1.5−20 sp RT reduction Au ascorbic acid arabic gum 90−4600 sp RT reduction Au sodium citrate, ascorbic acid, SDS 5−30 sp RT seed-growth, AgNO hydrazine, NaBH Au SDS 1−5 sp laser ablation Ag SDS 10 sp laser ablation Cu sodium citrate, hydrazine sodium formaldehyde 30 sp thermal reduction hydrate, sulfoxylate, PVA 92,93 Pt polyacrylate polyacrylate 4−18 cube, polygon Ar gas in RT Au ascorbic acid CTAB 37/200 × 17 sp/rod iterative RT seed-growth Au borohydride, ascorbic acid CTAB 20−100 (AR: 2−4) rod RT seed-growth Au ascorbic acid DTAB, CTAB 22−25 (W), 25−170 (L) rod RT reduction Au borohydride HTAB, CTAB 20−80 (W), 200−800 (L) elongated rod 40 °C thermal seed-growth Pt borohydride TTAB 12−14 cube, H gas pressure cuboctahedron Au borohydride ditri-tetra-EG <5 sp RT reduction Au lemon grass lemon grass 0.05−1.8 μm Triangle bioreduction Au PEI 25−100 sp thermal reduction Au BPEI BPEI 9.4 sp thermal reduction Cu hydrazine poly(allylamine) 40−50 sp, rod thermal reduction Au borohydride poly(methacrylic acid) 1.4−4 sp RT reduction Au borohydride PEO 3.2−7.4 sp RT reduction Au PVP PVP 83- 95 star steric effects Au PVP 25−50 polygon thermal reduction Pd ethylene glycol PVP 4−8 cubooctahedron thermal reduction Pd ascorbic acid PVP ∼9 truncated thermal reduction octahedron Pd−Pt ascorbic acid PVP ∼24 nanodentrites thermal reduction Au PDMA PMPC/PDMA ∼10 sp diblock copolymers Au borohydride PAA, PMEA, PHA, <5 sp RT reduction PVA, PEG-MA Au PEG200/8000 15−60 sp thermal reduction Cu borohydride/ascorbic acid PEG6000 4−28 sp multistep Au borohydride PEG-thiol 1−16 sp RT reduction Au borohydride, sodium citrate PEG-thiol 15−130 sp thermal seed-growth Au:D borohydride PEG-thiol 1.0−2.5 sp luminescent, D = Ag, Pt, Zn, Cu, Cd Ag borohydride, citrate PEG-thiol, PVP, citrate 10−12 sp Au polyaniline nanofibers 1−10000 sp-microsheet thermal reduction, memory devices Pd Pluronic copolymers 5−27 sp pH adjusted RT (PEO/PPO) Au@Pd@Pt ascorbic acid Pluronic copolymers 20−55 core/shell NP nanoporous (PEO/PPO/PEO) 4826 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 2. continued material reducing agent ligand/surfactant size (nm) shape other comments Au chitosan chitosan/TPP 5−300 sp, polygon cationic polysaccharide Au borohydride GSH 0.9 sp RT reduction Au borohydride GSH/NTA-lysine 2−6 sp RT reduction Au borohydride lysine 6.5 sp RT reduction Au lysine 32−95 Star 37 °C thermal seed-growth Au borohydride protein, antibody, lysine 5 → μmsp → rod freezing, −20 °C assembly Ag sorghum bran sorghum bran 50 sp RT reduction Ag ammonia glucose, galatose, 25−450 sp antimicrobial/bactericidal maltose, lactose Ag ascorbic acid BSA, lysozyme 50−60 triangle RT reduction GO/Ag luminol luminol 22 sp GSH sensing sp, spherical; rt, room temperature; PVP, poly(vinylpyrrolidone; EG, ethylene glycol; TEG, tetraethylene glycol; PEG, poly(ethylene glycol); SDS, sodium dodecyl sulfate; DTAB, decyltrimethylammonium bromide; PEI, polyethylenimine; BPEI, branched polyethylenimine; PEO, poly(ethylene oxide); PMPC, poly(2-methacryloyloxyethyl phosphorylcholine); PDMA, polydimethylsiloxane; PAA, peroxyacetic acid; PMEA, para- methoxyethylamphetamine; PHA, polyhydroxyalkanoate; PEG-MA, poly(ethylene glycol) methacrylate; TPP, triphenyl phosphine, GSH, b c d e f glutathione; NTA, nitrilotriacetic acid; GO, graphene oxide. Reference 120. Reference 121. Reference 122. Reference 123. Reference 124. g h I j k l m n o Reference 125. Reference 126. Reference 127. Reference 128. Reference 129. Reference 130. Reference 131. Reference 132. Reference p q r s t u v 133. Reference 134. Reference 135. Reference 136. Reference 137. Reference 138. Reference 139. Reference 140. the hydrophobicity of the ligand end group. Another group of co-workers employed the diblock copolymer (polystyrene-b- polymers that was successfully employed for NP synthesis are poly(acrylic acid) ) to create patchy NPs, which could further the block copolymers. Piao et al. reported the synthesis of be regioselectively functionalized with thiolated oligonucleo- palladium NPs (Pd NPs) by simply mixing aqueous solutions tides. This strategy opens up new possibilities in the control of palladium salts and triblock Pluronic copolymers, (poly- of NP assembly and presents an excellent example on the (ethylene oxide)−poly(propylene oxide)−poly(ethylene importance of choosing the appropriate ligand for NP coating. oxide)) in which the particle size (5−27 nm) and shape was Overall, the use of polymers as ligands for in situ or post controlled by varying the pH of the reaction mixtures. Later, synthetic NP coating purposes is quite broad and only a similar pluronic copolymers were used to synthesize triple- representative cross-section is provided here. Clearly, choosing layered Au@Pd@Pt core−shell NPs (25−55 nm), which an existing or new polymer type for a given NP synthesis contained nanopores inside of a multilayered NP. Addi- requires consideration of prior art in the field along with what tionally, polymers have also used in NP surface pattern- material exactly is desired. 105−107 ing. While the creation of surface-patterned or “patchy” Biomolecules and Other Ligands for Plasmonic NPs. Although not as common as previously discussed ligands, microparticles has been efficiently achieved, this is not the case for small inorganic NPs. Choueiri et al. proposed to coat NPs biomolecules have been reported in the synthesis of plasmonic with a uniformly thick polymer brush, which upon reduction in NPs. Often it is their functional end group (e.g., amine, solvent quality breaks into smaller micelles forming the phosphine, carboxylate, or thiol) that has been used to bind to the NP surface. For example, the thiol containing biomolecule patches. The driving forces behind this process are on the one hand attractive polymer−polymer interactions, and on the GSH can be used to stabilize Au NPs. As such, Brinas et al. other hand, the competition between the polymer grafting developed a size-controllable synthesis of Au NPs (2−6 nm) constraints and interfacial free energy reduction. This allows capped with GSH by varying the pH (5.5−8.0). Then they for NP surface patterning by segregation of the polymer prepared nitriloacetate (NTA) functionalized Au NPs by ligands. The authors validate this approach using a variety of adding a mixed solution of lysine-NTA-SH and GSH to a different NPs and polymers (e.g., Au NPs and thiolated solution of hydrogen tetrachloroaurate (HAuCl ). On the polystyrene including block-copolymers). Such “patchy” other hand, some biomolecules can also be used to stabilize Au particles were furthermore able to assemble into controlled NPs electrostatically. For example, lysine (Lys) could electro- structures such as dimers, trimers, or chains and thus statically stabilize anisotropic star-shaped Au NPs ranging from demonstrated the programmability derived from the precise 30 to 100 nm during their growth from 17 nm citrate-seed Au 105 109 placement of the polymer patches. Chen and co-workers NPs. Arabic gum-stabilized Au NPs ranging from 90 nm to similarly employed polymer segregation to create versatile 4.6 μm in diameter could be produced by controlling the solution pH, while using ascorbic acid as the reducing agent. synthetic handles on nanorods, bypiramids, and triangular prisms. They showed that by selecting the right kind of By using proteins as ligand, even the shape of Ag NPs could be polymer, which protected particles from aggregation, but also tuned. Besides these, other biomolecules, have been studied possessed fluidity and adjustability, site selectivity in multistep in conjunction with Au NP synthesis. Another increasingly NP synthesis was possible. The utilization of a polymer, which popular route for creating Au NPs is through green chemistry retains its fluidity while being highly stable yet modifiable methods. For example, the addition of boiled broth of presents the most critical step in this approach. The authors lemongrass leaf (Cymbopogon flexuosus) to a HAuCl solution showed that polystyrene-block-poly(acrylic acid) ligands on Au was used to induce the reduction of AuCl and to yield a high NRs could be selectively transformed through heating into percentage of thin, flat, single-crystalline Au nanotriangles. desired patches coating only parts of the Au NRs and even Also, β-D-glucose was used to synthesize 5.3 nm Ag NPs in the forming helical patterns. On the other hand, Weizmann and aqueous phase under moderate thermal reduction (40 °C) 4827 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review with the glucose hydroxyl groups acting to passivate and 110 dye via carbodiimide-assisted covalent bonding and used stabilize the NPs. Similarly, other types of saccharides for cellular imaging. VSOP C184 is a 4 nm citrate-capped (glucose, galatose, maltose, and lactose) have been used for iron oxide NP system synthesized via an optimized synthesizing antimicrobial/bacterial Ag NPs in the range of coprecipitation process in the presence of excess citric acid 25−450 nm in water. and is currently being utilized in a clinical investigation as a For the preparation of hybrid materials, He et al. developed potent MRI contrast agent. Beyond just iron oxide NPs, Lu a one-pot synthetic method for graphene oxide/silver NP et al. used citric acid to synthesize Au/Fe NPs comprising an (GO/Ag NPs) using luminol (5-amino-2,3-dihydrophthala- Au shell with a magnetite/maghemite inclusion. zine-1,4-dione) in an aqueous/ethanol mixture at room Recently, citric acid was also used to develop a low energy temperature. Apart from acting as a reducing agent, excess hydrothermal-reduction route to synthesize aqueous ferrofluids luminol stabilizes the Ag NPs via the formation of a Ag−N of negatively charged ∼10 nm Zn Fe O and ∼80 nm Fe O x 3‑x 4 3 4 147,148 covalent bonding during synthesis. The resulting Ag NPs for magnetic hyperthermia studies. Similarly, PEGylated demonstrated an average size of 22 nm with a relatively iron oxide NPs have been prepared (Figure 5) for MR/optical uniform size on the surface of GO. This hybrid system was lymph node imaging. In this method, biocompatible PEG used for GSH sensing, where the GSH enhanced the served as a solvent, capping agent, and reducing agent. chemiluminescence intensity between the GO/Ag nano- composites and hydrogen peroxide. Another example used sorghum bran extract as both the reducing and capping agent at room temperature to produce highly crystalline Ag NPs of ∼10 nm. There is also a lot of current interest in the synthesis of ultrasmall metal NCs using biomolecules including nucleic acids and proteins; these are discussed separately in the fluorescent NP section (vide infra). For more detailed information on the topic of plasmonic NPs, we refer readers 118,119 to dedicated relevant reviews. Table 2 presents a representative overview of the most popular chemical methods and ligands to synthesize a variety of functionalized metal NPs in aqueous media. 2.1.2. Magnetic Nanoparticles. A common synthetic Figure 5. Schematic illustration of the synthesis of PEGylated iron method for preparing iron oxide NPs in the form of magnetite oxide NPs. Reprinted with permission from ref 149. Copyright 2014 or maghemite (Fe O or γ-Fe O , respectively) is a 3 4 2 3 Royal Society of Chemistry. coprecipitation by aging a stoichiometric mixture of ferrous and ferric salts in an aqueous medium. The surface iron atoms of the iron oxide NPs act as Lewis acids and coordinate with molecules that donate lone pairs of electrons. Therefore, Mixed ferrites can also be prepared by modified in aqueous solutions, the Fe atoms coordinate with water, coprecipitation routes in aqueous media. However, micro- which dissociates readily to leave the iron oxide surface emulsion methods have been used more commonly and have hydroxyl functionalized. Dependent upon the pH of the been extended for the synthesis of water-soluble magnetic NPs solution, the amphoteric surface hydroxyl group of the using a water-in-oil phase approach. The synthesis of 4.2 nm magnetite will present a positive or negative charge. The Ni NPs by the reduction of nickel chloride with hydrazine in a actual size, shape, and composition of such magnetic NPs cationic water-in-oil microemulsions of water/CTAB/n-hex- depend upon the type of salts used (e.g., chlorides, sulfates, anol at 73 °C has also been studied. Similarly, a water-in-oil nitrates). Other functional groups, including carboxylates, microemulsion system (aqueous FeCl /CTAB/n-octane) was hydroxy, phosphates, and sulfates are known to bind to the used to prepare positively charged γ-Fe O or magnetite NPs 2 3 surface of magnetites in the aqueous phase. Hydrophilic ranging in diameter from 3.5 to 9.7 nm. polymers and micelles can also stabilize magnetic NPs as Sun et al. reported the size-controlled synthesis of Fe O 3 4 8,9 well. For example, Lee et al. prepared ultrafine Fe O NPs coated with glucose and gluconic acid by using a sucrose 3 4 particles (4−7 nm) by precipitation in an aqueous poly(vinyl bifunctional hydrothermal method. Sucrose was used as the alcohol) (PVA) solution. However, when using PVA chemical reducing agent of Fe(III), as well as a capping agent containing 0.1 mol % carboxyl groups as the stabilizing to prepare colloidal iron oxide NPs ranging from 4 to 16 nm in agent, the magnetite NPs precipitated in the form of chainlike size. Driven by the growing desire for greener synthesis of NPs, clusters. a rapid synthesis of 17−25 nm Fe O using brown seaweed ( 3 4 Various other types of carboxylated ligands have also been Sargassum muticum) extract solution has been demonstrated. used for stabilizing magnetic NPs, such as citric acid, gluconic This approach relied on the sulfated polysaccharide from acid, dimercaptosuccinic acid, and phosphorylcholine. For seaweed to act as a reducing agent as well as surface stabilizing example, 2−8 nm maghemite NPs could be prepared by the template of the NPs. In a similar vein, ethylene glycol was thermal oxidation of iron(III) nitrate in an alkaline medium in used to synthesize 9.2 nm Ni NPs using a hydrazine reduction 143 155 the presence of trisodium citrate. Later, it was reported that in the aqueous phase. In a different approach water-soluble the surface of magnetite NPs can also be stabilized by the magnetite NPs were produced by thermal decomposition of adsorption of citric acid during coprecipitation of iron oxide, Fe(acac) in 2-pyrrolidone. The experimental results here leading to a stable aqueous dispersion. The 5−20 nm citric revealed that 2-pyrrolidone not only serves as a media for high- acid-stabilized NPs were further conjugated with rhodamine temperature reaction but also involves surface coordination, 4828 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review which imparts colloidal stability to the water-soluble magnetite NPs. 2.1.3. Luminescent Nanoparticles. Semiconductors. Henglein et al. pioneered the aqueous colloidal synthesis of semiconductor quantum dots (QDs), as well as other NPs, by using Cd(ClO ) and Na S in Ludox HS30 silicon sol 4 2 2 (colloidal silica, SiO ) and studied their catalysis of free radical 157,158 reactions in 1982. In the past few years, aqueous syntheses have been intensely studied and now yields stable binary II−VI and IV−VI NPs such as CdS, CdTe, CdSe, ZnSe, HgTe, PbS, and other alloyed particles of good quality, free from defect emission and large polydispersity in size. In general, the synthesis process involves the formation of metal− thiol complexes in water by adjusting the pH, and the injection of a chalcogenide source into the deaerated reaction solution. Figure 6. (a,b) mPEG-TGA and mPEG-SH molecules used for the This results in the formation of metal−chalcogenide synthesis of CdTe nanoparticles. (c) Photographs of vials showing the precursors. Then, heating of the solution induces the time-dependent triphase transfer of CdTe/mPEG-SH nanoparticles nucleation and NP growth process. from toluene to water to chloroform under daylight. Reprinted with Common ligands for the stabilization of QDs in aqueous permission from ref 167. Copyright 2009 American Chemical Society. syntheses have been short alkyl chain thiols and phosphates. For example, CdTe and ZnTe NPs could be obtained directly developed by Shavel et al., who used thioglycerol, thioglycolic in water in the presence of hexametaphosphate. Similarly a acid, or 3-mercaptopropionic acid as stabilizers with a mixture of hexametaphosphate and mercapto propanediol, postpreparative treatment (irradiation with white light) leading as well as mercaptoethanol and thiolglycerol have been used to the formation of alloyed ZnSe(S) NPs with improved QYs successfully. Rogach and co-workers optimized the process up to 30%. GSH-capped ZnSe and Zn Cd Se alloyed 3−4 1−x x to obtain strongly photoluminescent CdTe NPs with nm QDs with tunable fluorescence between 360 and 500 nm, thioglycolic acid (18% quantum yield), and they revealed narrow bandwidths (19−32 nm), and QYs up to 50% have also a state-of-the-art preparation of visible to NIR (500−800 nm) been reported. Unfortunately, conditions for such aqueous emitting CdTe NPs with high quantum yields (QY ∼ 40− synthesis do not permit size tuning of ZnSe NP materials over 60%), coated with thioglycolic acid. a wide range, thereby limiting their luminescence to a very Similar to metallic NPs, GSH could also be utilized in the narrow path, typically 350−400 nm, which conversely drives synthesis of CdTe QDs resulting in GSH-capped QDs with the demand for alloyed ZnSe QDs. Incorporation of Cd into QYs as high as 45%, without any postsynthetic treatment. It GSH-stabilized ZnSe QDs helps to shift the photolumines- was further shown that peptides could be conjugated to them cence to longer wavelengths from 360 to 500 nm. Overall, for subsequent use in cells. Recently Zhou et al. published a the employment of a variety of ligands for the synthesis of high simple method to synthesize CdTe QDs, in which QDs were quality QDs in water has certainly matured as is evident from synthesized by stepwise addition of water, CdCl , thiol, their robust QYs, which now rival those obtained for QDs Na TeO , NaBH , and hydrazine. This method allowed synthesized in organic solvents. 2 3 4 the easy functionalization of the QDs with short thiol ligands Metal Nanoclusters. Many different types of ligands such as such as thioglycolic acid, mercaptopropionic acid, thioglycerol, dendrimers, thiols, peptides, etc., have been used so far to mercaptoethylamine, GSH, and L-cysteine, as well as create fluorescent metal NCs. Zheng et al. described the mercaptobenzoic acid, per-6-thio-α-cyclodextrin, and per-7- formation of size-tunable Au nanoclusters (Au NCs) that are thio-β-cyclodextrin. readily synthesized through the slow reduction of AuCl or Among different polymers, thiolated PEG has also been AuBr within aqueous polyamidoamine (PAMAM) solutions employed in the synthesis of CdTe QDs in both water and dendrimer solutions; the latter were used because they can be organic solvents (see Figure 6). Furthermore, Ning et al. obtained with well-defined sizes and serve to encapsulate the reported the fabrication of water-dispersible NP−amphiphilic nascent NC. Both the Au:PAMAM ratio as well as the copolymer composite microspheres, in which the mercapto- dendrimer generation of PAMAM allowed for optimization propionic acid-stabilized CdTe QDs were encapsulated by and tuning of the NC emission color. It was found that these dimethyl dioctadecyl ammonium bromide in chloroform and NCs showed orders of magnitude higher QYs compared to then transferred back into water by making a QD−polymer other NCs, which implied that amines play an important role composite with poly(ethylene glycol) diglycidyl-grafted poly- in Au NC formation. Later, water-soluble platinum nano- (maleic anhydride-alt-octadecene). Hybrid SiO −CdTe clusters (Pt NCs) were also grown by using PAMAM (G4- NPs have also been obtained where thioglycolic acid-stabilized OH). These Pt NCs showed decreased cytotoxicity and 2.6 nm green-emissive CdTe QDs were refluxed in the emitted more intensely at 470 nm in comparison to Au 2+ presence of Cd , thioglycolic acid, tetraethyl orthosilicate, and NCs. NH . The as-prepared hybrid SiO −CdTe NPs showed a In a different protocol, 1.1−1.7 nm diameter Au NPs with 3 2 red-shift in photoluminescence and changes in QY from 20 to size dependent fluorescent switching and quantum yields (QY) 55%. of ∼3% were prepared by using aqueous pentaerythryl Zn-based QDs have attracted scientific interest due to tetrakis(3-mercaptopropionate)-terminated polymethacrylic concerns about Cd toxicity and the amount of heavy metal acid. NIR fluorescent dihydrolipoic acid (DHLA) stabilized pollutants released into the environment. A successful aqueous Au NPs were recently prepared using a one-pot synthesis 175,176 synthesis of strong UV-blue emissive 2−3 nm ZnSe NPs was (Figure 7a). Although the particles were highly soluble in 4829 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 7. (a) Representative cartoon structure of Au@DHLA nanoparticles. Right side: b and b show the corresponding photographs of the 1 2 cluster under visible and UV light, respectively. Reprinted with permission from ref 176. Copyright 2009 American Chemical Society. (c) Scheme of the highly fluorescent Au@BSA NC synthesis. Inset shows the photograph of corresponding nanocluster under UV light. Reprinted with permission from ref 179. Copyright 2009 American Chemical Society. (d) TEM images of metal-doped Au NCs with TA-PEG ligand. Reprinted with permission from ref 135. Copyright 2016 American Chemical Society. water, they had relatively low QYs of 0.6−1.8%. Similar QY (0.04−0.3%). GSH has also been used in the synthesis approaches have been used to also synthesize Ag nanoclusters of highly fluorescent Pt NCs by using an etching approach. (Ag NCs). Oh et al. synthesized near-infrared emissive Au These NCs began in the Pt(I) oxidation state (90%) exhibiting NPs with bidentate TA-PEG (TA: thioctic acid, lipoic acid) an intense fluorescence in the yellow region (QY ∼ 17%, ligands in water that had higher QYs of 4−8%, and a variety of emission maximum at 570 nm), and etching with GSH led to terminal functional groups (amine, carboxyl, azide, and the formation of blue-emitting species over long periods of methoxy) available for further conjugation to biomolecules. time. Other biomolecules such as nucleic acids and proteins They demonstrated that these NCs were suitable for biological have also been used in the synthesis of NCs. For example Patel applications including cell-penetrating peptide-driven cellular et al. synthesized water-soluble 2.3 nm Ag NCs exhibiting uptake along with one- and two-photon cellular imaging. strong two-photon-induced fluorescence ranging from 660− They also synthesized metal-doped luminescent Au NCs and 710 nm by using 12-mer nucleic acids, while Sharma et al. modulated their emission from 670 to 820 nm by changing the reported the synthesis and photophysical properties of Ag NCs ratio of dopant (varied ratio (1−98%) with Ag and 2% of Pt, templated on DNA, with fluorescence excitation and emission at distinct wavelengths that are tuned to common laser Cu, Zn, and Cd) added (Figure 7c). Biomolecules have also been used for the fabrication of excitation wavelengths. The use of proteins for stabilizing metal NCs. For example, GSH-protected Au NCs were metal NCs was also demonstrated in the form of bovine serum synthesized in a water and methanol mixture by Link et al. albumin (BSA) stabilized Au NCs (Figure 7b), which showed However, these NCs were polydispersed and displayed a low relative high QYs of ∼6% in water with a red emission centered 4830 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review 4831 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Table 3. Plasmonic NPs Synthesized in Organic Media material precursors and reagents ligand/surfactant size (nm) shape solvent other comments Au AuCl /NaBH dodecanethiol 1−3 sp biphase 4 4 (water/toluene) Au AuCl /NaBH dodecylamine, 2.5−7 sp biphase 4 4 oleylamine (water/toluene) Au, Pt, Ag AuCl /THPC (NaBH for Ag, Pt) dodecanethiol 1−10 sp biphase THPC = tetrakis(hydroxymethyl)phosphonium 4 4 (hydrosol/toluene) chloride Au HAuCl PVP 30 sp formamide Au AuCl /NaBH TOPO, octadecylamine 8.6 sp TOPO octadecylamine yields spherical particles 4 4 (4-tert-butylpyridine) Au Au vapor dodecanethiol 4.5 sp acetone and multistep procedure, SMAD = solvated metal atom toluene/SMAD dispersion technique Ag AgNO /NaBH TOPO/octadecylamine bimodal distribution (2−3nm sp 4-tert-butylpyridine TOPO and alkyl phosphines required for controlled 3 4 and 10−15 nm) growth, amine dominant ligand Ag AgNO PVP cubic ethylene glycol/polyol conditions control shape and size process Ag, Au, Cu, Pt AuCl , hydrazine or TBA-borohydride dodecylamine, decanoic 1−15 sp toluene with single phase approach in toluene with ammonium acid surfactants surfactants Ag Ag myristate myristate 4.4 sp tertiary alkylamine solvent (NEt3) Ag AgNO PVP polyhedral pentanediol/polyol controlled synthesis of uniform polyhedral shapes and process sizes Ag Ag-phosphine complex OLA 8−20 sp o-dichlorobenzene CuS Cu(acac) , ammonium OA, 1-dodecanethiol 2−6 hexagonal OA, 1-dodecanethiol diethyldithiocarbamate faceted Cu Se CuCl, Se OLA 16 cuboctahedral ODE phosphine-free synthesis 2−x Cu In S Cu(acac) , In(acac) , TMS S hexadecyl-amine 4−5.6 sp octadecene, TOPO potential ligands: dodecylphosphonic acid, TOPO x y 2 2 3 2 Cu S and CuCl, S , Se OLA, OA 2.8−13.5 (Cu S) and 7.2− sp OLA, OA strong tunable NIR localized surface plasmon 2−x 8 2−x Cu Se 16.5 (Cu Se) resonance 2−x 2−x acac, acetylacetonate; ODE, octadecene; OA, oleic acid; OLA, oleylamine; PVP, polyvinylpyrrolidone; sp, sphere; TOPO, trioctylphosphine oxide; TMS, trimethylsilyl. Chemical Reviews Review Figure 8. Representative electron microscopy images of (a) truncated Ag nanocubes, (b) Cu I S QDs), (c) Cu Se nanoparticles, (d) Cu S x y 2 2−x 2−x QDs, (e) time-dependent evolution of Cu Se nanoparticles and nanodisks and (f) CuTe NPs. (a) Reprinted with permission from ref 194. 2−x Copyright 2002 Science. (b) Reprinted with permission from ref 196. Copyright 2012 American Chemical Society. (c) Reprinted with permission from ref 197. Copyright 2010 American Chemical Society. (d) Reprinted with permission from ref 198. Copyright 2011 Springer Nature. (e) Reprinted with permission from ref 199. Copyright 2013 Wiley. (f) Reprinted with permission from ref 200. Copyright 2013 American Chemical Society. 179 185,186 at ∼640 nm. Although the QY of noble metal clusters of Au and other noble metal NPs. A similar two phase synthesized in aqueous media is not quite at the same level as method was also developed to synthesize alkylamine-capped that of QDs, NCs remain very promising materials due to their Au NPs. small size and better biocompatibility as well as access to red- Han et al. demonstrated a nonaqueous route to synthesize shifted emissions within the NIR tissue transparency window. Au colloids coated with PVP by the chemical reduction of Because it is believed that their emission arises from a complex HAuCl in oxygen-free formamide. Here, the solvent acted metal-to-ligand charge transfer process, the ability to improve as the reducing agent in oxygen-free conditions at room their quantum yields will be directly correlated to the choice of temperature, yielding ∼30 nm diameter NPs. Inspired by the ligand used during synthesis. Thus, further research toward high-temperature colloidal synthesis of semiconductor NPs in increasing their QY with different ligand types can be expected tri-n-octylphosphine oxide (TOPO), which is detailed in in the near future. section 2.2.3, a one phase synthesis of Au NPs capped with organic ligands was developed. When the reduction of gold 2.2. Ligand Coating on Nanoparticles Synthesized in Organic Media chloride was carried out at 190 °C in TOPO, uncontrolled growth of the NPs was observed with a variety of shapes and In the organic solvents, it is usually feasible to synthesize NPs sizes (10−100 nm) being formed. Addition of octadecylamine of a narrow size distribution and crystal uniformity because of yielded spherical Au NPs with a diameter of ∼8.6 nm, the higher temperatures which can be achieved often involved highlighting the importance of ligands in the nucleation and during synthesis. The ligands are usually introduced prior to growth of NPs. Infrared spectroscopy showed the presence of the formation of the NPs and in many cases their roles are both TOPO and octadecylamine on the surface of Au NPs as multiple acting as solvents, forming complexes with metals to dispersed in organic solvents. This synthesis was later adapted generate the active species for NP nucleation and stabilizing to prepare plasmonic Ag NPs from silver(I) nitrate. TOPO the NPs by surface binding. A common characteristic of these alone was found to bind weakly to the silver surface and was ligands is that often they do not decompose at the elevated insufficient at providing stable colloids despite providing temperatures necessary for the NP nucleation and growth. controlled growth. On the other hand, octadecylamine was Postsynthesis functionalization by ligand exchange is also critical in this approach for providing stable colloids due to the feasible in organic media, and in most cases it is conducted at strong amine−silver interaction at the NP surface. elevated temperatures. Other alkylamines have also been used to stabilize Ag NPs in 2.2.1. Plasmonic Nanoparticles. One pioneering general organic-phase syntheses, including dodecylamine and oleyl- approach to synthesize relatively monodispersed Au NPs in amine. Jana et al. utilized dodecylamine as a stabilizing organic solvents known as the Brust−Schiffrin method is based ligand employing two reducing agents, hydrazine and on a two-phase surfactant-mediated approach. In this seminal tetrabutylammonium borohydride, to control the plasmonic methodology, Brust et al. introduced a procedure to transfer particle growth in toluene. Oleylamine has also been Au ions from the aqueous solution to toluene using the phase- employed not only as the reductant for a silver−phosphine transfer agent tetraoctylammonium bromide (TOAB). Then complex in ortho-dichlorobenzene, but also as a ligand to the gold ions were reduced by NaBH to form NPs that were stabilized by dodecanethiol, yielding organic soluble Au stabilize the resulting Ag NPs. In addition to amines, fatty 25 191 colloids. Dodecanethiol has also been used in the syntheses acids such as decanoic acid can act as stabilizers to 4832 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review synthesize Ag, Au, and other plasmonic NPs in organic media. primarily on broadly used NPs of cobalt, iron oxides, and For example, Yamamoto et al. described a one-pot process to iron−platinum as representative examples. Cobalt NPs (ε-Co) synthesize 4.4 nm Ag NPs via thermal decomposition of a have been prepared via the reduction of cobalt chloride in silver myristate-amine (1:2) at 80 °C. The fatty acid alkyl dioctylether at 200 °C. The NP growth was controlled by chain length determined the particle size and provided oleic acid and trialkylphosphines used in the reaction mixture, colloidal stability. The longer carbon chain length, with slower which also provided colloidal stability to the resulting NPs and diffusion, stearic acid resulted in the synthesis of smaller limited their oxidation. This procedure produced Co NPs from particles with a narrower size distribution, while the shorter 2 to 11 nm, where the size was predominantly controlled by carbon chain octanoic acid, with faster diffusion, yielded larger the use of trialkylphosphine. The use of the shorter particles with broader size distributions. Polyvinylpyrrolidone tributylphosphine as a synthetic ligand yielded larger particles, (PVP) has also been used to stabilize silver NPs synthesized while employment of the longer trioctylphosphine conversely using the polyol process, where silver nitrate is reduced in yielded smaller particles. Co NPs were also prepared by ethylene glycol in the presence of PVP. Depending on the thermal decomposition of octacarbonyl dicobalt [Co (CO) ] 2 8 experimental conditions nanocubes, nanowires, multiply in toluene and TOPO. The phase of cobalt formed was shown to be dependent on the amount of TOPO present in twinned particles, and other irregular shapes could be obtained. the reaction mixture. Adding oleic acid to the decomposition This method was further adapted to obtain Ag NPs with of Co (CO) in ortho-dichlorobenzene and TOPO provided a polyhedral shapes. Clearly there is a complex interplay of 2 8 means to control the size and shape of the Co NPs. In fact, processes at work within these types of syntheses. It is probable these conditions created Co nanodisks that were later prepared that a deep understanding of the underlying chemistry could in higher yields by adding alkylamines to the reaction lead to “plug-and-play” recipes for almost any desired noble mixture. See Figure 9 for some representative materials. metal NP shape. Currently, there is a rapidly growing field of research on nonmetallic nanomaterials that exhibit localized surface plasmon resonance (LSPR) where the ligands play critical roles both in NP synthesis and colloidal NP robustness. There are several methods to obtain these materials, and we focus on those prepared directly by colloidal synthesis in a one-step approach. Niezgoda et al. described the colloidal synthesis of Cu In S NPs exhibiting a LSPR in the infrared using TOPO, x y dodecylphosphonic acid, and hexadecylamine. The ratio of TOPO and hexadecylamine influenced the surface energy of the different crystallographic facets and determined whether spherical or rod-shaped NPs are formed. In another study, a phosphine-free synthesis of Cu Se NPs with a NIR LSPR 2−x utilized oleylamine as both the reductant and the stabilizing Figure 9. TEM images of (a) Co nanodisks, (b) Co nanowires prepared with oleic acid and oleylamine, and (c) high resolution ligand. However, byproducts were also formed and NP size image of γ-Fe O nanocrystals and corresponding energy filtered control was not explored. In contrast, control over Cu SNP 2 3 2−x images showing the distribution of Fe and O. (a) Adapted with size was achieved using 1-dodecanethiol and oleic acid. Liu permission from ref 204. Copyright 2002 American Chemical Society. et al. developed a protocol to make Cu E (E = S, Se) NPs, 2−x (b) Adapted with permission from ref 205. Copyright 2002 Wiley. (c) where the oleylamine and oleic acid ligands influenced the Reprinted with permission from ref 208. Copyright 2009 American resulting NP size and cation deficiency through a complex Chemical Society. interplay of reaction time and ligand preference for crystal phase. Furthermore, they also reported on the synthesis of CuTe NPs with different morphologies by reacting a copper Fatty acids (e.g., hexadecylamine and oleic acid) and salt with trioctylphosphine telluride in the presence of lithium alkylamines were used to synthesize Co NRs and nanowires 200 205,206 3 4 bis(trimethylsilyl)amide and oleylamine. from [Co(η -C H )(η -C H )] in anisole at 150 °C. 8 13 8 12 Table 3 concentrates some representative literature for a These examples serve to highlight the variety of ligands used to variety of plasmonic NPs synthesized in organic media and the stabilize NPs from agglomeration and also how they can ligands used in each case to highlight the diversity that is impact the resulting NP shape and crystal phase. achievable and Figure 8 shows some representative electron Magnetic iron oxide NPs can be made via formation of iron 207,208 microscopy images of these materials. particles that are subsequently oxidized or directly from Overall, the syntheses of organic-dispersible plasmonic NPs cationic metal complexes. As such, γ-Fe O NPs could be 2 3 is more established than water-based approaches providing for prepared from the thermal decomposition of an iron cupferon control over the size, shape, composition, and energy of the complex (FeCup ) in octylamine/trioctylamine at 300 °C. plasmonic feature. This is mainly due to the elevated This procedure provided particle sizes from 4 to 10 nm that temperatures used for NP formation in organic solvents, required postsynthetic size selective processing, yielding which allow further manipulation of NP nucleation and materials that were stable for weeks at RT. Using Fe(acac) , growth. However, especially for the case of Au and Ag NPs, the synthesis of Fe O NPs in the presence of phenyl ether, 3 4 aqueous approaches provide a broader scope for the synthesis 1,2-hexadecanediol, oleic acid, and oleylamine at 265 °C of a plethora of different shapes and sizes. without a size-selection procedure was possible. The larger 2.2.2. Magnetic Nanoparticles. While magnetic NPs NPs were prepared using the seed-mediated method with oleic with varying compositions have been synthesized in organic acid and oleylamine as stabilizers in addition to stearyl alcohol. media using a wide variety of ligand types, here we focus Contrastingly, Fe O NPs could be prepared from the pyrolysis 3 4 4833 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 4. Magnetic NPs Synthesized in Organic Media size material precursors and reagents ligand/surfactant (nm) shape solvent other comments Co CoCl , superhydride OA, 2−11 sp dioctylether particle size tuned by trialkylphosphines phosphine R groups Fe, Mn, Co oxides M-cupferron alkylamines 4−10 sp trioctylamine (approx) Co Co (CO) TOPO 20 ap toluene phase control with phosphine 2 8 FePt Pt(acac) and Fe(CO) OA, OLA 3−10 sp dioctylether modified polyol 2 5 Fe O Fe(CO) OA 4−16 sp octylether 2 3 5 [trimethylamine oxide] Co Co (CO) alkylamines, disk and o-dichlorobenzene, amines give higher yields of 2 8 TOPO, OA sp alkylamines, TOPO, OA disks Fe O Fe(acac) OA, OLA 4−20 sp phenyl ether, hexadecanediol 3 4 3 Co Co(n-C H )(n-C H ) hexadecylamine, rods anisole acids control aspect ratio of 8 13 8 12 fatty acids rods FePt Fe(acac) , Pt(acac) OA, OLA 2 sp dioctylether 3 2 (approx) Fe O iron-oleate OA 5−22 sp ODE large scale synthesis 3 4 acac, acetylacetonate; ODE, octadecene; OA, oleic acid; OLA, oleylamine; sp, sphere; TOPO, trioctylphosphine oxide; TMS, trimethylsilyl. of metal fatty acid salts (such as lauric, myristic, palmitic, Moreover, NPs of different sizes will likely have different ratios stearic, and oleic acids) in noncoordinating hydrocarbon and densities of surfactants on their surfaces. It is also worth solvents (such as octadecene, tetracosane, and n-eicosane). noting that one repeated theme across many, but not all, ligand In addition to reaction time, the concentration and size of the types is that the ligand size tends to correlate inversely with the stabilizing fatty acid ligands influenced the resulting NP size NP size obtained. and shape. Park et al. developed an experimental protocol for 2.2.3. Luminescent Nanoparticles. As for other types of the large scale synthesis of monodisperse iron oxide NPs from NPs, the size and morphology of colloidal QDs, and therefore inexpensive and nontoxic metal-oleate precursors in octade- their properties (in this case optoelectronic properties), cene and oleic acid. Recent work showed that iron oxide depend on the ligands employed for NP synthesis, which NPs could be converted into nanoclusters by replacing the influence nucleation, growth, and colloidal stabilization of the original oleic acid ligand coating with a “stripping ligand” such QDs. These ligands usually include an alkyl chain to provide as diethylene glycol (DEG), which functions to remove all of solubility in organic solvents, and an anchoring headgroup, the oleic acid from the surface. Nanoclusters made of iron which controls the binding strength and adsorption/ oxide multiple subunits arranged in a controlled topological desorption kinetics on the QD surface. On the basis of the 214−219 fashion have been also formed by utilizing polymers or binding fashion, the common surface ligands can be generally 220,221 227−229 categorized as either X-type or L-type ligands. X-type dendrimers as capping ligands. Iron alloys are also a large subset of magnetic NPs, including ligands donate one electron to the metal−ligand bond, L-type iron−platinum (FePt). In a polyol-based process, FePt NPs ligands donate two electrons to metal and Z-type ligands could be prepared from the reduction of Pt(acac) with 1,2- accept two electrons from the metal. Alkyl phosphonates, hexadecanediol and the thermal decomposition of Fe(CO) in phosphinates, carboxylates, and thiolates are considered X- dioctylether using oleic acid and oleylamine as stabilizing Type ligands while the most common L-type ligands often ligands. This synthesis allowed for NP size tuneability from used in QD synthesis are TOPO, trioctylphosphine (TOP), 230−232 3 to 10 nm with less than 5% standard deviation. Fe(CO) and alkylamine. could be replaced with the less hazardous Fe(acac) or Bawendi et al. first developed the synthesis of colloidal Fe(acac) to provide FePt NPs using a similar procedures. semiconductor QDs in organic solvents by reporting a hot The inorganic reducing agent superhydride (LiBEt H) has also injection method to synthesize a series of cadmium been employed to prepare FePt NPs from FeCl and Pt(acac) chalcogenide QDs (CdS, CdSe, and CdTe). Cadmium 2 2 in phenyl ether. Oleic acid and oleylamine were utilized to and chalcogenide precursors dissolved in TOP were swiftly stabilize the resulting 4 nm FePt NPs through preferential injected to TOPO at high temperature (∼300 °C). TOP and binging of the amine with platinum and the carboxylate groups TOPO were used as high boiling point coordinating solvents, with iron. Costanzo et al. also synthesized Co NPs with various ensuring colloidal stability and controlling the core growth diameters and uniform surfactant capping by regulating the kinetics. This work set the foundations for a broader use of solvation of the ligands. TOP/TOPO as solvents to synthesize various types of QDs, Table 4 compiles examples of ligands used in the synthesis although there are still questions related to role of impurities of various types of magnetic NPs, and Figure 9 shows some within these ligands. representative TEM images of magnetic NPs. The controlled Peng et al. demonstrated that the toxic and pyrophoric growth of magnetic NPs (and others) of different sizes requires precursor Cd(CH ) could be stabilized by alkylphosphonic 3 2 a balance between surfactants that will allow the NPs to grow acid, which is one of the major impurities in technical grade 235,236 and surfactants that bind strongly to the surface for providing TOPO. Theair stableCd−alkylphosphonic acid colloidal stability. This becomes more complicated when complexes successfully replaced Cd(CH ) to synthesize high 3 2 synthesizing bimetallic or metal oxide NPs such as FePt, quality CdSe QDs. Since then, the capability to synthesize Fe O , and Fe O because two different atoms are present on high-quality QDs with a variety of reagents and conditions has 2 3 3 4 the NP surface versus, for example, single component Co NPs. expanded tremendously. In depth analytical studies of the 4834 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review ligands present on the QD surface after synthesis have helped Upconversion NPs (UCNPs) are typically lanthanide-doped to provide key insight into their roles. P nuclear magnetic inorganic NPs, which convert a lower energy excitation light 250−256 resonance (NMR) studies of CdSe QDs synthesized using into a higher energy luminescence. Their unique technical grade TOPO revealed that the major ligands on the properties including sharp emission band, large Stokes shift, and high photochemical stability have made UCNPs attractive CdSe QDs’ surface were n-octylphosphonic acid (OPA) and as novel luminescent materials. While a variety of synthetic P,P′-(di-n-octyl)dihydrogen pyrophosphonic acid (PPA), methods have been demonstrated for preparing UCNPs, one which was formed via dehydrative condensation of OPA of the most successful approaches for monodispersed high- during the QD synthesis. Interestingly, the ligand displace- quality UCNPs coated with hydrophobic ligands is the thermal ment experiment also suggested that TOPO was completely 3+ decomposition method. In particular, NaYF doped with Yb / excluded from binding to the CdSe QD surface. A series of 4 3+ 3+ 3+ Er (or Yb /Tm ) have been recognized as one of the most NMR studies of CdSe QDs synthesized in the presence of efficient UCNPs and their synthetic methods through thermal octadecylphosphonic acid (ODPA), TOP, and TOPO were decomposition have been well explored. The NaYF -based carried out and the results indicated that the QD ligand shell UCNPs are typically synthesized with sodium trifluoroacetate consisted of 55% of ODPA and 45% of octadecylphosphonic and lanthanide trifluoroacetate in a mixture of ODE and oleic anhydride. NMR studies of CdTe QDs synthesized in the 257−261 acid (and oleylamine) at ∼300 °C or higher. Under presence of tetradecylphosphonic acid and oleylamine revealed these conditions the surface ligands are most likely oleic acid that the QD surface is covered by 90% of tetradecylphosphonic and/or oleylamine. TOPO (90%) was also used for NaYF - anhydride and 10% of oleylamine. based UCNP synthesis instead of oleic acid and oleylamine. Dialkylphosphinic acid is also one of the impurities in The latterNaYF -based UCNPs have smaller size with narrow technical grade TOPO and has been used to prepare the size distribution and higher upconversion luminescence metal precursors and control the NP core growth kinetics. A efficiency compared with the ones prepared with oleic acid series of fatty acids were also used as the surface ligands of Cd and oleylamine. Another facile route to prepare small and chalcogenide QDs. Fatty acids were introduced as the ligands monodispersed UCNPs is use of the coprecipitation method, coordinated to the metal precursors and controlled the core 241,242 which usually uses oleic acid as a capping ligand in growth kinetics during the NP synthesis. In parallel, NP 263−265 ODE. While metal oleates are used as lanthanide synthesis in noncoordinating solvents has also been developed precursors, NaOH and NH F in methanol have successfully such as the use of fatty acids including oleic acid and stearic worked as sodium and fluoride sources, respectively. acid. The benefit of using noncoordinating solvents for NP Recently, silicon (Si) NPs have attracted much attention as synthesis is that the precursor reactivity can be simply tuned by nanoscale emitters because silicon is abundant on earth and the type of coordinating ligand and the ligand concentration. 1- regarded as less toxic compared to the other conventional Octadecene (ODE) has been commonly used as a non- 266−274 semiconductor materials. Si NPs are typically synthe- coordinating solvent, primarily due to its low melting point sized by either etching of bulk silicon (top-down approach) or (∼15 °C) and high boiling point (∼315 °C). In a chemical reaction of silicon precursors (bottom-up approach). representative example of its versatility, Mulvaney et al. used The as-prepared Si NPs normally have either hydrogen- or a binary ligand system (bis(2,2,4-trimethylpentyl)phosphinic halide-terminated surfaces, which have to be further modified acid and oleic acid) in ODE to tune the nucleation and growth to ensure good colloidal stability in organic media. In contrast of CdSe QDs, and successfully synthesized QDs with different to conventional metal chalcogenide QDs, surface modification size range. of Si NPs requires the formation of covalent bonds between While we primarily focus on cadmium chalcogenide QDs, surface silicon atoms and carbon, nitrogen, or oxygen atoms. due to their popularity and the better understanding of their The Si−H surface bond can be modified by hydrosilylation properties, surface ligands on some other common QDs need with organic molecules functionalized with a carbon−carbon to be briefly addressed. High quality ZnSe QDs are typically double bond or triple bond end group in order to produce 244−246 synthesized by conventional hot injection methods such both hydrophobic and hydrophilic surface types. The Si-X (X as the decomposition of pyrophoric ZnEt and TOP:Se in alkyl = Cl or Br) surface bond can be replaced with a Grignard amine or the decomposition of air stable zinc stearate and reagent or alkyl lithium to form the alkyl-terminated surfaces. TOP:Se in octadecane. These reaction conditions indicate Similar surface modification strategies can be used to prepare that either the alkyl amine or alkyl carboxylate coordinates the hydrophilic surfaces using organic molecules with polar ZnSe QD surface and maintains colloidal stability. NMR functional groups including hydroxy, amino, and carboxyl studies of PbS QDs synthesized using PbCl and elemental 2 groups. sulfur in the presence of oleylamine and TOP revealed that the Recently perovskite nanocrystals of the CH NH PbX or 3 3 3 QD surface was solely passivated by oleylamine. The CsPbX (X = Cl, Br, I) type have received increased attention oleylamine ligands exhibited fast adsorption/desorption due to their sharp emission peaks and narrow band widths, behavior and were easily replaced by oleic acid. PbSe QDs high photoluminescence quantum yields, and emission color synthesized using Pb(OAc) and TOP:Se in the presence of tunability. As such they have found widespread optoelec- oleic acid were also studied in a similar fashion. Here, it was tronic applications, especially in light emitting devices (LEDs), found that the QD surface is composed of Pb atoms and which will be discussed later. The synthesis of organic− primarily coated by oleic acid with only 0−5% of TOP. Hens inorganic MAPbX perovskite nanoparticles relies on the et al. also synthesized CuInS QDs in the presence of amine reaction of a lead halide salt (PbX , X = Cl, Br, I) with ligands (1-octadecylamine or oleylamine). Their NMR methylammonium bromide and long or medium alkyl chain studies revealed that as-synthesized CuInS QDs have ammonium cations such as octylammonium bromide or charge-neutral QD surfaces, which are stabilized by L-type octadecylammonium bromide, which serve as the capping 277−279 amine ligands. ligands. On the other hand, all inorganic perovskite 4835 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review 4836 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Table 5. Representative Luminescent NPs Synthesized in Organic Media material precursors and reagents ligand/surfactant size (nm) shape solvent other comments ZnSe ZnEt , TOP:Se HDA, TOP sphere (sp) HDA, TOP ZnSe Zn stearate, TOP:Se stearic acid, TOP sp ODE ZnSe Zn stearate, TBP:Se stearic acid, ODA, TOP sp tetracosane, ODE ZnTe ZnEt , TOP:Te ODA, TOP 4.5 sp ODA, TOP ZnTe Zn(OAc) , TOP:Te, superhydride OA, TOP ∼5 sp benzyl ether CdS CdMe , (TMS) S TOP, TOPO sp TOP, TOPO 2 2 CdS CdO, S OA 2.0−5.3 sp ODE CdSe CdMe , TOP:Se or (TMS) Se TOP, TOPO 1.2−11.5 sp TOP, TOPO 2 2 CdSe CdO, TBP:Se TOPO, HPA (or TDPA) TOPO CdSe Cd(OAc) , TOP:Se TOP, TOPO, HDA, TDPA TOP, TOPO, HDA CdSe Cd(acac) , TOP:Se TOP, TOPO, HDA, HDDO sp TOP, TOPO, HDA CdSe Cd(acac) , TOP:Se TOP, TOPO, HDA, HDDO, HPA sp TOP, TOPO, HDA CdSe CdO, TOP:Se TMPPA, OA ∼1.8−5.6 sp ODE CdSe CdO, Se myristic acid ∼2−4.5 sp ODE heat-up method CdSe CdO, Se myristic acid ∼2.6−3.1 sp ODE heterogeneous ODE-Se precursor was injected. CdTe CdMe , TOP:Te or (BDMS) Te TOP/TOPO sp TOP, TOPO 2 2 CdTe CdO, TBP:Te OA (or ODPA, TDPA), TBP ∼2−11 sp ODE InP In(OAc) , (TMS) P myristic acid, 1-octylamine sp ODE 3 3 InP InCl , Zn undecylenate, (TMS) P stearic acid, HDA sp ODE 3 3 InP InCl , ZnCl , P(NMe ) OLA sp OLA 3 2 2 3 InAs InCl , (TMS) As TOP 2.3−6 sp TOP 3 3 InAs In stearate, (TMS) As stearic acid, TOP sp ODE PbS PbO, (TMS) S OA sp ODE PbS PbCl , S OLA sp OLA PbS Pb(OAc) , (TMS) S OA, TOP sp ODE 2 2 PbS PbCl , S OLA, TOP 3−10 sp OLA PbSe Pb oleate, TOP:Se OA, TOP 3.5−15 sp diphenyl ether PbSe PbO, TOP:Se OA, TOP 3−13 sp ODE CuInS CuI, InI , S TOP, OLA ODE 2 3 CuInS Cu(acac) , In(acac) , S OLA 6−12 sp o-dichlorobenzene 2 2 3 CuInS Cu(OAc), In(OAc) , DDT DDT 2−5 sp ODE 2 3 CuInS CuI, In(OAc) , DDT DDT sp ODE 2 3 CuInS CuI, In(OAc) , DDT OA, DDT 3.5−7.3 pyramidal ODE 2 3 CuInS CuI, In(OAc) , DDT DDT ∼2.2−3.8 tetrahedral DDT 2 3 Ag S Ag(DDTC) OA, ODA 10.2−40.1 sp ODE Ag S Ag(OAc), (TMS) S, S myristic acid, 1-octylamine 1.5−4.6 sp ODE 2 2 Ag S AgCl, (NH ) S OLA, TOP 2.1−2.8 sp OLA, TOP 2 4 2 Ag S DDT-functionalized AgNPs, TBBT DDT, TBBT 1.7 sp toluene photochemical reaction 3+ 3+ 3+ 258 NaYF :Yb ,Er (or Tm ) Na(CF COO), RE(CF COO) OA, OLA (1) ∼11−14 (1) polyhedra ODE RE: rare earth metal 4 3 3 3 (2) hexagonal plate (2) 187 × 71, 100 × 51 3+ 3+ 3+ 257 NaYF :Yb ,Er (or Tm ) Na(CF COO), RE(CF COO) OA 10−50 sp ODE 4 3 3 3 Chemical Reviews Review 4837 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Table 5. continued material precursors and reagents ligand/surfactant size (nm) shape solvent other comments 3+ 3+ NaYF :Yb ,Er (or Na(CF COO), RE(CF COO) TOPO, OLA, OA 5−20 sp ODE 4 3 3 3 3+ 3+ Ho ,Tm ) 3+ 3+ 3+ NaYF :Yb ,Er (or Tm ) RECl , NaOH, NH F OA (1) 21 (1) sp ODE 4 3 4 (2) 17 × 22 (2) ellipse (3) 30 × 45 (3) plate 3+ 3+ 3+ NaYF :Yb ,Er (or Tm ) NaCl, RECl ,NH F PEI ∼20 sp ethylene glycol 4 3 4 3+ 3+256 NaYF :Yb ,Er Na(CF COO), RE(CF COO) OA, TOP 18−200 hexagonal prism ODE 4 3 3 3 Si (1) Mg Si (or KSi, NaSi), SiCl (1) Cl 2−5 sp glyme R: alkyl group 2 4 (2) RLi or RMgCl (2) alkyl group Si diphenylsilane, octanol octanol 1.5−4 sp octanol, hexane Si (1) SiCl , TOAB, LiAlH (1) hydrogen 1.8 sp toluene 4 4 (2) H PtCl , 1-heptene (2) 1-heptene 2 6 Si (1) SiH (2) hydrogen sp (appr) (2) MeOH (2) HF/HNO (3) alkyl group (3) alkene (3) alkene Si SiCl , SiCl (hexyl), LiAlH hexyl group ∼3 sp toluene 4 3 4 Si SiCl , SiCl (allyl), LiAlH allyl group 3.7 sp toluene 4 3 4 CH NH PbBr PbBr ,CH NH Br, CH (CH ) NH Br or octylamonium bromide or 6 sp ODE/OA 3 3 3 2 3 3 3 2 7 3 CH (CH ) NH Br octadecylammonium bromide 3 2 17 3 CH NH PbX (X = Br, I) PbX , OLA, OA, CH NH OLA, OA (2) 35 (1) cubic ODE 3 3 3 2 3 2 (4) 10 (2) plate (3) wire (4) sp (dot) CH NH PbX (X = Cl, Br, I) PbX in OA/OLA, NMF OA, OLA 17−25 bulk, cubic DCB 3 3 3 2 (for X = Cl and Br), CHCl (for X = I) CsPbX (X = Cl, Br, I) Cs CO , PBX , OLA, OA OA, OLA 4−15 cubic ODE size control achieved by 3 2 3 2 varying injection temperature ZnEt , diethylzinc; TOP, trioctylphosphine; HDA, hexadecylamine; ODE, 1-octadecene; TBP, tributylphosphine; ODA, octadecylamine; Zn(OAc) , zinc acetate; OA, oleic acid; CdMe , 2 2 2 dimethylcadmium; (TMS) S, bis(trimethylsilyl) sulfide; TOPO, trioctylphosphine oxide; (TMS) Se, bis(trimethylsilyl)selenide; HPA, n-hexylphosphonic acid; TDPA, n-tetradecylphosphonic acid; 2 2 Cd(OAc) , cadmium acetate; Cd(acac) , cadmium acetylacetonate; HDDO, 1,2-hexadecanediol; TMPPA, bis(2,2,4-trimethylpentyl)phosphinic acid; MA, myristic acid; (BDMS) Te, bis(tert- 2 2 2 butyldimethylsilyl) telluride; ODPA, n-octadecylphosphonic acid; In(OAc) ,: indium acetate; (TMS) P, tris(trimethylsilyl)phosphine; SA, stearic acid; P(NMe ) , tris(dimethylamino)phosphine; OLA, 3 3 2 3 oleylamine; (TMS) As, tris(trimethylsilyl)arsine; Pb(OAc) , lead acetate; Cu(acac) , copper acetylacetonate; In(acac) , indium acetylacetonate; Cu(OAc), copper(I) acetate; DDT, 1-dodecanethiol; 3 2 2 3 Ag(DDTC), silver diethyldithiocarbamate; Ag(OAc), silver acetate; TBBT, 4-tert-butylbenzenethiol; RE, rare earth metal; PEI,: polyethylenimine; RLi, alkyl lithium; RMgCl, alkyl magnesium chloride; b c d e f g h TOAB, tetraoctylammonium bromide; NMF, n-methylformamide; DCB, dichlorobenzene. Reference 287. Reference 288. Reference 289. Reference 290. Reference 291. Reference 292. Reference I j k l m n o p q r s t 293. Reference 294. Reference 295. Reference 296. Reference 297. Reference 298. Reference 299. Reference 300. Reference 301. Reference 302. Reference 303. Reference 304. Reference u v w x y z 305. Reference 306. Reference 307. Reference 308. Reference 309. Reference 310. Reference 311. Chemical Reviews Review Figure 10. Representative TEM images of (a) ZnSe, (b) PbS, (c) CuInS2@ZnS, (d) Ag2S, (e) UCNPs, (f) Si NPs, and (g) MAPbX luminescent nanoparticles. (a) Reproduced with permission from ref 283. Copyright 2013 American Chemical Society. (b) Reproduced with permission from ref 247. Copyright 2011 American Chemical Society. (c) Reproduced with permission from ref 284. Copyright 2011 American Chemical Society. (d) Reprinted with permission from ref 285. Copyright 2016 Wiley. (e) Reprinted with permission from ref 263. Copyright 2008 Wiley. (f) Reprinted with permission from ref 286. Copyright 2011 Royal Society of Chemistry. (g) Reproduced with permission from ref 277. Copyright 2014 American Chemical Society. nanoparticles are generally produced via a hot-injection respectively. Contrastingly, a mixture of Zn(OAc) and oleic method that involves the reaction of cesium-oleate with a acid in ethanol, refluxed in the presence of tetramethylammo- lead halide in octadecene at high temperature (140−200 °C). nium hydroxide could be used to obtain ZnO NPs. The addition of equimolar amounts of oleic acid and TiO NPs have also found crucial roles in a wide variety of oleylamine stabilizes both the lead precursors as well as the applications including dye-sensitized solar cells, photocatalysis, 280 323−325 resulting cubic nanocrystals. More in depth discussions on and batteries. Colvin et al. adopted a hot injection the synthesis, properties, and applications of lead halide method to synthesize TiO NPs, using titanium halide and perovskite nanocrystals can be found in several informative titanium alkoxide in the presence of TOPO at 300 °C. 275,281,282 review articles. While the reactions without TOPO were fast and yielded Table 5 concentrates the literature from a variety of larger particle sizes (>10 nm), the reaction with TOPO was representative fluorescent NPs synthesized in organic media slower and resulted in smaller NPs (5.5 nm), suggesting that and highlights the relevant ligands employed along with the TOPO worked as the surface ligand and played a critical role diversity of materials obtained. Figure 10 shows some to control the NP growth. representative TEM images of some of these materials. As opposed to the nearly spherical NPs obtained through 2.2.4. Other Nanoparticles. Metal oxide NPs are often the use of TOPO, it was shown that by progressively replacing synthesized by sol−gel processes in which water is usually TOPO by a more facet-selective surfactant such as lauric acid required as a reactant. The as-prepared particles have anatase nanocrystals with increased anisotropy and branching hydroxylated polar surfaces. On the other hand, metal oxide are produced. NPs dispersible in organic media are synthesized by non- The most influential factor to control the shape of the TiO hydrolytic sol−gel methods, aiming for better crystallinity. nanoparticles is by manipulating their growth kinetics. The Among a series of metal oxides, ZnO and TiO have been presence of tertiary amines or quaternary ammonium extensively studied primarily due to their interesting electronic hydroxides as catalysts is essential to promote fast crystal- properties and their utility in a variety of electronic devices as lization under mild conditions and to synthesize TiO NRs 312−314 well as for catalysis. with a one-step, low temperature route. When only oleic acid is ZnO is one of the important wide band gap semiconducting present, slow hydrolysis reaction takes place and nearly materials and has a broad range of applications in spherical nanoparticles are formed. Anisotropic hyperbranched 315−317 optoelectronics and biomedicine. ZnO NPs can be organic capped TiO topologies have been achieved by obtained by a variety of approaches such as using ZnEt in the sequent exploitation of aminolysis and pyrolysis in a binary 318 329 presence of n-octylamine and TOPO or using dicyclohex- surfactant mixture (oleic acid and oleylamine). First- ylzinc and a series of alkylamine exposed to air at RT. generation branched nanoparticles initially formed upon the Furthermore, the thermal decomposition of Zn(OAc) in aminolysis reaction possess a strained monocrystalline alkylamines in the presence of tert-butylphosphonic acid was skeleton, while their corresponding second-generation deriva- demonstrated. The growth of ZnO NPs was governed by tives fed by pyrolysis pathways accommodate additional arms the molar ratio of Zn(OAc) and tert-butylphosphonic acid, crystallographically mismatched with the lattice underneath. suggesting that the phosphonic acids were the main surface Furthermore, more complex core−antenna structures have ligands. In contrast to spherical NP materials, ZnO NPs with been developed by a seed-mediated growth method. different shapes could be prepared via nonhydrolytic ester According to this, TiO nanoparticle seeds with well-defined elimination sol−gel reactions with Zn(OAc) and 1,12- shapes followed by the epitaxial growth of nanorod antennas dodecanediol. The use of TOPO, 1-hexadecylamine, and on the seeds along the (110) direction. In a typical synthesis, tetradecylphosphonic acid as the surface ligands in the reaction truncated octahedral bipyramidal nanoparticles are used as formed cone-, hexagonal cone-, and rod-shaped NPs, seeds, together with oleic acid and a Ti precursor, which are 4838 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 6. Metal Oxides Synthesized in Organic Media other material precursors and reagents ligand/surfactant size (nm) shape solvent comments ZnO ZnEt TOPO, octylamine <4.4 sp TOPO, octylamine, decane ZnO ZnCy HDA, DDA, octylamine Rod, disk THF ZnO Zn(OAc) alkylamine, 3−9 sp, elongated alkylamine tert-butylphosphonic acid ZnO Zn(OAc) , 1,12-dodecanediol (1) TOPO, OA (1) 70 × 170 (1) cone (1) dioctyl ether, TOPO (2) HDA (2) 40 × 29 (2) hexagonal cone (2) HDA (3) TOPO, TDPA (3) 5.5 × 23 (3) rod (3) dioctyl ether, TOPO ZnO Zn stearate, 1-octadecanol stearic acid, ODPA sp ODE ZnO Zn(OAc) OA 5 sp EtOH TiO TiX , Ti(OR) TOPO heptadecane X: halide 2 4 4 TiO Ti(O-iPr) OA <6 toluene 2 4 TiO Ti(O-iPr) , tertiary amine or OA 3−4 × <40 rod, sp (with OA 2 4 quaternary ammonium hydroxide (rod) ethylene glycol) TiO TiCl 4-tert-butylcatechol ∼5 sp benzyl alcohol 2 4 TiO Ti(O-iPr) OA, OLA 2 × 12−30 rod, sp ODE 2 4 (rod) 2.3 (sp) TiO Ti(COT) , DMSO TBP, TBPO, or TOPO 3−25 sp o-dichlorobenzene 2 2 Cy, cyclohexyl; DDA, dodecylamine; ODPA, octadecykphosphonic acid; ZnCy , dicyclohexylzinc; TiX , titanium halide; Ti(O-iPr) , titanium 2 4 4 isopropoxide; Ti(COT) , bis(cycloctatetraene)titanium; COT, cyclooctatetraene; TBP, tributylphosphine; TBPO, tributylphosphine oxide Reference 338. heated at high temperature (270 °C). The morphology of the particles transform from rhombic (OA/OM = 4/6) to antennas could be controlled by modifying the precursor truncated rhombic (OA/OM = 5/5) and spherical (OA/OM introduction rate. = 6/4). Solvothermal synthesis was also applied to synthesize TiO Table 6 presents some representative examples of ZnO and TiO NPs synthesized in organic media and the ligands used in NPs using Ti(iPrO) and oleic acid as precursor and each case while Figure 11 shows some representative TEM of surfactant, respectively. The reaction with this surfactant intermediaries and final examples of the latter. led to narrower size distribution than one without surfactant. Weller et al. demonstrated the synthesis of TiO NRs and spherical NPs using Ti(iPrO) and oleic acid in the presence of 3. LIGAND MODIFICATION FOR WELL-DISPERSED tertiary amines or quaternary ammonium hydroxide as a AND FUNCTIONAL NANOPARTICLES IN COMPLEX base. A similar procedure was performed for the synthesis of MEDIA TiO NRs and spherical NPs via aminolysis using oleyl- This section focuses on the important role of ligands for the amine. The low-valent organometallic complex, bis- colloidal dispersity and function of NPs in complex media such (cyclooctatetraene)titanium, and DMSO could also be utilized as precursors for TiO NPs, which were formed at temper- atures as low as RT. While the reaction without any ligand resulted in precipitation of amorphous TiO powder, the reaction with coordinating ligands such as tributylphosphine, tributylphosphine oxide, and TOPO produced a homogeneous solution with internally crystalline TiO NPs. The reaction between TiCl and benzyl alcohol with 4-tert-butylcatechol formed crystalline TiO NPs highly dispersible in organic solvents. H NMR analysis of these NPs revealed the presence of adsorbed 4-tert-butylcatechol and benzyl alcohol on the NP surface. Nanofibers of various sizes and layered structures were also fabricated at ambient conditions. This is the first time that phase transitions from the titanate nanostructures to TiO polymorphs take place readily in simple wet-chemical processes at ambient conditions. Hollow nanotubes observed when the obtained nanocrystals react with concentrated basic solution. More complex shapes of TiO nanocrystals such as rhombic, truncated rhombic, spherical, Figure 11. TEM images of (a) OA-stabilized ZnO NPs, (b) ZnO dog-bone, truncated and elongated rhombic, and bar have NRs, (c) OA-capped length tunable TiO NRs, and (c) dopamine- been synthesized by a simple variation of the oleic acid/ stabilized TiO NPs all synthesized in organic media. (a,b) Reprinted oleylamine ratio or the amount of titanium n-butoxide or with permission from ref 321. Copyright 2005 Wiley. c Reprinted reaction temperature enables a fine control of the growth rate with permission from ref 333. Copyright 2005 Wiley. (d) Reproduced of TiO NPs and, consequently, a control of the shape of these with permission from ref 335. Copyright 2004 American Chemical particles. By increasing the molar ratio of OA/OM the Society. 4839 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review as the ones often met in biomedicine, energy harvesting wide range of organic solvents, as well as exceptional capability devices, and catalytic systems. Different ligand modification to stabilize NPs against aggregation. One of the first examples strategies will be discussed for both biological and non- of the importance of these polymers in NP functionalization biological applications, including the direct functionalization was demonstrated during the development of Doxil, the first during the synthesis of NPs or the postsynthetic modification FDA liposomal nanoformulation of doxorubicin. Initially, of a NP surface. Particular emphasis will be given to the design most of the liposomes loaded with the anticancer drug of ligand coatings for NPs to be used as therapeutical and doxorubicin were accumulated in the spleen and liver rather diagnostic tools in biomedicine due to the combined relevance than the targeting tumor site. The solution came by the and challenging requirements associated with this field. functionalization of these liposomes with PEG brushes covering their surface, preventing the nonspecific adsorption 3.1. Ligand Coating of Nanoparticles for Biomedical of plasma proteins and thus resulting in effective minimization Applications of liposome accumulation into the liver and spleen. After It is well accepted that the NP ligand shell plays a significant these findings, the use of PEG became a common practice in role in the design of nanotherapeutic probes regulating their designing nanotherapeutics at both the research and pharmacokinetics, efficacy, and toxicity. Ligands that coat the commercial levels in order to stabilize NPs against aggregation, surface of NPs should exert adequate colloidal stabilization and prevent uptake by nontarget organs, increase their circulation NP sealing from other molecules in challenging biological time in blood, and enhance accumulation into targeted environments while functional ligands should increase NP organs. PEGylation of NPs can be achieved via various targetability and perform distinct biological roles. Especially for routes. The simplest way is the addition of PEG molecules in vivo applications it is critical to minimize NP aggregation by during NP synthesis. This approach is commonly employed to choice of appropriate ligands. The in vivo fate of NPs critically coat polymeric NPs, and it has also been demonstrated for the depends on their size. For example, for tumor targeting functionalization of inorganic NPs such as Au, Ag, and iron applications, NP size and characteristics have to be finely tuned oxide. It was shown that PEG can play multiple roles in accordance with the tumor state to achieve maximal tumor simultaneously, acting as a solvent/cosolvent, a reducing penetration. Increases in overall NP size, e.g., due to 79,346−349 agent as well as a capping agent. Despite the aggregation could inhibit tumor targeting. Additionally, very simplicity of the experimental protocols, the PEG molecules small NPs might leak into blood vessels, while very large NPs are only weakly bound to the NPs, and thus they can easily or aggregates of NPs might become subject to macrophage detach from the NP surface during various processing steps clearance without being able to fulfill their therapeutic role. (e.g., dilution/dialysis, centrifugation, heating, drying, aging, Therefore, it is of utmost importance to choose the right ligand mixing with other compounds, etc.). A strategy to make a coating for the desired biomedical application. It is also worth stable coating of PEGs on NPs has been recently demonstrated mentioning that for biomedical applications, ligand selection as illustrated in Figure 13. An amphiphilic polymer grafted should also consider the biocompatibility and biodegrad- with both alkyl chains and PEG molecules is self-assembled ability/excretion of the ligand as a general requirement for into micelles and coats the surface of NPs. The coating clinical use. stabilizes the NPs as a result of the large conformation entropy Various ligands such as carbohydrates, oligonucleotides, 80,350 repelling any foreign materials. Other strategies involve polymers, peptides, and proteins have been utilized in the functionalization of PEG molecules, with NP binding head biomedical applications, and in the following sections, we 341−343 groups such as thiols, amines, carboxylic acids, or discuss the ones most commonly employed. Figure 12 351−353 silanes. PEG-modified nanomaterials tend to reduce immunological reactions, which can be attributed to the repelling nature of PEG to proteins, as it tends to reduce total serum protein adsorption (opsonization) as a function of grafting density and 354−356 molecular weight of the polymer. However, some studies also suggest that PEG coating might facilitate the binding of other proteins (albumin for instance) and thereby blocking the way for immunoglobulins in a process 354−356,358 known as “dysopsonization”. While the stability of NPs grafted with PEG-containing ligands in vivo is still unclear, many in vitro experiments have been carried out to shed more light on this family of ligands. For example, Au NPs functionalized with mPEG-thiol (5 or 10 kDa) were found to Figure 12. Different ligands commonly used in NPs designed for be prone to ligand displacement by cysteine resulting in biomedical applications including antibodies, oligonucleotides, carbohydrates, proteins, polymers, and dyes. increased adsorption of serum proteins. Interestingly, in- troduction of alkyl moieties as hydrophobic spacers between shows some examples of ligands used for biomedical the thiol and the PEG prevented this displacement. applications while Table 7 summarizes selected examples of While PEG generally display little net-charge, adding nanotherapeutics that are commercially available or under functional end groups such as carboxyl or amine can infer a advanced clinical evaluation with various surface ligands. net negative or positive charge, respectively, altering the 3.1.1. Ethylene Glycol Containing Ligands. Poly- properties of the PEG ligand and interactions with ethylene glycol (PEG) is a unique category of various biomolecules. Additional functional groups can be em- molecular weights polymers, which possess fascinating proper- ployed for the further conjugation of PEG to biomolecules ties such as biocompatibility, high solubility in water and in a such as homing peptides or antibodies as well as fluorophores. 4840 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 7. Nanotherapeutic Agents in Clinical Trials and/or FDA Approved approval brand name indication modality surface ligand status Doxil anticancer liposome PEG FDA approved AuroLase anticancer silica core with gold PEG pilot study shell NP ThermoDox anticancer liposome thermoresponsive polymeric shell phase III NanoTherm anticancer iron oxide NP aminosilane FDA approved Ferinject iron deficient anemia iron oxide NP carboxymaltose FDA approved Feraheme iron deficient anemia in chronic kindey iron oxide NP (SPION) polyglucose sorbitol carboxymethyl ether FDA disease (CKD) approved Ferdex/Endorem imaging agent iron oxide NP (SPION) dextran FDA approved GastroMARK imaging agent iron oxide NP (SPION) silicone FDA approved NBTXR3 radiotherapy HfO NP not explicitly stated, but designed to have phase II/III antifouling activity Figure 13. Schematic illustration of NPs containing an inorganic core, coated with the amphiphilic polymer poly(maleic anhydride-alt-dodecene) (PMA) and fluorophore DY-636 (light blue). PEG chains of different MW or glucose (red) were attached to the NP surfaces. The resulting NPs are (a) FePt−PMA, (b) FePt−PMA-PEG750, (c) FePt−PMA-PEG5k, (d) FePt−PMA-PEG10k, (e) FePt−PMA-glucose, and (f) Fe O −PMA 3 4 respectively. TEM images of (g) FePt-PMA, (h) FePt−PMA-PEG750, (i) FePt−PMA-PEG5k, (j) FePt−PMA-PEG10k, and (k) FePt−PMA- glucose NPs (scale bar: 25 nm). (l) Mean core−shell radius rcs of the FePt NPs). Reprinted with permission from ref 350. Copyright 2015 American Chemical Society. Figure 14. (a)Chemical structures of cationic OEG ligands on Au NPs. (b) Chemical structure of zwitterionic OEG ligands used for Au NP synthesis and corresponding TEM images of zwitterionic Au NPs (2, 4, and 6 nm). (a) Reprinted from ref 367. Copyright 2014 American Chemical Society. (b) Reprinted with permission from ref 366. Copyright 2016 American Chemical Society. Bifunctional PEG molecules can also serve as cross-linkers/ shown for iron oxide NPs functionalized with the homo spacers, facilitating further grafting to biomolecules or other bifunctional linker gallic acid, for example. groups, while maintaining the stability of the system under Just like their larger counterparts, the smaller oligo-ethylene 360−363 different conditions. However, when using homo glycols (OEGs) have been used as ligand coatings for NPs bifunctional PEG (i.e., two identical end groups), care needs (e.g., see section 2.1.1). For example, carboxy-terminated to be taken in order to avoid NP aggregation through cross- OEG modified with a hydrophobic alkyl unit including a linking reactions, which can have detrimental effects on NP diacetylene group, which can be photo-cross-linked upon UV function as discussed in section 3.1. Cross-linking and irradiation and a terminal thiol for anchoring to the surface of therefore NP aggregation can generally be avoided by using Au NPs have been shown to result in Au NPs with excellent a large excess of such homo bifunctional linkers as has been stability toward changes in pH, ionic strength, or ligand 4841 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 15. Schematic illustration of the silanization strategy on TOPO-capped CdSeZnS core/shell particles. Briefly, the methoxysilane groups (Si- OCH ) hydrolyze into silanol groups (Si-OH) and produce a primary polymerization layer. Condensation leads to the formation of siloxane bonds and water molecules are released. Next, silane precursors are added into the shell to provide further functionality and finally, to block the shell growth by converting the remaining hydroxyl groups into methyl groups. Reprinted with permission from ref 371. Copyright 2001 American Chemical Society. displacement and could be selectively polymerized into chains condensation of the silanols, which finally leads to the and networks of Au NPs by tuning the density of ligands on formation of the siloxane bonds. A typical feature of the 353,365 the nanoparticle surface. Furthermore, both cationic and relevant sol−gel method is that usually condensation does not zwitterionic OEGs have been shown to provide Au NPs with go to completion under relatively mild reaction conditions, so 366,367 antimicrobial properties. As discussed for other OEGs, that a silanol-terminated surface is exhibited. This feature is these contained a thiol anchoring group as well as sulfonate exploited, both to ensure colloidal stability through repulsion and/or quaternary amine groups, which provide negative and among negatively charged surface core@shells and to enable positive charges respectively, thus providing electrostatic bioconjugation (Figure 15). The process of cross-linking of stabilization (see Figure 14). silicon-containing ligands offers the advantage of a well- 3.1.2. Silanes. Among the inorganic coatings used in the established sol−gel chemistry, which enables surface function- design of functional NPs for biomedical applications, silicon- alization either by reaction with common coupling agents, or containing ligands are the most widely used due to the by surface condensation of functional alkylsilanes (R′Si(OR) , combination of its hydrophilic features with chemical and R′R′′Si(OR) ,R′R′′R′′′SiOR) bearing a nonhydrolyzable physical stability. These kinds of ligands have been applied to a functional group R (Table 8). wide variety of functional NPs (metallic, magnetic, semi- Most silica-coating protocols have been adapted from the conductor) with the purpose of enabling or improving their Stöber process for the synthesis of SiO spheres, which relies dispersibility in aqueous media as well as their biocompati- on controlled hydrolysis and condensation of tetraethylortho- bility. In particular, the formation of a cross-linked shell of silicate (TEOS, Si(OC H ) ) under basic (ammonia) catalysis 2 5 4 silicon-containing ligands is a means to reduce particle in ethanolic or hydroalcoholic media. The basic idea behind aggregation in those cases where relevant chemical or physical the design of NP@SiO is that the Stöber process is carried out interactions take place. In the case of metal NPs and QDs, in the occurrence of a NP suspension and that the synthesis silica shields the functional core from the environment, parameters are adjusted in such a way that heterogeneous protecting the NPs toward oxidation and reducing their 368−370 nucleation of silanization on top of the NPs is highly favored as toxicity. compared to homogeneous nucleation. Several strategies have been devised for the fabrication of This approach was shown to be relatively straightforward in NP@SiO core@shell, often relying on the sol−gel synthesis of the case of oxide or oxyhydroxide NPs dispersible in ethanol or silica from an alkoxysilane, according to the following chemical water. A relevant example was reported by Xia and co-workers, reaction: who discussed that deposition of silica from TEOS onto a water-based commercial ferrofluid under ammonia catalysis Si(OR)+→ 2H O SiO+ 4ROH 42 2 results in iron oxide@silica with up to 70% of the core@shells containing a single core. By adjusting the TEOS amount, the The reaction, which requires the use of acid or basic shell thickness was varied from 2 to 100 nm, and further catalysis, occurs through a multistep equilibrium associated with the hydrolysis of all the alkoxy groups, followed by functionalization with aminopropyl trimethoxysilane (APTS) 4842 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 8. List of Some Commercially Available Silane Precursors for NP Coating and Functionalization enabled coupling with isothiocyanaterhodamine, producing Another more general modification of core@shell produc- tion based on Stöber-like silica shell formation relies on the use multifunctional core@shells for magnetic and optical detec- tion. On the other hand, in the case of metal and QD cores, of micelles, which are regarded as a nanometer-sized confined environment for controlled nucleation and growth of the silica the generation of a silica shell is less trivial, as the use of a shell. While early studies focused on the in situ formation of primer, with which the initial silica is bound to the NP surface, both the core and the silica shell within a micelle template (see is needed. The primer needs to have strong affinity for the core for example CdS@SiO in ref 377), nowadays the general surface. Most often vitreophilic groups (typically mercapto- approach is to make use of micelle-mediated silica shell propyltrimethoxysilane or aminopropyltrimethoxysilane) are deposition on preformed NPs. This is due to a number of used for initiating silica shell deposition. By this approach, reasons, including limited reproducibility associated with the silanization of several NPs, including Au, Ag, and CdS, has extremely high number of involved synthetic variables, the been achieved, provided that the original NPs did not possess 369,374 relatively detrimental effect of micelle synthesis on the covalently bound ligands on their surface. physicochemical properties of the inorganic core as compared Improvements of the Stöber approach to core@shell NP to high temperature synthetic routes and to the understanding design have focused on defining more general protocols, which that the vision of micelles as static templates is unrealistic. could include particles not stable in hydroalcoholic media or Recent strategies based on micelle-assisted synthesis take into with limited affinity toward silica. In particular, methoxy- account the complexity of the synthetic medium, including the poly(ethylene glycol)-thiol (mPEG-SH) was found to be possibility of interdroplet exchange due to, e.g., Brownian effective in promoting transfer into ethanol of gold spheres and motions, as well as the effect of the compositional variation in rods without aggregation, enabling subsequent SiO shell the system with particular reference to ethanol and water, growth by Stöber routes. A more general procedure which are directly involved in the sol−gel silica reactions, on 378,379 relatively independent of the nature of the core includes the the surfactants assemblies. However, the mechanism of use of an amphiphilic nonionic polymer, e.g., PVP, which is NP@SiO formation in microemulsion is not fully elucidated adsorbed on the NP surface, enabling the direct transfer of the to date. Nevertheless, Koole et al. provided insights in the NPs into an ammonia/ethanol mixture where silica coatings formation of core@shell NPs obtained by direct TEOS are grown by addition of TEOS. The method was found to be deposition in water-in-oil microemulsion on hydrophobic effective for the silanization of Au, Ag, boehmite rods, and QDs (CdSe, CdTe, PbSe), which was reported also for the 376 380 gibbsite platelets. case of CdSe@ZnS dots. It is demonstrated that hydrolyzed 4843 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review TEOS replaces the capping agent originally present on the coatings (1−2 nm) was shown to be highly advantageous in hydrophobic NP, enabling therefore transfer of the NP into the those applications requiring efficient interaction between the water phase of the microemulsion, where silica growth takes core and the biological environment, such as the case of iron place. This mechanism is supported by the features of the final oxide@silica NP contrast agents for magnetic resonance 389−392 imaging (MRI). core@shell NPs. Silica coating works well when hydrophobic QDs are initially coated with capping agents, which can be Silica coating has been demonstrated to be highly effective in easily exchanged by TEOS, leading to NPs with the core improving the applicability of functional NPs in biomedicine exactly in the center of the silica shell. On the other hand, because the pioneering work by Alivisatos and co-workers on the use of silanized QDs as tools for fluorescence imaging and capping agents with a high affinity result in morphologies with 381 393,394 probing of biological systems. State-of-the art design of off-center core (see Figure 16 a,b). silica-based core@shell NPs for biomedical use is focused on exploiting silica shells to achieve multiple functionality such as dual imaging or combined imaging and therapeutic ability (see Figure 17). Figure 17. Schematic illustration of a biomolecule−NP conjugate. The core/shell CdSe/ZnS NPs are surrounded by a siloxane shell. To obtain water solubility, stabilizing groups are embedded in the outer Figure 16. Coating of NPs by dense (a,b) and mesoporous SiO . (c). siloxane shell, examples of stabilizing groups include phosphonate, Silica coating of hydrophobic NPs is affected by the affinity of the PEG, or ammonium. In addition, amines, thiols, or carboxyl groups original ligands for the NP surface: TEM image of silica coating of are incorporated in the siloxane shell as functional groups. Reprinted NPs coated by ligands with (a) moderate and (b) high surface affinity. with permission from ref 394. Copyright 2002 American Chemical Silica with extended mesoporosity (c) may be required to exploit NPs Society. as affinity probes by providing high surface area and pores for size exclusion of undesired analytes. (a,b) Reprinted with permission from ref 381. Copyright 2008 American Chemical Society. (c) Reprinted Within the framework of multifunctional NP@SiO , the with permission from ref 382. Copyright 2014 The Royal Society of 2 synthesis of porous silica shells has been achieved, with Chemistry. particular reference to ordered mesoporous silica shells through Stöber-like approaches mediated by a templating Typical microemulsions are based on ternary systems agent such as CTAB. The mesoporosity of the silica shells has containing water, hexane, or cyclohexane as oil phase, and a been exploited to develop magnetically recoverable core@shell commercially available ionic or nonionic surfactant such as NPs for nucleic acid detection with a high, specific surface area, Igepal, Triton X-100, AOT, Synperonic NP-5, or CTAB, to and to design iron oxide@silica NPs for dual imaging name a few. To achieve controlled core@shell morphologies applications by hosting fluorescent dyes and NPs in the 395−397 many parameters need to be adjusted, which are relatively porous texture of the mesoporous silica shell. The key 383−387 independent from the composition of the core. role of the porous shell was recently demonstrated with the Recently, it was shown that direct silanization from TMOS fabrication of iron oxide NPs coated with mesoporous silica can be achieved in one pot during the synthesis of metal halide loaded with TiO NPs as a novel affinity probe for proteins. perovskites QDs. The formation of the core−shell particles is Taking advantage of the strong interaction of TiO to the postulated to be affected by the occurrence of oleylamine used carboxyl groups of the peptides, of the size-exclusion effect of as NP capping agent promoting the sol−gel silica shell the ordered mesopores, and of the high available surface area, formation by amine functionalitites. selective enrichment of endogenous peptides was successfully An alternative approach for core@shell NP/silica production achieved (see Figure 16c). relies on the use of silicic acid as the precursor for the silica Although the occurrence of a mesoporous shell may be shell. Likewise, in the so-called water glass process, silicic acid highly beneficial for the end-use of core@shell NPs in has to be prepared in situ, usually by passing sodium silicate biomedicine, the main limitation of the available synthetic through cation exchange columns. After addition of silicic acid strategies relies on the removal of the templating agent, which to the NP suspension, the pH is raised to a suitable value to generates the porous network. While calcination is the most promote controlled silica condensation on the NP surface. effective way to promote complete removal of the template and Although a water-based dispersion of the NPs is needed, this formation of the mesoporous ordered structure, it may alter approach offers the distinct advantage of enabling the the functionalities or compromise the dispersibility of the NPs. deposition of extremely thin and homogeneous silica shells, As an alternative, solvent extraction of the template can be whose thickness can be finely modulated by repeated layer carried out under mild conditions, which however, is usually deposition. In particular, the occurrence of very thin silica incomplete. A recent study on the deposition of SiO from 4844 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review TEOS on CTAB-stabilized AuNRs suggests that CTAB as compared to conjugates prepared via the “salt-aging” method.. expected promotes the formation of a mesoporous silica Another important factor influencing the stability of DNA-Au coating and can then be removed by extensive rinsing with NP conjugates is the choice of the anchoring group. As such, it ethanol taking advantage of dissolution through the porous has been shown that di- and trithiol linkages as well as silica shell. Besides limiting accessible porosity, residual bifunctional linkers such as thiol plus amine provide higher templating agent within the outer silica shell may lead to stability conjugates compared to monothiols. nonreproducible or undesired interactions between the core@ In certain environments, such as in cell culture media or in shell NPs and the biological environment. other challenging buffers, it is highly important to employ 429−431 3.1.3. Oligonucleotides. Their inherent properties of DNA-NPs that are colloidally stable. For example, Funk accurate addressability and programmability, high target and co-workers showed that Au NRs coated with a dense shell specificity, as well as ease of synthesis and functionalization of DNA could be coupled to DNA origami structures, which have made oligonucleotides attractive ligands for NP generally require high MgCl buffer concentrations to maintain functionalization. The various types of oligonucleotides do their structural integrity, by hybridization to complementary not only play essential roles within living organisms but also “handle sequences” on the DNA origami. These constructs have found widespread applications in different research areas could then be employed for the detection of mRNA both in ranging from antisense therapy and siRNA delivery to buffer and in human serum. On the other hand many reports hierarchical self-assembly for the creation of new materials. have investigated the use of densely functionalized DNA-Au On the other hand, chemically modified oligonucleotides, such NP conjugates for intracellular sensing or drug deliv- 404,412,433 as locked nucleic acids (LNA) or peptide nucleic acids (PNA), ery. Mirkin and co-workers showed that the DNA- have been developed to increase target binding affinity through shell on Au NPs facilitated the cellular uptake through increased base-stacking and to be enriched with high stability scavenger receptors and resulted in a high number of 434−437 toward nuclease digestion, respectively. Taking into account internalized particles compared to bare Au NPs. The the versatility of oligonucleotides, it is unsurprising, that number of uptaken particles was highly dependent on the oligonucleotides as ligands to coat NPs play an important role density of the oligonucleotide loading, with higher loading in the function of nanoparticulate systems. Over the last two resulting in higher uptake. Additionally a dense DNA loading decades DNA-coated NPs have become increasingly important greatly increased the stability of conjugates with respect to 23,401−403 404−414 438 for applications in biosensing, nanomedicine, degradation by nucleases. Similarly, the stability of siRNA 17,19,415−418 and metamaterials. The DNA ligand shell stabilizes was enhanced in siRNA-Au NP conjugates and showed great the NP core both through sterical and electrostatic interactions potential in in vitro gene silencing. resulting in NPs that are highly stable in a variety of complex Ag NPs can also be functionalized with thiol-terminated media. Different conjugation strategies based on direct DNA, although density functional theory (DFT) and ab initio oligonucleotide chemisorption, physisorption, or involving studies have shown that the nature of the Ag−S bond is much coupling chemistry have been developed. weaker than that of the Au−S bond, with the bond being less Oligonucleotide Conjugation to NPs by Drect Chem- than 35% covalent and more than 65% electrostatic in nature, isorption. Pioneering work by research groups led by therefore resulting in less stable DNA-Ag NP conjugates 419 420 24 Alivisatos and Mirkin in 1996 showed for first time compared to Au NPs. Similar to Au NPs, for creating a dense that it was feasible to attach thiol-modified oligonucleotides to DNA ligand shell, charge screening must be taken into Au NPs. While Mirkin and co-workers demonstrated that Au account. Both the use of triple cyclic disulfides, as well as 420,421 NPs can be modified with a dense DNA corona, monothiolated DNA have been shown to quickly conjugate to 441,442 Alivisatos and co-workers showed that it was equally possible Ag NPs. Furthermore, phosphorothioate (pt)-oligonu- to produce Au NPs conjugated to a discrete number of cleotides can be employed. Here a Sulfur atom replaces an 89,419,422,423 oligonucleotides. To obtain stable DNA-coated oxygen atom in the phosphate backbone of DNA, which does NPs for biomedical applications, the covalent conjugation of a not only render these oligonucleotides stable toward dense shell of DNA strands to NPs is often desirable. To degradation by nucleases but also allows for functionalization achieve high DNA loading on the NP surface, electrostatic of NPs through metal−S interactions. Because many repulsion between neighboring DNA strands, as well as phosphate groups can be replaced by phosphorothioate within between DNA and the anionic Au NP surface must be a DNA strand, multivalent interactions with a single NP can be minimized. This can be achieved by the gradual increase of achieved, resulting in high stability. As such it was shown that salts (e.g., by addition of NaCl), or adjustment of the pH, thus Ag NPs functionalized with 3, 6, or 9 pt-containing DNA utilizing either Na+ or H+ ions to minimize electrostatic strands displayed increasing stability with respect to strand 421,424,425 repulsion. On the other hand ehtylene glycol displacement by dithiothreitol (DTT) with increasing numbers containing molecules such as OEG can be included as spacers of phosphorothioate groups present. between the DNA and the Au surface, allowing high DNA Oligonucleotide Conjugation of NPs by Physisorption. loading without the need for additional charge screening by Although covalent conjugation strategies are among the most ions. Recently, a “freeze-and-thaw” conjugation method was popular, some other strategies have been reported in the past reported by Liu and co-workers where Au NPs and thiolated decade to coat NPs of various chemical compositions with DNA strands were simply frozen and thawed, resulting in very DNA, where covalent conjugation may not be directly 427 444,445 dense DNA loading on NPs. The authors hypothesized that possible. For example pt-DNA, similarly to the case of during water crystallization, DNA, Au NPs, and salt are Au and Ag NPs, has also been employed to functionalize CdS repelled out of the growing ice crystals, thus resulting in high QDs, which showed different binding affinities for pt-DNA 2+ local concentrations and facilitating DNA attachment kinetics. depending on their surface properties. For example, Cd -rich The resulting conjugates showed not only increased DNA QDs displayed a higher binding affinity toward pt-DNA 2− loading but also increased stability in high salt buffers compared to neutral or S -rich CdS QDs. The conjugation 4845 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 18. Different methods of functionalizing Au NPs with DNA. (a) physisorption through Adenine bases. (b) Conjugation via pt-DNA. (c) Conjugation via thiol-Au bond. (d) Different strategies to conjugate DNA to colloidal QDs. (a−c) Reprinted with permission from ref 450. Copyright 2014 American Chemical Society. (d) Reprinted with permission from ref 448. Copyright 2013 Springer Nature. mechanism is most likely electrostatic in nature, although it The adsorbed DNAs also form an “exclusion zone” toward was shown that CdS QDs displayed greater binding affinities other incoming DNA strands, thus limiting further adsorp- 446 449 for pt-DNA compared to unmodified DNA. On the other tion. DNA physisoption is highly specific to the DNA hand, His-tagged as well as thiolated DNA can be employed sequence used with the following ranking in adsorption for QD conjugation due to affinities for different metal ions on affinity: A > C > G > T. It was shown that the DNA bases 447,448 the QD surface. While QD-thiolated DNA conjugates can interact with the metal surface through its nitrogen atoms, displayed excellent stability at high concentrations, they were specifically through N-7 (circled in yellow in Figure 18) and highly sensitive to changes in pH, photo-oxidation, and N-9. Especially, oligonucleotides containing a poly adenine dilutions. His-tag DNA-QD conjugates suffer from limitations (poly A) tail, have shown superior adsorption properties. in their preparation, being highly pH sensitive. Furthermore, The stability of these DNA-Au NP conjugates was found to be achieving high DNA-loading with this method is difficult as the highly dependent on the length of the poly-A tail, with a longer His-linkers limit the adsorption of other incoming DNA tail resulting in decreased desorption upon temperature, pH. or strands due to steric hindrance. salt concentration due to increased binding interactions, i.e., A proposed model for DNA physisorption on citrate-capped more DNA bases anchoring to the NP surface. However, a Au NPs is that initially the polyanionic DNA adsorbs on the longer polyA tail also resulted in a decreased number of DNA Au surface and thereby displaces citrate anions. This can be strands anchored to the Au NPs, which in turn allowed for facilitated by the addition of cations. To maximize surface more precise control of DNA loading. Interestingly, it was contacts, DNA may undergo structural conformation changes. shown that Au NPs functionalized with an A30-tail were stable 4846 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review with only 15% of DNA desorption after being heated to 95 °C for 30 min. However, the overall stability of these conjugates was still found to be less than those formed with thiol or pt-DNA. Liu and co-workers proposed the combination of pt-DNA into polyA DNA to harness both the high stability as well as precise conjugation properties. Oligonucleotide Conjugation to NPs by Coupling Chemistries. Other types of NPs often cannot be directly functionalized with DNA, as they are stabilized by additional 453,454 ligands such as polymers containing variable functional end-groups such as hydroxyl, carboxyl, amine, alkyne, azide, or aldehydes for further modifications. These functional groups allow for conjugation to oligonucleotides via various different methods. For example azide-functionalized superparamagnetic iron oxide NPs (SPIONs) as well as NPs bearing azido- amphiphilic polymers could be modified with a dense layer of alkyne functionalized oligonucleotides using alkyie-azide click 19,455 chemistry. On the other hand, the EDC coupling method Figure 19. Roles of (poly-)peptides in determining the fate and can be employed to conjugate amine-modified oligonucleo- properties of NPs. Reprinted with permission from ref 462. Copyright tides to any NP functionalized with carboxyl terminated 2018 The Royal Society of Chemistry. ligands. For example, UCNPs were functionalized with DNA using the EDC coupling strategy and then used in conjunction with graphene oxide (GO) for the successful Peptide Conjugation to NPs by Chemisorption. Peptides detection of zeptomoles of target oligonucleotides in solution. offer various functional moieties such as Cys (-SH) or His This study was further exploited for the detection of mRNAs in (-imidazole), which could be used for conjugation to the NP 402,403 418,464−466 cell lysate and blood plasma. surface. In the case of Au or Ag NPs peptides can be Figure 18 summarizes the basic strategies for conjugation of directly conjugated to the NP surface via free thiol-containing NPs with oligonucleotides. cysteine side chains. An example of this strategy was 3.1.4. Small Peptides. Small peptides are built up from demonstrated by Levy and co-workers. They utilized the few amino acids linked by amide bonds and represent another (Cys-Ala-Leu-Asn-Asn) CALNN peptide and showed that it important class of biomolecules that have been widely presented an excellent ligand for the stabilization of Au NPs. employed for NP stabilization and biofunctionalization for a The major characteristic for the success of this peptide was its 457−459 variety of applications in biomedical sciences. Peptides amphiphilic character having two hydrophobic amino acids have gained attention due their potential role as therapeutic (alanine and leucine) near the binding site and two hydrophilic agents in diverse areas such as oncology and infectious disease, amino acids (asparagine) further from the binding site. The as well as metal ion or molecular detection systems such as in amino acid cysteine is able to bind to the AuNPs whereas colorimetric assays for detection of a wide range of alanine and leucine (hydrophobic) induce peptide self- 460,461 biomolecular targets. The conjugation of peptides to assembly. This configuration facilitated a firm and stable NPs can not only result in increased reactivity due to a high coating of the peptides around the NPs, ensuring their local concentration but also enables multiplexing, thus solubility in water and providing a good stability at distinct pH harnessing the properties of different peptides at the same values and in different buffer ionic strengths. Recently, Kanaras time, and ref 462, figure 3.7, illustrates some of the roles and co-workers showed that Au NPs coated with a mixed peptides play in determining NP functionality and stability monolayer of CALNN and the skin penetrating peptide (Figure 19). CALNNR7 (or CALNNTAT) were able to penetrate through Similar to the case of oligonucleotides, the grafting density human skin, highlighting the important role of NP of peptides on the surface of the NP has to be carefully functionality and its direct correlation to NPs properties. controlled, as it will dictate the overall stability, activity, and Furthermore it was demonstrated that Au NPs functionalized properties of the resulting peptide−NP conjugate. It also has to with DNA binding peptides could be directed to assemble on be noted that while a dense coating might provide greater NP DNA templates in a specific manner to form ordered NP stability, it may also have a negative impact on the activity of assemblies. The formation and or destruction of such the peptides. Commonly used peptides for NP conjugation assemblies can be triggered by protease action or metal-ion 468−470 include cell-penetrating peptides (CPPs), which can enhance complexation methods. Poly histidine (HIS)-tags have uptake and delivery of drugs across membranes and improve been utilized by Mattoussi and co-workers to conjugate the efficiency of cell uptake of nanoparticulate systems, as well peptides to DHLA-coated QDs. Another recent study as homing peptides, which are designed to target cells, tumors, showed that QDs could be modified with a virus-derived lytic and tumor-associated microenvironments. One prominent peptide fused to a maltose-binding protein containing a hexa example of a CPP is the HIV-derived Tat peptide, which HIS-tag resulting in stable QDs, able to perforate the cell facilitates the cellular internalization of Au NPs in HeLa membrane. cells. Various strategies have been reported for the Peptide Conjugation to NPs by Coupling Chemistries. functionalization of NPs with peptides, tailored to the NP’s Besides direct conjugation, peptides can also be indirectly chemical composition. In general, the peptide can be attached to ligands already covering a NP surface. For example, incorporated either by direct chemisorption or by various Bartczak et al. reported a “one-pot” EDC/sulfo-NHS coupling coupling chemistries. strategy to functionalized OEG-capped NPs with peptides 4847 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review (Figure 20). Then, the same group demonstrated that antibodies can be achieved by direct chemical covalent peptide-capped Au NPs could be successfully employed to conjugation or electrostatic interactions. As discussed previously, noncovalent methods are based on hydrophobic and/or ionic interactions. Although this method of function- alization is generally straightforward and does not involve complex chemistry, it suffers from some disadvantages compared to covalent strategies. For example, in the case of antibodies, nonspecific binding to NPs can result in the loss of antibody activity as well as the destabilization of colloidal NPs. On the other hand, covalent methods use specific sites on the protein for NP conjugation. These are usually present in the form of chemical linkers or employ common protein binding 484,485 interactions (e.g., streptavidin and biotin). The choice of conjugation method and site should be carefully considered as proteins could be impaired, unfold, and/or lose their properties if an inappropriate method and/or conjugation site was chosen. Therefore, several efforts have been developed to optimize and control the orientation, density, activity, and accessibility of the protein after functionalization, as will be discussed in the following sections: Protein Conjugation to NPs by Chemisorption. The covalent conjugation of proteins to NPs can allow for greater control of protein activity but also to control aggregation behavior. Among the most commonly employed proteins for NP modification is avidin (found in egg white). The interaction of avidin/streptavidin with biotin (vitamin H) is one of the strongest noncovalent interactions in biology, and it has been heavily employed in targeting applications and assay Figure 20. Schematic overview of amide bond formation among the 487,488 methods. While most conjugation strategies rely on KPQPRPLS Peptide (blue) and OEG NPs (red shape) using EDC physisorption, a covalent functionalization method was (red) and sulfo-NHS (green) strategies. Reprinted with permission reported, which employed cysteamine and glutaraldehyde to from ref 473. Copyright 2011 American Chemical Society. link streptavidin to Au-magnetic NPs. Covalently conjugated streptavidin coated NPs showed an increase in stability in PBS containing SDS compared to NPs with a physisorbed study interactions of Au NPs with endothelial cells as well as 464,473−479 streptavidin coating. However, it was found that when manipulate angiogenesis both in vitro and in vivo. compared to conjugation by physisorption, streptavidin Peptide-coated CdSe/ZnS QDs have also been shown to be loading was lower. Simonian and co-workers demonstrated able to target the lung, blood, and/or lymphatic vessels. that small Au NPs (1.4 nm) displaying a sulfo-NHS or 3.1.5. Proteins. Proteins, generally defined as polypeptides malemeide reactive group could be conjugated with the consisting of more than 50 amino acids, play one of the most enzyme organophosphate hydrolase (OPH) through primary diverse roles within a living organism, ranging from receptor or amines from lysine residues or sulfhydryl groups from cystein membrane channel formation to molecular transport and residues. The resulting conjugates were then used for the catalysis of biochemical reactions. Therefore, it is not detection of the neurotoxin paraoxon. surprising that many diseases are the result of protein Protein Conjugation to NPs by Physisorption. Physisorp- malfunction due to mutations or misfolding. However, this tion represents the simplest way to functionalize NPs with also presents an opportunity to use proteins as therapeutic proteins. Resulting conjugates have the advantage that agents, an area that has become increasingly popular since the 481−483 conjugation is usually reversible, which can facilitate delivery report of the first protein therapeutic, insulin. On the and sensing applications. As discussed previously, the other hand, the use of protein−ligand interactions plays an functionalization of NPs with streptavidin is generally important role and can be harnessed for nanoscale protein self- straightforward and mainly relies on electrostatic interactions. assembly. For example, it was shown that avidin strongly absorbs onto Similar to their smaller peptide counterparts, the con- DHLA-coated QDs due to charge interactions. Even jugation of proteins to NPs can be advantageous for various particles with a controlled number of avidin (or streptavidin) reasons, such as increase in overall protein activity resulting 176,492 moieties per particle could be prepared. from the high local concentration at the microenvironment, An interesting work by Murphy and co-workers demon- increased stability or self-assembly. Hence protein−NP strated the successful assembly of Au NRs using biotin and conjugates have emerged as effective and promising tools for a wide range of applications, including diagnosis and streptavidin linkers. Interestingly, linkage was mostly observed therapeutics. In terms of biomedical applications, the protein in an end to end fashion. The group attributed this observation coating can be designed to modulate the stability of the NPs, to the higher reactivity of Au NRs’ edges due to their lower determine the clearance of NPs in vivo or to target specific coverage with CTAB. On the other hand, the functionaliza- biological sites. Thus, there has been an increased interest to tion of spherical Au NPs with lipases via a PEG-biotin design NP−protein conjugates for biomedical applications. In streptavidin−biotin linker was demonstrated. These protein general, functionalization of NPs with proteins such as functionalized particles were able to digest cubosomes 4848 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review following a different mechanism in comparison to free lipase. Protein Conjugation to NPs by Coupling Chemistries. It is The variation of the digestion mechanism was attributed to the important to mention that bioconjugation of NP surfaces overall size of the nanoparticulate system, which restricted achieved by alternative approaches, such as biotechnological strategies, may have benefits when designing NPs for access to the inner parts of the cubosomes. biomedicine. For instance, Ma et al. developed a systematic Streptavidin−biotin interactions were also used for signal method to bioconjugate recombinant proteins to NPs without amplification particularly coupled to electrochemical sensing of the need for modification for each specific protein-NPs microRNA. MicroRNAs are noncoding RNAs that can serve as tumor markers and therapeutic targets for some cancers. conjugate. A glutathione S-transferase-SpyCatcher fusion protein conjugated to Au NPs allowed for assembling of Biotinylated nucleotides were used to incorporate biotin into additional proteins through the Spy- Catcher/SpyTag system, the hybridized microRNA complex. Afterward, Au NPs loaded resulting in a two-step synthesis. First, the Au NPs were with large amounts of streptavidin were used to amplify the modified by glutathione S-transferase (GTS) trough Au−S signal. Signal amplification was based on the ability of the Au− bonds, and second, a covalent link between a SpyCatcher and streptavidin scaffold to capture both biotinylated nucleotides the SpyTag peptide was formed (by spontaneous formation of and biotinylated alkaline phosphatase. The enzyme catalyzed an isopeptide bond). Importantly, in this second step, a variety the conversion of the electrochemically inactive molecule 1- of recombinant proteins could be employed in a reproducible naphthyl phosphate present in the buffering solution into the manner, resulting in stable NP−protein conjugates. The active naphthol, thereby amplifying the resulting signal. The authors provided a universal platform to immobilize proteins specificity of the methods allowed for a single nucleotide on the surface of Au NPs, suitable for a wide range of discrimination between microRNA family members. applications. Figure 21 summarizes electrostatic and Another important protein broadly exploited in literature is covalent strategies for protein conjugation to NPs. bovine serum albumin (BSA). Albumin is biodegradable, nontoxic, and easy to handle, rendering it a good candidate for intravenous applications. Albumin, being a blood protein was exploited for its ability to minimize recognition and internalization of NPs and thereby prolonging their circulation half-life. Luminescent porous Si NPs are nanomaterials with great potentials for imaging and photothermal therapy. Nevertheless, these particles are susceptible to fast biode- gradation, resulting in fluorescence quenching compromising their use in long-term tumor imaging. To overcome this limitation, alkyl-thiol terminated NPs were encapsulated with BSA via hydrophobic interactions, generating stealth products with improved water dispersibility and long-term fluorescence under physiological conditions. 111,498−503 BSA has also been used during NPs synthesis. It was shown that when reducing AgNO with NaBH in the 3 4 presence of BSA, BSA-coated Ag NPs could be produced. Importantly, the secondary structure of BSA was not affected by the conjugation to Ag. Moreover, albumin can serve as a great platform for the delivery of therapeutic agents. Qi et al. Figure 21. Schematic illustration of different strategies for the prepared human serum albumin (HSA) NPs functionalized formation of NP−protein conjugates. (a) Electrostatic interactions via with glycyrrhetinic acid and loaded with the anticancer drug direct adsorption onto the NP surface. (b) Electrostatic interactions doxorubicin for liver cancer targeting. Doxorubicin was of protein with ligand/monolayer on the NP. (c) Covalent conjugation through active groups (e.g., Cys-SH or Lys-NH ). (d) encapsulated into the NPs with an efficacy up to 75% and 2 Covalent conjugation through a bifunctional linker. demonstrated superior cytotoxicity compared to untargeted particles. A universal method to prepare protein-capped QDs has been 3.1.6. Carbohydrates. Carbohydrates and carbohydrate- described by Clapp et al., who demonstrated that both HIS- conjugated molecules such as glycoproteins are integral to tags as well as leucine zipper units could be employed to multiple biological processes. For example, carbohydrates conjugate proteins such as avidin, the maltose binding protein present on the cell surface are central to cellular recognition (MBP) or the immunoglobulin-G-binding β2 domain of processes. Inflammatory processes and immunological re- streptococcal protein G (PG). sponses are also mediated by carbohydrates expressed on the Furthermore, it should be mentioned that when NPs are in outer surface of the cells. On the other hand, carbohydrates contact with biological fluids, biomacromolecules, including can serve as an excellent indicator for different diseases. For proteins may naturally adsorb to the surface of colloidal instance, carbohydrates present on the protein surface are particles, often impairing the behavior and properties of NPs important for proper protein folding, and thereby, abnormal 507,508 and influencing their behavior both in vitro and in vivo, protein glycosylation can be highly suggestive for different this effect is commonly referred to as protein corona diseases including cancer, hepatic, and immune diseases. 508−510 formation. In particular HSA, which is abundant in Carbohydrates are stable, hydrophilic, and exhibit good blood, tends to form a dense corona on NPs. For detailed biocompatibility and biodegradability in vivo. Furthermore, discussions on protein coronae, the reader is referred to their derivable reactive groups such as amino, carboxyl, and 512−514 detailed reviews on the topic. hydroxyl groups allow for successful conjugation to NPs. 4849 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Therefore, carbohydrate−protein interactions have been technique for various biomolecules including influenza anti- utilized to generate controlled nanoparticulate drug delivery body, DNA, and apoferritin. systems. For the synthesis of those conjugates, several methods Carbohydrate-functionalized NPs were also investigated as have been proposed including: (i) the formation of potential photothermal agents for cancer ablation. Although polyelectrolyte complexes of opposite charge, (ii) the antibody functionalization can achieve selective targeting of formulation of amphiphilic polysaccharides that can self- NPs to cancerous tissue, it is faced with several obstacles, assemble into NPs, and (iii) the use of cross-linkers which including the stability of the antibody itself and the increased facilitate the formation of stable carbohydrate−NP conjugates. cost upon large scaling. Cancer cells express more glycolytic However, the type of carbohydrate, valency, ligand, and density enzymes and glucose transporters than normal tissues, owing could influence the carbohydrate−NP conjugate, requiring to their increased need of glucose in a phenomenon called the optimized conjugation methods. For instance, Wu et al. Warburg effect. Taking into account this effect, iron oxide reported on mesoporous silica NPs, coated with mannose, as magnetic NPs were functionalized with glucose-6-phosphate nanocontainers for various cargos, which were encapsulated and then incubated with cancerous cells from different cell into the pores by the construction of Concavillin A nanogates. lines. Cells were then irradiated with near infrared (NIR laser The release of the cargo could be triggered by either a decrease light). Superior cellular uptake was demonstrated for function- in pH (e.g., in tumor vasculature) or an increased level of alized particles as compared to the plain ones. glucose (e.g., in diabetes). On the other hand, carbohydrate-functionalized NPs were Different types of carbohydrate-coated NPs interact differ- also exploited for targeting resistant bacterial species. ently with cells. This was demonstrated by functionalizing Mycobacterium smegmatis was used as model bacteria for different NPs, including iron oxide and QDs with three Mycobacterium tuberculosis, a Gram-positive bacterial causing different sugars: glucose, galactose, and dextrans of varying the serious infectious disease tuberculosis. Mycobacterium molecular weights. Functionalization was carried out by tuberculosis possesses a thick lipid wall, rendering resistance applying cyanoborohydride-based conjugation chemistry. toward many drugs. Nevertheless, small hydrophilic molecules Amine-terminated NPs were reacted with the reactive end may penetrate the pores known as porins. As such, trehalose on the carbohydrate via cyanoborohydride-based reductive was selected for the targeting of such bacteria due to the amination. Enhanced selectively of carbohydrate-modified NPs presence of the high affinity trehalose transporter system. for glycoporteins was reported, as well as reduced nonspecific Trehalose was coupled to NPs via photocoupling chemistry. cellular interactions of dextran-coated NPs when incubated These functional particles demonstrated superior interactions with HeLa cells. These nonspecific cell interactions became with cells compared to glucose- or dextran-coated particles. more prominent when a higher molecular weight dextran was TEM imaging revealed the presence of particles in the cell wall used as the surface ligand. On the other hand, galactose and the cytoplasm, opening the door for the management of functionalized NPs showed increased cellular internalization Gram-positive bacteria and especially Mycobacterium tuber- compared to bare NPs (Figure 22). culosis. 3.2. Ligand Coating of Nanoparticles for Other Applications Inorganic NPs feature optoelectronic properties that are strongly dependent on the size and shape of the particles. For instance, size-dependent discrete energy levels and Coulomb-blocked charge transport effects have been observed in metallic NPs while semiconductor QDs can be charged like molecules. The unique size-related structures, together with their transport and thermal properties, render NPs efficient nanoscale functional components for different applications in 231,523 524,525 526 photodetectors, solar cells, sensors, and catal- ysis. Moreover, colloidal dispersions of NPs are ideal candidates for inexpensive device fabrication via solution-based Figure 22. Uptake of galactose QDs exposed to the human liver techniques including spin-casting, dip-coating, and inkjet cancer cell line (HepG2). Higher internalization is observed when printing, which can be further scalable through roll-to-roll functionalized QD−galactose is exposed to HePpG2 cells (a) as processing. compared with bare QDs (b). Reprinted with permission from ref Toward the design and development of NP-based devices, it 519. Copyright 2012 The Royal Society of Chemistry. is well understood that the organic ligands and/or surface termination of colloidal NPs strongly affect their application performance, particularly in technological applications where charge carrier transfer/transport and chemical reactivity/ In another study, iron oxide NPs were functionalized with affinity play an important role. For instance, NPs’ ligands glucose (α and β forms) and mannose via click coupling may significantly affect the position of the energy levels in chemistry. Carbohydrate functionalization aimed to target semiconductor NPs. Furthermore, when considering NPs for sugar binding proteins (e.g., lecithin) present on particular cell electronic and optoelectronic applications, one should keep in types. Conjugation with lecithin, although weak, was amplified by the multivacancy of the interaction through the presence of mind that the actual device active element may not be multiple sugar molecules. Mannose-specificbinding was individual NPs but rather macroscopic assemblies or NP demonstrated by the increased cellular uptake of conjugated superstructures. In this case, the nature of the ligand coating NPs. Such system could be exploited for MRI as a detection plays a crucial role for the electronic/optical communication 4850 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 23. (a) Schematic representation of a NP-based photodetector. (b) Effect of the CdSe NPs surface treatment on the carrier mobility. (c) Photodetectos performance using NP film with different surface treatment (dark current-responsivity measurements). Reprinted by permission from ref 539. Copyright 2006 Macmillan Publishers Ltd., Nature 2006. (a) Reprinted with permission from ref 530. Copyright 2016 Macmillan Publishers Ltd.: Nature Photonics. (b) Reprinted from ref 531. Copyright 2010 American Chemical Society. (c) Reprinted with permission from ref 539. Copyright 2006 Macmillan Publishers Ltd., Nature. and the macroscopic physical behavior of the final assembly. environment, the type of the capping layer, the NP surface The interparticle distance, the colloidal dispersion and the passivation, and the interparticle distances due to the ligand packing density, as well as the mutual NPs’ orientation in the length in the close-packed film determine the electrical colloidal medium, are parameters that can be strongly conductivity in photodetectors and consequently the device’s influenced by the ligand nature/coverage and must be taken efficiency. NPs’ termination molecules significantly affect the into account in the development of the respective devices. position of the energy levels in semiconductor NPs but also 3.2.1. Photodetectors. Single phase inorganic semi- play roles in the charge carrier mobility. The ligand chain conductor NPs have been utilized for photon detection due length, density of the ligands, and degree of inductive effects to their narrower band gaps compared to that of conductive have a strong impact on the electron trap density, the carrier polymers and small molecules, which limited their absorption multiplication efficiency, and the multiexciton lifetime and to the visible spectral range. For example, inorganic NPs of have to be optimized to achieve an improved detectivity and PbS, PbSe, PbTe, HgTe, InAs, and InSb have been employed detector response time. as ideal candidates for application requiring light absorption in Photoconductive Detectors. A NP-based photoconductor the near-IR region; the band gap of such NPs can be precisely comprises a thin homogeneous film of semiconductor NPs tuned from the visible up to 35 μm. Various types of deposited onto a prepatterned electrode structure (Figure photodetectors using such NPs have been developed, including 23a). The electrical conductivity in such devices can be 527 528 529 photoconductors, photodiodes, and phototransistors. altered under illumination due to the generation of additional Τhe intraparticle characteristics (chemical phase, morphology, charge carriers. The photoconductivity in a close-packed NP size, or dispersity of individual NPs), but also the surface structure is dependent on intraparticle characteristics such as 4851 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review the morphology, size, or dispersity but also on the surface acid and poly(9,9-dihexylfluorene) (PFH) polymer hybrids. environment such as NP surface passivation, capping layer, and It was observed that even though the ligand coating improved interparticle distances. For instance, photoconductivity the miscibility of the NPs and PFH, the charge-transfer barrier studies in CdSe NPs capped with TOPO-TOP organic ligands suppressed the charge transport and lowered the photo- revealed that free carriers originate from photogenerated sensitivity of the device. electron−hole pairs within the NPs. The charge separation 3.2.2. Photovoltaic Devices. Semiconductor NPs exhibit in these nanoparticulate systems is much slower compared to a completely different behavior from their bulk materials of the the interband relaxation, while the charge transport is same stoichiometry due to quantum confinement size effects. dominated by tunneling of carriers through the interparticle As a consequence, the bandgap of the NPs can be simply tuned 542,543 medium. Moreover, the ionization rate is dependent on by varying the NPs’ size. This property enables the use of intraparticle characteristics such as size and surface passivation. a single material with different bandgaps to harvest a broad Different density of surface passivation of CdSe QDs with spectral range of the solar radiation. Their fascinating amines have been studied in order to evaluate the effect on properties together with their colloidal form, which is 533,534 their photocurrent. The changes in the photocurrent in compatible with solution-processing technologies, including conjunction to NP surface alterations were attributed to an the low-cost roll-to-roll device fabrication, make these increase of the exciton ionization efficiency due to variations in materials ideal candidates forphotovoltaic applications. the interparticle distances. This is regardless of whether the Using such technologies, NPs can be easily incorporated into molecules used for treatment were conjugated or cross-linked the different layers comprising the solar cell architecture. As a to the QDs. Possible treatment with a base may remove the result, different functionalities have been exploited, leading to capping molecules and shorten the interparticle distances, enhanced light harvesting, solar energy conversion efficiency, increasing the electron transport between the neighboring and device stability. Semiconductor NPs have been incorpo- particles through an interparticle hopping process. Electron rated in (a) hybrid organic/inorganic bulk heterojunction and hole mobilities increase exponentially with decreasing the (BHJ), (b) Schottky-based, (c) depleted heterojunction ligand length, demonstrating the inverse relationship between (DHJ), and (d) NP-sensitized solar cells, with the DHJ to coupling energy and interparticle distance (Figure 23b). be the most efficient NPs-based photovoltaic technology to The energy barrier width through which carriers need to date (Figure 24). tunnel to reach an adjacent NP can be tuned by the spatial separation of the neighboring NPs. The spatial separation and consequently their macroscopic optoelectronic properties can be modified by exchange or functionalization with a new ligand or “chemical cap”. Thus, ligand chain length, density of ligands, and degree of inductive effects are some parameters, which can be optimized to achieve the desired carrier transport 535−538 properties. Upon careful design of the capping agent properties, carrier multiplication efficiency, multiexciton life- time, and charge injection through the device can be improved, leading to enhanced detection efficiency. Moreover, a way to control the chemistry of the surface states which act as electron traps affecting the detector’s response time was found. This was realized by treating NP layers with different molecules (i.e., butylamine, formic acid, small thiols, etc.). The optimum characteristics were obtained after treating the films with methanol in an inert atmosphere, followed by controllable surface oxidation (Figure 23c). The high gain measured for the fabricated devices was attributed to the presence of long-living electron traps generated by chemical treatment of the NPs’ surface. Hybrid Photodetectors. This type of NP-based photo- detector is based on mixing narrow gap NPs, which act as excellent sensitizers, and organic semiconductor materials. The Figure 24. (a) Typical structure and (b) working principle of NP- performance of photodetectors is dependent on the synergy of based solar cells. (a) Reprinted with permission from ref 544. light harvesting and charge transport processes. Higher Copyright 2010 The Royal Society of Chemistry. (b) Reproduced responsivity and spectral response extension to the infrared with permission from ref 545. Copyright 2010 American Chemical spectral region have been recorded for small molecules or π- Society. conjugated polymers. A 3 orders of magnitude enhancement of photocurrent was achieved by sensitizing crystalline arrays of Despite the rapid improvement of the solar cell efficiency, C with CdSe NPs. This enhancement was attributed to NP-based photovoltaics still have to overcome many obstacles the efficient light absorption of CdSe NPs, fast electron in order to meet the requirement of large-scale commercializa- transfer from NPs to the C and high carrier mobility within tion and long-term usage. While much progress has been made the array of C molecules. in terms of the device architecture optimization, several The influence of the capping ligand layer on the UV material design aspects remain largely unexplored. The role of detection was studied by comparing two kinds of ultraviolet the interfaces among the randomly distributed crystalline NPs photodetectors based on TiO NPs, bare or capped with oleic in the charge transport is crucial. Such interfaces include large 4852 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 25. Schematic representation of the BHJ OPV cell with three types of NPs embedded into the active layer, (i) bare, (ii) TOAB-terminated, and (iii) P3HT-terminated J−V curves of the devices with configurations (a) ITO/PEDOT:PSS/P3HT:PCBM/Al and (b) ITO/PEDOT:PSS/ P3HT:ICBA/Ca/Al respectively. Reprinted with permission from ref 524. Copyright 2015 American Chemical Society. surface area junctions between photoelectron donors and The conductivity of the linker molecule itself may be acceptors, the intralayer grain boundaries within the absorber, important in enhancing carrier transport among the particles. Solar cells utilizing PbSe NPs capped with benzenedithiol have and the interfaces between photoactive layers and the top and demonstrated a power conversion efficiency of 3.6% along with bottom contacts. Controlling the charge collection and enhanced stability. Indeed, the ligand exchange of oleate minimizing the trapping of charge carriers at these boundaries molecules with a molecular conducting ligand such as can lead to further improvement of the solar cell efficiency. benzenedithiol resulted in a more effective pathway for Therefore, a deep understanding of the electronic coupling electron transfer. As a consequence, both electron and hole between the NP and its surface ligands and the physical mobilities were increased by more than 1 order of magnitude mechanisms responsible for the charge transport among the and an efficiency of 7% was reached for the respective DHJ neighboring particles is required to achieve higher solar cell device. Additionally, the cross- linking with the benzenedi- efficiencies. Consequently, a robust NP surface passivation thiol appears to offer a longer-lived NP−metal interface than and a controllable compact packing of the randomly oriented 546 amine ligands. In particular, halide anions introduced during NPs are required. Much attention has therefore been solid-state film treatments led to a marked reduction in the devoted to the development of new ligand strategies that density of trap states deep within the bandgap of the colloidal minimize the interparticle spacing to promote carrier transport NP solid. The mechanism proposed for such behavior was that and lower the defect density to reduce the recombination the as-exchanged NPs were dominated by a large density of losses. nonpassivated surface states, which were filled in with the Electron and hole mobility is dependent on the intrinsic atomic halide ligands. characteristics of the material, the size/morphology of the NPs Toward efficient inorganic NP-based photovoltaics, a and the disorder at the surface. Additionally it was recently different ligand strategy utilizing monovalent inorganic ligand found that it is also dependent on the ligand length. Shallow 551 (halide anions) passivation was proposed. It was shown that traps originate from the surface disorder and reconstructions, such an approach enabled good passivation of surface defects, whereas deep traps are due to low coordinated atoms on the high carrier mobility, and good device stability, while using 546,548 NPs surface. Carrier mobilities in semiconducting inexpensive chemicals readily processed at ambient conditions. alkanedithiol-treated PbSe were found to decrease exponen- Both time-resolved infrared spectroscopy and transient device tially with increasing ligand length. While complete removal characterization indicated that the scheme led to a shallower of the organic insulating ligands led to marked improvements trap state distribution than the best organic ligands. This in transport performance. For this reason, only the shortest atomic passivation strategy resulted in enhancement of the organic ligands were retained for surface passivation, allowing mobility-lifetime product in comparison to ethanedithiol sufficient interconnection between the NPs. Moreover, the passivation by a factor of 20, indicating superior charge carrier exchange of trioctylphosphine oxide and dodecylamine with diffusion in the atomic-ligand-passivated films. The respective 1,2-ethanedithiol or 1,2-ethanediamine was found to signifi- photovoltaic devices exhibited a solar power conversion cantly improve the exciton dissociation yield and/or charge efficiency of 6%. carrier mobility while a ligand exchange with 3-mercapto- The ligand shell of the metallic NPs also plays an important propionic acid quenched the band edge emission and role in the performance of plasmonic BHJ organic photovoltaic enhanced deep trap emission. devices (Figure 25). It is argued that the plasmonic effect 4853 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 26. (a) Schematic representation of the NP-based LED, (b) electronic energy levels of each material in the device, and (c) EQE dependence of the LED device on interparticle distance. Reprinted with permission from ref 555. Copyright 2012 Macmillan Publishers Ltd.. accountable for the performance enhancement takes place only oleic acid ligand were approximately 1000 cd/m greater and if the NPs core is in direct contact with the active layer 1.5 times higher, respectively, than those of the LEDs with the polymer donor. This can be achieved with the utilization of TOPO ligand. These results showed that if the physical length either ligand-free NPs or NPs terminated with the same of the surface ligand is relatively long, decreasing the surface polymer donor as the active layer. Using this concept an area would result in increased injection of electrons and holes enhanced efficiency of 7.16% in OPV devices incorporating the into the NPs, increasing the luminance and efficiency. In poly(3-hexylthiophene-2,5-diyl) (P3HT):Indene-C bisad- addition, an order of magnitude improvement in device duct (ICBA) active layer was achieved. On the contrary, efficiency was obtained by changing the long-chain oleate devices with ligand-terminated Au NPs showed lower ligand on the QDs surface with thiol and carboxylic acid units performances, even compared to the reference (NP free) (Figure 26a,b). At the same time, when the interparticle device due to the deteriorated active layer morphology spacing increased from 5.4 to 6.1 nm, the external quantum attained. efficiency (EQE) increased by a factor of ∼150 (Figure 26c). According to the above literature, the role of the interfaces Efficient ligand exchange of the core−shell particles replacing including the large surface area junctions between photo- the oleate ligand with octanethiol has also been reported and electron donors and acceptors, the intralayer grain boundaries resulted in a double increased electron mobility and greater within the absorber (interfaces among the NPs), and the balanced carrier injection, leading to the highest EQE of interfaces between photoactive layers and the top and bottom 12.2%. Alternatively, the use of 1- dodecanethiol as contacts are the main factors affecting the efficiency of the exchange ligand was reported. The device developed showed photovoltaic devices. NPs free of ligands or terminated with the highest EQE up to 20.5% and a long operational lifetime of the same polymer donor as the active layer could lead to more than 100000 h at 100 cd/m , representing one of the enhanced efficiency of BHJ organic photovoltaic devices. best-performing solution-processed red NP-based LEDs to Controlling the charge collection and minimizing the trapping date. of charge carriers at these boundaries by including short-length Recently, several examples of LEDs utilizing perovskite NPs 557−560 or conductive capping ligands can also lead to an improvement have been demonstrated. While perovskite NPs are very in efficiency. Atomic passivation methods such as monovalent efficient light emitters, their main disadvantage is that they inorganic ligand (halide anions) passivation are important to degrade rather quickly. To tackle this problem, recent studies eliminate surface defects and reduce carrier diffusion leading to have focused on the encapsulation of perovskite NPs in 561,562 improved device stability. polymers. However, in all these cases the particles are 3.2.3. Light-Emitting Devices. Colloidal semiconductor encapsulated as a bulk, losing their colloidal dispersity, which NPs have been explored as the principal emitters for thin film may be important when fine films of NPs are required. A new LEDs. These NPs are a unique class of light emitters with size- approach to tackle this issue by introducing the low molecular tunable emission wavelengths, saturated emission colors, near- weight polymer poly(maleic anhydride-alt-1-octadecene) unity luminance efficiency, inherent photo and thermal (PMA) during the synthesis of the perovskite NPs was stability, and excellent solution processability. The high color recently demonstrated. The PMA results in stabilization of purity together with the color-tunable emission make NP- the NPs by tightening the ligand binding and thus decreasing based LEDs promising candidates for next-generation displays interactions of the surface with the surrounding medium. The and solid-state lighting applications. A schematic represen- polymer capped perovskite NPs retained their colloidal tation of a modern NP-based LED device is illustrated in dispersity and were utilized to produce both monochromatic Figure 26a,b. green and white LEDs. The electrical characteristics of the NPs can vary depending For NPs of different and more stable chemical compositions on the surface modulation, which can change the luminance in comparison to perovskite NPs, such as CdSe, several other and emission efficiency. In view of this, understanding surface ligands have been employed to improve their blending and ligand effects is essential for improving the performance of function in NP-based optoelectronic devices. Specifically: (i) such devices. Evaluation of the LED properties as a Branched ligands, namely entropic ligands for NPs, were dependence of the ligand length has been performed by the developed, leading to better charge transport and higher 563,564 exchange of the 1.1 nm long TOPO ligand with the 1.7 nm EQE, (ii) multifunctional dendrimer ligands that serve as long oleic acid ligand. With all other conditions being the charge injection controlling layer as well as the adhesive identical, the luminance and efficiency of the LEDs with an layer at the interfaces between the NPs and the electron 4854 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 27. (a) Au-nanowire flexible pressure sensor, (b) FET sensor, and (c) FET gas sensor. (a) Reprinted with permission from ref 572. Copyright 2014 Macmillan Publishers Ltd., Nature. (b) Reproduced with permission from ref 573. Copyright (2005) Elsevier. (c) Reproduced with permission from ref 574. Copyright 2013 American Chemical Society. transport layer (ETL), which gave promising results, and 27). Among the different NPs-based sensors developed to date, (iii) conjugated organic polymers such as block copolymer nanowire-based field effect transistors (FETs) have been ligands directly linked on the surface of the NPs. The widely used for detection of a variety of biological and copolymers consisted of both semiconductor and reactive chemical species, of pH value, of metal ions, viruses, proteins, functional blocks that contained multidentate thiol-based etc. In most of these applications, the mechanism of sensing is anchor groups. The key to the success of this architecture based on the functionalization of a homogeneous semi- was that by being bound to the semiconductor NP surface, the conductor nanowire, such as silicon and In O . The extreme 2 3 semiconductor ligands improved hole injection into the NPs sensitivity of nanowire and nanotube field-effect sensors and resulted in improved device performance (increased originates from their one-dimensional structure that enables electroluminescence intensity and quantum efficiency) com- efficient charge transfer between the surface-anchored pared with a similar device containing unmodified NPs. molecules and the nanostructures. The efficiency of LED devices is affected mainly by the To use nanomaterials as sensors, the understanding of the luminescence quality and the emission efficiency of the peculiarities of both the synthesis and interaction mechanism nanoparticulate light emitters. If the ligand length is relatively during the sensing procedure is required. A sensor can ideally long, the luminescence and the device efficiency is increased. satisfy some important requirements: (i) specificity for the The efficiency is 1.5 higher by using oleic acid capped NPs target species, (ii) sensitivity to changes in target-species instead of utilizing TOPO-capped ones, or is increased from concentrations, (iii) fast response time, (iv) extended lifetime, 12.2 to 20.5% when octanethiol is replaced by 1-dodecanethiol. and (v) reduced size (miniaturization) together with low-cost Furthermore, the type of the capping ligand is important in the manufacture. Noble metals, metal oxides, or rare-earth 567,568 hole-injection into the NPs but also the stability of the doped NPs have been extensively utilized in such semiconductor NPs, especially in the case of perovskite NPs. applications. NP ligands should play an important role in To obtain colloidal stability, which is important for the absorption/adsorption of organic volatile molecules and gases formation of very thin films, polymeric capping ligands of low- taking place during the sensing process. Furthermore, during molecular weight are introduced. Particular attention should be the fabrication of sensors, NP film formation is driven by paid to the retention of the luminance quality. electrostatic interactions and van der Waals dispersion 3.2.4. Sensors. A sensor is an analytical device that detects interparticle forces. Such interactions are determined by the physical or chemical changes (e.g., in temperature, pressure, NPs’ surface ligand coverage. light, concentration, etc.) and converts them into measurable Indeed, it has been widely reported that careful selection and signals. In recent years, the interest of researchers and design of ligands strongly influence the sensitivity and engineers to gas- and liquid-sensitive materials has grown selectivity of a NP-based sensor. For example, Au NPs substantially due to the progress in nanotechnology (Figure functionalized with 1,10-phenanthroline have been utilized 4855 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 28. Effect of the ligand on the signal of the vapor and catalytic sensors. (a) Electrical responses of 4-mercaptophenol functionalized (referred to as “OH” NPs) and 4-methylbenzenethiol functionalized gold NPs (referred to as “CH3” NPs) to the nonpolar solvent dichloromethane (DCM) and to methanol. (b) Maximum relative resistance vs concentration of the analyte vapors of 1-propanol, acetone, and cyclohexane for mixed-ligand NPs (S1, Au NPs with 50% chlorobenzenemethanethiol (CBMT):50% n-octanethiol (OT) mixed ligand; S2, Au NPs with 33.3% CBMT:66.7% OT mixed ligand; S3, Au NPs with 16.7% CBMT:83.4% OT mixed ligand). (c) Activation period for the Pt NPs-based catalytic gas sensor for hydrogen sensing. The NPs is covered with different molecules such as phenylenediamine (PDA), 1,8-diaminooctane (DAO), bipyridine (BiPy), aniline, and hexadecylamine (HDA). (a) Reprinted with permission from ref 571. Copyright 2002 IOP Publishing. (b) Reprinted with permission from ref 575. Copyright 2005 Elsevier. (c) Reprinted with permission from ref 576. Copyright 2014 Royal Society of Chemistry. for the detection of Li ions. This type of ligand binds surface properties (Figure 28b). The respective sensors selectively to the Li by forming a 2:1 ligand−metal complex, experienced repeated cycles of analyte vapors (1-propanol, causing Au NPs to aggregate. Such aggregation causes a shift in acetone, and cyclohexane) and blank air gas, while the analyte the extinction spectrum accompanied by a concomitant color concentrations were varied. It was observed that the variations change, providing a useful optical method of detecting Li in in compositions of the ligand molecules resulted in remarkable aqueous solution. Furthermore, the electrical response to differences in signal amplitudes. chemical vapors adsorbed on Au NPs films has been found to Finally, it should be mentioned that the stability of NP- based sensors is also affected by the ligand coating. For vary markedly by the surface functional groups. In particular, two types of ligands namely, 4-mercaptophenol instance, a series of amine ligands (mono- and bifunctional (referred to as “OH” ligand) and 4-methylbenzenethiol alkyl- and aryl amines) have been used to stabilize Pt NPs as (referred to as “CH ” ligand) have been utilized to function- catalytic materials for H gas sensing (Figure 28c). 3 2 alize Au NPs. It was found that the conductivity of the Depending on the ligand coating used, remarkable differences respective CH −NP film dropped by ∼70% from the initial in the sensor performance, both in terms of the catalytic value, while that of the OH-NP film showed a decrease by only performance, the activation period as well as stability have ∼10% (Figure 28a). Two physical effects were reported to been observed. explain such conductivity changes. Under high partial pressure, Careful selection of the NP ligand coating is essential, as the change in NP core−core separation was the main ligands strongly influence the sensitivity, the stability and the contribution to the conductivity change and generally selectivity of the NP-based sensors. Specific type of ligands can deteriorated the conductivity. However, for relatively low selectively bind to metal-anions and produce changes in color partial pressures the adsorption of vapor molecules lead to or conductivity alterations. Different types of ligands attached permittivity changes that tend to enhance the conductivity. to NPs in the same device can be used for different chemical Adifferent sensing approach is the use of mixed-ligand Au selectivity. Remarkable differences in the signal amplitude can NPs for vapor sensing. In particular, Au NPs with a mixture be originated from variations in compositions of the ligand of ligands (chlorobenzenemethanethiol (CBMT) and n- molecules. octanethiol) have been synthesized in order to study the 3.2.5. Memory Devices. Memory elements are the different chemical selectivity due to the modification of the integral parts of computers, identity document (ID) cards, 4856 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 29. (a) Digital memory device utilizing Pt NPs. (b) Hysteresis loops for NPs functionalized with different capping agents. (c) Magnetization curves for individual γ-Fe O NPs and for their ensembles (aggregates and chains). (a) Reprinted with permission from ref 583. Copyright 2006 2 3 Macmillan Publishers Ltd., Nature. (b) Reprinted with permission from ref 585. Copyright 2015 Elsevier. (c) Reprinted with permission from ref 590. Copyright 2008 Wiley. and various consumer electronics. Memory devices utilizing superparamagnetism. Their magnetization can be affected 215,585,586 NPs have been extensively explored during the past decade as strongly by the surface capping ligand (Figure 29b). In possible solutions to overcome the scaling issues and improve addition, magnetic NPs can be present in the form of powders, endurance of nonvolatile memories and hard-disk drives. NPs dispersions, or embedded in a matrix, which gives rise to a provide an opportunity to precisely control electronic and variation in the interparticle spacing and therefore in the 584,587−589 magnetic properties of materials by tuning their size and shape. interparticle interactions. Ensembles of NPs show The possibility of device fabrication using colloidal solutions properties that may be quite different from those of individual allows significant cost reduction, which is very important for ones (Figure 29c). The dipolar interactions between products such as wireless identification tags and smart cards magnetic NPs determine their collective state, which shows 591,592 where the prime criterion is cost and miniaturization rather the features of the magnetic glassy behavior. Therefore, than outstanding performance. ensembles of magnetic NPs show an increase in the blocking Ferromagnetic NPs are promising candidates for a density temperature, T , compared to that of individual particles 2 590 increase of magnetic storage devices toward 100 Gbit/inch up (Figure 29c). Chains of γ-Fe O NPs showed a 40K 2 3 to a few Tbit/inch . Until recently, increasing the recording increase in T and a faster approach to saturation of density simply meant down-scaling all of the components in a magnetization on variation of magnetic field in comparison recording system, but what has become clear over the past with individual γ-Fe O NPs and their aggregates. 2 3 decade is that the design of magnetic media and the continued Because of the small size of the NPs, a large fraction of the increase in density storage is fast encroaching upon the atoms in the NP is surface atoms. Because the ratio of surface fundamental physical limits imposed by the nature of atoms to the bulk atoms is large, surface contribution to magnetism on the nanoscale. To be applicable for magnetic magnetization becomes significant. The surface atoms storage media, the magnetization direction in a material should experience a different environment compared to the atoms of be very stable and not reverse due to thermal fluctuations. the core. Various defects from atomic vacancies to dangling From a simple geometry viewpoint, the smaller the bonds and lattice disorders exist on the NP surface and ferromagnetic NPs, the higher the recording areal density is. determine the macroscopic magnetic behavior. The type of the But considering the superparamagnetic limit of the ferromag- capping ligand is a crucial parameter for the fabrication of netic NPs, there should be a balance between NP size and ultrasmall NPs of narrow size distribution, but it is also thermal stability of the NP-based recording media. For responsible for the disordered spin structure on the surface. commercially viable recording media, the energy barrier Furthermore, the capping ligand length determines the required to reverse the magnetization from one direction to distance between the particles in an assembly and consequently another should be at least 60 times higher than the thermal the dipolar interactions between magnetic NPs. Numerous 579 580 581 energy (KV/k T ≥ 60). NPs of FePt, CoPt and approaches have been proposed correlating the dipole−dipole SmCo (characterized by a high anisotropy energy) are and exchange interactions to the nature of the assemblies’ among promising candidates for high-density magnetic record- cooperative magnetic behavior. 3.2.6. Thermoelectric Applications. Thermoelectric ing. A data storage device derived from self-assembled Pt NPs is materials can be utilized for conversion of heat to electricity, illustrated in Figure 29a. The device showed basic memory through the Seebeck effect or for cooling or refrigeration operations, such as operating voltages, data retention, and cycle through the converse Peltier effect. The basic architecture of a ability. The current−voltage characteristics of the device thermoelectric device consists of an element placed between a showed bistable states with an ON/OFF ratio larger than 3 heat source, e.g., corresponding to waste heat generation and orders of magnitude. the ambient (heat sink). The transfer of heat from the The magnetic behavior of an assembly of magnetic NPs with source to the sink is either through the motion of the carriers a randomly oriented easy axis represents a complex and (electrons/holes) or through the lattice (through collective challenging problem. This complexity arises from the lattice vibration modes/phonons). The carrier transport results coexistence of finite size and surface effects as well as the in the development of a potential difference, the Seebeck presence of interparticle interactions. Below a critical size, voltage (ΔV). The thermopower/Seebeck coefficient S is then magnetic NPs can exhibit unique phenomena such as the ratio of ΔV to the temperature difference (ΔT). 4857 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Thermal to electrical energy conversion, through thermo- transport properties, but partial sintering of NPs can modify electric and thermionic materials, has been proven to be much the distribution and even the chemical phase as it leaves a more efficient in materials at the nanoscale and can provide residual carbon layer that may limit thermoelectric perform- large values of the figure of merit, ZT, which is defined as ZT = ance. To minimize the effect of the annealing process and the S σΤ/k, where T is the average temperature of the hot and cold amount of residual carbon, the original surface ligands can be sides, and σ and k are the electrical and thermal conductivity of replaced in a previous step with shorter and weakly the material; k is the direct sum of the contributions from both coordinating molecules such as pyridine, hydrazine, ammonia, 594,595 the carriers (k ) and the lattice (k ). Quantum wells, and n-butylamine. Once the original bulky ligands have been e L nanowires, and semiconductor NPs are some of the low- fully replaced, a mild thermal treatment, generally with the NPs dimensional morphologies, which have been used in such already assembled/aggregated, can be applied. The impact applications. The thermoelectric figure of merit can be of surface-bound small molecules on the thermoelectric improved by maximizing the power factor (P = Sσ) and/or properties of the final-formed film was also demonstrated in minimizing the thermal conductivity. The power factor can be the case of self-assembled silver telluride (Ag Te) NP thin maximized by the development of new low-dimensional films which were fabricated by a layer-by-layer (LBL) dip- materials or optimization of the existing ones by doping coating process. Investigations on the electrical conductivity processes while the thermal conductivity can be minimized and Seebeck coefficient on the Ag Te NC thin films containing through nanostructuring and use of materials with intrinsically hydrazine, 1,2-ethanedithiol, and ethylenediamine between low thermal conductivity. Specifically, in the nanostructured 300 and 400 K indicated that these molecules could serve as materials, the thermoelectric performance is mainly attributed beneficial components to build NC-based thermoelectric to strong decrease of the lattice thermal conductivity (k ), devices operating at low temperature. The power factor probably by effectively scattering phonons that otherwise could also be improved by 2 orders of magnitude by tuning would have relatively long mean free paths, rather than an ligand-coupling symmetry (tuning the functionality of the increase in the electrical power factor. polar headgroup and the coupling symmetry of the organic Surface engineering of the NPs for thermoeletric applica- linkers) through layer-by-layer assembly methods in the case of tions is necessary to control NP growth, drive their assembly, Cu Se NC thin films. These resulted in the highest power 2x and modulate their functional properties. This requires factor measured for QD-based thermoelectric inorganic 3 2 600 additional understanding not only of the surface influence on organic composite materials of ∼30 μW/m K . properties related to such applications but on the effect of each Both the ligand type and ligand removal influence the surface treatment on the final surface composition. In thin-film properties of NP. The suitability of the strategy used for ligand and nanowire thermoelectrics, the free surface in contact with removal/replacement is dependent on the type of bonding to vacuum or the atmosphere may also be an important the NP surface. Modifications of the NP surface chemistry interface. The role of the interfaces in the thermoelectric have been evaluated to improve transport properties of NPs performance is beneficial as they contribute to the reduction of through introduction of inorganic surface ligands with the thermal conductivity, k, and under certain conditions, to relatively high charge carrier mobilities. The charge carrier the enhancement of the Seebeck coefficient, S. However, concentration can also be adjusted by balancing the ratio of interfaces also usually increase the electrical resistivity, ρ, due surface cations and anions in polar compounds through the use the insulating capping layer. Improvement of the ZT requires of proper surface ligands. Surface ligands can also act that the proportional reduction in electronic carrier mobility themselves as donating or accepting dopants. A stripping resulting from increased interfacial scattering is less than the method using a strong inorganic acid (HCl) was recently corresponding reduction in thermal conductivity. Thus, demonstrated for removal of the carboxylic acids from the NP balancing the electronic and thermal properties of the surface capped with oleic acid in solution. Chlorine (Cl ) ions, interfaces is critical to tailor a material for optimal thermo- initially located on the NP surface diffuse, upon a consolidation electric performance. Interfaces are effective in scattering long step, inside the crystal structure to act as a donor, providing the mean-free-path electrons and phonons but have minor effects nanomaterial with n-type electrical conductivity and a tunable when the mean-free-paths are smaller than the spacing charge carrier concentration. The procedure takes advant- between interfaces. If the interface is a barrier to electronic age of a ligand displacement step to incorporate controlled transport due to the insulating layer and not just a single concentrations of halide ions while removing carboxylic acids scattering site, it may have a significant effect on the transport from the NP surface. Halide passivation and metal cations on and the ZT. The thermoelectric performance can be the surface have been proven to control the net NP surface improved by surface engineering through (i) increasing the charge while at the same time preventing the formation of deep grain boundaries population, (ii) selection of a conducting electronic traps by avoiding oxygen absorption. In a ligand, (iii) removal/modification of the surface ligands, and different approach, metal salts were used to eliminate the (iv) ligand modification for optimum self-assembly. organic surface ligands without introducing extrinsic impurities Ideally, improved thermoelectric performance can be in the final nanomaterial. A6-foldincrease ofthe obtained by increasing the grain boundary population toward thermoelectric figure of merit of Ag Te was obtained when specific interfaces without decreasing the electronic transport. organic ligands were displaced by AgNO . This can be done with approaches of introducing high Finally, the choice of a proper ligand can affect the synthesis densities of relatively well-ordered interfaces such as twin of well-dispersed and monodispersed NPs as well the well- and domain boundaries. Such techniques to increase the twin- ordered self-assembly process. Self-assembly/superlattice boundary density through repeated strain−anneal cycles have procedures depend both on interactions between NP building been studied widely in metals and could be transferred to blocks and on the process kinetics. The interactions thermoelectric materials such as Bi Te and related between NPs can be van der Waals, dipole−dipole, magnetic, 2 3 596,597 alloys. Annealing results in nanomaterials with enhanced or electrostatic. Thus, assembly is usually triggered by 4858 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 30. Effect of NP capping agent on the catalytic activity. (a) Rate and induction time of 4-aminophenol reduction of functionalized Au NPs with citrate and PEG-SH. The correlation between the reduction rate and the free catalytic site density on Au NPs is shown as well. (b) Iron oxide nanoparticles covered with polyphenylenepyridyl dendrons of the second and third generations with dodecyl periphery and the effect of the different coverage on the catalytic performance in the selective hydrogenation of dimethylethynylcarbinol (DMEC) to dimethylvinylcarbinol (DMVC). (a) Reproduced with permission from ref 621. Copyright 2016 American Chemical Society. (b) Reprinted with permission from ref 622. Copyright 2014 American Chemical Society. adjusting the surface/ligand-related interactions. The most compounds. These magnetic particles can be of a single 608 609 commonly used strategy to produce organized superlattices is phase or core−shell double-phase structures. The to force a slow NP assembly in solution by increasing the separation of the nanocatalysts is an important process and concentration through solvent evaporation. This procedure is time and energy consuming, often with environmental requires NPs with a very high colloidal stability and narrow- implications. Magnetically recoverable catalysts have size distribution, which are both affected by the type of surface attracted considerable attention due to their potential to ligand. combine catalytic properties and efficient materials’ recovery 3.2.7. Catalysis. Nanocatalysis, which involves the using an external magnetic field, thus minimizing the total cost 611−618 utilization of NPs to catalyze reactions, has attracted and helping to preserve the environment. Generally, considerable attention during the past decade, both for these catalysts consist of a magnetic part and a noble metal. In homogeneous and heterogeneous catalysis applications. bulk noble metal catalysts, the metal particles tend to aggregate Because NPs exhibit a large surface-to-volume ratio compared during the reaction process, leading to the reduction of the to bulk materials, they are promising candidates for use as catalytic activity. However, multifunctional, Fe O -noble metal 3 4 catalysts. NPs of different chemical phases, e.g., metals, hybrid nanoparticles present ideal nanomaterials to overcome semiconductors, oxides, and other compounds, have been this limitation. widely used for such applications. The chemical reaction is The most important issue to consider when designing a performed on the surface of a catalyst particle at a high nanocatalyst for use in a solution is to prevent the NPs from temperaturewhile thecatalystparticleisinagaseous aggregating as this limits the specific sites at the surface for environment or in a liquid. In many cases, the chemistry and catalytic reactions. The careful choice of the capping agent structure of a catalyst particle during a catalytic reaction could can eliminate aggregation, allowing the nanomaterials in the be different from those before catalysis. The challenging issue colloidal solution to be used for recyclable catalysts. The role of nanocatalysis research is to produce catalysts with high of the ligand and the packing density on the catalytic reduction selectivity, high activity, low energy consumption, and long of 4-nitrophenol has been studied by utilizing PEG-thiol- lifetime. This can be achieved by a material design process by functionalized Au NPs (Figure 30a). A direct relationship precisely controlling the size, shape, spatial distribution, surface between the chain length and packing density of the PEG and composition, electronic structure, and thermal/chemical the Au NP catalytic activity was found. High surface coverage stability of the individual nanocomponents. Catalytic chemical of low molecular weight PEG (1 kDa) completely inhibited the reactions mainly include oxidation reactions, reduction catalytic activity of Au NPs. Increasing the molecular weight reactions, coupling reactions, and electrochemical reactions. and decreasing surface coverage was found to correlate directly Ferrite NPs have also been applied in catalytic reactions with increasing rate constants and decreasing induction time. mainly in processes of synthesis and destruction of organic Instead, the selective blocking of more active sites by adsorbed 4859 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review thiol functionality was attributed to the induction period and the appropriate selection of ligands, including their hydro- reduced catalytic activity. phobic/hydrophilic nature as well as their density and packing Adifferent system proving the important role of the capping on the NP surface, which is directly correlated to their agent on the final catalytic activity is a magnetically recoverable reactivity. Equally, the use of NPs in a vast range of catalyst, obtained via encapsulation of Pd NPs in dendron/ optoelectronic applications requires them to be able to easily dendrimer shells of ferrimagnetic magnetite nanoparticles. transfer carriers across their ligand shells and to adequately High densities of well-separated metallic NPs could be formed disperse in media, such as polymers. The NP ligand choice in and supported at specific sites on the porous surface of the these cases is critical and directly correlated with the topology nanoparticles. This system was subsequently tested for its of the active blends, which in turn influences the performance functionality in the selective hydrogenation of dimethylethy- characteristics of devices. nylcarbinol to dimethylvinylcarbinol (Figure 30b). The Although the field of NP design has seen an unprecedented catalytic activity in these systems is dependent on the growth in the last two decades, we still have to gain further dendrimer generation, which determined the specific sites for experimental knowledge, which correlates the physicochemical the growth of the Pd NPs as well as their size. The highest characteristics of NPs to their desired function. This is also turnover frequency in the hydrogenation was found for an important in order to better inform the NP design to the optimum Pd NP size around ∼1.5 nm. The catalytic activity suitable choice of ligands. The appropriate selection of ligands was also examined for larger (∼3 nm) and smaller (∼0.9 nm) to grow NPs in large scales with narrow size distribution and Pd NPs, but the catalytic performance was proved weaker. adequate manipulation of their morphology as well as the Importantly, the stability of this system was demonstrated by control of ligand density and hydrophilicity on the NP surface its repeated use in up to three catalytic cycles. These hybrid are essential goals to achieve. An important question that needs nanostructures could then exhibit high catalytic performance more elucidation is the exact interactions between ligands and and fast recovery in the presence of an external magnetic field. NP. While for some ligands the type of bonding interactions Various research groups have studied the photocatalytic are well-understood, this is by far not the case for other ligand properties of semiconductor nanocrystals capped with different types. For example, the bond between gold and thiols is often organic molecules. The photocatalytic activity was found to be discussed to be a covalent one. However, all that is known is higher in the case of the oleic acid-capped TiO nanocrystals that the bond is very strong. As discussed in section 2, the most than both their tri-n-phosphine oxide-capped counterparts and commonly accepted model for thiol−Au interaction is the commercial TiO P25 Degussa. It is proposed that efficient binding of the deprotonated sulfhydryl group (forming a thiyl catalysis strictly depend on microscopic mechanisms that occur radical) to Au with coordination-type bonds. Proper at the catalyst surface, basically involving specificdye understanding of the details of the internal structure and adsorption and local density of terminal OH moieties. stability of an organic thiolate ligand shell around a metal NP is Furthermore, Vorontsov et al. investigated the photocatalytic crucial for adequately controlling important ligand-exchange behavior of different TiO samples with different surface reactions and requires more in depth research. With respect to area. They found that the size and surface does not have a semiconductor NPs, many ligands are classified as L, X, or Z direct influence on photocatalytic activity but it is rather type depending on the number of electrons donated or surface properties such as surface acidity and hydroxyl groups. accepted when interacting with a metal center. This notation The nanosized TiO photocatalysts prepared by employing 2 could be equally useful for the classification of ligands on long chain acids, octanoic and palmitic acid, showed better metallic NPs. However, in many cases, the exact ligand−metal photocatalytic activity than the commercial Degussa P25. interactions remain not fully understood and thus this presents Apart from acid ligands, another ligand, which increases the an important area of research needing to be addressed. photocatalytic activity of the TiO nanostructures, is the low- 2 Additionally, the nature of the surface ligands will determine cost sensitizer PVP. This ligand improves the photocatalytic the final application of the NPs. For example, in biomedicine, a activity of the NPs through a ligand-to-metal charge transfer popular type of Au NPs commonly employed in phototherapy mechanism. and drug delivery are those with a rod- or branched- shape. Careful choice of the ligand type and density can improve However, in most cases, these particles are synthesized using the catalytic activity, the selectivity, and the lifetime of toxic cationic surfactants such as CTAB and CTAC. Although nanocatalysts. The capping ligand prevents the NPs from several ligand exchange steps can be performed to remove aggregating which would have a detrimental effect on the these ligands prior to their use in biomedical applications, this catalytic activity. They also determine the specific sites for is not cost- and time- effective. New methods to produce these growth of well separated metallic NPs in hybrid magnetic- NPs directly with nontoxic ligands or biomolecules of interest metallic systems. would be highly beneficial for their broader application. On the other hand, one of the bottlenecks hindering industrial 4. CONCLUSIONS AND FUTURE PERSPECTIVES applications of NPs is the difficulty of scaling up their synthesis. While many published protocols are ideal for The accurate synthesis and functionalization of inorganic NPs producing certain types of NPs at the milligram scale, they is critical for their colloidal stability and their performance in are not appropriate for larger scale production, so cheap challenging environments. From applications in biology to applications in physical sciences, the choice of NP surface approaches to larger scale production is one of the challenges chemistry defines the NP activity and dispersibility and the in the field to be answered. In applications such as observations can be very different between particles with photovoltaics, photodetectors and sensors, the performance adequately designed surface chemistry in comparison to poorly of the final devices is determined primarily by the designed surface chemistry. NP toxicity, targeting ability, drug morphological and structural features of the NPs but also by delivery efficiency, circulation in the body, and interaction with the alignment of the NPs during their assembly. Upon proteins, cells, or more complex biological systems depend on assembly, the ligands block the active surface sites and/or 4860 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review prevent the formation of smooth films that are free of cracks. AUTHOR INFORMATION Different methods have been proposed for such an assembly, Corresponding Author but there are many parameters during these processes which *Phone: (0)23 8059 2466. E-mail: a.kanaras@soton.ac.uk. are still unexplored or incomprehensible. The removal of the ORCID capping ligands in such applications is a necessity in order to fabricate devices with high efficiency. Methods used to remove Neus Feliu: 0000-0002-7886-1711 these ligands typically result in release of NPs from the surface Indranath Chakraborty: 0000-0003-4195-9384 or cause undesired growth of the NP core. This poses an issue Eunkeu Oh: 0000-0003-1641-522X for the stability of the devices. The development of new Kimihiro Susumu: 0000-0003-4389-2574 strategies or improvement of the existing methods for the Igor L. Medintz: 0000-0002-8902-4687 effective removal of the capping ligands without affecting their Emmanuel Stratakis: 0000-0002-1908-8618 morphology and structure is a necessity. Wolfgang J. Parak: 0000-0003-1672-6650 4.1. Stability of NPs Antonios G. Kanaras: 0000-0002-9847-6706 Present Address The use of dispersible NPs in complex media is very important and directly linked to the function of NPs as already discussed A.H.-J.: Ludwig-Maximilians-UniversitatM ̈ ünchen, 80539 earlier. A vital element for the successful design of well- Munich, Germany. dispersible and functional NPs is a thorough analytical Notes characterization during their synthesis, something that is The authors declare no competing financial interest. missing in various published studies. Understanding the way that ligands pack on the NP surface, the strength of ligand−NP Biographies surface interaction, the net charge on the microenvironment Amelie Heuer-Jungemann obtained her degree in Chemistry with around the NP, and how these characteristics change when NP Biochemistry from Heriot-Watt University, Edinburgh (2011), and a size and morphology is varied are critical parameters to control Ph.D. in Physics from the University of Southampton (2015), the stability and function of NPs. Gaining deeper insight and working on biomolecule−nanoparticle conjugates for biomedical control over these parameters are important goals to be applications in the Laboratory for Inorganic Nanoparticles and focused on. Applications. She undertook postdoctoral research at the University of Furthermore, in some cases, for example when NPs are used Southampton until 2016, and she is currently a postdoctoral fellow at for in vivo applications, it is required that after the NPs the Ludwig-Maximilians-University, Munich, where her research is complete their role they can be cleared from the organism for focused on applications of DNA origami. example by degradation and extraction through the kidneys. Neus Feliu graduated in Chemistry from the Universitat de Barcelona Thus, further work toward the direction NP ligand coatings (UB) in 2007 and obtained her Master of Science degree in that facilitate NP degradation is desirable and will significantly Biomedical Materials from the Royal Institute of Technology (KTH) benefit the elimination of their toxicity. in Stockholm in 2009. She obtained her Ph.D. in Medical Science 4.2. Density and Steric Configuration of Surface Ligands from Karolinska Institutet (KI), Stockholm, in the field of Engineered Nanomaterials for Biomedical Applications in 2014. Then, she was a The reactivity and multifunctional ability of the NPs strongly postdoctoral researcher at the Department of Clinical Science and depends on the presentation and number/type of ligands on Technology (CLINTEC) at KI. Then, she joined the Department of the NP surface. Although there are methods to quantify the Laboratory Medicine (LABMED), Clinical research Center, KI, number of ligands for certain types of NPs such as gold, for Stockholm, as a Vinmer Fellow and Marie Curie Fellow. Currently, most of the cases of various other types of NPs, this is still a she is a Research Associate at the Center for Hybrid Nanostructures great challenge. Also in most cases it remains quite difficult to (CHyN), Hamburg University (HUU). Her research interest focuses measure the reactivity of individual functional molecules such on understanding the interactions between nanoparticles and as antibodies anchored on the NP surface. Therefore, future biological systems and to explore their use in medical field. developments in these directions will strongly benefit the Ioanna Bakaimi received her degree in Physics from the Aristotle better understanding of NP design and their most suitable University of Thessaloniki and a Masters degree in Applied Physics applicability. Additionally, the development of new imaging from the University of Silecia. Then she obtained a Ph.D. degree in methods to accurately visualize the conformation of ligands on Physical Sciences from the Department of Physics, University of the NP surface could significantly inform a better NP design Crete, and the Institute of Electronic Structure and Laser, FORTH, and improve functionality. Especially with a view on using specializing on the magnetic properties of materials. Currently, she is biomolecules such as peptides, proteins, or oligonucleotides as a Research Fellow at the School of Chemistry, University of ligands, it would be extremely beneficial to be able to directly Southampton, UK, working on materials synthesis and character- visualize their conformation on the NP surface as this directly ization for applications in Energy. influences their biological activity. Majd Hamaly obtained a B.Sc. in Pharmacy and a master degree in To conclude, this review article focused on highlighting the Pharmaceutical Sciences from the University of Jordan before joining importance of ligands on (a) NP synthesis, (b) dispersibility of the King Hussein Cancer Center. Her research focus is the biomedical NPs in complex media, and (c) the effectiveness in application of nanotechnology. applications ranging from biology to physics as well as giving an outlook to challenges, which yet remain to be fully Allaldin Alkilany completed a B.Sc. in Pharmacy (Jordan University of addressed and give opportunities for exciting future research. Science and Technology), a Ph.D. in Chemistry (the University of We believe that it will be a valuable addition in setting the Illinois, USA) and postdoctoral training (Georgia Regents University, scene for future developments to come in the field. USA) before joining the academic staff at the University of Jordan. Dr 4861 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Alkilany is an Associate Professor of Nanoscience and Pharmaceutical biocompatible quantum dots and gold nanoparticles for biosensing Technology at the School of Pharmacy (University of Jordan) and the and imaging technologies. Specifically, his recent research interest Alexander von Humboldt fellow at the University of Hamburg, includes (i) synthesis of a series of core/shell quantum dots and (ii) Germany. Dr. Alkilany’s research focuses on nanotechnology and its design and synthesis of a series of multifunctional surface coating biomedical applications, understanding the nanobio interface, and ligands to enhance the biocompatibility of quantum dots and gold engineering novel drug delivery systems. nanoparticles. Indranath Chakraborty received a Ph.D. in chemistry from the Indian Michael H. Stewart received a BSc. in chemistry from Wittenberg Institute of Technology, Madras. He was a research associate at the University (2002) and a Ph.D. in materials chemistry from the University of Illinois at Urbana−Champaign, IL, USA. Later, he was University of Michigan (2007). As an NRC postdoctoral fellow at the an Alexander von Humboldt Postdoctoral Research Fellow at Philipps U.S. Naval Research Laboratory (NRL), he developed hydrophilic University of Marburg, Germany. Currently, he is a research associate colloidal semiconductor quantum dots as advanced biosensing at Center for Hybrid Nanostructure, University of Hamburg, platforms. He is currently a federal scientist in the Optical Sciences Germany. His research area is focused on tuning surfaces of Division at NRL, where his research efforts focus on advancing plasmonic and fluorescent nanoparticles for biomedical applications. colloidal nanocrystal-based technologies for biological and photonic He is a recipient of the J. C. Bose Patent Award and the Malhotra applications. He is a recipient of the Sigma Xi Young Investigator Weikfield Foundation Nanoscience Fellowship Award. Award and Delores M. Etter Top Navy Scientist of the Year Award. Atif Masood received his M.Sc. in Medical Physics from from PIEAS, Igor L. Medintz received a Ph.D. in Molecular, Cellular and Islamabad. In 2018, he received a Ph.D. from the Faculty of Physics, Developmental Biology from the City University of New York in Phillips University Marburg, specializing on the synthesis, surface 1999. This was followed by a National Cancer Institute Fellowship modification, and bioconjugation of inorganic (QDs, plasmonic, with Prof. Richard Mathies of the College of Chemistry, University of magnetic, catalytic TiO ) NPs. Since 2018, he is a Senior Medical California, Berkeley, and some industrial experience with Vertex Scientist at Karachi Institute of Radiotherapy and Nuclear Medicine Pharmaceuticals. He began at NRL as a National Research Council (KIRAN), Karachi, Pakistan.. Fellow in 2002 and as a Research Biologist in 2004. He currently serves as the Senior Scientist for Biosensors and Biomaterials with the Maria Francesca Casula received her Ph.D. in Chemistry from the Center for Bio/Molecular Science and Engineering. His research University of Cagliari, where she currently is Associate Professor of interests include how nanoparticles engage in energy transfer and how General and Inorganic Chemistry. She has been a visiting researcher biological processes are altered at a nanoparticle interface. at the University of California, Berkeley, as a postdoctoral fellow. Her research area is focused on the design of functional nanomaterials for Emmanuel Stratakis is a Research Director at the Foundation for biomedical, catalytic, and environmental applications. Synthesis− Research and TechnologyHellas (FORTH). He received his Ph.D. properties relationships of the developed nanomaterials is achieved by in Physics from the University of Crete in 2001, and then he joined a multitechnique textural and structural characterization, and the the University of California, Berkeley, as a visiting researcher. He is corresponding results are reported in 115 scientific papers in peer- currently leading the Ultrafast Laser Micro- and Nano- Processing reviewed journals and two book chapters. group of FORTH (https://www.iesl.forth.gr/ULMNP). He has over 170 SCI publications and more than 6000 citations, and he has Athanasia Kostopoulou received her B.Sc. degree in Physics (2004) coordinated many National and EU grants. Since 2015, he is the and her M.Sc. degree (2006) on Materials Physics & Technology Director of the European Nanoscience Facility of FORTH, part of the from the Physics Department at the Aristotle University of NFFA-Europe EU Infrastructure, where he is a member of the Thessaloniki. In 2012, she received her Ph.D. from the Department General Assembly. He is a National Representative to the High-Level of Chemistry at the University of Crete, and since then she was a Group of EU on Nanosciences, Nanotechnology and Advanced Postdoctoral Fellow in the Institute of Electronic Structure and Laser Materials and a National Expert in the NMBP Program Committee of at FORTH in Heraklion. Since 2016, she is part of the group of the the Horizon 2020. He is a member of the Scientific Committee of Ultrafast Laser Micro and Nano Processing (ULMNP) Laboratory COST, of the Physical Sciences sectoral scientific council of the and she is working on the chemical synthesis and elucidation of the National Council for Research & Innovation of Greece, and national microscopic physical or photoinduced mechanisms involving nano- delegate of the OECD Working Party on Bio-, Nano-, and crystal systems. The last few months she is the coordinator of a Converging Tech (BNCT). project funded from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Wolfgang Parak studied physics at the Technische Universitat Technology (GSRT) related to perovskite nanomaterials for photo- München and obtained his Ph.D. in 1999 at the Ludwig Maximilians voltaic applications. UniversitatM ̈ ünchen. After a postdoctoral stay from 2000−2002 at the Department of Chemistry at the University of California at Eunkeu Oh received an M.Sc in physics from Pohang University of Berkeley, he started his own group in the framework of an Emmy Science and Technology (POSTECH) and worked for Samsung since Noether fellowship at the Ludwig Maximilias UniversitatM ̈ ünchen, 1996. In 2006, she obtained a Ph.D. in biological science from Korean which is equivalent to Assistant Professor. In 2005, he held there a Advanced Institute of Science and Technology (KAIST) on temporary position as Associate Professor for Physical Chemistry. In developing biosensors utilizing the property of energy transfer 2007, he became Full Professor at the Physics Department at the between quantum dots and gold nanoparticles. She subsequently Philipps Universitaẗ Marburg. Since 2013, he is also group leader at joined the Naval Research Laboratory through a postdoctoral CIC Bimagune in San Sebastian, Spain. In 2017 he moved to the fellowship of Johns Hopkins University. Currently, she focuses on the development of nanoparticle-based optical materials and their Universitat Hamburg as a Full Professsor in physics. He is also biological application. Associate Editor of ACS Nano. Kimihiro Susumu is a Research Chemist in the Optical Sciences Antonios G. Kanaras obtained his degree in Chemistry from the Division at the Naval Research Laboratory through KeyW University of Crete, and a Master’s degree in Bioinorganic Chemistry Corporation. His research has focused on the development of from the University of Ioannina. Then he received a Ph.D. degree 4862 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review from the Department of Chemistry, University of Liverpool, working DMSO dimethylsulfoxide on the organization of gold nanoparticles using biomolecular tools. DMVC dimethylvinylcarbinol He was a postdoctoral scientist at the Department of Chemistry, DNA deoxyribonucleic acid University of California, Berkeley, and Lawrence Berkeley Lab, DTAB decyltrimethylammonium bromide working on the synthesis and energy applications of semiconductor DTT dithiothreitol nanoparticles. Currently, he is a Professor/Chair at the School of EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Physics and Astronomy, University of Southampton, and the Head of EG ethylene glycol the Laboratory for Inorganic Nanoparticles and Applications. EQE external quantum efficiency Antonios’ research is highly multidisciplinary working at the interface ETL electron transport layer of Physics, Chemistry, Biology, and Materials Science. He is Fellow of FDA Food and Drug Administration the Higher Education Academy, Fellow of the Royal Society of FET field-effect transistor Chemistry, Fellow of the Royal Society of Biology, and Fellow of the GO graphene oxide Institute of Physics. GSH glutathione GTS glutathione S-transferase HDA hexadecylamine ACKNOWLEDGMENTS His histidine A.H-J. was funded by the Leverhulme Trust (ref RPG-2015- HIV human immunodeficiency virus 005). A.M. was supported by HEC/DAAD with a Ph.D. HPA n-hexylphosphonic acid fellowship. I.C. was funded by an Alexander von Humboldt HRTEM high resolution transmission electron microscopy postdoctoral fellowship. N.F. acknowledges funding from the HSA human serum albumin Swedish Governmental Agency for Innovation Systems ICBA indene-C bisadduct (Vinnova). A.F. was funded by DAAD/HEC. W.J.P. acknowl- ID identity document edges funding from the German Research Foundation (DFG ITO indium titatium oxide grant PA 794/28-1). M.F.C. acknowledges funding from LBL layer-by-layer University of Cagliari (under FIR 2018). A.G.K. acknowledges LED light emitting diode funding from BBSRC (BB/N021150/1, BB/P017711/1). A.K. Leu leucine acknowledges funding from the Hellenic Foundation for LNA locked nucleic acid Research and Innovation (HFRI) and the General Secretariat LSPR localized surface plasmon resonance for Research and Technology (GSRT), under grand agreement Lys lysine no. 1179. MBP maltose binding protein mPEG methoxy poylethylene gylcol ABBREVIATIONS USED MRI magnetic resonance imaging NC nanocluster Acac acetlyacetonate NHS N-hydroxysuccinimide Ala alanine NIR near infrared APTS aminopropyl trimethoxysilane NMF n-methylformamide Asn asparagine NMR nuclear magnetic resonance Au NP gold nanoparticle NP nanoparticle Au NR gold nanorod NTA nitriloacetate Ag NP silver nanoparticle OA oleic acid Ag NC silver nanocluster ODA ocatdecylamine Ag Te silver telluride ODE octadecene BHJ bulk heterojunction ODPA octadecylphosphonic acid BPEI branched polyethyleneimine OEG oligoethylene glycol BSA bovine serum albumin OLA oleylamine BSPP bis(p-sulfonatophenyl)phenyl) phosphine dehy- OPA n-octylphosphonic acid drate OPH organophosphate hydrolase CBMT chlorobenzenemethanethiol OPV organic photovoltaic CKD chronic kidney disease OT n-octanethiol Co NP cobalt nanoparticle P3HT poly(3-hexylthiophene-2,5-diyl) CPP cell-penetrating peptide PAA peroxyacetic acid CTAB cetyltrimethylammonium bromide PAMAM polyamidoamine CTAC cetyltrimethylammonium chloride PBS phosphate buffered saline Cu NP copper nanoparticle Pd NP palladium nanoparticle Cys cysteine PDMA polydimethylsiloxane Da Dalton PEDOT poly(3,4-ethylenedioxythiophene) DCB dichlorobenzene PEG polyethylene glycol DDA dodecylamine PEG-MA poly(ethylene glycol) methacrylate DDT 1-dodecane thiol PEG-SH poly(ethylene glycol) thiol DEG diethylene glycol PEI polyethyleneimine DFT density functional theory PEO poly(ethylene oxide) DHJ depleted heterojunction PFH poly(9,9-diheylfluorene) DHLA dihydrolipoic acid PHA polyhydroxyalkanoate DMEC dimethylethynylcarbinol 4863 DOI: 10.1021/acs.chemrev.8b00733 Chem. 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This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. Review pubs.acs.org/CR Cite This: Chem. Rev. 2019, 119, 4819−4880 The Role of Ligands in the Chemical Synthesis and Applications of Inorganic Nanoparticles †,◇ ‡,⊥ ■ § ∥,⊥ Amelie Heuer-Jungemann, Neus Feliu, Ioanna Bakaimi, Majd Hamaly, Alaaldin Alkilany, ⊥ + #,^ ∇ ○,◆ Indranath Chakraborty, Atif Masood, Maria F. Casula, Athanasia Kostopoulou, Eunkeu Oh, ○,◆ ◆ ¶ ∇ Kimihiro Susumu, Michael H. Stewart, Igor L. Medintz, Emmanuel Stratakis, ⊥ ,† Wolfgang J. Parak, and Antonios G. Kanaras* School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO17 1BJ, U.K. Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm 171 77, Sweden King Hussein Cancer Center, P. O. Box 1269, Al-Jubeiha, Amman 11941, Jordan Department of Pharmaceutics & Pharmaceutical Technology, School of Pharmacy, The University of Jordan, Amman 11942, Jordan Fachbereich Physik, CHyN, Universitaẗ Hamburg, 22607 Hamburg, Germany INSTM and Department of Chemical and Geological Sciences, University of Cagliari, 09042 Monserrato, Cagliari, Italy Institute of Electronic Structure and Laser, Foundation for Research and TechnologyHellas, Heraklion, 71110 Crete, Greece KeyW Corporation, Hanover, Maryland 21076, United States Optical Sciences Division, Code 5600, U.S. Naval Research Laboratory, Washington, D.C. 20375, United States Center for Bio/Molecular Science and Engineering, Code 6900, U.S. Naval Research Laboratory, Washington, D.C. 20375, United States Fachbereich Physik, Philipps Universitaẗ Marburg, 30357 Marburg, Germany School of Chemistry, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO171BJ, U.K. Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy ABSTRACT: The design of nanoparticles is critical for their efficient use in many applications ranging from biomedicine to sensing and energy. While shape and size are responsible for the properties of the inorganic nanoparticle core, the choice of ligands is of utmost importance for the colloidal stability and function of the nanoparticles. Moreover, the selection of ligands employed in nanoparticle synthesis can determine their final size and shape. Ligands added after nanoparticle synthesis infer both new properties as well as provide enhanced colloidal stability. In this article, we provide a comprehensive review on the role of the ligands with respect to the nanoparticle morphology, stability, and function. We analyze the interaction of nanoparticle surface and ligands with different chemical groups, the types of bonding, the final dispersibility of ligand-coated nanoparticles in complex media, their reactivity, and their performance in biomedicine, photodetectors, photovoltaic devices, light-emitting devices, sensors, memory devices, thermoelectric applications, and catalysis. 2.2.2. Magnetic Nanoparticles 4833 CONTENTS 2.2.3. Luminescent Nanoparticles 4834 1. Introduction 4820 2.2.4. Other Nanoparticles 4838 2. Surface Stabilization of Colloidal Nanoparticles 4822 3. Ligand Modification for Well-Dispersed and 2.1. Ligand Coating on Inorganic Nanoparticles Functional Nanoparticles in Complex Media 4839 Synthesized in Aqueous Media 4822 3.1. Ligand Coating of Nanoparticles for Bio- 2.1.1. Plasmonic Nanoparticles 4822 medical Applications 4840 2.1.2. Magnetic Nanoparticles 4828 3.1.1. Ethylene Glycol Containing Ligands 4840 2.1.3. Luminescent Nanoparticles 4829 2.2. Ligand Coating on Nanoparticles Synthe- sized in Organic Media 4832 Received: December 3, 2018 2.2.1. Plasmonic Nanoparticles 4832 Published: March 28, 2019 © 2019 American Chemical Society 4819 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Downloaded via 78.15.220.100 on May 5, 2019 at 17:49:23 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Chemical Reviews Review 3.1.2. Silanes 4842 manner. For example, NPs can be equipped with targeting and 3.1.3. Oligonucleotides 4845 cargo delivery abilities, engineered to be biocompatible or 15−23 3.1.4. Small Peptides 4847 designed to assemble in an ordered manner. The ability to 3.1.5. Proteins 4848 attach a large number of various types of ligands to the surface 3.1.6. Carbohydrates 4849 of a single NP offers additional benefits such as higher 3.2. Ligand Coating of Nanoparticles for Other reactivity at the local microenvironment around the NP core Applications 4850 and multitasking performance. Therefore, the appropriate 3.2.1. Photodetectors 4851 choice of ligands plays a critical role in the structure, colloidal 3.2.2. Photovoltaic Devices 4852 stability, and function of NPs. Appropriate protocols to coat 3.2.3. Light-Emitting Devices 4854 the NP surface with ligands or perform secondary conjugation 3.2.4. Sensors 4855 ligand reactions define the quality of NPs. To choose suitable 3.2.5. Memory Devices 4856 ligands for either direct synthesis of NPs or postsynthetic 3.2.6. Thermoelectric Applications 4857 modification of a NP surface, there are many important 3.2.7. Catalysis 4859 parameters to consider which will directly affect intended 4. Conclusions and Future Perspectives 4860 application. These include: (1) The chemical composition of the 4.1. Stability of NPs 4861 NP surface: The nature and strength of bonding between the 4.2. Density and Steric Configuration of Surface ligand and NP surface is strongly correlated to the individual Ligands 4861 characteristics of each NP type. For example, carboxyl and Author Information 4861 hydroxyl groups have a strong binding affinity for iron oxide Corresponding Author 4861 NPs, whereas thiols have high affinity to gold surfaces. The ORCID 4861 strength of ligand binding is critical to the long-term colloidal Present Address 4861 stability of NPs, and when they are coated with weak affinity Notes 4861 ligands they must be stored either as powders or in an excess Biographies 4861 amount of free ligand in solution to retain sufficient ligand Acknowledgments 4863 coverage. The use of multidentate anchoring groups on ligands Abbreviations Used 4863 can additionally aid in increasing binding strength and hence References 4864 colloidal particle stability. Table 1 shows an overview of some Table 1. Different NPs and Common Anchoring Groups 1. INTRODUCTION Used for Ligand Conjugation Nanoparticles (NPs) have attracted great research interest due common anchoring group for ligand to their unique properties, which derive from a combination of NP composition conjugation their intrinsic characteristics such as chemical composition, noble metal thiol (−SH) size, shape, and the type of molecules employed to coat their amine (−NH ) surface. Owing to the inorganic core composition, metallic carboxyl (−COOH) NPs (especially gold and silver) can exhibit strong optical phosphine (−PR ) 1−4 absorption and scattering, while semiconductor quantum dots (e.g., cadmium selenide (CdSe) or cadmium telluride semiconducting quantum dot phosphine oxide (O = PR ) (CdTe), lead sulfide (PbS), and perovskite NPs (e.g., thiol (−SH) methylammonium or cesium lead halides) can be highly phosphonyl (−PO(OR) ) 5−7 fluorescent as a result of their electronic band structure. On carboxyl (−COOH) the other hand, NPs synthesized from magnetic materials (e.g., iron oxide or cobalt) can exhibit unique magnetic phenomena transition metal oxide carboxyl (−COOH) such as superparamagnetism, which are not encountered in the hydroxyl (−OH) 8,9 corresponding bulk counterparts. These properties have phosphonyl (−PO(OH) ) rendered NPs highly interesting candidates for a vast variety of amine (−NH ) 6,10−13 applications. One of the key parameters to synthesize robust and well crystalline NPs of defined morphologies and function is the choice of surface ligands. Ligands play multiple of the NPs discussed in this review as well as common roles ranging from the regulation of the solubility and anchoring groups for ligand attachment. Figure 1 shows an availability of active components during NP synthesis to the example of the variety of different ligands and anchoring post synthetic minimization of surface energy of NPs (required groups available for NP functionalization, illustrated here for for their colloidal stability) as well as the encoding of NP the case of colloidal quantum dots (QDs). This figure functionality. The type of ligands employed to fulfill these epitomizes the diversity of NP ligand chemistry using the roles include small organic compounds with redox properties example of QDs and surface ligand strategies applied for or ability to complexate with active components (e.g., biological applications. First it highlights how different trisodium citrate, oleic acid, etc.), large polymers (e.g., strategies can be utilized to attach a ligand to the QD surface polyethylene glycols) with tunable polarity to preferentially by direct coordination or hydrophilic interdigitating of ligands bind crystallographic domains on the NP surface, or other to the native moiety present on the as-synthesized QD. A functional biomolecules (such as peptides, proteins, and variety of different mechanisms can be utilized to stabilize QDs oligonucleotides), which enrich NPs with additional proper- such as charge or the hydrophilicity of ethylene glycol repeats. ties. An additional feature of surface ligands is the option to The different sizes of ligands, impact the overall hydrodynamic offer multiple functionalities, which can act in a synergistic radius of the nanoparticles, and any downstream utility 4820 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 1. (A) Ligand binding at the QD surface. (B) Association of an amphipol (blue) with the native QD ligands (red). (C) Ligand chemistries (i) thioalkyl acids, (ii) PEGylated ligands, (iii) zwitterionic ligands, (iv) dihydrolipoic acid ligands and (v) PEGylated, (vi) zwitterionic and (vii) modular derivatives thereof, (viii) multidentate charged, and (ix) multidentate PEGylated ligands. (D) Amphipol coatings (i) phospholipid micelles, (ii) hydrophilic polymer backbones grafted with alkyl chains, (iii) triblock copolymers, and (iv) alternating copolymers that hydrolyzeto acids or (v) are grafted with PEG chains. (E) Copolymers with pendant PEG oligomers and (i) dithiol or (ii) imidazole groups. Discrete moieties for (a) QD binding, (b) solubility, and (c) bioconjugation are identified where applicable (green). The arrows illustrate a conceptual progression and not synthetic pathways or chronological development. Reprinted with permission from ref 27. Copyright 2011 American Chemical Society. especially in a biological context. The end groups displayed on range of different pH values, buffers, and biological or organic the ligands are also important for bioconjugation of functional media. For example, intracellular applications will limit the molecules to the QD. (2) The environment the particles are choice of ligands to the ones that are biocompatible and can designed for: The appropriate selection of a ligand to coat NPs ideally protect the particles from nonspecific binding of is directly correlated to the actual environment that the biomolecules (e.g., proteins) and will also require ligands particles will be utilized in. NPs may need to be dispersed in a that bind strongly to the NPs surface and remain bound in 4821 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review complex biological media and buffers. (3) The desired NP ligands retain their colloidal stability via repulsion forces, while morphology: Ligands will have different binding energies, ligands that occupy significant space stabilize the NPs via steric diffusion rates, and packing characteristics near the NP surface, effects. The surface stabilizing ligands can be present during which, in turn, influences the final morphology imparted to the the nucleation and growth of the NPs (surface passivation NPs during synthesis. For example, the presence of thiols during synthesis), or they can be added post synthetically to during the reduction of gold salts to form gold NPs (Au NPs) exchange ligands to the NPs’ surface. In the following section, usually favors the growth of smaller size particles ranging from we focus on the synthesis of NPs in the presence of the surface 1 to 10 nm. On the other hand, the use of weakly interacting stabilizing ligands. This route represents the most straightfor- ligands (such as citrate ions, which bind electrostatically to Au ward approach to introduce surface functionalization on the NPs) allows the growth of colloidal particles ranging from 2 NP surface and provides a significant example on the nm up to 100 nm and beyond. Other types of ligands, such multifaceted and powerful role of ligands. as the amphiphilic cetyltrimethylammonium bromide (CTAB), 2.1.1. Plasmonic Nanoparticles. Surface Passivation act as a stabilizing agent and shape directing agent due to its during Synthesis. One of the first chemical syntheses of gold differential adsorption to gold facets and thus driving the NPs (Au NPs) was reported by Michael Faraday in 1857. growth not only of spherical but also anisotropic nanomaterials Gold hydrosols were prepared by the reduction of an aqueous such as gold nanorods (Au NRs), cubes, and stars. (4) The solution of chloroaurate and phosphorus (or hydrogen) need for secondary chemical modification of the ligand shell: For dissolved in carbon disulfide. Later, Turkevich published an secondary modification of NPs with biomolecules or other alternative chemical method to synthesize spherical gold desired polymers, specific functional groups are needed to NPs, which involved the thermal reduction of gold ions in an provide a chemical handles for subsequent coupling chemistry. aqueous trisodium citrate solution. When the trisodium citrate In many cases, these groups are placed at a ligand’s termini or was added to the boiling aqueous solution of gold salt under periphery. However, these functional groups can limit the vigorous stirring, a color change from purple to ruby-red could choice of a ligand due to potential additional unwanted be observed, indicating the formation of spherical Au NPs. The interactions with the NP surface. The number and availability method was further developed by G. Frens to enable control of these groups are important factors in any subsequent over the Au NP size by varying the ratio of gold salt to sodium chemistry as is their propensity for cross-linking. In other cases, citrate. Since then, numerous modifications and detailed biomolecules can be attached directly to a NP surface but this kinetic studies of the Turkevich process have been may be at the cost of displacing some of the stabilizing ligands 32−37 reported. It was also found that sodium citrate plays or even losing biological activity of the biomolecules due to multiple roles during the reaction. Besides reducing the gold their interactions with the NP surface. Clearly, the salt and stabilizing the NP surface via electrostatic repulsion, experimental protocols for ligand conjugation to NPs must citrate also plays a crucial role in determining the reaction pH, be customized to the various types of ligands available in which in turn is correlated with the final size and dispersity of conjunction with what is desired in the final application. the resulting NPs. Citrate adsorbs onto the gold surface Fortunately, the depth and diversity of this field continues to through its carboxyl groups with different possible binding grow at an astounding rate and this serves to provide a strong modes. It was shown that changes in pH drastically alter its literature resource from which to draw. This review will focus affinity to gold. While at neutral pH, only the central on the role of the ligands in determining the formation, carboxylate group is adsorbed on the surface, at pH ≥ 11 all functionalities, and applications of NPs. Various postsynthetic of the carboxyl and hydroxyl groups are adsorbed. The strategies to functionalize and stabilize NPs of different negative charge of citrate provides colloidal stability through chemical composition (metal, metal oxide, semiconductor, electrostatic repulsion and electrostatically coated colloids are organic) and morphologies dispersed in aqueous or organic well-dispersed in water. However, a disadvantage of the media are discussed. As extensive research in the field of NPs’ electrostatic stabilization is the inherent susceptibility of the design has demonstrated that the use of ligands during NPs to irreversible aggregation induced by high salt synthesis has a dramatic effect on the resulting size, shape, concentrations and pH changes. On the other hand, the crystal structure, dispersion, and colloidal stability, the ligands weak binding of citrate can also be of benefit when a employed to assist NPs synthesis in aqueous or organic media postsynthetic ligand exchange is required. Post ligand will also be reviewed. Furthermore, commonly chosen ligands exchange is highly feasible for citrate protected Au NPs by to coat various types of NPs for specific biomedical or energy applications will be discussed. Representative examples of considering the weak binding of citrate to the Au NPs (6.7 kJ/ ligands and their utility from the literature are employed to mol). Ligand exchange with numerous other ligands of 42−45 accentuate this discussion and highlight key approaches along different anchoring groups such as thiolates and 43,46,47 with many of the remaining issues. Clearly, the vastness of this amines have been reported, which also enhance their 44,48,49 field precludes us from doing a comprehensive review of every colloidal stabilities and biocompatibilities. Among these, example and our apologies are extended for any and all thiol exchange has been found more effective and extensively omissions. used because thiol interacts strongly with the gold surface 50,51 (126−167 kJ/mol). Although citrate is often utilized as a capping agent for Au NPs, other types of metal NPs made from 2. SURFACE STABILIZATION OF COLLOIDAL NANOPARTICLES Ag, Pt, Pd, or Cu have also been synthesized using sodium citrate. For example, it was shown that triangular core−shell 2.1. Ligand Coating on Inorganic Nanoparticles gold−silver nanoprisms with a citrate coating could be grown Synthesized in Aqueous Media from citrate Au NPs used as seeds, by irradiating at the Ligands enable the colloidal stability of NPs via electrostatic plasmon frequency. In a systematic study, Zhang et al. and/or steric interactions. NPs stabilized with highly charged similarly described how to obtain different sizes/shapes of Ag 4822 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 2. Synthetic scheme and corresponding TEM images of Au@citrate NP synthesis of tunable size. In the first step, NP seeds of 3.6 nm are formed. Subsequent injection steps yield larger NPs with excellent size monodispersity. Reprinted with permission from ref 55. Copyright 2016 American Chemical Society. nanoplates by using a combination of citrate, PVP, polyol (EG, Although often used in conjunction with sodium citrate, tannic acid has also been employed on its own for the synthesis PEG, TEG, DEG), and hydrogen peroxide. of Ag NPs with sizes ranging from 3.3 to 22.1 nm. Besides Sodium citrate has also been used in conjunction with tannic citrate and tannic acid, sodium acrylate has also been reported acid to produce highly monodisperse Au NPs with sizes 54,55 for the synthesis of highly monodisperse Au NPs (2% ranging from 3.6 to 200 nm. The method included a polydispersity index) with sizes ranging from 10 to 100 nm. multistep seed-mediated growth reaction as shown in Figure 55 Here, repetitive additions of the Au−ligand complex were used 2. In another report, sodium citrate has also been used in to control the resulting particle size. Both tannic acid and conjunction with hydroquinone to prepare monodispersed Au sodium acrylate follow similar mechanisms for NP formation NPs at room temperature. as in the case of citrate, acting both as reducing agents and A similar synthetic route employing sodium citrate and stabilizing the NPs through carboxylate groups. tannic acid was also reported for the formation of highly Surfactants as Capping Agents. Cetyltrimethylammonium monodisperse silver NPs (Ag NPs) with sizes ranging from 14 bromide (CTAB) has been widely utilized in the synthesis of to 200 nm. Following on the early work of Henglein et al., both spherical and anisotropic NPs such as gold nanorods (Au the uniformity, final size, and crystallinity of Ag NPs could be NRs). Murphy and co-workers as well as other groups carried changed as a function of the concentration of citrate because out comprehensive studies to prepare high quality Au these NPs coalesce at lower citrate concentrations. nanorods (Au NRs) employing a seed-mediated wet chemistry 4823 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 3. Schematic illustration of the synthesis of a β-cyclodextrin-functionalized Au NP, which can be loaded via a host−guest interaction with an adamantane−Pt(IV) complex. Reprinted with permission from ref 87. Copyright 2013 American Chemical Society. protocol, in which CTAB was used as a stabilizing and shape Unlike citrate, alkyl ammonium halide ligands provide the directing ligand (promoting the formation of rod shaped NP with a net positive charge. Similar to citrate, alkyl 61−64 particles). Although the exact mechanism for the ammonium halides bind weakly to the NP surface, allowing for facile ligand exchange reactions with stronger binding formation of Au NRs still remains somewhat unclear, it is ligands (e.g., thiol containing compounds), which can render evident that CTAB binds preferentially to the (100) crystal the NPs appropriate for biomedical applications. plane on the side of the NR promoting an anisotropic crystal Thiol Containing Ligands on NPs. Because of the strong growth (unidirectionally) on the (111) facets at the tips. On −1 Au−thiol interaction (bond strength of 40−50 kcal mol ), the another example, branched Au NPs with different degrees of synthesis of Au NPs with thiolated ligands results in NPs which branching were prepared in the presence of CTAB, ascorbic typically have excellent colloidal stability. The most acid, and silver. The degree of NP branching and size were also commonly accepted model for thiol−Au interaction is the tuned by regulating the amounts of the reducing agent ascorbic binding of the deprotonated sulfhydryl group (forming a thiyl acid and inducing preferential binding of CTAB and silver. radical) to Au. In its protonated form, SH is only able to bind The use of surfactant mixture such as sodium oleate combined to gold through the lone pair electrons on the sulfur, forming with CTAB was shown to be a successful strategy to obtain Au coordination-type bonds. For example, it was shown that the NRs with superior quality (percentage of rod-shape particles), small thiol-containing biomolecule glutathione (GSH), a dimensional tunabiltity and even stability under oxidizing 67 common antioxidant, could be used to produce ultrasmall conditions. Furthermore, the inclusion of aromatic additives Au NPs (0.9 nm) in a methanol−water mixture (2:3). Some during CTAB-mediated Au NR growth can narrow the size other examples of thiols used to produce ultrasmall Au NPs distribution of the resulting NRs. The aromatic additives can be found in ref 76. On the other hand, slightly larger Au intercalate in the CTAB micelle altering its micelle behavior. NPs with diameters ranging from 2.3 to 10 nm could be The micellar packing can be tuned according to the type of prepared by mixing an aqueous solution of gold salt with additive used to derive monodisperse micelles. The use of mercaptopropionate and citrate under reflux. Dithiol other additional cosurfactants such as cetyltrimethylammo- containing compounds such dihydrolipoic acid (DHLA) have nium chloride (CTAC) and decyltrimethylammonium bro- also shown great promise for the synthesis of Au NPs. While mide (DTAB) was shown to result in shorter aspect ratio rods the thiol−gold bond provides strong ligand binding, the but with a poorer yield of Au NRs. These observations were terminal carboxylate moiety provides the particles with attributed to the direct influence of chlorine counterions and electrostatic stabilization and further offers a site for additional DTAB to the CTAB micelles. CTAC has further been used postsynthetic modification. In addition, it was found that the in the synthesis of triangular Au nanoplatelets in combination displacement of the DHLA ligands was more difficult with iodine ions. The gold nanoplatelets’ growth is promoted compared to other thiol-containing ligands, which was by the preferential binding of I− ions to the Au (111) facet as attributed to the dithiol binding versus monothiol binding. well as through oxidative etching, removing less stable nuclei. Another very popular coating for NPs are (thiolated) ethylene 79,80 Tetradecyltrimethylammonium bromide (TTAB) is another glycols and their derivatives. Alkyl-thiol containing ligands micelle-forming ligand, which has been employed to synthesize such as thioalkylated tetraethylene glycol (TTG) have also cubic and cuboctahedra shape of platinum NPs (Pt NPs) been used to stabilize Au NPs. This ligand was superior as during a borohydride reduction. opposed to traditional PEG coatings due to its dual functional 4824 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review properties. While its hydrophobic part could firmly assemble and pack to a monolayer around the hydrophobic Au core, the hydrophilic part (ethylene glycol) rendered the particles very stable in water and challenging biological environments. A one- pot synthesis of Au NPs by using bidentate thiolated PEG (M : 550−750 Da), via room temperature Au reduction with sodium borohydride (for 1−16 nm Au NPs), and a seeded growth method in boiling water (for 10−130 nm) was also reported by Oh et al.. The thiolated PEG ligands allowed for the functionalization of Au NPs with various biomolecules through amide bond formation (amine-PEG-Au NPs, carboxyl- 82−84 PEG-Au NPs) and click chemistry (azide-PEG-Au NPs). Furthermore, the thiolated PEG ligands provided enhanced colloidal stability to Au NPs under a wide range of conditions with respect to their monothiolated counterparts. Thio- sulfates (Bunte salts) have also been used as ligand precursors to synthesize Au NPs (1.5−20 nm) stabilized with mercaptoethoxyethoxyethanol, 9-mercaptononanoic acid, and mercaptopentyl(trimethylammonium) chloride. Beyond these types of thiols, cage-like molecules such as β- cyclodextrin have also been used as ligands for Au NPs. Si et al. reported a per-6-thio-β-cyclodextrin protected Au NP of size Figure 4. Structure of the BSPP ligand (a). TEM image (b) and 4.7 ± 1.1 nm (Figure 3), which can be used as a cargo for the HRTEM image (c) of BSPP-stabilized Au NPs prepared in aqueous delivery of a cisplatin prodrug (oxoplatin−adamentane solvent at room temperature. Adapted with permission from ref 88. Copyright 2011 Elsevier. conjugate). This binding is due to the well-known strong host−guest interaction between adamantane and β-cyclo- dextrin. presence of sodium polyacrylate, where the concentration ratio Phosphines as Ligands. Triphenyl phosphine (TPP) and of polyacrylate to Pt determined whether cubic, tetrahedral, its derivatives have been widely used as ligands to synthesize or icosahedral, cuboctahedral, or irregular-prismatic NPs were 91−93 coat Au NPs. While TPP is soluble in organic solvents, many formed. Another interesting study revealed that poly(vinyl of its derivatives, such as as bis(p-sulfonatophenyl)phenyl) pyrrolidone) (PVP)-stabilized Au NPs showed changes in their phosphine dehydrate (BSPP), are soluble in aqueous solvent. optical properties due to energy transfer between the PVP and Zhong et al. synthesized monodisperse Au NPs using BSPP as Au NP core. In hot water, dispersed PVP molecules served the ligand (figure 2.3 ). The particle size could be adjusted by not only as a surface ligand but also governed clustering and controlling the pH of the solution. Synthesis at higher pH growth of polygonal Au NPs (25−50 nm in diameter) using (using NaOH, pH ∼ 12) yielded ultrasmall sized nanoclusters small polymer templates. PVP was also used to synthesize 4−8 (NCs), whereas synthesis at neutral pH yielded 4 nm Au NPs nm cuboctahedral Pd NPs by a polyol reduction method using as presented in Figure 4. ethylene glycol. A good summary of the roles of PVP in the BSPP and other related derivatives introduced by Schmid et synthesis of colloidal NPs can be found in this perspective al., have been used extensively for the stabilization of Au article: Similar to PVP, poly(vinyl alcohol) (PVA) has also 89,90 nanospheres among other materials. Unlike thiols, been shown as a suitable ligand for NP synthesis. Copper NPs phosphines bind to Au via the phosphorus’ lone electron (Cu NPs) could be formed by reduction with citrate in the pair. This type of bond is stronger than the electrostatic presence of sodium formaldehyde sulfoxylate (SFS) and interactions between citrate or alkyl halides and Au, but still PVA. PEG was also tested for stabilizing the Cu NPs during not as strong as the sulfur−Au bond, thus allowing for facile reduction with borohydride/ascorbic acid, and the size (4−28 ligand exchange. The mechanism by which NPs are stabilized nm) was controlled by changing the amount of PEG with by phosphines is believed to arise from both charge and steric concomitant plasmon band shifts observed near 560−570 interactions owing to the bulky aromatic rings on TPP nm. Near-monodisperse 1.4−4 nm Au NPs were synthesized derivatives. Additionally, an advantage of using charged in an aqueous solution of alkyl thioether end-functionalized phosphines such as BSPP as a capping agent is the ability to poly(methacrylic acid), where the desired product size again redisperse aggregated NPs previously precipitated by the depended on the ratio of polymer to Au. Various sizes of addition of salt. This allows for the concentration of AuNP polyelectrolyte-protected Au NPs have been obtained directly solutions by centrifugation, which is an important preparatory by heating AuCl in an aqueous solution of amine-containing step for many subsequent applications. On the other hand, polyelectrolytes such as poly(ethylenimine) and poly- citrate capped particles can display irreversible aggregation (allylamine hydrochloride). Wang et al. reported a one- behavior due to the weak binding to the Au surface. step aqueous preparation of highly monodisperse Au NPs with Polymers and Plasmonic NPs. Polymers can sterically and diameters below 5 nm using thioether- and thiol-functionalized electrostatically stabilize NPs by physisorption or chemisorp- polymer ligands: dodecanethiol (DDT)-poly(acrylic acid), tion to the NP surface. During NP synthesis, polymers can DDT-poly(methacrylic acid), DDT-poly(vinylsulfonic acid), bind preferentially to specific crystallographic planes of the NP DDT-poly(vinylpyrrolidone), DDT-poly (hydroxyethyl acryl- surface and promote preferential anisotropic crystal growth or ate), and DDT-poly(ethyleneglycol methacrylate). Here act as a matrix for nanocrystal growth. For example, the shape particle uniformity and colloidal stability as a function of of colloidal platinum NPs (Pt NPs) could be controlled in the changes in ionic strength and pH were strongly dependent on 4825 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 2. Metal NPs Synthesized in Aqueous Media material reducing agent ligand/surfactant size (nm) shape other comments Au sodium citrate sodium citrate 20 sphere (sp) thermal single phase Au reduction Au sodium citrate sodium citrate 16−149 sp thermal single phase Au reduction Au sodium citrate sodium citrate 20−100 sp RT seed-growth Ag sodium citrate sodium citrate 5−30 sp RT reduction/coalescence Ag sodium citrate sodium citrate, tannic 14−200 sp thermal seed-growth acid Au citrate, ascorbic acid sodium citrate 9−120 sp thermal/UV reduction Au pottasium citrate sodium citrate 18−100 sp/polygon thermal single phase Au reduction with pH variation c 59 Au/Ag tannic acid tannic acid 2−10/3.3-21.1 sp pH adjusted RT Au:Ag sodium citrate sodium citrate 32−172 sp thermal seed-growth Ag borohydride sodium citrate/PVP, ∼50 nanoplate, wire H O 2 2 EG, TEG, PEG Au phosphorus carbon sulfide sp Au H carbon sulfide Rod Au hydroxylamine hydroxylamine 20−119 sp RT seed-growth hydrochloride Au hydroxylamine hydroxylamine 12.7 × 11.7−116 × 112, 13.7 × sp/rod iterative RT seed-growth 11.2−233.6 × 74.2 Au borohydride alkyl thiosulfates 1.5−20 sp RT reduction Au ascorbic acid arabic gum 90−4600 sp RT reduction Au sodium citrate, ascorbic acid, SDS 5−30 sp RT seed-growth, AgNO hydrazine, NaBH Au SDS 1−5 sp laser ablation Ag SDS 10 sp laser ablation Cu sodium citrate, hydrazine sodium formaldehyde 30 sp thermal reduction hydrate, sulfoxylate, PVA 92,93 Pt polyacrylate polyacrylate 4−18 cube, polygon Ar gas in RT Au ascorbic acid CTAB 37/200 × 17 sp/rod iterative RT seed-growth Au borohydride, ascorbic acid CTAB 20−100 (AR: 2−4) rod RT seed-growth Au ascorbic acid DTAB, CTAB 22−25 (W), 25−170 (L) rod RT reduction Au borohydride HTAB, CTAB 20−80 (W), 200−800 (L) elongated rod 40 °C thermal seed-growth Pt borohydride TTAB 12−14 cube, H gas pressure cuboctahedron Au borohydride ditri-tetra-EG <5 sp RT reduction Au lemon grass lemon grass 0.05−1.8 μm Triangle bioreduction Au PEI 25−100 sp thermal reduction Au BPEI BPEI 9.4 sp thermal reduction Cu hydrazine poly(allylamine) 40−50 sp, rod thermal reduction Au borohydride poly(methacrylic acid) 1.4−4 sp RT reduction Au borohydride PEO 3.2−7.4 sp RT reduction Au PVP PVP 83- 95 star steric effects Au PVP 25−50 polygon thermal reduction Pd ethylene glycol PVP 4−8 cubooctahedron thermal reduction Pd ascorbic acid PVP ∼9 truncated thermal reduction octahedron Pd−Pt ascorbic acid PVP ∼24 nanodentrites thermal reduction Au PDMA PMPC/PDMA ∼10 sp diblock copolymers Au borohydride PAA, PMEA, PHA, <5 sp RT reduction PVA, PEG-MA Au PEG200/8000 15−60 sp thermal reduction Cu borohydride/ascorbic acid PEG6000 4−28 sp multistep Au borohydride PEG-thiol 1−16 sp RT reduction Au borohydride, sodium citrate PEG-thiol 15−130 sp thermal seed-growth Au:D borohydride PEG-thiol 1.0−2.5 sp luminescent, D = Ag, Pt, Zn, Cu, Cd Ag borohydride, citrate PEG-thiol, PVP, citrate 10−12 sp Au polyaniline nanofibers 1−10000 sp-microsheet thermal reduction, memory devices Pd Pluronic copolymers 5−27 sp pH adjusted RT (PEO/PPO) Au@Pd@Pt ascorbic acid Pluronic copolymers 20−55 core/shell NP nanoporous (PEO/PPO/PEO) 4826 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 2. continued material reducing agent ligand/surfactant size (nm) shape other comments Au chitosan chitosan/TPP 5−300 sp, polygon cationic polysaccharide Au borohydride GSH 0.9 sp RT reduction Au borohydride GSH/NTA-lysine 2−6 sp RT reduction Au borohydride lysine 6.5 sp RT reduction Au lysine 32−95 Star 37 °C thermal seed-growth Au borohydride protein, antibody, lysine 5 → μmsp → rod freezing, −20 °C assembly Ag sorghum bran sorghum bran 50 sp RT reduction Ag ammonia glucose, galatose, 25−450 sp antimicrobial/bactericidal maltose, lactose Ag ascorbic acid BSA, lysozyme 50−60 triangle RT reduction GO/Ag luminol luminol 22 sp GSH sensing sp, spherical; rt, room temperature; PVP, poly(vinylpyrrolidone; EG, ethylene glycol; TEG, tetraethylene glycol; PEG, poly(ethylene glycol); SDS, sodium dodecyl sulfate; DTAB, decyltrimethylammonium bromide; PEI, polyethylenimine; BPEI, branched polyethylenimine; PEO, poly(ethylene oxide); PMPC, poly(2-methacryloyloxyethyl phosphorylcholine); PDMA, polydimethylsiloxane; PAA, peroxyacetic acid; PMEA, para- methoxyethylamphetamine; PHA, polyhydroxyalkanoate; PEG-MA, poly(ethylene glycol) methacrylate; TPP, triphenyl phosphine, GSH, b c d e f glutathione; NTA, nitrilotriacetic acid; GO, graphene oxide. Reference 120. Reference 121. Reference 122. Reference 123. Reference 124. g h I j k l m n o Reference 125. Reference 126. Reference 127. Reference 128. Reference 129. Reference 130. Reference 131. Reference 132. Reference p q r s t u v 133. Reference 134. Reference 135. Reference 136. Reference 137. Reference 138. Reference 139. Reference 140. the hydrophobicity of the ligand end group. Another group of co-workers employed the diblock copolymer (polystyrene-b- polymers that was successfully employed for NP synthesis are poly(acrylic acid) ) to create patchy NPs, which could further the block copolymers. Piao et al. reported the synthesis of be regioselectively functionalized with thiolated oligonucleo- palladium NPs (Pd NPs) by simply mixing aqueous solutions tides. This strategy opens up new possibilities in the control of palladium salts and triblock Pluronic copolymers, (poly- of NP assembly and presents an excellent example on the (ethylene oxide)−poly(propylene oxide)−poly(ethylene importance of choosing the appropriate ligand for NP coating. oxide)) in which the particle size (5−27 nm) and shape was Overall, the use of polymers as ligands for in situ or post controlled by varying the pH of the reaction mixtures. Later, synthetic NP coating purposes is quite broad and only a similar pluronic copolymers were used to synthesize triple- representative cross-section is provided here. Clearly, choosing layered Au@Pd@Pt core−shell NPs (25−55 nm), which an existing or new polymer type for a given NP synthesis contained nanopores inside of a multilayered NP. Addi- requires consideration of prior art in the field along with what tionally, polymers have also used in NP surface pattern- material exactly is desired. 105−107 ing. While the creation of surface-patterned or “patchy” Biomolecules and Other Ligands for Plasmonic NPs. Although not as common as previously discussed ligands, microparticles has been efficiently achieved, this is not the case for small inorganic NPs. Choueiri et al. proposed to coat NPs biomolecules have been reported in the synthesis of plasmonic with a uniformly thick polymer brush, which upon reduction in NPs. Often it is their functional end group (e.g., amine, solvent quality breaks into smaller micelles forming the phosphine, carboxylate, or thiol) that has been used to bind to the NP surface. For example, the thiol containing biomolecule patches. The driving forces behind this process are on the one hand attractive polymer−polymer interactions, and on the GSH can be used to stabilize Au NPs. As such, Brinas et al. other hand, the competition between the polymer grafting developed a size-controllable synthesis of Au NPs (2−6 nm) constraints and interfacial free energy reduction. This allows capped with GSH by varying the pH (5.5−8.0). Then they for NP surface patterning by segregation of the polymer prepared nitriloacetate (NTA) functionalized Au NPs by ligands. The authors validate this approach using a variety of adding a mixed solution of lysine-NTA-SH and GSH to a different NPs and polymers (e.g., Au NPs and thiolated solution of hydrogen tetrachloroaurate (HAuCl ). On the polystyrene including block-copolymers). Such “patchy” other hand, some biomolecules can also be used to stabilize Au particles were furthermore able to assemble into controlled NPs electrostatically. For example, lysine (Lys) could electro- structures such as dimers, trimers, or chains and thus statically stabilize anisotropic star-shaped Au NPs ranging from demonstrated the programmability derived from the precise 30 to 100 nm during their growth from 17 nm citrate-seed Au 105 109 placement of the polymer patches. Chen and co-workers NPs. Arabic gum-stabilized Au NPs ranging from 90 nm to similarly employed polymer segregation to create versatile 4.6 μm in diameter could be produced by controlling the solution pH, while using ascorbic acid as the reducing agent. synthetic handles on nanorods, bypiramids, and triangular prisms. They showed that by selecting the right kind of By using proteins as ligand, even the shape of Ag NPs could be polymer, which protected particles from aggregation, but also tuned. Besides these, other biomolecules, have been studied possessed fluidity and adjustability, site selectivity in multistep in conjunction with Au NP synthesis. Another increasingly NP synthesis was possible. The utilization of a polymer, which popular route for creating Au NPs is through green chemistry retains its fluidity while being highly stable yet modifiable methods. For example, the addition of boiled broth of presents the most critical step in this approach. The authors lemongrass leaf (Cymbopogon flexuosus) to a HAuCl solution showed that polystyrene-block-poly(acrylic acid) ligands on Au was used to induce the reduction of AuCl and to yield a high NRs could be selectively transformed through heating into percentage of thin, flat, single-crystalline Au nanotriangles. desired patches coating only parts of the Au NRs and even Also, β-D-glucose was used to synthesize 5.3 nm Ag NPs in the forming helical patterns. On the other hand, Weizmann and aqueous phase under moderate thermal reduction (40 °C) 4827 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review with the glucose hydroxyl groups acting to passivate and 110 dye via carbodiimide-assisted covalent bonding and used stabilize the NPs. Similarly, other types of saccharides for cellular imaging. VSOP C184 is a 4 nm citrate-capped (glucose, galatose, maltose, and lactose) have been used for iron oxide NP system synthesized via an optimized synthesizing antimicrobial/bacterial Ag NPs in the range of coprecipitation process in the presence of excess citric acid 25−450 nm in water. and is currently being utilized in a clinical investigation as a For the preparation of hybrid materials, He et al. developed potent MRI contrast agent. Beyond just iron oxide NPs, Lu a one-pot synthetic method for graphene oxide/silver NP et al. used citric acid to synthesize Au/Fe NPs comprising an (GO/Ag NPs) using luminol (5-amino-2,3-dihydrophthala- Au shell with a magnetite/maghemite inclusion. zine-1,4-dione) in an aqueous/ethanol mixture at room Recently, citric acid was also used to develop a low energy temperature. Apart from acting as a reducing agent, excess hydrothermal-reduction route to synthesize aqueous ferrofluids luminol stabilizes the Ag NPs via the formation of a Ag−N of negatively charged ∼10 nm Zn Fe O and ∼80 nm Fe O x 3‑x 4 3 4 147,148 covalent bonding during synthesis. The resulting Ag NPs for magnetic hyperthermia studies. Similarly, PEGylated demonstrated an average size of 22 nm with a relatively iron oxide NPs have been prepared (Figure 5) for MR/optical uniform size on the surface of GO. This hybrid system was lymph node imaging. In this method, biocompatible PEG used for GSH sensing, where the GSH enhanced the served as a solvent, capping agent, and reducing agent. chemiluminescence intensity between the GO/Ag nano- composites and hydrogen peroxide. Another example used sorghum bran extract as both the reducing and capping agent at room temperature to produce highly crystalline Ag NPs of ∼10 nm. There is also a lot of current interest in the synthesis of ultrasmall metal NCs using biomolecules including nucleic acids and proteins; these are discussed separately in the fluorescent NP section (vide infra). For more detailed information on the topic of plasmonic NPs, we refer readers 118,119 to dedicated relevant reviews. Table 2 presents a representative overview of the most popular chemical methods and ligands to synthesize a variety of functionalized metal NPs in aqueous media. 2.1.2. Magnetic Nanoparticles. A common synthetic Figure 5. Schematic illustration of the synthesis of PEGylated iron method for preparing iron oxide NPs in the form of magnetite oxide NPs. Reprinted with permission from ref 149. Copyright 2014 or maghemite (Fe O or γ-Fe O , respectively) is a 3 4 2 3 Royal Society of Chemistry. coprecipitation by aging a stoichiometric mixture of ferrous and ferric salts in an aqueous medium. The surface iron atoms of the iron oxide NPs act as Lewis acids and coordinate with molecules that donate lone pairs of electrons. Therefore, Mixed ferrites can also be prepared by modified in aqueous solutions, the Fe atoms coordinate with water, coprecipitation routes in aqueous media. However, micro- which dissociates readily to leave the iron oxide surface emulsion methods have been used more commonly and have hydroxyl functionalized. Dependent upon the pH of the been extended for the synthesis of water-soluble magnetic NPs solution, the amphoteric surface hydroxyl group of the using a water-in-oil phase approach. The synthesis of 4.2 nm magnetite will present a positive or negative charge. The Ni NPs by the reduction of nickel chloride with hydrazine in a actual size, shape, and composition of such magnetic NPs cationic water-in-oil microemulsions of water/CTAB/n-hex- depend upon the type of salts used (e.g., chlorides, sulfates, anol at 73 °C has also been studied. Similarly, a water-in-oil nitrates). Other functional groups, including carboxylates, microemulsion system (aqueous FeCl /CTAB/n-octane) was hydroxy, phosphates, and sulfates are known to bind to the used to prepare positively charged γ-Fe O or magnetite NPs 2 3 surface of magnetites in the aqueous phase. Hydrophilic ranging in diameter from 3.5 to 9.7 nm. polymers and micelles can also stabilize magnetic NPs as Sun et al. reported the size-controlled synthesis of Fe O 3 4 8,9 well. For example, Lee et al. prepared ultrafine Fe O NPs coated with glucose and gluconic acid by using a sucrose 3 4 particles (4−7 nm) by precipitation in an aqueous poly(vinyl bifunctional hydrothermal method. Sucrose was used as the alcohol) (PVA) solution. However, when using PVA chemical reducing agent of Fe(III), as well as a capping agent containing 0.1 mol % carboxyl groups as the stabilizing to prepare colloidal iron oxide NPs ranging from 4 to 16 nm in agent, the magnetite NPs precipitated in the form of chainlike size. Driven by the growing desire for greener synthesis of NPs, clusters. a rapid synthesis of 17−25 nm Fe O using brown seaweed ( 3 4 Various other types of carboxylated ligands have also been Sargassum muticum) extract solution has been demonstrated. used for stabilizing magnetic NPs, such as citric acid, gluconic This approach relied on the sulfated polysaccharide from acid, dimercaptosuccinic acid, and phosphorylcholine. For seaweed to act as a reducing agent as well as surface stabilizing example, 2−8 nm maghemite NPs could be prepared by the template of the NPs. In a similar vein, ethylene glycol was thermal oxidation of iron(III) nitrate in an alkaline medium in used to synthesize 9.2 nm Ni NPs using a hydrazine reduction 143 155 the presence of trisodium citrate. Later, it was reported that in the aqueous phase. In a different approach water-soluble the surface of magnetite NPs can also be stabilized by the magnetite NPs were produced by thermal decomposition of adsorption of citric acid during coprecipitation of iron oxide, Fe(acac) in 2-pyrrolidone. The experimental results here leading to a stable aqueous dispersion. The 5−20 nm citric revealed that 2-pyrrolidone not only serves as a media for high- acid-stabilized NPs were further conjugated with rhodamine temperature reaction but also involves surface coordination, 4828 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review which imparts colloidal stability to the water-soluble magnetite NPs. 2.1.3. Luminescent Nanoparticles. Semiconductors. Henglein et al. pioneered the aqueous colloidal synthesis of semiconductor quantum dots (QDs), as well as other NPs, by using Cd(ClO ) and Na S in Ludox HS30 silicon sol 4 2 2 (colloidal silica, SiO ) and studied their catalysis of free radical 157,158 reactions in 1982. In the past few years, aqueous syntheses have been intensely studied and now yields stable binary II−VI and IV−VI NPs such as CdS, CdTe, CdSe, ZnSe, HgTe, PbS, and other alloyed particles of good quality, free from defect emission and large polydispersity in size. In general, the synthesis process involves the formation of metal− thiol complexes in water by adjusting the pH, and the injection of a chalcogenide source into the deaerated reaction solution. Figure 6. (a,b) mPEG-TGA and mPEG-SH molecules used for the This results in the formation of metal−chalcogenide synthesis of CdTe nanoparticles. (c) Photographs of vials showing the precursors. Then, heating of the solution induces the time-dependent triphase transfer of CdTe/mPEG-SH nanoparticles nucleation and NP growth process. from toluene to water to chloroform under daylight. Reprinted with Common ligands for the stabilization of QDs in aqueous permission from ref 167. Copyright 2009 American Chemical Society. syntheses have been short alkyl chain thiols and phosphates. For example, CdTe and ZnTe NPs could be obtained directly developed by Shavel et al., who used thioglycerol, thioglycolic in water in the presence of hexametaphosphate. Similarly a acid, or 3-mercaptopropionic acid as stabilizers with a mixture of hexametaphosphate and mercapto propanediol, postpreparative treatment (irradiation with white light) leading as well as mercaptoethanol and thiolglycerol have been used to the formation of alloyed ZnSe(S) NPs with improved QYs successfully. Rogach and co-workers optimized the process up to 30%. GSH-capped ZnSe and Zn Cd Se alloyed 3−4 1−x x to obtain strongly photoluminescent CdTe NPs with nm QDs with tunable fluorescence between 360 and 500 nm, thioglycolic acid (18% quantum yield), and they revealed narrow bandwidths (19−32 nm), and QYs up to 50% have also a state-of-the-art preparation of visible to NIR (500−800 nm) been reported. Unfortunately, conditions for such aqueous emitting CdTe NPs with high quantum yields (QY ∼ 40− synthesis do not permit size tuning of ZnSe NP materials over 60%), coated with thioglycolic acid. a wide range, thereby limiting their luminescence to a very Similar to metallic NPs, GSH could also be utilized in the narrow path, typically 350−400 nm, which conversely drives synthesis of CdTe QDs resulting in GSH-capped QDs with the demand for alloyed ZnSe QDs. Incorporation of Cd into QYs as high as 45%, without any postsynthetic treatment. It GSH-stabilized ZnSe QDs helps to shift the photolumines- was further shown that peptides could be conjugated to them cence to longer wavelengths from 360 to 500 nm. Overall, for subsequent use in cells. Recently Zhou et al. published a the employment of a variety of ligands for the synthesis of high simple method to synthesize CdTe QDs, in which QDs were quality QDs in water has certainly matured as is evident from synthesized by stepwise addition of water, CdCl , thiol, their robust QYs, which now rival those obtained for QDs Na TeO , NaBH , and hydrazine. This method allowed synthesized in organic solvents. 2 3 4 the easy functionalization of the QDs with short thiol ligands Metal Nanoclusters. Many different types of ligands such as such as thioglycolic acid, mercaptopropionic acid, thioglycerol, dendrimers, thiols, peptides, etc., have been used so far to mercaptoethylamine, GSH, and L-cysteine, as well as create fluorescent metal NCs. Zheng et al. described the mercaptobenzoic acid, per-6-thio-α-cyclodextrin, and per-7- formation of size-tunable Au nanoclusters (Au NCs) that are thio-β-cyclodextrin. readily synthesized through the slow reduction of AuCl or Among different polymers, thiolated PEG has also been AuBr within aqueous polyamidoamine (PAMAM) solutions employed in the synthesis of CdTe QDs in both water and dendrimer solutions; the latter were used because they can be organic solvents (see Figure 6). Furthermore, Ning et al. obtained with well-defined sizes and serve to encapsulate the reported the fabrication of water-dispersible NP−amphiphilic nascent NC. Both the Au:PAMAM ratio as well as the copolymer composite microspheres, in which the mercapto- dendrimer generation of PAMAM allowed for optimization propionic acid-stabilized CdTe QDs were encapsulated by and tuning of the NC emission color. It was found that these dimethyl dioctadecyl ammonium bromide in chloroform and NCs showed orders of magnitude higher QYs compared to then transferred back into water by making a QD−polymer other NCs, which implied that amines play an important role composite with poly(ethylene glycol) diglycidyl-grafted poly- in Au NC formation. Later, water-soluble platinum nano- (maleic anhydride-alt-octadecene). Hybrid SiO −CdTe clusters (Pt NCs) were also grown by using PAMAM (G4- NPs have also been obtained where thioglycolic acid-stabilized OH). These Pt NCs showed decreased cytotoxicity and 2.6 nm green-emissive CdTe QDs were refluxed in the emitted more intensely at 470 nm in comparison to Au 2+ presence of Cd , thioglycolic acid, tetraethyl orthosilicate, and NCs. NH . The as-prepared hybrid SiO −CdTe NPs showed a In a different protocol, 1.1−1.7 nm diameter Au NPs with 3 2 red-shift in photoluminescence and changes in QY from 20 to size dependent fluorescent switching and quantum yields (QY) 55%. of ∼3% were prepared by using aqueous pentaerythryl Zn-based QDs have attracted scientific interest due to tetrakis(3-mercaptopropionate)-terminated polymethacrylic concerns about Cd toxicity and the amount of heavy metal acid. NIR fluorescent dihydrolipoic acid (DHLA) stabilized pollutants released into the environment. A successful aqueous Au NPs were recently prepared using a one-pot synthesis 175,176 synthesis of strong UV-blue emissive 2−3 nm ZnSe NPs was (Figure 7a). Although the particles were highly soluble in 4829 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 7. (a) Representative cartoon structure of Au@DHLA nanoparticles. Right side: b and b show the corresponding photographs of the 1 2 cluster under visible and UV light, respectively. Reprinted with permission from ref 176. Copyright 2009 American Chemical Society. (c) Scheme of the highly fluorescent Au@BSA NC synthesis. Inset shows the photograph of corresponding nanocluster under UV light. Reprinted with permission from ref 179. Copyright 2009 American Chemical Society. (d) TEM images of metal-doped Au NCs with TA-PEG ligand. Reprinted with permission from ref 135. Copyright 2016 American Chemical Society. water, they had relatively low QYs of 0.6−1.8%. Similar QY (0.04−0.3%). GSH has also been used in the synthesis approaches have been used to also synthesize Ag nanoclusters of highly fluorescent Pt NCs by using an etching approach. (Ag NCs). Oh et al. synthesized near-infrared emissive Au These NCs began in the Pt(I) oxidation state (90%) exhibiting NPs with bidentate TA-PEG (TA: thioctic acid, lipoic acid) an intense fluorescence in the yellow region (QY ∼ 17%, ligands in water that had higher QYs of 4−8%, and a variety of emission maximum at 570 nm), and etching with GSH led to terminal functional groups (amine, carboxyl, azide, and the formation of blue-emitting species over long periods of methoxy) available for further conjugation to biomolecules. time. Other biomolecules such as nucleic acids and proteins They demonstrated that these NCs were suitable for biological have also been used in the synthesis of NCs. For example Patel applications including cell-penetrating peptide-driven cellular et al. synthesized water-soluble 2.3 nm Ag NCs exhibiting uptake along with one- and two-photon cellular imaging. strong two-photon-induced fluorescence ranging from 660− They also synthesized metal-doped luminescent Au NCs and 710 nm by using 12-mer nucleic acids, while Sharma et al. modulated their emission from 670 to 820 nm by changing the reported the synthesis and photophysical properties of Ag NCs ratio of dopant (varied ratio (1−98%) with Ag and 2% of Pt, templated on DNA, with fluorescence excitation and emission at distinct wavelengths that are tuned to common laser Cu, Zn, and Cd) added (Figure 7c). Biomolecules have also been used for the fabrication of excitation wavelengths. The use of proteins for stabilizing metal NCs. For example, GSH-protected Au NCs were metal NCs was also demonstrated in the form of bovine serum synthesized in a water and methanol mixture by Link et al. albumin (BSA) stabilized Au NCs (Figure 7b), which showed However, these NCs were polydispersed and displayed a low relative high QYs of ∼6% in water with a red emission centered 4830 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review 4831 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Table 3. Plasmonic NPs Synthesized in Organic Media material precursors and reagents ligand/surfactant size (nm) shape solvent other comments Au AuCl /NaBH dodecanethiol 1−3 sp biphase 4 4 (water/toluene) Au AuCl /NaBH dodecylamine, 2.5−7 sp biphase 4 4 oleylamine (water/toluene) Au, Pt, Ag AuCl /THPC (NaBH for Ag, Pt) dodecanethiol 1−10 sp biphase THPC = tetrakis(hydroxymethyl)phosphonium 4 4 (hydrosol/toluene) chloride Au HAuCl PVP 30 sp formamide Au AuCl /NaBH TOPO, octadecylamine 8.6 sp TOPO octadecylamine yields spherical particles 4 4 (4-tert-butylpyridine) Au Au vapor dodecanethiol 4.5 sp acetone and multistep procedure, SMAD = solvated metal atom toluene/SMAD dispersion technique Ag AgNO /NaBH TOPO/octadecylamine bimodal distribution (2−3nm sp 4-tert-butylpyridine TOPO and alkyl phosphines required for controlled 3 4 and 10−15 nm) growth, amine dominant ligand Ag AgNO PVP cubic ethylene glycol/polyol conditions control shape and size process Ag, Au, Cu, Pt AuCl , hydrazine or TBA-borohydride dodecylamine, decanoic 1−15 sp toluene with single phase approach in toluene with ammonium acid surfactants surfactants Ag Ag myristate myristate 4.4 sp tertiary alkylamine solvent (NEt3) Ag AgNO PVP polyhedral pentanediol/polyol controlled synthesis of uniform polyhedral shapes and process sizes Ag Ag-phosphine complex OLA 8−20 sp o-dichlorobenzene CuS Cu(acac) , ammonium OA, 1-dodecanethiol 2−6 hexagonal OA, 1-dodecanethiol diethyldithiocarbamate faceted Cu Se CuCl, Se OLA 16 cuboctahedral ODE phosphine-free synthesis 2−x Cu In S Cu(acac) , In(acac) , TMS S hexadecyl-amine 4−5.6 sp octadecene, TOPO potential ligands: dodecylphosphonic acid, TOPO x y 2 2 3 2 Cu S and CuCl, S , Se OLA, OA 2.8−13.5 (Cu S) and 7.2− sp OLA, OA strong tunable NIR localized surface plasmon 2−x 8 2−x Cu Se 16.5 (Cu Se) resonance 2−x 2−x acac, acetylacetonate; ODE, octadecene; OA, oleic acid; OLA, oleylamine; PVP, polyvinylpyrrolidone; sp, sphere; TOPO, trioctylphosphine oxide; TMS, trimethylsilyl. Chemical Reviews Review Figure 8. Representative electron microscopy images of (a) truncated Ag nanocubes, (b) Cu I S QDs), (c) Cu Se nanoparticles, (d) Cu S x y 2 2−x 2−x QDs, (e) time-dependent evolution of Cu Se nanoparticles and nanodisks and (f) CuTe NPs. (a) Reprinted with permission from ref 194. 2−x Copyright 2002 Science. (b) Reprinted with permission from ref 196. Copyright 2012 American Chemical Society. (c) Reprinted with permission from ref 197. Copyright 2010 American Chemical Society. (d) Reprinted with permission from ref 198. Copyright 2011 Springer Nature. (e) Reprinted with permission from ref 199. Copyright 2013 Wiley. (f) Reprinted with permission from ref 200. Copyright 2013 American Chemical Society. 179 185,186 at ∼640 nm. Although the QY of noble metal clusters of Au and other noble metal NPs. A similar two phase synthesized in aqueous media is not quite at the same level as method was also developed to synthesize alkylamine-capped that of QDs, NCs remain very promising materials due to their Au NPs. small size and better biocompatibility as well as access to red- Han et al. demonstrated a nonaqueous route to synthesize shifted emissions within the NIR tissue transparency window. Au colloids coated with PVP by the chemical reduction of Because it is believed that their emission arises from a complex HAuCl in oxygen-free formamide. Here, the solvent acted metal-to-ligand charge transfer process, the ability to improve as the reducing agent in oxygen-free conditions at room their quantum yields will be directly correlated to the choice of temperature, yielding ∼30 nm diameter NPs. Inspired by the ligand used during synthesis. Thus, further research toward high-temperature colloidal synthesis of semiconductor NPs in increasing their QY with different ligand types can be expected tri-n-octylphosphine oxide (TOPO), which is detailed in in the near future. section 2.2.3, a one phase synthesis of Au NPs capped with organic ligands was developed. When the reduction of gold 2.2. Ligand Coating on Nanoparticles Synthesized in Organic Media chloride was carried out at 190 °C in TOPO, uncontrolled growth of the NPs was observed with a variety of shapes and In the organic solvents, it is usually feasible to synthesize NPs sizes (10−100 nm) being formed. Addition of octadecylamine of a narrow size distribution and crystal uniformity because of yielded spherical Au NPs with a diameter of ∼8.6 nm, the higher temperatures which can be achieved often involved highlighting the importance of ligands in the nucleation and during synthesis. The ligands are usually introduced prior to growth of NPs. Infrared spectroscopy showed the presence of the formation of the NPs and in many cases their roles are both TOPO and octadecylamine on the surface of Au NPs as multiple acting as solvents, forming complexes with metals to dispersed in organic solvents. This synthesis was later adapted generate the active species for NP nucleation and stabilizing to prepare plasmonic Ag NPs from silver(I) nitrate. TOPO the NPs by surface binding. A common characteristic of these alone was found to bind weakly to the silver surface and was ligands is that often they do not decompose at the elevated insufficient at providing stable colloids despite providing temperatures necessary for the NP nucleation and growth. controlled growth. On the other hand, octadecylamine was Postsynthesis functionalization by ligand exchange is also critical in this approach for providing stable colloids due to the feasible in organic media, and in most cases it is conducted at strong amine−silver interaction at the NP surface. elevated temperatures. Other alkylamines have also been used to stabilize Ag NPs in 2.2.1. Plasmonic Nanoparticles. One pioneering general organic-phase syntheses, including dodecylamine and oleyl- approach to synthesize relatively monodispersed Au NPs in amine. Jana et al. utilized dodecylamine as a stabilizing organic solvents known as the Brust−Schiffrin method is based ligand employing two reducing agents, hydrazine and on a two-phase surfactant-mediated approach. In this seminal tetrabutylammonium borohydride, to control the plasmonic methodology, Brust et al. introduced a procedure to transfer particle growth in toluene. Oleylamine has also been Au ions from the aqueous solution to toluene using the phase- employed not only as the reductant for a silver−phosphine transfer agent tetraoctylammonium bromide (TOAB). Then complex in ortho-dichlorobenzene, but also as a ligand to the gold ions were reduced by NaBH to form NPs that were stabilized by dodecanethiol, yielding organic soluble Au stabilize the resulting Ag NPs. In addition to amines, fatty 25 191 colloids. Dodecanethiol has also been used in the syntheses acids such as decanoic acid can act as stabilizers to 4832 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review synthesize Ag, Au, and other plasmonic NPs in organic media. primarily on broadly used NPs of cobalt, iron oxides, and For example, Yamamoto et al. described a one-pot process to iron−platinum as representative examples. Cobalt NPs (ε-Co) synthesize 4.4 nm Ag NPs via thermal decomposition of a have been prepared via the reduction of cobalt chloride in silver myristate-amine (1:2) at 80 °C. The fatty acid alkyl dioctylether at 200 °C. The NP growth was controlled by chain length determined the particle size and provided oleic acid and trialkylphosphines used in the reaction mixture, colloidal stability. The longer carbon chain length, with slower which also provided colloidal stability to the resulting NPs and diffusion, stearic acid resulted in the synthesis of smaller limited their oxidation. This procedure produced Co NPs from particles with a narrower size distribution, while the shorter 2 to 11 nm, where the size was predominantly controlled by carbon chain octanoic acid, with faster diffusion, yielded larger the use of trialkylphosphine. The use of the shorter particles with broader size distributions. Polyvinylpyrrolidone tributylphosphine as a synthetic ligand yielded larger particles, (PVP) has also been used to stabilize silver NPs synthesized while employment of the longer trioctylphosphine conversely using the polyol process, where silver nitrate is reduced in yielded smaller particles. Co NPs were also prepared by ethylene glycol in the presence of PVP. Depending on the thermal decomposition of octacarbonyl dicobalt [Co (CO) ] 2 8 experimental conditions nanocubes, nanowires, multiply in toluene and TOPO. The phase of cobalt formed was shown to be dependent on the amount of TOPO present in twinned particles, and other irregular shapes could be obtained. the reaction mixture. Adding oleic acid to the decomposition This method was further adapted to obtain Ag NPs with of Co (CO) in ortho-dichlorobenzene and TOPO provided a polyhedral shapes. Clearly there is a complex interplay of 2 8 means to control the size and shape of the Co NPs. In fact, processes at work within these types of syntheses. It is probable these conditions created Co nanodisks that were later prepared that a deep understanding of the underlying chemistry could in higher yields by adding alkylamines to the reaction lead to “plug-and-play” recipes for almost any desired noble mixture. See Figure 9 for some representative materials. metal NP shape. Currently, there is a rapidly growing field of research on nonmetallic nanomaterials that exhibit localized surface plasmon resonance (LSPR) where the ligands play critical roles both in NP synthesis and colloidal NP robustness. There are several methods to obtain these materials, and we focus on those prepared directly by colloidal synthesis in a one-step approach. Niezgoda et al. described the colloidal synthesis of Cu In S NPs exhibiting a LSPR in the infrared using TOPO, x y dodecylphosphonic acid, and hexadecylamine. The ratio of TOPO and hexadecylamine influenced the surface energy of the different crystallographic facets and determined whether spherical or rod-shaped NPs are formed. In another study, a phosphine-free synthesis of Cu Se NPs with a NIR LSPR 2−x utilized oleylamine as both the reductant and the stabilizing Figure 9. TEM images of (a) Co nanodisks, (b) Co nanowires prepared with oleic acid and oleylamine, and (c) high resolution ligand. However, byproducts were also formed and NP size image of γ-Fe O nanocrystals and corresponding energy filtered control was not explored. In contrast, control over Cu SNP 2 3 2−x images showing the distribution of Fe and O. (a) Adapted with size was achieved using 1-dodecanethiol and oleic acid. Liu permission from ref 204. Copyright 2002 American Chemical Society. et al. developed a protocol to make Cu E (E = S, Se) NPs, 2−x (b) Adapted with permission from ref 205. Copyright 2002 Wiley. (c) where the oleylamine and oleic acid ligands influenced the Reprinted with permission from ref 208. Copyright 2009 American resulting NP size and cation deficiency through a complex Chemical Society. interplay of reaction time and ligand preference for crystal phase. Furthermore, they also reported on the synthesis of CuTe NPs with different morphologies by reacting a copper Fatty acids (e.g., hexadecylamine and oleic acid) and salt with trioctylphosphine telluride in the presence of lithium alkylamines were used to synthesize Co NRs and nanowires 200 205,206 3 4 bis(trimethylsilyl)amide and oleylamine. from [Co(η -C H )(η -C H )] in anisole at 150 °C. 8 13 8 12 Table 3 concentrates some representative literature for a These examples serve to highlight the variety of ligands used to variety of plasmonic NPs synthesized in organic media and the stabilize NPs from agglomeration and also how they can ligands used in each case to highlight the diversity that is impact the resulting NP shape and crystal phase. achievable and Figure 8 shows some representative electron Magnetic iron oxide NPs can be made via formation of iron 207,208 microscopy images of these materials. particles that are subsequently oxidized or directly from Overall, the syntheses of organic-dispersible plasmonic NPs cationic metal complexes. As such, γ-Fe O NPs could be 2 3 is more established than water-based approaches providing for prepared from the thermal decomposition of an iron cupferon control over the size, shape, composition, and energy of the complex (FeCup ) in octylamine/trioctylamine at 300 °C. plasmonic feature. This is mainly due to the elevated This procedure provided particle sizes from 4 to 10 nm that temperatures used for NP formation in organic solvents, required postsynthetic size selective processing, yielding which allow further manipulation of NP nucleation and materials that were stable for weeks at RT. Using Fe(acac) , growth. However, especially for the case of Au and Ag NPs, the synthesis of Fe O NPs in the presence of phenyl ether, 3 4 aqueous approaches provide a broader scope for the synthesis 1,2-hexadecanediol, oleic acid, and oleylamine at 265 °C of a plethora of different shapes and sizes. without a size-selection procedure was possible. The larger 2.2.2. Magnetic Nanoparticles. While magnetic NPs NPs were prepared using the seed-mediated method with oleic with varying compositions have been synthesized in organic acid and oleylamine as stabilizers in addition to stearyl alcohol. media using a wide variety of ligand types, here we focus Contrastingly, Fe O NPs could be prepared from the pyrolysis 3 4 4833 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 4. Magnetic NPs Synthesized in Organic Media size material precursors and reagents ligand/surfactant (nm) shape solvent other comments Co CoCl , superhydride OA, 2−11 sp dioctylether particle size tuned by trialkylphosphines phosphine R groups Fe, Mn, Co oxides M-cupferron alkylamines 4−10 sp trioctylamine (approx) Co Co (CO) TOPO 20 ap toluene phase control with phosphine 2 8 FePt Pt(acac) and Fe(CO) OA, OLA 3−10 sp dioctylether modified polyol 2 5 Fe O Fe(CO) OA 4−16 sp octylether 2 3 5 [trimethylamine oxide] Co Co (CO) alkylamines, disk and o-dichlorobenzene, amines give higher yields of 2 8 TOPO, OA sp alkylamines, TOPO, OA disks Fe O Fe(acac) OA, OLA 4−20 sp phenyl ether, hexadecanediol 3 4 3 Co Co(n-C H )(n-C H ) hexadecylamine, rods anisole acids control aspect ratio of 8 13 8 12 fatty acids rods FePt Fe(acac) , Pt(acac) OA, OLA 2 sp dioctylether 3 2 (approx) Fe O iron-oleate OA 5−22 sp ODE large scale synthesis 3 4 acac, acetylacetonate; ODE, octadecene; OA, oleic acid; OLA, oleylamine; sp, sphere; TOPO, trioctylphosphine oxide; TMS, trimethylsilyl. of metal fatty acid salts (such as lauric, myristic, palmitic, Moreover, NPs of different sizes will likely have different ratios stearic, and oleic acids) in noncoordinating hydrocarbon and densities of surfactants on their surfaces. It is also worth solvents (such as octadecene, tetracosane, and n-eicosane). noting that one repeated theme across many, but not all, ligand In addition to reaction time, the concentration and size of the types is that the ligand size tends to correlate inversely with the stabilizing fatty acid ligands influenced the resulting NP size NP size obtained. and shape. Park et al. developed an experimental protocol for 2.2.3. Luminescent Nanoparticles. As for other types of the large scale synthesis of monodisperse iron oxide NPs from NPs, the size and morphology of colloidal QDs, and therefore inexpensive and nontoxic metal-oleate precursors in octade- their properties (in this case optoelectronic properties), cene and oleic acid. Recent work showed that iron oxide depend on the ligands employed for NP synthesis, which NPs could be converted into nanoclusters by replacing the influence nucleation, growth, and colloidal stabilization of the original oleic acid ligand coating with a “stripping ligand” such QDs. These ligands usually include an alkyl chain to provide as diethylene glycol (DEG), which functions to remove all of solubility in organic solvents, and an anchoring headgroup, the oleic acid from the surface. Nanoclusters made of iron which controls the binding strength and adsorption/ oxide multiple subunits arranged in a controlled topological desorption kinetics on the QD surface. On the basis of the 214−219 fashion have been also formed by utilizing polymers or binding fashion, the common surface ligands can be generally 220,221 227−229 categorized as either X-type or L-type ligands. X-type dendrimers as capping ligands. Iron alloys are also a large subset of magnetic NPs, including ligands donate one electron to the metal−ligand bond, L-type iron−platinum (FePt). In a polyol-based process, FePt NPs ligands donate two electrons to metal and Z-type ligands could be prepared from the reduction of Pt(acac) with 1,2- accept two electrons from the metal. Alkyl phosphonates, hexadecanediol and the thermal decomposition of Fe(CO) in phosphinates, carboxylates, and thiolates are considered X- dioctylether using oleic acid and oleylamine as stabilizing Type ligands while the most common L-type ligands often ligands. This synthesis allowed for NP size tuneability from used in QD synthesis are TOPO, trioctylphosphine (TOP), 230−232 3 to 10 nm with less than 5% standard deviation. Fe(CO) and alkylamine. could be replaced with the less hazardous Fe(acac) or Bawendi et al. first developed the synthesis of colloidal Fe(acac) to provide FePt NPs using a similar procedures. semiconductor QDs in organic solvents by reporting a hot The inorganic reducing agent superhydride (LiBEt H) has also injection method to synthesize a series of cadmium been employed to prepare FePt NPs from FeCl and Pt(acac) chalcogenide QDs (CdS, CdSe, and CdTe). Cadmium 2 2 in phenyl ether. Oleic acid and oleylamine were utilized to and chalcogenide precursors dissolved in TOP were swiftly stabilize the resulting 4 nm FePt NPs through preferential injected to TOPO at high temperature (∼300 °C). TOP and binging of the amine with platinum and the carboxylate groups TOPO were used as high boiling point coordinating solvents, with iron. Costanzo et al. also synthesized Co NPs with various ensuring colloidal stability and controlling the core growth diameters and uniform surfactant capping by regulating the kinetics. This work set the foundations for a broader use of solvation of the ligands. TOP/TOPO as solvents to synthesize various types of QDs, Table 4 compiles examples of ligands used in the synthesis although there are still questions related to role of impurities of various types of magnetic NPs, and Figure 9 shows some within these ligands. representative TEM images of magnetic NPs. The controlled Peng et al. demonstrated that the toxic and pyrophoric growth of magnetic NPs (and others) of different sizes requires precursor Cd(CH ) could be stabilized by alkylphosphonic 3 2 a balance between surfactants that will allow the NPs to grow acid, which is one of the major impurities in technical grade 235,236 and surfactants that bind strongly to the surface for providing TOPO. Theair stableCd−alkylphosphonic acid colloidal stability. This becomes more complicated when complexes successfully replaced Cd(CH ) to synthesize high 3 2 synthesizing bimetallic or metal oxide NPs such as FePt, quality CdSe QDs. Since then, the capability to synthesize Fe O , and Fe O because two different atoms are present on high-quality QDs with a variety of reagents and conditions has 2 3 3 4 the NP surface versus, for example, single component Co NPs. expanded tremendously. In depth analytical studies of the 4834 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review ligands present on the QD surface after synthesis have helped Upconversion NPs (UCNPs) are typically lanthanide-doped to provide key insight into their roles. P nuclear magnetic inorganic NPs, which convert a lower energy excitation light 250−256 resonance (NMR) studies of CdSe QDs synthesized using into a higher energy luminescence. Their unique technical grade TOPO revealed that the major ligands on the properties including sharp emission band, large Stokes shift, and high photochemical stability have made UCNPs attractive CdSe QDs’ surface were n-octylphosphonic acid (OPA) and as novel luminescent materials. While a variety of synthetic P,P′-(di-n-octyl)dihydrogen pyrophosphonic acid (PPA), methods have been demonstrated for preparing UCNPs, one which was formed via dehydrative condensation of OPA of the most successful approaches for monodispersed high- during the QD synthesis. Interestingly, the ligand displace- quality UCNPs coated with hydrophobic ligands is the thermal ment experiment also suggested that TOPO was completely 3+ decomposition method. In particular, NaYF doped with Yb / excluded from binding to the CdSe QD surface. A series of 4 3+ 3+ 3+ Er (or Yb /Tm ) have been recognized as one of the most NMR studies of CdSe QDs synthesized in the presence of efficient UCNPs and their synthetic methods through thermal octadecylphosphonic acid (ODPA), TOP, and TOPO were decomposition have been well explored. The NaYF -based carried out and the results indicated that the QD ligand shell UCNPs are typically synthesized with sodium trifluoroacetate consisted of 55% of ODPA and 45% of octadecylphosphonic and lanthanide trifluoroacetate in a mixture of ODE and oleic anhydride. NMR studies of CdTe QDs synthesized in the 257−261 acid (and oleylamine) at ∼300 °C or higher. Under presence of tetradecylphosphonic acid and oleylamine revealed these conditions the surface ligands are most likely oleic acid that the QD surface is covered by 90% of tetradecylphosphonic and/or oleylamine. TOPO (90%) was also used for NaYF - anhydride and 10% of oleylamine. based UCNP synthesis instead of oleic acid and oleylamine. Dialkylphosphinic acid is also one of the impurities in The latterNaYF -based UCNPs have smaller size with narrow technical grade TOPO and has been used to prepare the size distribution and higher upconversion luminescence metal precursors and control the NP core growth kinetics. A efficiency compared with the ones prepared with oleic acid series of fatty acids were also used as the surface ligands of Cd and oleylamine. Another facile route to prepare small and chalcogenide QDs. Fatty acids were introduced as the ligands monodispersed UCNPs is use of the coprecipitation method, coordinated to the metal precursors and controlled the core 241,242 which usually uses oleic acid as a capping ligand in growth kinetics during the NP synthesis. In parallel, NP 263−265 ODE. While metal oleates are used as lanthanide synthesis in noncoordinating solvents has also been developed precursors, NaOH and NH F in methanol have successfully such as the use of fatty acids including oleic acid and stearic worked as sodium and fluoride sources, respectively. acid. The benefit of using noncoordinating solvents for NP Recently, silicon (Si) NPs have attracted much attention as synthesis is that the precursor reactivity can be simply tuned by nanoscale emitters because silicon is abundant on earth and the type of coordinating ligand and the ligand concentration. 1- regarded as less toxic compared to the other conventional Octadecene (ODE) has been commonly used as a non- 266−274 semiconductor materials. Si NPs are typically synthe- coordinating solvent, primarily due to its low melting point sized by either etching of bulk silicon (top-down approach) or (∼15 °C) and high boiling point (∼315 °C). In a chemical reaction of silicon precursors (bottom-up approach). representative example of its versatility, Mulvaney et al. used The as-prepared Si NPs normally have either hydrogen- or a binary ligand system (bis(2,2,4-trimethylpentyl)phosphinic halide-terminated surfaces, which have to be further modified acid and oleic acid) in ODE to tune the nucleation and growth to ensure good colloidal stability in organic media. In contrast of CdSe QDs, and successfully synthesized QDs with different to conventional metal chalcogenide QDs, surface modification size range. of Si NPs requires the formation of covalent bonds between While we primarily focus on cadmium chalcogenide QDs, surface silicon atoms and carbon, nitrogen, or oxygen atoms. due to their popularity and the better understanding of their The Si−H surface bond can be modified by hydrosilylation properties, surface ligands on some other common QDs need with organic molecules functionalized with a carbon−carbon to be briefly addressed. High quality ZnSe QDs are typically double bond or triple bond end group in order to produce 244−246 synthesized by conventional hot injection methods such both hydrophobic and hydrophilic surface types. The Si-X (X as the decomposition of pyrophoric ZnEt and TOP:Se in alkyl = Cl or Br) surface bond can be replaced with a Grignard amine or the decomposition of air stable zinc stearate and reagent or alkyl lithium to form the alkyl-terminated surfaces. TOP:Se in octadecane. These reaction conditions indicate Similar surface modification strategies can be used to prepare that either the alkyl amine or alkyl carboxylate coordinates the hydrophilic surfaces using organic molecules with polar ZnSe QD surface and maintains colloidal stability. NMR functional groups including hydroxy, amino, and carboxyl studies of PbS QDs synthesized using PbCl and elemental 2 groups. sulfur in the presence of oleylamine and TOP revealed that the Recently perovskite nanocrystals of the CH NH PbX or 3 3 3 QD surface was solely passivated by oleylamine. The CsPbX (X = Cl, Br, I) type have received increased attention oleylamine ligands exhibited fast adsorption/desorption due to their sharp emission peaks and narrow band widths, behavior and were easily replaced by oleic acid. PbSe QDs high photoluminescence quantum yields, and emission color synthesized using Pb(OAc) and TOP:Se in the presence of tunability. As such they have found widespread optoelec- oleic acid were also studied in a similar fashion. Here, it was tronic applications, especially in light emitting devices (LEDs), found that the QD surface is composed of Pb atoms and which will be discussed later. The synthesis of organic− primarily coated by oleic acid with only 0−5% of TOP. Hens inorganic MAPbX perovskite nanoparticles relies on the et al. also synthesized CuInS QDs in the presence of amine reaction of a lead halide salt (PbX , X = Cl, Br, I) with ligands (1-octadecylamine or oleylamine). Their NMR methylammonium bromide and long or medium alkyl chain studies revealed that as-synthesized CuInS QDs have ammonium cations such as octylammonium bromide or charge-neutral QD surfaces, which are stabilized by L-type octadecylammonium bromide, which serve as the capping 277−279 amine ligands. ligands. On the other hand, all inorganic perovskite 4835 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review 4836 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Table 5. Representative Luminescent NPs Synthesized in Organic Media material precursors and reagents ligand/surfactant size (nm) shape solvent other comments ZnSe ZnEt , TOP:Se HDA, TOP sphere (sp) HDA, TOP ZnSe Zn stearate, TOP:Se stearic acid, TOP sp ODE ZnSe Zn stearate, TBP:Se stearic acid, ODA, TOP sp tetracosane, ODE ZnTe ZnEt , TOP:Te ODA, TOP 4.5 sp ODA, TOP ZnTe Zn(OAc) , TOP:Te, superhydride OA, TOP ∼5 sp benzyl ether CdS CdMe , (TMS) S TOP, TOPO sp TOP, TOPO 2 2 CdS CdO, S OA 2.0−5.3 sp ODE CdSe CdMe , TOP:Se or (TMS) Se TOP, TOPO 1.2−11.5 sp TOP, TOPO 2 2 CdSe CdO, TBP:Se TOPO, HPA (or TDPA) TOPO CdSe Cd(OAc) , TOP:Se TOP, TOPO, HDA, TDPA TOP, TOPO, HDA CdSe Cd(acac) , TOP:Se TOP, TOPO, HDA, HDDO sp TOP, TOPO, HDA CdSe Cd(acac) , TOP:Se TOP, TOPO, HDA, HDDO, HPA sp TOP, TOPO, HDA CdSe CdO, TOP:Se TMPPA, OA ∼1.8−5.6 sp ODE CdSe CdO, Se myristic acid ∼2−4.5 sp ODE heat-up method CdSe CdO, Se myristic acid ∼2.6−3.1 sp ODE heterogeneous ODE-Se precursor was injected. CdTe CdMe , TOP:Te or (BDMS) Te TOP/TOPO sp TOP, TOPO 2 2 CdTe CdO, TBP:Te OA (or ODPA, TDPA), TBP ∼2−11 sp ODE InP In(OAc) , (TMS) P myristic acid, 1-octylamine sp ODE 3 3 InP InCl , Zn undecylenate, (TMS) P stearic acid, HDA sp ODE 3 3 InP InCl , ZnCl , P(NMe ) OLA sp OLA 3 2 2 3 InAs InCl , (TMS) As TOP 2.3−6 sp TOP 3 3 InAs In stearate, (TMS) As stearic acid, TOP sp ODE PbS PbO, (TMS) S OA sp ODE PbS PbCl , S OLA sp OLA PbS Pb(OAc) , (TMS) S OA, TOP sp ODE 2 2 PbS PbCl , S OLA, TOP 3−10 sp OLA PbSe Pb oleate, TOP:Se OA, TOP 3.5−15 sp diphenyl ether PbSe PbO, TOP:Se OA, TOP 3−13 sp ODE CuInS CuI, InI , S TOP, OLA ODE 2 3 CuInS Cu(acac) , In(acac) , S OLA 6−12 sp o-dichlorobenzene 2 2 3 CuInS Cu(OAc), In(OAc) , DDT DDT 2−5 sp ODE 2 3 CuInS CuI, In(OAc) , DDT DDT sp ODE 2 3 CuInS CuI, In(OAc) , DDT OA, DDT 3.5−7.3 pyramidal ODE 2 3 CuInS CuI, In(OAc) , DDT DDT ∼2.2−3.8 tetrahedral DDT 2 3 Ag S Ag(DDTC) OA, ODA 10.2−40.1 sp ODE Ag S Ag(OAc), (TMS) S, S myristic acid, 1-octylamine 1.5−4.6 sp ODE 2 2 Ag S AgCl, (NH ) S OLA, TOP 2.1−2.8 sp OLA, TOP 2 4 2 Ag S DDT-functionalized AgNPs, TBBT DDT, TBBT 1.7 sp toluene photochemical reaction 3+ 3+ 3+ 258 NaYF :Yb ,Er (or Tm ) Na(CF COO), RE(CF COO) OA, OLA (1) ∼11−14 (1) polyhedra ODE RE: rare earth metal 4 3 3 3 (2) hexagonal plate (2) 187 × 71, 100 × 51 3+ 3+ 3+ 257 NaYF :Yb ,Er (or Tm ) Na(CF COO), RE(CF COO) OA 10−50 sp ODE 4 3 3 3 Chemical Reviews Review 4837 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Table 5. continued material precursors and reagents ligand/surfactant size (nm) shape solvent other comments 3+ 3+ NaYF :Yb ,Er (or Na(CF COO), RE(CF COO) TOPO, OLA, OA 5−20 sp ODE 4 3 3 3 3+ 3+ Ho ,Tm ) 3+ 3+ 3+ NaYF :Yb ,Er (or Tm ) RECl , NaOH, NH F OA (1) 21 (1) sp ODE 4 3 4 (2) 17 × 22 (2) ellipse (3) 30 × 45 (3) plate 3+ 3+ 3+ NaYF :Yb ,Er (or Tm ) NaCl, RECl ,NH F PEI ∼20 sp ethylene glycol 4 3 4 3+ 3+256 NaYF :Yb ,Er Na(CF COO), RE(CF COO) OA, TOP 18−200 hexagonal prism ODE 4 3 3 3 Si (1) Mg Si (or KSi, NaSi), SiCl (1) Cl 2−5 sp glyme R: alkyl group 2 4 (2) RLi or RMgCl (2) alkyl group Si diphenylsilane, octanol octanol 1.5−4 sp octanol, hexane Si (1) SiCl , TOAB, LiAlH (1) hydrogen 1.8 sp toluene 4 4 (2) H PtCl , 1-heptene (2) 1-heptene 2 6 Si (1) SiH (2) hydrogen sp (appr) (2) MeOH (2) HF/HNO (3) alkyl group (3) alkene (3) alkene Si SiCl , SiCl (hexyl), LiAlH hexyl group ∼3 sp toluene 4 3 4 Si SiCl , SiCl (allyl), LiAlH allyl group 3.7 sp toluene 4 3 4 CH NH PbBr PbBr ,CH NH Br, CH (CH ) NH Br or octylamonium bromide or 6 sp ODE/OA 3 3 3 2 3 3 3 2 7 3 CH (CH ) NH Br octadecylammonium bromide 3 2 17 3 CH NH PbX (X = Br, I) PbX , OLA, OA, CH NH OLA, OA (2) 35 (1) cubic ODE 3 3 3 2 3 2 (4) 10 (2) plate (3) wire (4) sp (dot) CH NH PbX (X = Cl, Br, I) PbX in OA/OLA, NMF OA, OLA 17−25 bulk, cubic DCB 3 3 3 2 (for X = Cl and Br), CHCl (for X = I) CsPbX (X = Cl, Br, I) Cs CO , PBX , OLA, OA OA, OLA 4−15 cubic ODE size control achieved by 3 2 3 2 varying injection temperature ZnEt , diethylzinc; TOP, trioctylphosphine; HDA, hexadecylamine; ODE, 1-octadecene; TBP, tributylphosphine; ODA, octadecylamine; Zn(OAc) , zinc acetate; OA, oleic acid; CdMe , 2 2 2 dimethylcadmium; (TMS) S, bis(trimethylsilyl) sulfide; TOPO, trioctylphosphine oxide; (TMS) Se, bis(trimethylsilyl)selenide; HPA, n-hexylphosphonic acid; TDPA, n-tetradecylphosphonic acid; 2 2 Cd(OAc) , cadmium acetate; Cd(acac) , cadmium acetylacetonate; HDDO, 1,2-hexadecanediol; TMPPA, bis(2,2,4-trimethylpentyl)phosphinic acid; MA, myristic acid; (BDMS) Te, bis(tert- 2 2 2 butyldimethylsilyl) telluride; ODPA, n-octadecylphosphonic acid; In(OAc) ,: indium acetate; (TMS) P, tris(trimethylsilyl)phosphine; SA, stearic acid; P(NMe ) , tris(dimethylamino)phosphine; OLA, 3 3 2 3 oleylamine; (TMS) As, tris(trimethylsilyl)arsine; Pb(OAc) , lead acetate; Cu(acac) , copper acetylacetonate; In(acac) , indium acetylacetonate; Cu(OAc), copper(I) acetate; DDT, 1-dodecanethiol; 3 2 2 3 Ag(DDTC), silver diethyldithiocarbamate; Ag(OAc), silver acetate; TBBT, 4-tert-butylbenzenethiol; RE, rare earth metal; PEI,: polyethylenimine; RLi, alkyl lithium; RMgCl, alkyl magnesium chloride; b c d e f g h TOAB, tetraoctylammonium bromide; NMF, n-methylformamide; DCB, dichlorobenzene. Reference 287. Reference 288. Reference 289. Reference 290. Reference 291. Reference 292. Reference I j k l m n o p q r s t 293. Reference 294. Reference 295. Reference 296. Reference 297. Reference 298. Reference 299. Reference 300. Reference 301. Reference 302. Reference 303. Reference 304. Reference u v w x y z 305. Reference 306. Reference 307. Reference 308. Reference 309. Reference 310. Reference 311. Chemical Reviews Review Figure 10. Representative TEM images of (a) ZnSe, (b) PbS, (c) CuInS2@ZnS, (d) Ag2S, (e) UCNPs, (f) Si NPs, and (g) MAPbX luminescent nanoparticles. (a) Reproduced with permission from ref 283. Copyright 2013 American Chemical Society. (b) Reproduced with permission from ref 247. Copyright 2011 American Chemical Society. (c) Reproduced with permission from ref 284. Copyright 2011 American Chemical Society. (d) Reprinted with permission from ref 285. Copyright 2016 Wiley. (e) Reprinted with permission from ref 263. Copyright 2008 Wiley. (f) Reprinted with permission from ref 286. Copyright 2011 Royal Society of Chemistry. (g) Reproduced with permission from ref 277. Copyright 2014 American Chemical Society. nanoparticles are generally produced via a hot-injection respectively. Contrastingly, a mixture of Zn(OAc) and oleic method that involves the reaction of cesium-oleate with a acid in ethanol, refluxed in the presence of tetramethylammo- lead halide in octadecene at high temperature (140−200 °C). nium hydroxide could be used to obtain ZnO NPs. The addition of equimolar amounts of oleic acid and TiO NPs have also found crucial roles in a wide variety of oleylamine stabilizes both the lead precursors as well as the applications including dye-sensitized solar cells, photocatalysis, 280 323−325 resulting cubic nanocrystals. More in depth discussions on and batteries. Colvin et al. adopted a hot injection the synthesis, properties, and applications of lead halide method to synthesize TiO NPs, using titanium halide and perovskite nanocrystals can be found in several informative titanium alkoxide in the presence of TOPO at 300 °C. 275,281,282 review articles. While the reactions without TOPO were fast and yielded Table 5 concentrates the literature from a variety of larger particle sizes (>10 nm), the reaction with TOPO was representative fluorescent NPs synthesized in organic media slower and resulted in smaller NPs (5.5 nm), suggesting that and highlights the relevant ligands employed along with the TOPO worked as the surface ligand and played a critical role diversity of materials obtained. Figure 10 shows some to control the NP growth. representative TEM images of some of these materials. As opposed to the nearly spherical NPs obtained through 2.2.4. Other Nanoparticles. Metal oxide NPs are often the use of TOPO, it was shown that by progressively replacing synthesized by sol−gel processes in which water is usually TOPO by a more facet-selective surfactant such as lauric acid required as a reactant. The as-prepared particles have anatase nanocrystals with increased anisotropy and branching hydroxylated polar surfaces. On the other hand, metal oxide are produced. NPs dispersible in organic media are synthesized by non- The most influential factor to control the shape of the TiO hydrolytic sol−gel methods, aiming for better crystallinity. nanoparticles is by manipulating their growth kinetics. The Among a series of metal oxides, ZnO and TiO have been presence of tertiary amines or quaternary ammonium extensively studied primarily due to their interesting electronic hydroxides as catalysts is essential to promote fast crystal- properties and their utility in a variety of electronic devices as lization under mild conditions and to synthesize TiO NRs 312−314 well as for catalysis. with a one-step, low temperature route. When only oleic acid is ZnO is one of the important wide band gap semiconducting present, slow hydrolysis reaction takes place and nearly materials and has a broad range of applications in spherical nanoparticles are formed. Anisotropic hyperbranched 315−317 optoelectronics and biomedicine. ZnO NPs can be organic capped TiO topologies have been achieved by obtained by a variety of approaches such as using ZnEt in the sequent exploitation of aminolysis and pyrolysis in a binary 318 329 presence of n-octylamine and TOPO or using dicyclohex- surfactant mixture (oleic acid and oleylamine). First- ylzinc and a series of alkylamine exposed to air at RT. generation branched nanoparticles initially formed upon the Furthermore, the thermal decomposition of Zn(OAc) in aminolysis reaction possess a strained monocrystalline alkylamines in the presence of tert-butylphosphonic acid was skeleton, while their corresponding second-generation deriva- demonstrated. The growth of ZnO NPs was governed by tives fed by pyrolysis pathways accommodate additional arms the molar ratio of Zn(OAc) and tert-butylphosphonic acid, crystallographically mismatched with the lattice underneath. suggesting that the phosphonic acids were the main surface Furthermore, more complex core−antenna structures have ligands. In contrast to spherical NP materials, ZnO NPs with been developed by a seed-mediated growth method. different shapes could be prepared via nonhydrolytic ester According to this, TiO nanoparticle seeds with well-defined elimination sol−gel reactions with Zn(OAc) and 1,12- shapes followed by the epitaxial growth of nanorod antennas dodecanediol. The use of TOPO, 1-hexadecylamine, and on the seeds along the (110) direction. In a typical synthesis, tetradecylphosphonic acid as the surface ligands in the reaction truncated octahedral bipyramidal nanoparticles are used as formed cone-, hexagonal cone-, and rod-shaped NPs, seeds, together with oleic acid and a Ti precursor, which are 4838 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 6. Metal Oxides Synthesized in Organic Media other material precursors and reagents ligand/surfactant size (nm) shape solvent comments ZnO ZnEt TOPO, octylamine <4.4 sp TOPO, octylamine, decane ZnO ZnCy HDA, DDA, octylamine Rod, disk THF ZnO Zn(OAc) alkylamine, 3−9 sp, elongated alkylamine tert-butylphosphonic acid ZnO Zn(OAc) , 1,12-dodecanediol (1) TOPO, OA (1) 70 × 170 (1) cone (1) dioctyl ether, TOPO (2) HDA (2) 40 × 29 (2) hexagonal cone (2) HDA (3) TOPO, TDPA (3) 5.5 × 23 (3) rod (3) dioctyl ether, TOPO ZnO Zn stearate, 1-octadecanol stearic acid, ODPA sp ODE ZnO Zn(OAc) OA 5 sp EtOH TiO TiX , Ti(OR) TOPO heptadecane X: halide 2 4 4 TiO Ti(O-iPr) OA <6 toluene 2 4 TiO Ti(O-iPr) , tertiary amine or OA 3−4 × <40 rod, sp (with OA 2 4 quaternary ammonium hydroxide (rod) ethylene glycol) TiO TiCl 4-tert-butylcatechol ∼5 sp benzyl alcohol 2 4 TiO Ti(O-iPr) OA, OLA 2 × 12−30 rod, sp ODE 2 4 (rod) 2.3 (sp) TiO Ti(COT) , DMSO TBP, TBPO, or TOPO 3−25 sp o-dichlorobenzene 2 2 Cy, cyclohexyl; DDA, dodecylamine; ODPA, octadecykphosphonic acid; ZnCy , dicyclohexylzinc; TiX , titanium halide; Ti(O-iPr) , titanium 2 4 4 isopropoxide; Ti(COT) , bis(cycloctatetraene)titanium; COT, cyclooctatetraene; TBP, tributylphosphine; TBPO, tributylphosphine oxide Reference 338. heated at high temperature (270 °C). The morphology of the particles transform from rhombic (OA/OM = 4/6) to antennas could be controlled by modifying the precursor truncated rhombic (OA/OM = 5/5) and spherical (OA/OM introduction rate. = 6/4). Solvothermal synthesis was also applied to synthesize TiO Table 6 presents some representative examples of ZnO and TiO NPs synthesized in organic media and the ligands used in NPs using Ti(iPrO) and oleic acid as precursor and each case while Figure 11 shows some representative TEM of surfactant, respectively. The reaction with this surfactant intermediaries and final examples of the latter. led to narrower size distribution than one without surfactant. Weller et al. demonstrated the synthesis of TiO NRs and spherical NPs using Ti(iPrO) and oleic acid in the presence of 3. LIGAND MODIFICATION FOR WELL-DISPERSED tertiary amines or quaternary ammonium hydroxide as a AND FUNCTIONAL NANOPARTICLES IN COMPLEX base. A similar procedure was performed for the synthesis of MEDIA TiO NRs and spherical NPs via aminolysis using oleyl- This section focuses on the important role of ligands for the amine. The low-valent organometallic complex, bis- colloidal dispersity and function of NPs in complex media such (cyclooctatetraene)titanium, and DMSO could also be utilized as precursors for TiO NPs, which were formed at temper- atures as low as RT. While the reaction without any ligand resulted in precipitation of amorphous TiO powder, the reaction with coordinating ligands such as tributylphosphine, tributylphosphine oxide, and TOPO produced a homogeneous solution with internally crystalline TiO NPs. The reaction between TiCl and benzyl alcohol with 4-tert-butylcatechol formed crystalline TiO NPs highly dispersible in organic solvents. H NMR analysis of these NPs revealed the presence of adsorbed 4-tert-butylcatechol and benzyl alcohol on the NP surface. Nanofibers of various sizes and layered structures were also fabricated at ambient conditions. This is the first time that phase transitions from the titanate nanostructures to TiO polymorphs take place readily in simple wet-chemical processes at ambient conditions. Hollow nanotubes observed when the obtained nanocrystals react with concentrated basic solution. More complex shapes of TiO nanocrystals such as rhombic, truncated rhombic, spherical, Figure 11. TEM images of (a) OA-stabilized ZnO NPs, (b) ZnO dog-bone, truncated and elongated rhombic, and bar have NRs, (c) OA-capped length tunable TiO NRs, and (c) dopamine- been synthesized by a simple variation of the oleic acid/ stabilized TiO NPs all synthesized in organic media. (a,b) Reprinted oleylamine ratio or the amount of titanium n-butoxide or with permission from ref 321. Copyright 2005 Wiley. c Reprinted reaction temperature enables a fine control of the growth rate with permission from ref 333. Copyright 2005 Wiley. (d) Reproduced of TiO NPs and, consequently, a control of the shape of these with permission from ref 335. Copyright 2004 American Chemical particles. By increasing the molar ratio of OA/OM the Society. 4839 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review as the ones often met in biomedicine, energy harvesting wide range of organic solvents, as well as exceptional capability devices, and catalytic systems. Different ligand modification to stabilize NPs against aggregation. One of the first examples strategies will be discussed for both biological and non- of the importance of these polymers in NP functionalization biological applications, including the direct functionalization was demonstrated during the development of Doxil, the first during the synthesis of NPs or the postsynthetic modification FDA liposomal nanoformulation of doxorubicin. Initially, of a NP surface. Particular emphasis will be given to the design most of the liposomes loaded with the anticancer drug of ligand coatings for NPs to be used as therapeutical and doxorubicin were accumulated in the spleen and liver rather diagnostic tools in biomedicine due to the combined relevance than the targeting tumor site. The solution came by the and challenging requirements associated with this field. functionalization of these liposomes with PEG brushes covering their surface, preventing the nonspecific adsorption 3.1. Ligand Coating of Nanoparticles for Biomedical of plasma proteins and thus resulting in effective minimization Applications of liposome accumulation into the liver and spleen. After It is well accepted that the NP ligand shell plays a significant these findings, the use of PEG became a common practice in role in the design of nanotherapeutic probes regulating their designing nanotherapeutics at both the research and pharmacokinetics, efficacy, and toxicity. Ligands that coat the commercial levels in order to stabilize NPs against aggregation, surface of NPs should exert adequate colloidal stabilization and prevent uptake by nontarget organs, increase their circulation NP sealing from other molecules in challenging biological time in blood, and enhance accumulation into targeted environments while functional ligands should increase NP organs. PEGylation of NPs can be achieved via various targetability and perform distinct biological roles. Especially for routes. The simplest way is the addition of PEG molecules in vivo applications it is critical to minimize NP aggregation by during NP synthesis. This approach is commonly employed to choice of appropriate ligands. The in vivo fate of NPs critically coat polymeric NPs, and it has also been demonstrated for the depends on their size. For example, for tumor targeting functionalization of inorganic NPs such as Au, Ag, and iron applications, NP size and characteristics have to be finely tuned oxide. It was shown that PEG can play multiple roles in accordance with the tumor state to achieve maximal tumor simultaneously, acting as a solvent/cosolvent, a reducing penetration. Increases in overall NP size, e.g., due to 79,346−349 agent as well as a capping agent. Despite the aggregation could inhibit tumor targeting. Additionally, very simplicity of the experimental protocols, the PEG molecules small NPs might leak into blood vessels, while very large NPs are only weakly bound to the NPs, and thus they can easily or aggregates of NPs might become subject to macrophage detach from the NP surface during various processing steps clearance without being able to fulfill their therapeutic role. (e.g., dilution/dialysis, centrifugation, heating, drying, aging, Therefore, it is of utmost importance to choose the right ligand mixing with other compounds, etc.). A strategy to make a coating for the desired biomedical application. It is also worth stable coating of PEGs on NPs has been recently demonstrated mentioning that for biomedical applications, ligand selection as illustrated in Figure 13. An amphiphilic polymer grafted should also consider the biocompatibility and biodegrad- with both alkyl chains and PEG molecules is self-assembled ability/excretion of the ligand as a general requirement for into micelles and coats the surface of NPs. The coating clinical use. stabilizes the NPs as a result of the large conformation entropy Various ligands such as carbohydrates, oligonucleotides, 80,350 repelling any foreign materials. Other strategies involve polymers, peptides, and proteins have been utilized in the functionalization of PEG molecules, with NP binding head biomedical applications, and in the following sections, we 341−343 groups such as thiols, amines, carboxylic acids, or discuss the ones most commonly employed. Figure 12 351−353 silanes. PEG-modified nanomaterials tend to reduce immunological reactions, which can be attributed to the repelling nature of PEG to proteins, as it tends to reduce total serum protein adsorption (opsonization) as a function of grafting density and 354−356 molecular weight of the polymer. However, some studies also suggest that PEG coating might facilitate the binding of other proteins (albumin for instance) and thereby blocking the way for immunoglobulins in a process 354−356,358 known as “dysopsonization”. While the stability of NPs grafted with PEG-containing ligands in vivo is still unclear, many in vitro experiments have been carried out to shed more light on this family of ligands. For example, Au NPs functionalized with mPEG-thiol (5 or 10 kDa) were found to Figure 12. Different ligands commonly used in NPs designed for be prone to ligand displacement by cysteine resulting in biomedical applications including antibodies, oligonucleotides, carbohydrates, proteins, polymers, and dyes. increased adsorption of serum proteins. Interestingly, in- troduction of alkyl moieties as hydrophobic spacers between shows some examples of ligands used for biomedical the thiol and the PEG prevented this displacement. applications while Table 7 summarizes selected examples of While PEG generally display little net-charge, adding nanotherapeutics that are commercially available or under functional end groups such as carboxyl or amine can infer a advanced clinical evaluation with various surface ligands. net negative or positive charge, respectively, altering the 3.1.1. Ethylene Glycol Containing Ligands. Poly- properties of the PEG ligand and interactions with ethylene glycol (PEG) is a unique category of various biomolecules. Additional functional groups can be em- molecular weights polymers, which possess fascinating proper- ployed for the further conjugation of PEG to biomolecules ties such as biocompatibility, high solubility in water and in a such as homing peptides or antibodies as well as fluorophores. 4840 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 7. Nanotherapeutic Agents in Clinical Trials and/or FDA Approved approval brand name indication modality surface ligand status Doxil anticancer liposome PEG FDA approved AuroLase anticancer silica core with gold PEG pilot study shell NP ThermoDox anticancer liposome thermoresponsive polymeric shell phase III NanoTherm anticancer iron oxide NP aminosilane FDA approved Ferinject iron deficient anemia iron oxide NP carboxymaltose FDA approved Feraheme iron deficient anemia in chronic kindey iron oxide NP (SPION) polyglucose sorbitol carboxymethyl ether FDA disease (CKD) approved Ferdex/Endorem imaging agent iron oxide NP (SPION) dextran FDA approved GastroMARK imaging agent iron oxide NP (SPION) silicone FDA approved NBTXR3 radiotherapy HfO NP not explicitly stated, but designed to have phase II/III antifouling activity Figure 13. Schematic illustration of NPs containing an inorganic core, coated with the amphiphilic polymer poly(maleic anhydride-alt-dodecene) (PMA) and fluorophore DY-636 (light blue). PEG chains of different MW or glucose (red) were attached to the NP surfaces. The resulting NPs are (a) FePt−PMA, (b) FePt−PMA-PEG750, (c) FePt−PMA-PEG5k, (d) FePt−PMA-PEG10k, (e) FePt−PMA-glucose, and (f) Fe O −PMA 3 4 respectively. TEM images of (g) FePt-PMA, (h) FePt−PMA-PEG750, (i) FePt−PMA-PEG5k, (j) FePt−PMA-PEG10k, and (k) FePt−PMA- glucose NPs (scale bar: 25 nm). (l) Mean core−shell radius rcs of the FePt NPs). Reprinted with permission from ref 350. Copyright 2015 American Chemical Society. Figure 14. (a)Chemical structures of cationic OEG ligands on Au NPs. (b) Chemical structure of zwitterionic OEG ligands used for Au NP synthesis and corresponding TEM images of zwitterionic Au NPs (2, 4, and 6 nm). (a) Reprinted from ref 367. Copyright 2014 American Chemical Society. (b) Reprinted with permission from ref 366. Copyright 2016 American Chemical Society. Bifunctional PEG molecules can also serve as cross-linkers/ shown for iron oxide NPs functionalized with the homo spacers, facilitating further grafting to biomolecules or other bifunctional linker gallic acid, for example. groups, while maintaining the stability of the system under Just like their larger counterparts, the smaller oligo-ethylene 360−363 different conditions. However, when using homo glycols (OEGs) have been used as ligand coatings for NPs bifunctional PEG (i.e., two identical end groups), care needs (e.g., see section 2.1.1). For example, carboxy-terminated to be taken in order to avoid NP aggregation through cross- OEG modified with a hydrophobic alkyl unit including a linking reactions, which can have detrimental effects on NP diacetylene group, which can be photo-cross-linked upon UV function as discussed in section 3.1. Cross-linking and irradiation and a terminal thiol for anchoring to the surface of therefore NP aggregation can generally be avoided by using Au NPs have been shown to result in Au NPs with excellent a large excess of such homo bifunctional linkers as has been stability toward changes in pH, ionic strength, or ligand 4841 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 15. Schematic illustration of the silanization strategy on TOPO-capped CdSeZnS core/shell particles. Briefly, the methoxysilane groups (Si- OCH ) hydrolyze into silanol groups (Si-OH) and produce a primary polymerization layer. Condensation leads to the formation of siloxane bonds and water molecules are released. Next, silane precursors are added into the shell to provide further functionality and finally, to block the shell growth by converting the remaining hydroxyl groups into methyl groups. Reprinted with permission from ref 371. Copyright 2001 American Chemical Society. displacement and could be selectively polymerized into chains condensation of the silanols, which finally leads to the and networks of Au NPs by tuning the density of ligands on formation of the siloxane bonds. A typical feature of the 353,365 the nanoparticle surface. Furthermore, both cationic and relevant sol−gel method is that usually condensation does not zwitterionic OEGs have been shown to provide Au NPs with go to completion under relatively mild reaction conditions, so 366,367 antimicrobial properties. As discussed for other OEGs, that a silanol-terminated surface is exhibited. This feature is these contained a thiol anchoring group as well as sulfonate exploited, both to ensure colloidal stability through repulsion and/or quaternary amine groups, which provide negative and among negatively charged surface core@shells and to enable positive charges respectively, thus providing electrostatic bioconjugation (Figure 15). The process of cross-linking of stabilization (see Figure 14). silicon-containing ligands offers the advantage of a well- 3.1.2. Silanes. Among the inorganic coatings used in the established sol−gel chemistry, which enables surface function- design of functional NPs for biomedical applications, silicon- alization either by reaction with common coupling agents, or containing ligands are the most widely used due to the by surface condensation of functional alkylsilanes (R′Si(OR) , combination of its hydrophilic features with chemical and R′R′′Si(OR) ,R′R′′R′′′SiOR) bearing a nonhydrolyzable physical stability. These kinds of ligands have been applied to a functional group R (Table 8). wide variety of functional NPs (metallic, magnetic, semi- Most silica-coating protocols have been adapted from the conductor) with the purpose of enabling or improving their Stöber process for the synthesis of SiO spheres, which relies dispersibility in aqueous media as well as their biocompati- on controlled hydrolysis and condensation of tetraethylortho- bility. In particular, the formation of a cross-linked shell of silicate (TEOS, Si(OC H ) ) under basic (ammonia) catalysis 2 5 4 silicon-containing ligands is a means to reduce particle in ethanolic or hydroalcoholic media. The basic idea behind aggregation in those cases where relevant chemical or physical the design of NP@SiO is that the Stöber process is carried out interactions take place. In the case of metal NPs and QDs, in the occurrence of a NP suspension and that the synthesis silica shields the functional core from the environment, parameters are adjusted in such a way that heterogeneous protecting the NPs toward oxidation and reducing their 368−370 nucleation of silanization on top of the NPs is highly favored as toxicity. compared to homogeneous nucleation. Several strategies have been devised for the fabrication of This approach was shown to be relatively straightforward in NP@SiO core@shell, often relying on the sol−gel synthesis of the case of oxide or oxyhydroxide NPs dispersible in ethanol or silica from an alkoxysilane, according to the following chemical water. A relevant example was reported by Xia and co-workers, reaction: who discussed that deposition of silica from TEOS onto a water-based commercial ferrofluid under ammonia catalysis Si(OR)+→ 2H O SiO+ 4ROH 42 2 results in iron oxide@silica with up to 70% of the core@shells containing a single core. By adjusting the TEOS amount, the The reaction, which requires the use of acid or basic shell thickness was varied from 2 to 100 nm, and further catalysis, occurs through a multistep equilibrium associated with the hydrolysis of all the alkoxy groups, followed by functionalization with aminopropyl trimethoxysilane (APTS) 4842 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Table 8. List of Some Commercially Available Silane Precursors for NP Coating and Functionalization enabled coupling with isothiocyanaterhodamine, producing Another more general modification of core@shell produc- tion based on Stöber-like silica shell formation relies on the use multifunctional core@shells for magnetic and optical detec- tion. On the other hand, in the case of metal and QD cores, of micelles, which are regarded as a nanometer-sized confined environment for controlled nucleation and growth of the silica the generation of a silica shell is less trivial, as the use of a shell. While early studies focused on the in situ formation of primer, with which the initial silica is bound to the NP surface, both the core and the silica shell within a micelle template (see is needed. The primer needs to have strong affinity for the core for example CdS@SiO in ref 377), nowadays the general surface. Most often vitreophilic groups (typically mercapto- approach is to make use of micelle-mediated silica shell propyltrimethoxysilane or aminopropyltrimethoxysilane) are deposition on preformed NPs. This is due to a number of used for initiating silica shell deposition. By this approach, reasons, including limited reproducibility associated with the silanization of several NPs, including Au, Ag, and CdS, has extremely high number of involved synthetic variables, the been achieved, provided that the original NPs did not possess 369,374 relatively detrimental effect of micelle synthesis on the covalently bound ligands on their surface. physicochemical properties of the inorganic core as compared Improvements of the Stöber approach to core@shell NP to high temperature synthetic routes and to the understanding design have focused on defining more general protocols, which that the vision of micelles as static templates is unrealistic. could include particles not stable in hydroalcoholic media or Recent strategies based on micelle-assisted synthesis take into with limited affinity toward silica. In particular, methoxy- account the complexity of the synthetic medium, including the poly(ethylene glycol)-thiol (mPEG-SH) was found to be possibility of interdroplet exchange due to, e.g., Brownian effective in promoting transfer into ethanol of gold spheres and motions, as well as the effect of the compositional variation in rods without aggregation, enabling subsequent SiO shell the system with particular reference to ethanol and water, growth by Stöber routes. A more general procedure which are directly involved in the sol−gel silica reactions, on 378,379 relatively independent of the nature of the core includes the the surfactants assemblies. However, the mechanism of use of an amphiphilic nonionic polymer, e.g., PVP, which is NP@SiO formation in microemulsion is not fully elucidated adsorbed on the NP surface, enabling the direct transfer of the to date. Nevertheless, Koole et al. provided insights in the NPs into an ammonia/ethanol mixture where silica coatings formation of core@shell NPs obtained by direct TEOS are grown by addition of TEOS. The method was found to be deposition in water-in-oil microemulsion on hydrophobic effective for the silanization of Au, Ag, boehmite rods, and QDs (CdSe, CdTe, PbSe), which was reported also for the 376 380 gibbsite platelets. case of CdSe@ZnS dots. It is demonstrated that hydrolyzed 4843 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review TEOS replaces the capping agent originally present on the coatings (1−2 nm) was shown to be highly advantageous in hydrophobic NP, enabling therefore transfer of the NP into the those applications requiring efficient interaction between the water phase of the microemulsion, where silica growth takes core and the biological environment, such as the case of iron place. This mechanism is supported by the features of the final oxide@silica NP contrast agents for magnetic resonance 389−392 imaging (MRI). core@shell NPs. Silica coating works well when hydrophobic QDs are initially coated with capping agents, which can be Silica coating has been demonstrated to be highly effective in easily exchanged by TEOS, leading to NPs with the core improving the applicability of functional NPs in biomedicine exactly in the center of the silica shell. On the other hand, because the pioneering work by Alivisatos and co-workers on the use of silanized QDs as tools for fluorescence imaging and capping agents with a high affinity result in morphologies with 381 393,394 probing of biological systems. State-of-the art design of off-center core (see Figure 16 a,b). silica-based core@shell NPs for biomedical use is focused on exploiting silica shells to achieve multiple functionality such as dual imaging or combined imaging and therapeutic ability (see Figure 17). Figure 17. Schematic illustration of a biomolecule−NP conjugate. The core/shell CdSe/ZnS NPs are surrounded by a siloxane shell. To obtain water solubility, stabilizing groups are embedded in the outer Figure 16. Coating of NPs by dense (a,b) and mesoporous SiO . (c). siloxane shell, examples of stabilizing groups include phosphonate, Silica coating of hydrophobic NPs is affected by the affinity of the PEG, or ammonium. In addition, amines, thiols, or carboxyl groups original ligands for the NP surface: TEM image of silica coating of are incorporated in the siloxane shell as functional groups. Reprinted NPs coated by ligands with (a) moderate and (b) high surface affinity. with permission from ref 394. Copyright 2002 American Chemical Silica with extended mesoporosity (c) may be required to exploit NPs Society. as affinity probes by providing high surface area and pores for size exclusion of undesired analytes. (a,b) Reprinted with permission from ref 381. Copyright 2008 American Chemical Society. (c) Reprinted Within the framework of multifunctional NP@SiO , the with permission from ref 382. Copyright 2014 The Royal Society of 2 synthesis of porous silica shells has been achieved, with Chemistry. particular reference to ordered mesoporous silica shells through Stöber-like approaches mediated by a templating Typical microemulsions are based on ternary systems agent such as CTAB. The mesoporosity of the silica shells has containing water, hexane, or cyclohexane as oil phase, and a been exploited to develop magnetically recoverable core@shell commercially available ionic or nonionic surfactant such as NPs for nucleic acid detection with a high, specific surface area, Igepal, Triton X-100, AOT, Synperonic NP-5, or CTAB, to and to design iron oxide@silica NPs for dual imaging name a few. To achieve controlled core@shell morphologies applications by hosting fluorescent dyes and NPs in the 395−397 many parameters need to be adjusted, which are relatively porous texture of the mesoporous silica shell. The key 383−387 independent from the composition of the core. role of the porous shell was recently demonstrated with the Recently, it was shown that direct silanization from TMOS fabrication of iron oxide NPs coated with mesoporous silica can be achieved in one pot during the synthesis of metal halide loaded with TiO NPs as a novel affinity probe for proteins. perovskites QDs. The formation of the core−shell particles is Taking advantage of the strong interaction of TiO to the postulated to be affected by the occurrence of oleylamine used carboxyl groups of the peptides, of the size-exclusion effect of as NP capping agent promoting the sol−gel silica shell the ordered mesopores, and of the high available surface area, formation by amine functionalitites. selective enrichment of endogenous peptides was successfully An alternative approach for core@shell NP/silica production achieved (see Figure 16c). relies on the use of silicic acid as the precursor for the silica Although the occurrence of a mesoporous shell may be shell. Likewise, in the so-called water glass process, silicic acid highly beneficial for the end-use of core@shell NPs in has to be prepared in situ, usually by passing sodium silicate biomedicine, the main limitation of the available synthetic through cation exchange columns. After addition of silicic acid strategies relies on the removal of the templating agent, which to the NP suspension, the pH is raised to a suitable value to generates the porous network. While calcination is the most promote controlled silica condensation on the NP surface. effective way to promote complete removal of the template and Although a water-based dispersion of the NPs is needed, this formation of the mesoporous ordered structure, it may alter approach offers the distinct advantage of enabling the the functionalities or compromise the dispersibility of the NPs. deposition of extremely thin and homogeneous silica shells, As an alternative, solvent extraction of the template can be whose thickness can be finely modulated by repeated layer carried out under mild conditions, which however, is usually deposition. In particular, the occurrence of very thin silica incomplete. A recent study on the deposition of SiO from 4844 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review TEOS on CTAB-stabilized AuNRs suggests that CTAB as compared to conjugates prepared via the “salt-aging” method.. expected promotes the formation of a mesoporous silica Another important factor influencing the stability of DNA-Au coating and can then be removed by extensive rinsing with NP conjugates is the choice of the anchoring group. As such, it ethanol taking advantage of dissolution through the porous has been shown that di- and trithiol linkages as well as silica shell. Besides limiting accessible porosity, residual bifunctional linkers such as thiol plus amine provide higher templating agent within the outer silica shell may lead to stability conjugates compared to monothiols. nonreproducible or undesired interactions between the core@ In certain environments, such as in cell culture media or in shell NPs and the biological environment. other challenging buffers, it is highly important to employ 429−431 3.1.3. Oligonucleotides. Their inherent properties of DNA-NPs that are colloidally stable. For example, Funk accurate addressability and programmability, high target and co-workers showed that Au NRs coated with a dense shell specificity, as well as ease of synthesis and functionalization of DNA could be coupled to DNA origami structures, which have made oligonucleotides attractive ligands for NP generally require high MgCl buffer concentrations to maintain functionalization. The various types of oligonucleotides do their structural integrity, by hybridization to complementary not only play essential roles within living organisms but also “handle sequences” on the DNA origami. These constructs have found widespread applications in different research areas could then be employed for the detection of mRNA both in ranging from antisense therapy and siRNA delivery to buffer and in human serum. On the other hand many reports hierarchical self-assembly for the creation of new materials. have investigated the use of densely functionalized DNA-Au On the other hand, chemically modified oligonucleotides, such NP conjugates for intracellular sensing or drug deliv- 404,412,433 as locked nucleic acids (LNA) or peptide nucleic acids (PNA), ery. Mirkin and co-workers showed that the DNA- have been developed to increase target binding affinity through shell on Au NPs facilitated the cellular uptake through increased base-stacking and to be enriched with high stability scavenger receptors and resulted in a high number of 434−437 toward nuclease digestion, respectively. Taking into account internalized particles compared to bare Au NPs. The the versatility of oligonucleotides, it is unsurprising, that number of uptaken particles was highly dependent on the oligonucleotides as ligands to coat NPs play an important role density of the oligonucleotide loading, with higher loading in the function of nanoparticulate systems. Over the last two resulting in higher uptake. Additionally a dense DNA loading decades DNA-coated NPs have become increasingly important greatly increased the stability of conjugates with respect to 23,401−403 404−414 438 for applications in biosensing, nanomedicine, degradation by nucleases. Similarly, the stability of siRNA 17,19,415−418 and metamaterials. The DNA ligand shell stabilizes was enhanced in siRNA-Au NP conjugates and showed great the NP core both through sterical and electrostatic interactions potential in in vitro gene silencing. resulting in NPs that are highly stable in a variety of complex Ag NPs can also be functionalized with thiol-terminated media. Different conjugation strategies based on direct DNA, although density functional theory (DFT) and ab initio oligonucleotide chemisorption, physisorption, or involving studies have shown that the nature of the Ag−S bond is much coupling chemistry have been developed. weaker than that of the Au−S bond, with the bond being less Oligonucleotide Conjugation to NPs by Drect Chem- than 35% covalent and more than 65% electrostatic in nature, isorption. Pioneering work by research groups led by therefore resulting in less stable DNA-Ag NP conjugates 419 420 24 Alivisatos and Mirkin in 1996 showed for first time compared to Au NPs. Similar to Au NPs, for creating a dense that it was feasible to attach thiol-modified oligonucleotides to DNA ligand shell, charge screening must be taken into Au NPs. While Mirkin and co-workers demonstrated that Au account. Both the use of triple cyclic disulfides, as well as 420,421 NPs can be modified with a dense DNA corona, monothiolated DNA have been shown to quickly conjugate to 441,442 Alivisatos and co-workers showed that it was equally possible Ag NPs. Furthermore, phosphorothioate (pt)-oligonu- to produce Au NPs conjugated to a discrete number of cleotides can be employed. Here a Sulfur atom replaces an 89,419,422,423 oligonucleotides. To obtain stable DNA-coated oxygen atom in the phosphate backbone of DNA, which does NPs for biomedical applications, the covalent conjugation of a not only render these oligonucleotides stable toward dense shell of DNA strands to NPs is often desirable. To degradation by nucleases but also allows for functionalization achieve high DNA loading on the NP surface, electrostatic of NPs through metal−S interactions. Because many repulsion between neighboring DNA strands, as well as phosphate groups can be replaced by phosphorothioate within between DNA and the anionic Au NP surface must be a DNA strand, multivalent interactions with a single NP can be minimized. This can be achieved by the gradual increase of achieved, resulting in high stability. As such it was shown that salts (e.g., by addition of NaCl), or adjustment of the pH, thus Ag NPs functionalized with 3, 6, or 9 pt-containing DNA utilizing either Na+ or H+ ions to minimize electrostatic strands displayed increasing stability with respect to strand 421,424,425 repulsion. On the other hand ehtylene glycol displacement by dithiothreitol (DTT) with increasing numbers containing molecules such as OEG can be included as spacers of phosphorothioate groups present. between the DNA and the Au surface, allowing high DNA Oligonucleotide Conjugation of NPs by Physisorption. loading without the need for additional charge screening by Although covalent conjugation strategies are among the most ions. Recently, a “freeze-and-thaw” conjugation method was popular, some other strategies have been reported in the past reported by Liu and co-workers where Au NPs and thiolated decade to coat NPs of various chemical compositions with DNA strands were simply frozen and thawed, resulting in very DNA, where covalent conjugation may not be directly 427 444,445 dense DNA loading on NPs. The authors hypothesized that possible. For example pt-DNA, similarly to the case of during water crystallization, DNA, Au NPs, and salt are Au and Ag NPs, has also been employed to functionalize CdS repelled out of the growing ice crystals, thus resulting in high QDs, which showed different binding affinities for pt-DNA 2+ local concentrations and facilitating DNA attachment kinetics. depending on their surface properties. For example, Cd -rich The resulting conjugates showed not only increased DNA QDs displayed a higher binding affinity toward pt-DNA 2− loading but also increased stability in high salt buffers compared to neutral or S -rich CdS QDs. The conjugation 4845 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 18. Different methods of functionalizing Au NPs with DNA. (a) physisorption through Adenine bases. (b) Conjugation via pt-DNA. (c) Conjugation via thiol-Au bond. (d) Different strategies to conjugate DNA to colloidal QDs. (a−c) Reprinted with permission from ref 450. Copyright 2014 American Chemical Society. (d) Reprinted with permission from ref 448. Copyright 2013 Springer Nature. mechanism is most likely electrostatic in nature, although it The adsorbed DNAs also form an “exclusion zone” toward was shown that CdS QDs displayed greater binding affinities other incoming DNA strands, thus limiting further adsorp- 446 449 for pt-DNA compared to unmodified DNA. On the other tion. DNA physisoption is highly specific to the DNA hand, His-tagged as well as thiolated DNA can be employed sequence used with the following ranking in adsorption for QD conjugation due to affinities for different metal ions on affinity: A > C > G > T. It was shown that the DNA bases 447,448 the QD surface. While QD-thiolated DNA conjugates can interact with the metal surface through its nitrogen atoms, displayed excellent stability at high concentrations, they were specifically through N-7 (circled in yellow in Figure 18) and highly sensitive to changes in pH, photo-oxidation, and N-9. Especially, oligonucleotides containing a poly adenine dilutions. His-tag DNA-QD conjugates suffer from limitations (poly A) tail, have shown superior adsorption properties. in their preparation, being highly pH sensitive. Furthermore, The stability of these DNA-Au NP conjugates was found to be achieving high DNA-loading with this method is difficult as the highly dependent on the length of the poly-A tail, with a longer His-linkers limit the adsorption of other incoming DNA tail resulting in decreased desorption upon temperature, pH. or strands due to steric hindrance. salt concentration due to increased binding interactions, i.e., A proposed model for DNA physisorption on citrate-capped more DNA bases anchoring to the NP surface. However, a Au NPs is that initially the polyanionic DNA adsorbs on the longer polyA tail also resulted in a decreased number of DNA Au surface and thereby displaces citrate anions. This can be strands anchored to the Au NPs, which in turn allowed for facilitated by the addition of cations. To maximize surface more precise control of DNA loading. Interestingly, it was contacts, DNA may undergo structural conformation changes. shown that Au NPs functionalized with an A30-tail were stable 4846 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review with only 15% of DNA desorption after being heated to 95 °C for 30 min. However, the overall stability of these conjugates was still found to be less than those formed with thiol or pt-DNA. Liu and co-workers proposed the combination of pt-DNA into polyA DNA to harness both the high stability as well as precise conjugation properties. Oligonucleotide Conjugation to NPs by Coupling Chemistries. Other types of NPs often cannot be directly functionalized with DNA, as they are stabilized by additional 453,454 ligands such as polymers containing variable functional end-groups such as hydroxyl, carboxyl, amine, alkyne, azide, or aldehydes for further modifications. These functional groups allow for conjugation to oligonucleotides via various different methods. For example azide-functionalized superparamagnetic iron oxide NPs (SPIONs) as well as NPs bearing azido- amphiphilic polymers could be modified with a dense layer of alkyne functionalized oligonucleotides using alkyie-azide click 19,455 chemistry. On the other hand, the EDC coupling method Figure 19. Roles of (poly-)peptides in determining the fate and can be employed to conjugate amine-modified oligonucleo- properties of NPs. Reprinted with permission from ref 462. Copyright tides to any NP functionalized with carboxyl terminated 2018 The Royal Society of Chemistry. ligands. For example, UCNPs were functionalized with DNA using the EDC coupling strategy and then used in conjunction with graphene oxide (GO) for the successful Peptide Conjugation to NPs by Chemisorption. Peptides detection of zeptomoles of target oligonucleotides in solution. offer various functional moieties such as Cys (-SH) or His This study was further exploited for the detection of mRNAs in (-imidazole), which could be used for conjugation to the NP 402,403 418,464−466 cell lysate and blood plasma. surface. In the case of Au or Ag NPs peptides can be Figure 18 summarizes the basic strategies for conjugation of directly conjugated to the NP surface via free thiol-containing NPs with oligonucleotides. cysteine side chains. An example of this strategy was 3.1.4. Small Peptides. Small peptides are built up from demonstrated by Levy and co-workers. They utilized the few amino acids linked by amide bonds and represent another (Cys-Ala-Leu-Asn-Asn) CALNN peptide and showed that it important class of biomolecules that have been widely presented an excellent ligand for the stabilization of Au NPs. employed for NP stabilization and biofunctionalization for a The major characteristic for the success of this peptide was its 457−459 variety of applications in biomedical sciences. Peptides amphiphilic character having two hydrophobic amino acids have gained attention due their potential role as therapeutic (alanine and leucine) near the binding site and two hydrophilic agents in diverse areas such as oncology and infectious disease, amino acids (asparagine) further from the binding site. The as well as metal ion or molecular detection systems such as in amino acid cysteine is able to bind to the AuNPs whereas colorimetric assays for detection of a wide range of alanine and leucine (hydrophobic) induce peptide self- 460,461 biomolecular targets. The conjugation of peptides to assembly. This configuration facilitated a firm and stable NPs can not only result in increased reactivity due to a high coating of the peptides around the NPs, ensuring their local concentration but also enables multiplexing, thus solubility in water and providing a good stability at distinct pH harnessing the properties of different peptides at the same values and in different buffer ionic strengths. Recently, Kanaras time, and ref 462, figure 3.7, illustrates some of the roles and co-workers showed that Au NPs coated with a mixed peptides play in determining NP functionality and stability monolayer of CALNN and the skin penetrating peptide (Figure 19). CALNNR7 (or CALNNTAT) were able to penetrate through Similar to the case of oligonucleotides, the grafting density human skin, highlighting the important role of NP of peptides on the surface of the NP has to be carefully functionality and its direct correlation to NPs properties. controlled, as it will dictate the overall stability, activity, and Furthermore it was demonstrated that Au NPs functionalized properties of the resulting peptide−NP conjugate. It also has to with DNA binding peptides could be directed to assemble on be noted that while a dense coating might provide greater NP DNA templates in a specific manner to form ordered NP stability, it may also have a negative impact on the activity of assemblies. The formation and or destruction of such the peptides. Commonly used peptides for NP conjugation assemblies can be triggered by protease action or metal-ion 468−470 include cell-penetrating peptides (CPPs), which can enhance complexation methods. Poly histidine (HIS)-tags have uptake and delivery of drugs across membranes and improve been utilized by Mattoussi and co-workers to conjugate the efficiency of cell uptake of nanoparticulate systems, as well peptides to DHLA-coated QDs. Another recent study as homing peptides, which are designed to target cells, tumors, showed that QDs could be modified with a virus-derived lytic and tumor-associated microenvironments. One prominent peptide fused to a maltose-binding protein containing a hexa example of a CPP is the HIV-derived Tat peptide, which HIS-tag resulting in stable QDs, able to perforate the cell facilitates the cellular internalization of Au NPs in HeLa membrane. cells. Various strategies have been reported for the Peptide Conjugation to NPs by Coupling Chemistries. functionalization of NPs with peptides, tailored to the NP’s Besides direct conjugation, peptides can also be indirectly chemical composition. In general, the peptide can be attached to ligands already covering a NP surface. For example, incorporated either by direct chemisorption or by various Bartczak et al. reported a “one-pot” EDC/sulfo-NHS coupling coupling chemistries. strategy to functionalized OEG-capped NPs with peptides 4847 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review (Figure 20). Then, the same group demonstrated that antibodies can be achieved by direct chemical covalent peptide-capped Au NPs could be successfully employed to conjugation or electrostatic interactions. As discussed previously, noncovalent methods are based on hydrophobic and/or ionic interactions. Although this method of function- alization is generally straightforward and does not involve complex chemistry, it suffers from some disadvantages compared to covalent strategies. For example, in the case of antibodies, nonspecific binding to NPs can result in the loss of antibody activity as well as the destabilization of colloidal NPs. On the other hand, covalent methods use specific sites on the protein for NP conjugation. These are usually present in the form of chemical linkers or employ common protein binding 484,485 interactions (e.g., streptavidin and biotin). The choice of conjugation method and site should be carefully considered as proteins could be impaired, unfold, and/or lose their properties if an inappropriate method and/or conjugation site was chosen. Therefore, several efforts have been developed to optimize and control the orientation, density, activity, and accessibility of the protein after functionalization, as will be discussed in the following sections: Protein Conjugation to NPs by Chemisorption. The covalent conjugation of proteins to NPs can allow for greater control of protein activity but also to control aggregation behavior. Among the most commonly employed proteins for NP modification is avidin (found in egg white). The interaction of avidin/streptavidin with biotin (vitamin H) is one of the strongest noncovalent interactions in biology, and it has been heavily employed in targeting applications and assay Figure 20. Schematic overview of amide bond formation among the 487,488 methods. While most conjugation strategies rely on KPQPRPLS Peptide (blue) and OEG NPs (red shape) using EDC physisorption, a covalent functionalization method was (red) and sulfo-NHS (green) strategies. Reprinted with permission reported, which employed cysteamine and glutaraldehyde to from ref 473. Copyright 2011 American Chemical Society. link streptavidin to Au-magnetic NPs. Covalently conjugated streptavidin coated NPs showed an increase in stability in PBS containing SDS compared to NPs with a physisorbed study interactions of Au NPs with endothelial cells as well as 464,473−479 streptavidin coating. However, it was found that when manipulate angiogenesis both in vitro and in vivo. compared to conjugation by physisorption, streptavidin Peptide-coated CdSe/ZnS QDs have also been shown to be loading was lower. Simonian and co-workers demonstrated able to target the lung, blood, and/or lymphatic vessels. that small Au NPs (1.4 nm) displaying a sulfo-NHS or 3.1.5. Proteins. Proteins, generally defined as polypeptides malemeide reactive group could be conjugated with the consisting of more than 50 amino acids, play one of the most enzyme organophosphate hydrolase (OPH) through primary diverse roles within a living organism, ranging from receptor or amines from lysine residues or sulfhydryl groups from cystein membrane channel formation to molecular transport and residues. The resulting conjugates were then used for the catalysis of biochemical reactions. Therefore, it is not detection of the neurotoxin paraoxon. surprising that many diseases are the result of protein Protein Conjugation to NPs by Physisorption. Physisorp- malfunction due to mutations or misfolding. However, this tion represents the simplest way to functionalize NPs with also presents an opportunity to use proteins as therapeutic proteins. Resulting conjugates have the advantage that agents, an area that has become increasingly popular since the 481−483 conjugation is usually reversible, which can facilitate delivery report of the first protein therapeutic, insulin. On the and sensing applications. As discussed previously, the other hand, the use of protein−ligand interactions plays an functionalization of NPs with streptavidin is generally important role and can be harnessed for nanoscale protein self- straightforward and mainly relies on electrostatic interactions. assembly. For example, it was shown that avidin strongly absorbs onto Similar to their smaller peptide counterparts, the con- DHLA-coated QDs due to charge interactions. Even jugation of proteins to NPs can be advantageous for various particles with a controlled number of avidin (or streptavidin) reasons, such as increase in overall protein activity resulting 176,492 moieties per particle could be prepared. from the high local concentration at the microenvironment, An interesting work by Murphy and co-workers demon- increased stability or self-assembly. Hence protein−NP strated the successful assembly of Au NRs using biotin and conjugates have emerged as effective and promising tools for a wide range of applications, including diagnosis and streptavidin linkers. Interestingly, linkage was mostly observed therapeutics. In terms of biomedical applications, the protein in an end to end fashion. The group attributed this observation coating can be designed to modulate the stability of the NPs, to the higher reactivity of Au NRs’ edges due to their lower determine the clearance of NPs in vivo or to target specific coverage with CTAB. On the other hand, the functionaliza- biological sites. Thus, there has been an increased interest to tion of spherical Au NPs with lipases via a PEG-biotin design NP−protein conjugates for biomedical applications. In streptavidin−biotin linker was demonstrated. These protein general, functionalization of NPs with proteins such as functionalized particles were able to digest cubosomes 4848 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review following a different mechanism in comparison to free lipase. Protein Conjugation to NPs by Coupling Chemistries. It is The variation of the digestion mechanism was attributed to the important to mention that bioconjugation of NP surfaces overall size of the nanoparticulate system, which restricted achieved by alternative approaches, such as biotechnological strategies, may have benefits when designing NPs for access to the inner parts of the cubosomes. biomedicine. For instance, Ma et al. developed a systematic Streptavidin−biotin interactions were also used for signal method to bioconjugate recombinant proteins to NPs without amplification particularly coupled to electrochemical sensing of the need for modification for each specific protein-NPs microRNA. MicroRNAs are noncoding RNAs that can serve as tumor markers and therapeutic targets for some cancers. conjugate. A glutathione S-transferase-SpyCatcher fusion protein conjugated to Au NPs allowed for assembling of Biotinylated nucleotides were used to incorporate biotin into additional proteins through the Spy- Catcher/SpyTag system, the hybridized microRNA complex. Afterward, Au NPs loaded resulting in a two-step synthesis. First, the Au NPs were with large amounts of streptavidin were used to amplify the modified by glutathione S-transferase (GTS) trough Au−S signal. Signal amplification was based on the ability of the Au− bonds, and second, a covalent link between a SpyCatcher and streptavidin scaffold to capture both biotinylated nucleotides the SpyTag peptide was formed (by spontaneous formation of and biotinylated alkaline phosphatase. The enzyme catalyzed an isopeptide bond). Importantly, in this second step, a variety the conversion of the electrochemically inactive molecule 1- of recombinant proteins could be employed in a reproducible naphthyl phosphate present in the buffering solution into the manner, resulting in stable NP−protein conjugates. The active naphthol, thereby amplifying the resulting signal. The authors provided a universal platform to immobilize proteins specificity of the methods allowed for a single nucleotide on the surface of Au NPs, suitable for a wide range of discrimination between microRNA family members. applications. Figure 21 summarizes electrostatic and Another important protein broadly exploited in literature is covalent strategies for protein conjugation to NPs. bovine serum albumin (BSA). Albumin is biodegradable, nontoxic, and easy to handle, rendering it a good candidate for intravenous applications. Albumin, being a blood protein was exploited for its ability to minimize recognition and internalization of NPs and thereby prolonging their circulation half-life. Luminescent porous Si NPs are nanomaterials with great potentials for imaging and photothermal therapy. Nevertheless, these particles are susceptible to fast biode- gradation, resulting in fluorescence quenching compromising their use in long-term tumor imaging. To overcome this limitation, alkyl-thiol terminated NPs were encapsulated with BSA via hydrophobic interactions, generating stealth products with improved water dispersibility and long-term fluorescence under physiological conditions. 111,498−503 BSA has also been used during NPs synthesis. It was shown that when reducing AgNO with NaBH in the 3 4 presence of BSA, BSA-coated Ag NPs could be produced. Importantly, the secondary structure of BSA was not affected by the conjugation to Ag. Moreover, albumin can serve as a great platform for the delivery of therapeutic agents. Qi et al. Figure 21. Schematic illustration of different strategies for the prepared human serum albumin (HSA) NPs functionalized formation of NP−protein conjugates. (a) Electrostatic interactions via with glycyrrhetinic acid and loaded with the anticancer drug direct adsorption onto the NP surface. (b) Electrostatic interactions doxorubicin for liver cancer targeting. Doxorubicin was of protein with ligand/monolayer on the NP. (c) Covalent conjugation through active groups (e.g., Cys-SH or Lys-NH ). (d) encapsulated into the NPs with an efficacy up to 75% and 2 Covalent conjugation through a bifunctional linker. demonstrated superior cytotoxicity compared to untargeted particles. A universal method to prepare protein-capped QDs has been 3.1.6. Carbohydrates. Carbohydrates and carbohydrate- described by Clapp et al., who demonstrated that both HIS- conjugated molecules such as glycoproteins are integral to tags as well as leucine zipper units could be employed to multiple biological processes. For example, carbohydrates conjugate proteins such as avidin, the maltose binding protein present on the cell surface are central to cellular recognition (MBP) or the immunoglobulin-G-binding β2 domain of processes. Inflammatory processes and immunological re- streptococcal protein G (PG). sponses are also mediated by carbohydrates expressed on the Furthermore, it should be mentioned that when NPs are in outer surface of the cells. On the other hand, carbohydrates contact with biological fluids, biomacromolecules, including can serve as an excellent indicator for different diseases. For proteins may naturally adsorb to the surface of colloidal instance, carbohydrates present on the protein surface are particles, often impairing the behavior and properties of NPs important for proper protein folding, and thereby, abnormal 507,508 and influencing their behavior both in vitro and in vivo, protein glycosylation can be highly suggestive for different this effect is commonly referred to as protein corona diseases including cancer, hepatic, and immune diseases. 508−510 formation. In particular HSA, which is abundant in Carbohydrates are stable, hydrophilic, and exhibit good blood, tends to form a dense corona on NPs. For detailed biocompatibility and biodegradability in vivo. Furthermore, discussions on protein coronae, the reader is referred to their derivable reactive groups such as amino, carboxyl, and 512−514 detailed reviews on the topic. hydroxyl groups allow for successful conjugation to NPs. 4849 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Therefore, carbohydrate−protein interactions have been technique for various biomolecules including influenza anti- utilized to generate controlled nanoparticulate drug delivery body, DNA, and apoferritin. systems. For the synthesis of those conjugates, several methods Carbohydrate-functionalized NPs were also investigated as have been proposed including: (i) the formation of potential photothermal agents for cancer ablation. Although polyelectrolyte complexes of opposite charge, (ii) the antibody functionalization can achieve selective targeting of formulation of amphiphilic polysaccharides that can self- NPs to cancerous tissue, it is faced with several obstacles, assemble into NPs, and (iii) the use of cross-linkers which including the stability of the antibody itself and the increased facilitate the formation of stable carbohydrate−NP conjugates. cost upon large scaling. Cancer cells express more glycolytic However, the type of carbohydrate, valency, ligand, and density enzymes and glucose transporters than normal tissues, owing could influence the carbohydrate−NP conjugate, requiring to their increased need of glucose in a phenomenon called the optimized conjugation methods. For instance, Wu et al. Warburg effect. Taking into account this effect, iron oxide reported on mesoporous silica NPs, coated with mannose, as magnetic NPs were functionalized with glucose-6-phosphate nanocontainers for various cargos, which were encapsulated and then incubated with cancerous cells from different cell into the pores by the construction of Concavillin A nanogates. lines. Cells were then irradiated with near infrared (NIR laser The release of the cargo could be triggered by either a decrease light). Superior cellular uptake was demonstrated for function- in pH (e.g., in tumor vasculature) or an increased level of alized particles as compared to the plain ones. glucose (e.g., in diabetes). On the other hand, carbohydrate-functionalized NPs were Different types of carbohydrate-coated NPs interact differ- also exploited for targeting resistant bacterial species. ently with cells. This was demonstrated by functionalizing Mycobacterium smegmatis was used as model bacteria for different NPs, including iron oxide and QDs with three Mycobacterium tuberculosis, a Gram-positive bacterial causing different sugars: glucose, galactose, and dextrans of varying the serious infectious disease tuberculosis. Mycobacterium molecular weights. Functionalization was carried out by tuberculosis possesses a thick lipid wall, rendering resistance applying cyanoborohydride-based conjugation chemistry. toward many drugs. Nevertheless, small hydrophilic molecules Amine-terminated NPs were reacted with the reactive end may penetrate the pores known as porins. As such, trehalose on the carbohydrate via cyanoborohydride-based reductive was selected for the targeting of such bacteria due to the amination. Enhanced selectively of carbohydrate-modified NPs presence of the high affinity trehalose transporter system. for glycoporteins was reported, as well as reduced nonspecific Trehalose was coupled to NPs via photocoupling chemistry. cellular interactions of dextran-coated NPs when incubated These functional particles demonstrated superior interactions with HeLa cells. These nonspecific cell interactions became with cells compared to glucose- or dextran-coated particles. more prominent when a higher molecular weight dextran was TEM imaging revealed the presence of particles in the cell wall used as the surface ligand. On the other hand, galactose and the cytoplasm, opening the door for the management of functionalized NPs showed increased cellular internalization Gram-positive bacteria and especially Mycobacterium tuber- compared to bare NPs (Figure 22). culosis. 3.2. Ligand Coating of Nanoparticles for Other Applications Inorganic NPs feature optoelectronic properties that are strongly dependent on the size and shape of the particles. For instance, size-dependent discrete energy levels and Coulomb-blocked charge transport effects have been observed in metallic NPs while semiconductor QDs can be charged like molecules. The unique size-related structures, together with their transport and thermal properties, render NPs efficient nanoscale functional components for different applications in 231,523 524,525 526 photodetectors, solar cells, sensors, and catal- ysis. Moreover, colloidal dispersions of NPs are ideal candidates for inexpensive device fabrication via solution-based Figure 22. Uptake of galactose QDs exposed to the human liver techniques including spin-casting, dip-coating, and inkjet cancer cell line (HepG2). Higher internalization is observed when printing, which can be further scalable through roll-to-roll functionalized QD−galactose is exposed to HePpG2 cells (a) as processing. compared with bare QDs (b). Reprinted with permission from ref Toward the design and development of NP-based devices, it 519. Copyright 2012 The Royal Society of Chemistry. is well understood that the organic ligands and/or surface termination of colloidal NPs strongly affect their application performance, particularly in technological applications where charge carrier transfer/transport and chemical reactivity/ In another study, iron oxide NPs were functionalized with affinity play an important role. For instance, NPs’ ligands glucose (α and β forms) and mannose via click coupling may significantly affect the position of the energy levels in chemistry. Carbohydrate functionalization aimed to target semiconductor NPs. Furthermore, when considering NPs for sugar binding proteins (e.g., lecithin) present on particular cell electronic and optoelectronic applications, one should keep in types. Conjugation with lecithin, although weak, was amplified by the multivacancy of the interaction through the presence of mind that the actual device active element may not be multiple sugar molecules. Mannose-specificbinding was individual NPs but rather macroscopic assemblies or NP demonstrated by the increased cellular uptake of conjugated superstructures. In this case, the nature of the ligand coating NPs. Such system could be exploited for MRI as a detection plays a crucial role for the electronic/optical communication 4850 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 23. (a) Schematic representation of a NP-based photodetector. (b) Effect of the CdSe NPs surface treatment on the carrier mobility. (c) Photodetectos performance using NP film with different surface treatment (dark current-responsivity measurements). Reprinted by permission from ref 539. Copyright 2006 Macmillan Publishers Ltd., Nature 2006. (a) Reprinted with permission from ref 530. Copyright 2016 Macmillan Publishers Ltd.: Nature Photonics. (b) Reprinted from ref 531. Copyright 2010 American Chemical Society. (c) Reprinted with permission from ref 539. Copyright 2006 Macmillan Publishers Ltd., Nature. and the macroscopic physical behavior of the final assembly. environment, the type of the capping layer, the NP surface The interparticle distance, the colloidal dispersion and the passivation, and the interparticle distances due to the ligand packing density, as well as the mutual NPs’ orientation in the length in the close-packed film determine the electrical colloidal medium, are parameters that can be strongly conductivity in photodetectors and consequently the device’s influenced by the ligand nature/coverage and must be taken efficiency. NPs’ termination molecules significantly affect the into account in the development of the respective devices. position of the energy levels in semiconductor NPs but also 3.2.1. Photodetectors. Single phase inorganic semi- play roles in the charge carrier mobility. The ligand chain conductor NPs have been utilized for photon detection due length, density of the ligands, and degree of inductive effects to their narrower band gaps compared to that of conductive have a strong impact on the electron trap density, the carrier polymers and small molecules, which limited their absorption multiplication efficiency, and the multiexciton lifetime and to the visible spectral range. For example, inorganic NPs of have to be optimized to achieve an improved detectivity and PbS, PbSe, PbTe, HgTe, InAs, and InSb have been employed detector response time. as ideal candidates for application requiring light absorption in Photoconductive Detectors. A NP-based photoconductor the near-IR region; the band gap of such NPs can be precisely comprises a thin homogeneous film of semiconductor NPs tuned from the visible up to 35 μm. Various types of deposited onto a prepatterned electrode structure (Figure photodetectors using such NPs have been developed, including 23a). The electrical conductivity in such devices can be 527 528 529 photoconductors, photodiodes, and phototransistors. altered under illumination due to the generation of additional Τhe intraparticle characteristics (chemical phase, morphology, charge carriers. The photoconductivity in a close-packed NP size, or dispersity of individual NPs), but also the surface structure is dependent on intraparticle characteristics such as 4851 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review the morphology, size, or dispersity but also on the surface acid and poly(9,9-dihexylfluorene) (PFH) polymer hybrids. environment such as NP surface passivation, capping layer, and It was observed that even though the ligand coating improved interparticle distances. For instance, photoconductivity the miscibility of the NPs and PFH, the charge-transfer barrier studies in CdSe NPs capped with TOPO-TOP organic ligands suppressed the charge transport and lowered the photo- revealed that free carriers originate from photogenerated sensitivity of the device. electron−hole pairs within the NPs. The charge separation 3.2.2. Photovoltaic Devices. Semiconductor NPs exhibit in these nanoparticulate systems is much slower compared to a completely different behavior from their bulk materials of the the interband relaxation, while the charge transport is same stoichiometry due to quantum confinement size effects. dominated by tunneling of carriers through the interparticle As a consequence, the bandgap of the NPs can be simply tuned 542,543 medium. Moreover, the ionization rate is dependent on by varying the NPs’ size. This property enables the use of intraparticle characteristics such as size and surface passivation. a single material with different bandgaps to harvest a broad Different density of surface passivation of CdSe QDs with spectral range of the solar radiation. Their fascinating amines have been studied in order to evaluate the effect on properties together with their colloidal form, which is 533,534 their photocurrent. The changes in the photocurrent in compatible with solution-processing technologies, including conjunction to NP surface alterations were attributed to an the low-cost roll-to-roll device fabrication, make these increase of the exciton ionization efficiency due to variations in materials ideal candidates forphotovoltaic applications. the interparticle distances. This is regardless of whether the Using such technologies, NPs can be easily incorporated into molecules used for treatment were conjugated or cross-linked the different layers comprising the solar cell architecture. As a to the QDs. Possible treatment with a base may remove the result, different functionalities have been exploited, leading to capping molecules and shorten the interparticle distances, enhanced light harvesting, solar energy conversion efficiency, increasing the electron transport between the neighboring and device stability. Semiconductor NPs have been incorpo- particles through an interparticle hopping process. Electron rated in (a) hybrid organic/inorganic bulk heterojunction and hole mobilities increase exponentially with decreasing the (BHJ), (b) Schottky-based, (c) depleted heterojunction ligand length, demonstrating the inverse relationship between (DHJ), and (d) NP-sensitized solar cells, with the DHJ to coupling energy and interparticle distance (Figure 23b). be the most efficient NPs-based photovoltaic technology to The energy barrier width through which carriers need to date (Figure 24). tunnel to reach an adjacent NP can be tuned by the spatial separation of the neighboring NPs. The spatial separation and consequently their macroscopic optoelectronic properties can be modified by exchange or functionalization with a new ligand or “chemical cap”. Thus, ligand chain length, density of ligands, and degree of inductive effects are some parameters, which can be optimized to achieve the desired carrier transport 535−538 properties. Upon careful design of the capping agent properties, carrier multiplication efficiency, multiexciton life- time, and charge injection through the device can be improved, leading to enhanced detection efficiency. Moreover, a way to control the chemistry of the surface states which act as electron traps affecting the detector’s response time was found. This was realized by treating NP layers with different molecules (i.e., butylamine, formic acid, small thiols, etc.). The optimum characteristics were obtained after treating the films with methanol in an inert atmosphere, followed by controllable surface oxidation (Figure 23c). The high gain measured for the fabricated devices was attributed to the presence of long-living electron traps generated by chemical treatment of the NPs’ surface. Hybrid Photodetectors. This type of NP-based photo- detector is based on mixing narrow gap NPs, which act as excellent sensitizers, and organic semiconductor materials. The Figure 24. (a) Typical structure and (b) working principle of NP- performance of photodetectors is dependent on the synergy of based solar cells. (a) Reprinted with permission from ref 544. light harvesting and charge transport processes. Higher Copyright 2010 The Royal Society of Chemistry. (b) Reproduced responsivity and spectral response extension to the infrared with permission from ref 545. Copyright 2010 American Chemical spectral region have been recorded for small molecules or π- Society. conjugated polymers. A 3 orders of magnitude enhancement of photocurrent was achieved by sensitizing crystalline arrays of Despite the rapid improvement of the solar cell efficiency, C with CdSe NPs. This enhancement was attributed to NP-based photovoltaics still have to overcome many obstacles the efficient light absorption of CdSe NPs, fast electron in order to meet the requirement of large-scale commercializa- transfer from NPs to the C and high carrier mobility within tion and long-term usage. While much progress has been made the array of C molecules. in terms of the device architecture optimization, several The influence of the capping ligand layer on the UV material design aspects remain largely unexplored. The role of detection was studied by comparing two kinds of ultraviolet the interfaces among the randomly distributed crystalline NPs photodetectors based on TiO NPs, bare or capped with oleic in the charge transport is crucial. Such interfaces include large 4852 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 25. Schematic representation of the BHJ OPV cell with three types of NPs embedded into the active layer, (i) bare, (ii) TOAB-terminated, and (iii) P3HT-terminated J−V curves of the devices with configurations (a) ITO/PEDOT:PSS/P3HT:PCBM/Al and (b) ITO/PEDOT:PSS/ P3HT:ICBA/Ca/Al respectively. Reprinted with permission from ref 524. Copyright 2015 American Chemical Society. surface area junctions between photoelectron donors and The conductivity of the linker molecule itself may be acceptors, the intralayer grain boundaries within the absorber, important in enhancing carrier transport among the particles. Solar cells utilizing PbSe NPs capped with benzenedithiol have and the interfaces between photoactive layers and the top and demonstrated a power conversion efficiency of 3.6% along with bottom contacts. Controlling the charge collection and enhanced stability. Indeed, the ligand exchange of oleate minimizing the trapping of charge carriers at these boundaries molecules with a molecular conducting ligand such as can lead to further improvement of the solar cell efficiency. benzenedithiol resulted in a more effective pathway for Therefore, a deep understanding of the electronic coupling electron transfer. As a consequence, both electron and hole between the NP and its surface ligands and the physical mobilities were increased by more than 1 order of magnitude mechanisms responsible for the charge transport among the and an efficiency of 7% was reached for the respective DHJ neighboring particles is required to achieve higher solar cell device. Additionally, the cross- linking with the benzenedi- efficiencies. Consequently, a robust NP surface passivation thiol appears to offer a longer-lived NP−metal interface than and a controllable compact packing of the randomly oriented 546 amine ligands. In particular, halide anions introduced during NPs are required. Much attention has therefore been solid-state film treatments led to a marked reduction in the devoted to the development of new ligand strategies that density of trap states deep within the bandgap of the colloidal minimize the interparticle spacing to promote carrier transport NP solid. The mechanism proposed for such behavior was that and lower the defect density to reduce the recombination the as-exchanged NPs were dominated by a large density of losses. nonpassivated surface states, which were filled in with the Electron and hole mobility is dependent on the intrinsic atomic halide ligands. characteristics of the material, the size/morphology of the NPs Toward efficient inorganic NP-based photovoltaics, a and the disorder at the surface. Additionally it was recently different ligand strategy utilizing monovalent inorganic ligand found that it is also dependent on the ligand length. Shallow 551 (halide anions) passivation was proposed. It was shown that traps originate from the surface disorder and reconstructions, such an approach enabled good passivation of surface defects, whereas deep traps are due to low coordinated atoms on the high carrier mobility, and good device stability, while using 546,548 NPs surface. Carrier mobilities in semiconducting inexpensive chemicals readily processed at ambient conditions. alkanedithiol-treated PbSe were found to decrease exponen- Both time-resolved infrared spectroscopy and transient device tially with increasing ligand length. While complete removal characterization indicated that the scheme led to a shallower of the organic insulating ligands led to marked improvements trap state distribution than the best organic ligands. This in transport performance. For this reason, only the shortest atomic passivation strategy resulted in enhancement of the organic ligands were retained for surface passivation, allowing mobility-lifetime product in comparison to ethanedithiol sufficient interconnection between the NPs. Moreover, the passivation by a factor of 20, indicating superior charge carrier exchange of trioctylphosphine oxide and dodecylamine with diffusion in the atomic-ligand-passivated films. The respective 1,2-ethanedithiol or 1,2-ethanediamine was found to signifi- photovoltaic devices exhibited a solar power conversion cantly improve the exciton dissociation yield and/or charge efficiency of 6%. carrier mobility while a ligand exchange with 3-mercapto- The ligand shell of the metallic NPs also plays an important propionic acid quenched the band edge emission and role in the performance of plasmonic BHJ organic photovoltaic enhanced deep trap emission. devices (Figure 25). It is argued that the plasmonic effect 4853 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 26. (a) Schematic representation of the NP-based LED, (b) electronic energy levels of each material in the device, and (c) EQE dependence of the LED device on interparticle distance. Reprinted with permission from ref 555. Copyright 2012 Macmillan Publishers Ltd.. accountable for the performance enhancement takes place only oleic acid ligand were approximately 1000 cd/m greater and if the NPs core is in direct contact with the active layer 1.5 times higher, respectively, than those of the LEDs with the polymer donor. This can be achieved with the utilization of TOPO ligand. These results showed that if the physical length either ligand-free NPs or NPs terminated with the same of the surface ligand is relatively long, decreasing the surface polymer donor as the active layer. Using this concept an area would result in increased injection of electrons and holes enhanced efficiency of 7.16% in OPV devices incorporating the into the NPs, increasing the luminance and efficiency. In poly(3-hexylthiophene-2,5-diyl) (P3HT):Indene-C bisad- addition, an order of magnitude improvement in device duct (ICBA) active layer was achieved. On the contrary, efficiency was obtained by changing the long-chain oleate devices with ligand-terminated Au NPs showed lower ligand on the QDs surface with thiol and carboxylic acid units performances, even compared to the reference (NP free) (Figure 26a,b). At the same time, when the interparticle device due to the deteriorated active layer morphology spacing increased from 5.4 to 6.1 nm, the external quantum attained. efficiency (EQE) increased by a factor of ∼150 (Figure 26c). According to the above literature, the role of the interfaces Efficient ligand exchange of the core−shell particles replacing including the large surface area junctions between photo- the oleate ligand with octanethiol has also been reported and electron donors and acceptors, the intralayer grain boundaries resulted in a double increased electron mobility and greater within the absorber (interfaces among the NPs), and the balanced carrier injection, leading to the highest EQE of interfaces between photoactive layers and the top and bottom 12.2%. Alternatively, the use of 1- dodecanethiol as contacts are the main factors affecting the efficiency of the exchange ligand was reported. The device developed showed photovoltaic devices. NPs free of ligands or terminated with the highest EQE up to 20.5% and a long operational lifetime of the same polymer donor as the active layer could lead to more than 100000 h at 100 cd/m , representing one of the enhanced efficiency of BHJ organic photovoltaic devices. best-performing solution-processed red NP-based LEDs to Controlling the charge collection and minimizing the trapping date. of charge carriers at these boundaries by including short-length Recently, several examples of LEDs utilizing perovskite NPs 557−560 or conductive capping ligands can also lead to an improvement have been demonstrated. While perovskite NPs are very in efficiency. Atomic passivation methods such as monovalent efficient light emitters, their main disadvantage is that they inorganic ligand (halide anions) passivation are important to degrade rather quickly. To tackle this problem, recent studies eliminate surface defects and reduce carrier diffusion leading to have focused on the encapsulation of perovskite NPs in 561,562 improved device stability. polymers. However, in all these cases the particles are 3.2.3. Light-Emitting Devices. Colloidal semiconductor encapsulated as a bulk, losing their colloidal dispersity, which NPs have been explored as the principal emitters for thin film may be important when fine films of NPs are required. A new LEDs. These NPs are a unique class of light emitters with size- approach to tackle this issue by introducing the low molecular tunable emission wavelengths, saturated emission colors, near- weight polymer poly(maleic anhydride-alt-1-octadecene) unity luminance efficiency, inherent photo and thermal (PMA) during the synthesis of the perovskite NPs was stability, and excellent solution processability. The high color recently demonstrated. The PMA results in stabilization of purity together with the color-tunable emission make NP- the NPs by tightening the ligand binding and thus decreasing based LEDs promising candidates for next-generation displays interactions of the surface with the surrounding medium. The and solid-state lighting applications. A schematic represen- polymer capped perovskite NPs retained their colloidal tation of a modern NP-based LED device is illustrated in dispersity and were utilized to produce both monochromatic Figure 26a,b. green and white LEDs. The electrical characteristics of the NPs can vary depending For NPs of different and more stable chemical compositions on the surface modulation, which can change the luminance in comparison to perovskite NPs, such as CdSe, several other and emission efficiency. In view of this, understanding surface ligands have been employed to improve their blending and ligand effects is essential for improving the performance of function in NP-based optoelectronic devices. Specifically: (i) such devices. Evaluation of the LED properties as a Branched ligands, namely entropic ligands for NPs, were dependence of the ligand length has been performed by the developed, leading to better charge transport and higher 563,564 exchange of the 1.1 nm long TOPO ligand with the 1.7 nm EQE, (ii) multifunctional dendrimer ligands that serve as long oleic acid ligand. With all other conditions being the charge injection controlling layer as well as the adhesive identical, the luminance and efficiency of the LEDs with an layer at the interfaces between the NPs and the electron 4854 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 27. (a) Au-nanowire flexible pressure sensor, (b) FET sensor, and (c) FET gas sensor. (a) Reprinted with permission from ref 572. Copyright 2014 Macmillan Publishers Ltd., Nature. (b) Reproduced with permission from ref 573. Copyright (2005) Elsevier. (c) Reproduced with permission from ref 574. Copyright 2013 American Chemical Society. transport layer (ETL), which gave promising results, and 27). Among the different NPs-based sensors developed to date, (iii) conjugated organic polymers such as block copolymer nanowire-based field effect transistors (FETs) have been ligands directly linked on the surface of the NPs. The widely used for detection of a variety of biological and copolymers consisted of both semiconductor and reactive chemical species, of pH value, of metal ions, viruses, proteins, functional blocks that contained multidentate thiol-based etc. In most of these applications, the mechanism of sensing is anchor groups. The key to the success of this architecture based on the functionalization of a homogeneous semi- was that by being bound to the semiconductor NP surface, the conductor nanowire, such as silicon and In O . The extreme 2 3 semiconductor ligands improved hole injection into the NPs sensitivity of nanowire and nanotube field-effect sensors and resulted in improved device performance (increased originates from their one-dimensional structure that enables electroluminescence intensity and quantum efficiency) com- efficient charge transfer between the surface-anchored pared with a similar device containing unmodified NPs. molecules and the nanostructures. The efficiency of LED devices is affected mainly by the To use nanomaterials as sensors, the understanding of the luminescence quality and the emission efficiency of the peculiarities of both the synthesis and interaction mechanism nanoparticulate light emitters. If the ligand length is relatively during the sensing procedure is required. A sensor can ideally long, the luminescence and the device efficiency is increased. satisfy some important requirements: (i) specificity for the The efficiency is 1.5 higher by using oleic acid capped NPs target species, (ii) sensitivity to changes in target-species instead of utilizing TOPO-capped ones, or is increased from concentrations, (iii) fast response time, (iv) extended lifetime, 12.2 to 20.5% when octanethiol is replaced by 1-dodecanethiol. and (v) reduced size (miniaturization) together with low-cost Furthermore, the type of the capping ligand is important in the manufacture. Noble metals, metal oxides, or rare-earth 567,568 hole-injection into the NPs but also the stability of the doped NPs have been extensively utilized in such semiconductor NPs, especially in the case of perovskite NPs. applications. NP ligands should play an important role in To obtain colloidal stability, which is important for the absorption/adsorption of organic volatile molecules and gases formation of very thin films, polymeric capping ligands of low- taking place during the sensing process. Furthermore, during molecular weight are introduced. Particular attention should be the fabrication of sensors, NP film formation is driven by paid to the retention of the luminance quality. electrostatic interactions and van der Waals dispersion 3.2.4. Sensors. A sensor is an analytical device that detects interparticle forces. Such interactions are determined by the physical or chemical changes (e.g., in temperature, pressure, NPs’ surface ligand coverage. light, concentration, etc.) and converts them into measurable Indeed, it has been widely reported that careful selection and signals. In recent years, the interest of researchers and design of ligands strongly influence the sensitivity and engineers to gas- and liquid-sensitive materials has grown selectivity of a NP-based sensor. For example, Au NPs substantially due to the progress in nanotechnology (Figure functionalized with 1,10-phenanthroline have been utilized 4855 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 28. Effect of the ligand on the signal of the vapor and catalytic sensors. (a) Electrical responses of 4-mercaptophenol functionalized (referred to as “OH” NPs) and 4-methylbenzenethiol functionalized gold NPs (referred to as “CH3” NPs) to the nonpolar solvent dichloromethane (DCM) and to methanol. (b) Maximum relative resistance vs concentration of the analyte vapors of 1-propanol, acetone, and cyclohexane for mixed-ligand NPs (S1, Au NPs with 50% chlorobenzenemethanethiol (CBMT):50% n-octanethiol (OT) mixed ligand; S2, Au NPs with 33.3% CBMT:66.7% OT mixed ligand; S3, Au NPs with 16.7% CBMT:83.4% OT mixed ligand). (c) Activation period for the Pt NPs-based catalytic gas sensor for hydrogen sensing. The NPs is covered with different molecules such as phenylenediamine (PDA), 1,8-diaminooctane (DAO), bipyridine (BiPy), aniline, and hexadecylamine (HDA). (a) Reprinted with permission from ref 571. Copyright 2002 IOP Publishing. (b) Reprinted with permission from ref 575. Copyright 2005 Elsevier. (c) Reprinted with permission from ref 576. Copyright 2014 Royal Society of Chemistry. for the detection of Li ions. This type of ligand binds surface properties (Figure 28b). The respective sensors selectively to the Li by forming a 2:1 ligand−metal complex, experienced repeated cycles of analyte vapors (1-propanol, causing Au NPs to aggregate. Such aggregation causes a shift in acetone, and cyclohexane) and blank air gas, while the analyte the extinction spectrum accompanied by a concomitant color concentrations were varied. It was observed that the variations change, providing a useful optical method of detecting Li in in compositions of the ligand molecules resulted in remarkable aqueous solution. Furthermore, the electrical response to differences in signal amplitudes. chemical vapors adsorbed on Au NPs films has been found to Finally, it should be mentioned that the stability of NP- based sensors is also affected by the ligand coating. For vary markedly by the surface functional groups. In particular, two types of ligands namely, 4-mercaptophenol instance, a series of amine ligands (mono- and bifunctional (referred to as “OH” ligand) and 4-methylbenzenethiol alkyl- and aryl amines) have been used to stabilize Pt NPs as (referred to as “CH ” ligand) have been utilized to function- catalytic materials for H gas sensing (Figure 28c). 3 2 alize Au NPs. It was found that the conductivity of the Depending on the ligand coating used, remarkable differences respective CH −NP film dropped by ∼70% from the initial in the sensor performance, both in terms of the catalytic value, while that of the OH-NP film showed a decrease by only performance, the activation period as well as stability have ∼10% (Figure 28a). Two physical effects were reported to been observed. explain such conductivity changes. Under high partial pressure, Careful selection of the NP ligand coating is essential, as the change in NP core−core separation was the main ligands strongly influence the sensitivity, the stability and the contribution to the conductivity change and generally selectivity of the NP-based sensors. Specific type of ligands can deteriorated the conductivity. However, for relatively low selectively bind to metal-anions and produce changes in color partial pressures the adsorption of vapor molecules lead to or conductivity alterations. Different types of ligands attached permittivity changes that tend to enhance the conductivity. to NPs in the same device can be used for different chemical Adifferent sensing approach is the use of mixed-ligand Au selectivity. Remarkable differences in the signal amplitude can NPs for vapor sensing. In particular, Au NPs with a mixture be originated from variations in compositions of the ligand of ligands (chlorobenzenemethanethiol (CBMT) and n- molecules. octanethiol) have been synthesized in order to study the 3.2.5. Memory Devices. Memory elements are the different chemical selectivity due to the modification of the integral parts of computers, identity document (ID) cards, 4856 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 29. (a) Digital memory device utilizing Pt NPs. (b) Hysteresis loops for NPs functionalized with different capping agents. (c) Magnetization curves for individual γ-Fe O NPs and for their ensembles (aggregates and chains). (a) Reprinted with permission from ref 583. Copyright 2006 2 3 Macmillan Publishers Ltd., Nature. (b) Reprinted with permission from ref 585. Copyright 2015 Elsevier. (c) Reprinted with permission from ref 590. Copyright 2008 Wiley. and various consumer electronics. Memory devices utilizing superparamagnetism. Their magnetization can be affected 215,585,586 NPs have been extensively explored during the past decade as strongly by the surface capping ligand (Figure 29b). In possible solutions to overcome the scaling issues and improve addition, magnetic NPs can be present in the form of powders, endurance of nonvolatile memories and hard-disk drives. NPs dispersions, or embedded in a matrix, which gives rise to a provide an opportunity to precisely control electronic and variation in the interparticle spacing and therefore in the 584,587−589 magnetic properties of materials by tuning their size and shape. interparticle interactions. Ensembles of NPs show The possibility of device fabrication using colloidal solutions properties that may be quite different from those of individual allows significant cost reduction, which is very important for ones (Figure 29c). The dipolar interactions between products such as wireless identification tags and smart cards magnetic NPs determine their collective state, which shows 591,592 where the prime criterion is cost and miniaturization rather the features of the magnetic glassy behavior. Therefore, than outstanding performance. ensembles of magnetic NPs show an increase in the blocking Ferromagnetic NPs are promising candidates for a density temperature, T , compared to that of individual particles 2 590 increase of magnetic storage devices toward 100 Gbit/inch up (Figure 29c). Chains of γ-Fe O NPs showed a 40K 2 3 to a few Tbit/inch . Until recently, increasing the recording increase in T and a faster approach to saturation of density simply meant down-scaling all of the components in a magnetization on variation of magnetic field in comparison recording system, but what has become clear over the past with individual γ-Fe O NPs and their aggregates. 2 3 decade is that the design of magnetic media and the continued Because of the small size of the NPs, a large fraction of the increase in density storage is fast encroaching upon the atoms in the NP is surface atoms. Because the ratio of surface fundamental physical limits imposed by the nature of atoms to the bulk atoms is large, surface contribution to magnetism on the nanoscale. To be applicable for magnetic magnetization becomes significant. The surface atoms storage media, the magnetization direction in a material should experience a different environment compared to the atoms of be very stable and not reverse due to thermal fluctuations. the core. Various defects from atomic vacancies to dangling From a simple geometry viewpoint, the smaller the bonds and lattice disorders exist on the NP surface and ferromagnetic NPs, the higher the recording areal density is. determine the macroscopic magnetic behavior. The type of the But considering the superparamagnetic limit of the ferromag- capping ligand is a crucial parameter for the fabrication of netic NPs, there should be a balance between NP size and ultrasmall NPs of narrow size distribution, but it is also thermal stability of the NP-based recording media. For responsible for the disordered spin structure on the surface. commercially viable recording media, the energy barrier Furthermore, the capping ligand length determines the required to reverse the magnetization from one direction to distance between the particles in an assembly and consequently another should be at least 60 times higher than the thermal the dipolar interactions between magnetic NPs. Numerous 579 580 581 energy (KV/k T ≥ 60). NPs of FePt, CoPt and approaches have been proposed correlating the dipole−dipole SmCo (characterized by a high anisotropy energy) are and exchange interactions to the nature of the assemblies’ among promising candidates for high-density magnetic record- cooperative magnetic behavior. 3.2.6. Thermoelectric Applications. Thermoelectric ing. A data storage device derived from self-assembled Pt NPs is materials can be utilized for conversion of heat to electricity, illustrated in Figure 29a. The device showed basic memory through the Seebeck effect or for cooling or refrigeration operations, such as operating voltages, data retention, and cycle through the converse Peltier effect. The basic architecture of a ability. The current−voltage characteristics of the device thermoelectric device consists of an element placed between a showed bistable states with an ON/OFF ratio larger than 3 heat source, e.g., corresponding to waste heat generation and orders of magnitude. the ambient (heat sink). The transfer of heat from the The magnetic behavior of an assembly of magnetic NPs with source to the sink is either through the motion of the carriers a randomly oriented easy axis represents a complex and (electrons/holes) or through the lattice (through collective challenging problem. This complexity arises from the lattice vibration modes/phonons). The carrier transport results coexistence of finite size and surface effects as well as the in the development of a potential difference, the Seebeck presence of interparticle interactions. Below a critical size, voltage (ΔV). The thermopower/Seebeck coefficient S is then magnetic NPs can exhibit unique phenomena such as the ratio of ΔV to the temperature difference (ΔT). 4857 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Thermal to electrical energy conversion, through thermo- transport properties, but partial sintering of NPs can modify electric and thermionic materials, has been proven to be much the distribution and even the chemical phase as it leaves a more efficient in materials at the nanoscale and can provide residual carbon layer that may limit thermoelectric perform- large values of the figure of merit, ZT, which is defined as ZT = ance. To minimize the effect of the annealing process and the S σΤ/k, where T is the average temperature of the hot and cold amount of residual carbon, the original surface ligands can be sides, and σ and k are the electrical and thermal conductivity of replaced in a previous step with shorter and weakly the material; k is the direct sum of the contributions from both coordinating molecules such as pyridine, hydrazine, ammonia, 594,595 the carriers (k ) and the lattice (k ). Quantum wells, and n-butylamine. Once the original bulky ligands have been e L nanowires, and semiconductor NPs are some of the low- fully replaced, a mild thermal treatment, generally with the NPs dimensional morphologies, which have been used in such already assembled/aggregated, can be applied. The impact applications. The thermoelectric figure of merit can be of surface-bound small molecules on the thermoelectric improved by maximizing the power factor (P = Sσ) and/or properties of the final-formed film was also demonstrated in minimizing the thermal conductivity. The power factor can be the case of self-assembled silver telluride (Ag Te) NP thin maximized by the development of new low-dimensional films which were fabricated by a layer-by-layer (LBL) dip- materials or optimization of the existing ones by doping coating process. Investigations on the electrical conductivity processes while the thermal conductivity can be minimized and Seebeck coefficient on the Ag Te NC thin films containing through nanostructuring and use of materials with intrinsically hydrazine, 1,2-ethanedithiol, and ethylenediamine between low thermal conductivity. Specifically, in the nanostructured 300 and 400 K indicated that these molecules could serve as materials, the thermoelectric performance is mainly attributed beneficial components to build NC-based thermoelectric to strong decrease of the lattice thermal conductivity (k ), devices operating at low temperature. The power factor probably by effectively scattering phonons that otherwise could also be improved by 2 orders of magnitude by tuning would have relatively long mean free paths, rather than an ligand-coupling symmetry (tuning the functionality of the increase in the electrical power factor. polar headgroup and the coupling symmetry of the organic Surface engineering of the NPs for thermoeletric applica- linkers) through layer-by-layer assembly methods in the case of tions is necessary to control NP growth, drive their assembly, Cu Se NC thin films. These resulted in the highest power 2x and modulate their functional properties. This requires factor measured for QD-based thermoelectric inorganic 3 2 600 additional understanding not only of the surface influence on organic composite materials of ∼30 μW/m K . properties related to such applications but on the effect of each Both the ligand type and ligand removal influence the surface treatment on the final surface composition. In thin-film properties of NP. The suitability of the strategy used for ligand and nanowire thermoelectrics, the free surface in contact with removal/replacement is dependent on the type of bonding to vacuum or the atmosphere may also be an important the NP surface. Modifications of the NP surface chemistry interface. The role of the interfaces in the thermoelectric have been evaluated to improve transport properties of NPs performance is beneficial as they contribute to the reduction of through introduction of inorganic surface ligands with the thermal conductivity, k, and under certain conditions, to relatively high charge carrier mobilities. The charge carrier the enhancement of the Seebeck coefficient, S. However, concentration can also be adjusted by balancing the ratio of interfaces also usually increase the electrical resistivity, ρ, due surface cations and anions in polar compounds through the use the insulating capping layer. Improvement of the ZT requires of proper surface ligands. Surface ligands can also act that the proportional reduction in electronic carrier mobility themselves as donating or accepting dopants. A stripping resulting from increased interfacial scattering is less than the method using a strong inorganic acid (HCl) was recently corresponding reduction in thermal conductivity. Thus, demonstrated for removal of the carboxylic acids from the NP balancing the electronic and thermal properties of the surface capped with oleic acid in solution. Chlorine (Cl ) ions, interfaces is critical to tailor a material for optimal thermo- initially located on the NP surface diffuse, upon a consolidation electric performance. Interfaces are effective in scattering long step, inside the crystal structure to act as a donor, providing the mean-free-path electrons and phonons but have minor effects nanomaterial with n-type electrical conductivity and a tunable when the mean-free-paths are smaller than the spacing charge carrier concentration. The procedure takes advant- between interfaces. If the interface is a barrier to electronic age of a ligand displacement step to incorporate controlled transport due to the insulating layer and not just a single concentrations of halide ions while removing carboxylic acids scattering site, it may have a significant effect on the transport from the NP surface. Halide passivation and metal cations on and the ZT. The thermoelectric performance can be the surface have been proven to control the net NP surface improved by surface engineering through (i) increasing the charge while at the same time preventing the formation of deep grain boundaries population, (ii) selection of a conducting electronic traps by avoiding oxygen absorption. In a ligand, (iii) removal/modification of the surface ligands, and different approach, metal salts were used to eliminate the (iv) ligand modification for optimum self-assembly. organic surface ligands without introducing extrinsic impurities Ideally, improved thermoelectric performance can be in the final nanomaterial. A6-foldincrease ofthe obtained by increasing the grain boundary population toward thermoelectric figure of merit of Ag Te was obtained when specific interfaces without decreasing the electronic transport. organic ligands were displaced by AgNO . This can be done with approaches of introducing high Finally, the choice of a proper ligand can affect the synthesis densities of relatively well-ordered interfaces such as twin of well-dispersed and monodispersed NPs as well the well- and domain boundaries. Such techniques to increase the twin- ordered self-assembly process. Self-assembly/superlattice boundary density through repeated strain−anneal cycles have procedures depend both on interactions between NP building been studied widely in metals and could be transferred to blocks and on the process kinetics. The interactions thermoelectric materials such as Bi Te and related between NPs can be van der Waals, dipole−dipole, magnetic, 2 3 596,597 alloys. Annealing results in nanomaterials with enhanced or electrostatic. Thus, assembly is usually triggered by 4858 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Figure 30. Effect of NP capping agent on the catalytic activity. (a) Rate and induction time of 4-aminophenol reduction of functionalized Au NPs with citrate and PEG-SH. The correlation between the reduction rate and the free catalytic site density on Au NPs is shown as well. (b) Iron oxide nanoparticles covered with polyphenylenepyridyl dendrons of the second and third generations with dodecyl periphery and the effect of the different coverage on the catalytic performance in the selective hydrogenation of dimethylethynylcarbinol (DMEC) to dimethylvinylcarbinol (DMVC). (a) Reproduced with permission from ref 621. Copyright 2016 American Chemical Society. (b) Reprinted with permission from ref 622. Copyright 2014 American Chemical Society. adjusting the surface/ligand-related interactions. The most compounds. These magnetic particles can be of a single 608 609 commonly used strategy to produce organized superlattices is phase or core−shell double-phase structures. The to force a slow NP assembly in solution by increasing the separation of the nanocatalysts is an important process and concentration through solvent evaporation. This procedure is time and energy consuming, often with environmental requires NPs with a very high colloidal stability and narrow- implications. Magnetically recoverable catalysts have size distribution, which are both affected by the type of surface attracted considerable attention due to their potential to ligand. combine catalytic properties and efficient materials’ recovery 3.2.7. Catalysis. Nanocatalysis, which involves the using an external magnetic field, thus minimizing the total cost 611−618 utilization of NPs to catalyze reactions, has attracted and helping to preserve the environment. Generally, considerable attention during the past decade, both for these catalysts consist of a magnetic part and a noble metal. In homogeneous and heterogeneous catalysis applications. bulk noble metal catalysts, the metal particles tend to aggregate Because NPs exhibit a large surface-to-volume ratio compared during the reaction process, leading to the reduction of the to bulk materials, they are promising candidates for use as catalytic activity. However, multifunctional, Fe O -noble metal 3 4 catalysts. NPs of different chemical phases, e.g., metals, hybrid nanoparticles present ideal nanomaterials to overcome semiconductors, oxides, and other compounds, have been this limitation. widely used for such applications. The chemical reaction is The most important issue to consider when designing a performed on the surface of a catalyst particle at a high nanocatalyst for use in a solution is to prevent the NPs from temperaturewhile thecatalystparticleisinagaseous aggregating as this limits the specific sites at the surface for environment or in a liquid. In many cases, the chemistry and catalytic reactions. The careful choice of the capping agent structure of a catalyst particle during a catalytic reaction could can eliminate aggregation, allowing the nanomaterials in the be different from those before catalysis. The challenging issue colloidal solution to be used for recyclable catalysts. The role of nanocatalysis research is to produce catalysts with high of the ligand and the packing density on the catalytic reduction selectivity, high activity, low energy consumption, and long of 4-nitrophenol has been studied by utilizing PEG-thiol- lifetime. This can be achieved by a material design process by functionalized Au NPs (Figure 30a). A direct relationship precisely controlling the size, shape, spatial distribution, surface between the chain length and packing density of the PEG and composition, electronic structure, and thermal/chemical the Au NP catalytic activity was found. High surface coverage stability of the individual nanocomponents. Catalytic chemical of low molecular weight PEG (1 kDa) completely inhibited the reactions mainly include oxidation reactions, reduction catalytic activity of Au NPs. Increasing the molecular weight reactions, coupling reactions, and electrochemical reactions. and decreasing surface coverage was found to correlate directly Ferrite NPs have also been applied in catalytic reactions with increasing rate constants and decreasing induction time. mainly in processes of synthesis and destruction of organic Instead, the selective blocking of more active sites by adsorbed 4859 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review thiol functionality was attributed to the induction period and the appropriate selection of ligands, including their hydro- reduced catalytic activity. phobic/hydrophilic nature as well as their density and packing Adifferent system proving the important role of the capping on the NP surface, which is directly correlated to their agent on the final catalytic activity is a magnetically recoverable reactivity. Equally, the use of NPs in a vast range of catalyst, obtained via encapsulation of Pd NPs in dendron/ optoelectronic applications requires them to be able to easily dendrimer shells of ferrimagnetic magnetite nanoparticles. transfer carriers across their ligand shells and to adequately High densities of well-separated metallic NPs could be formed disperse in media, such as polymers. The NP ligand choice in and supported at specific sites on the porous surface of the these cases is critical and directly correlated with the topology nanoparticles. This system was subsequently tested for its of the active blends, which in turn influences the performance functionality in the selective hydrogenation of dimethylethy- characteristics of devices. nylcarbinol to dimethylvinylcarbinol (Figure 30b). The Although the field of NP design has seen an unprecedented catalytic activity in these systems is dependent on the growth in the last two decades, we still have to gain further dendrimer generation, which determined the specific sites for experimental knowledge, which correlates the physicochemical the growth of the Pd NPs as well as their size. The highest characteristics of NPs to their desired function. This is also turnover frequency in the hydrogenation was found for an important in order to better inform the NP design to the optimum Pd NP size around ∼1.5 nm. The catalytic activity suitable choice of ligands. The appropriate selection of ligands was also examined for larger (∼3 nm) and smaller (∼0.9 nm) to grow NPs in large scales with narrow size distribution and Pd NPs, but the catalytic performance was proved weaker. adequate manipulation of their morphology as well as the Importantly, the stability of this system was demonstrated by control of ligand density and hydrophilicity on the NP surface its repeated use in up to three catalytic cycles. These hybrid are essential goals to achieve. An important question that needs nanostructures could then exhibit high catalytic performance more elucidation is the exact interactions between ligands and and fast recovery in the presence of an external magnetic field. NP. While for some ligands the type of bonding interactions Various research groups have studied the photocatalytic are well-understood, this is by far not the case for other ligand properties of semiconductor nanocrystals capped with different types. For example, the bond between gold and thiols is often organic molecules. The photocatalytic activity was found to be discussed to be a covalent one. However, all that is known is higher in the case of the oleic acid-capped TiO nanocrystals that the bond is very strong. As discussed in section 2, the most than both their tri-n-phosphine oxide-capped counterparts and commonly accepted model for thiol−Au interaction is the commercial TiO P25 Degussa. It is proposed that efficient binding of the deprotonated sulfhydryl group (forming a thiyl catalysis strictly depend on microscopic mechanisms that occur radical) to Au with coordination-type bonds. Proper at the catalyst surface, basically involving specificdye understanding of the details of the internal structure and adsorption and local density of terminal OH moieties. stability of an organic thiolate ligand shell around a metal NP is Furthermore, Vorontsov et al. investigated the photocatalytic crucial for adequately controlling important ligand-exchange behavior of different TiO samples with different surface reactions and requires more in depth research. With respect to area. They found that the size and surface does not have a semiconductor NPs, many ligands are classified as L, X, or Z direct influence on photocatalytic activity but it is rather type depending on the number of electrons donated or surface properties such as surface acidity and hydroxyl groups. accepted when interacting with a metal center. This notation The nanosized TiO photocatalysts prepared by employing 2 could be equally useful for the classification of ligands on long chain acids, octanoic and palmitic acid, showed better metallic NPs. However, in many cases, the exact ligand−metal photocatalytic activity than the commercial Degussa P25. interactions remain not fully understood and thus this presents Apart from acid ligands, another ligand, which increases the an important area of research needing to be addressed. photocatalytic activity of the TiO nanostructures, is the low- 2 Additionally, the nature of the surface ligands will determine cost sensitizer PVP. This ligand improves the photocatalytic the final application of the NPs. For example, in biomedicine, a activity of the NPs through a ligand-to-metal charge transfer popular type of Au NPs commonly employed in phototherapy mechanism. and drug delivery are those with a rod- or branched- shape. Careful choice of the ligand type and density can improve However, in most cases, these particles are synthesized using the catalytic activity, the selectivity, and the lifetime of toxic cationic surfactants such as CTAB and CTAC. Although nanocatalysts. The capping ligand prevents the NPs from several ligand exchange steps can be performed to remove aggregating which would have a detrimental effect on the these ligands prior to their use in biomedical applications, this catalytic activity. They also determine the specific sites for is not cost- and time- effective. New methods to produce these growth of well separated metallic NPs in hybrid magnetic- NPs directly with nontoxic ligands or biomolecules of interest metallic systems. would be highly beneficial for their broader application. On the other hand, one of the bottlenecks hindering industrial 4. CONCLUSIONS AND FUTURE PERSPECTIVES applications of NPs is the difficulty of scaling up their synthesis. While many published protocols are ideal for The accurate synthesis and functionalization of inorganic NPs producing certain types of NPs at the milligram scale, they is critical for their colloidal stability and their performance in are not appropriate for larger scale production, so cheap challenging environments. From applications in biology to applications in physical sciences, the choice of NP surface approaches to larger scale production is one of the challenges chemistry defines the NP activity and dispersibility and the in the field to be answered. In applications such as observations can be very different between particles with photovoltaics, photodetectors and sensors, the performance adequately designed surface chemistry in comparison to poorly of the final devices is determined primarily by the designed surface chemistry. NP toxicity, targeting ability, drug morphological and structural features of the NPs but also by delivery efficiency, circulation in the body, and interaction with the alignment of the NPs during their assembly. Upon proteins, cells, or more complex biological systems depend on assembly, the ligands block the active surface sites and/or 4860 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review prevent the formation of smooth films that are free of cracks. AUTHOR INFORMATION Different methods have been proposed for such an assembly, Corresponding Author but there are many parameters during these processes which *Phone: (0)23 8059 2466. E-mail: a.kanaras@soton.ac.uk. are still unexplored or incomprehensible. The removal of the ORCID capping ligands in such applications is a necessity in order to fabricate devices with high efficiency. Methods used to remove Neus Feliu: 0000-0002-7886-1711 these ligands typically result in release of NPs from the surface Indranath Chakraborty: 0000-0003-4195-9384 or cause undesired growth of the NP core. This poses an issue Eunkeu Oh: 0000-0003-1641-522X for the stability of the devices. The development of new Kimihiro Susumu: 0000-0003-4389-2574 strategies or improvement of the existing methods for the Igor L. Medintz: 0000-0002-8902-4687 effective removal of the capping ligands without affecting their Emmanuel Stratakis: 0000-0002-1908-8618 morphology and structure is a necessity. Wolfgang J. Parak: 0000-0003-1672-6650 4.1. Stability of NPs Antonios G. Kanaras: 0000-0002-9847-6706 Present Address The use of dispersible NPs in complex media is very important and directly linked to the function of NPs as already discussed A.H.-J.: Ludwig-Maximilians-UniversitatM ̈ ünchen, 80539 earlier. A vital element for the successful design of well- Munich, Germany. dispersible and functional NPs is a thorough analytical Notes characterization during their synthesis, something that is The authors declare no competing financial interest. missing in various published studies. Understanding the way that ligands pack on the NP surface, the strength of ligand−NP Biographies surface interaction, the net charge on the microenvironment Amelie Heuer-Jungemann obtained her degree in Chemistry with around the NP, and how these characteristics change when NP Biochemistry from Heriot-Watt University, Edinburgh (2011), and a size and morphology is varied are critical parameters to control Ph.D. in Physics from the University of Southampton (2015), the stability and function of NPs. Gaining deeper insight and working on biomolecule−nanoparticle conjugates for biomedical control over these parameters are important goals to be applications in the Laboratory for Inorganic Nanoparticles and focused on. Applications. She undertook postdoctoral research at the University of Furthermore, in some cases, for example when NPs are used Southampton until 2016, and she is currently a postdoctoral fellow at for in vivo applications, it is required that after the NPs the Ludwig-Maximilians-University, Munich, where her research is complete their role they can be cleared from the organism for focused on applications of DNA origami. example by degradation and extraction through the kidneys. Neus Feliu graduated in Chemistry from the Universitat de Barcelona Thus, further work toward the direction NP ligand coatings (UB) in 2007 and obtained her Master of Science degree in that facilitate NP degradation is desirable and will significantly Biomedical Materials from the Royal Institute of Technology (KTH) benefit the elimination of their toxicity. in Stockholm in 2009. She obtained her Ph.D. in Medical Science 4.2. Density and Steric Configuration of Surface Ligands from Karolinska Institutet (KI), Stockholm, in the field of Engineered Nanomaterials for Biomedical Applications in 2014. Then, she was a The reactivity and multifunctional ability of the NPs strongly postdoctoral researcher at the Department of Clinical Science and depends on the presentation and number/type of ligands on Technology (CLINTEC) at KI. Then, she joined the Department of the NP surface. Although there are methods to quantify the Laboratory Medicine (LABMED), Clinical research Center, KI, number of ligands for certain types of NPs such as gold, for Stockholm, as a Vinmer Fellow and Marie Curie Fellow. Currently, most of the cases of various other types of NPs, this is still a she is a Research Associate at the Center for Hybrid Nanostructures great challenge. Also in most cases it remains quite difficult to (CHyN), Hamburg University (HUU). Her research interest focuses measure the reactivity of individual functional molecules such on understanding the interactions between nanoparticles and as antibodies anchored on the NP surface. Therefore, future biological systems and to explore their use in medical field. developments in these directions will strongly benefit the Ioanna Bakaimi received her degree in Physics from the Aristotle better understanding of NP design and their most suitable University of Thessaloniki and a Masters degree in Applied Physics applicability. Additionally, the development of new imaging from the University of Silecia. Then she obtained a Ph.D. degree in methods to accurately visualize the conformation of ligands on Physical Sciences from the Department of Physics, University of the NP surface could significantly inform a better NP design Crete, and the Institute of Electronic Structure and Laser, FORTH, and improve functionality. Especially with a view on using specializing on the magnetic properties of materials. Currently, she is biomolecules such as peptides, proteins, or oligonucleotides as a Research Fellow at the School of Chemistry, University of ligands, it would be extremely beneficial to be able to directly Southampton, UK, working on materials synthesis and character- visualize their conformation on the NP surface as this directly ization for applications in Energy. influences their biological activity. Majd Hamaly obtained a B.Sc. in Pharmacy and a master degree in To conclude, this review article focused on highlighting the Pharmaceutical Sciences from the University of Jordan before joining importance of ligands on (a) NP synthesis, (b) dispersibility of the King Hussein Cancer Center. Her research focus is the biomedical NPs in complex media, and (c) the effectiveness in application of nanotechnology. applications ranging from biology to physics as well as giving an outlook to challenges, which yet remain to be fully Allaldin Alkilany completed a B.Sc. in Pharmacy (Jordan University of addressed and give opportunities for exciting future research. Science and Technology), a Ph.D. in Chemistry (the University of We believe that it will be a valuable addition in setting the Illinois, USA) and postdoctoral training (Georgia Regents University, scene for future developments to come in the field. USA) before joining the academic staff at the University of Jordan. Dr 4861 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review Alkilany is an Associate Professor of Nanoscience and Pharmaceutical biocompatible quantum dots and gold nanoparticles for biosensing Technology at the School of Pharmacy (University of Jordan) and the and imaging technologies. Specifically, his recent research interest Alexander von Humboldt fellow at the University of Hamburg, includes (i) synthesis of a series of core/shell quantum dots and (ii) Germany. Dr. Alkilany’s research focuses on nanotechnology and its design and synthesis of a series of multifunctional surface coating biomedical applications, understanding the nanobio interface, and ligands to enhance the biocompatibility of quantum dots and gold engineering novel drug delivery systems. nanoparticles. Indranath Chakraborty received a Ph.D. in chemistry from the Indian Michael H. Stewart received a BSc. in chemistry from Wittenberg Institute of Technology, Madras. He was a research associate at the University (2002) and a Ph.D. in materials chemistry from the University of Illinois at Urbana−Champaign, IL, USA. Later, he was University of Michigan (2007). As an NRC postdoctoral fellow at the an Alexander von Humboldt Postdoctoral Research Fellow at Philipps U.S. Naval Research Laboratory (NRL), he developed hydrophilic University of Marburg, Germany. Currently, he is a research associate colloidal semiconductor quantum dots as advanced biosensing at Center for Hybrid Nanostructure, University of Hamburg, platforms. He is currently a federal scientist in the Optical Sciences Germany. His research area is focused on tuning surfaces of Division at NRL, where his research efforts focus on advancing plasmonic and fluorescent nanoparticles for biomedical applications. colloidal nanocrystal-based technologies for biological and photonic He is a recipient of the J. C. Bose Patent Award and the Malhotra applications. He is a recipient of the Sigma Xi Young Investigator Weikfield Foundation Nanoscience Fellowship Award. Award and Delores M. Etter Top Navy Scientist of the Year Award. Atif Masood received his M.Sc. in Medical Physics from from PIEAS, Igor L. Medintz received a Ph.D. in Molecular, Cellular and Islamabad. In 2018, he received a Ph.D. from the Faculty of Physics, Developmental Biology from the City University of New York in Phillips University Marburg, specializing on the synthesis, surface 1999. This was followed by a National Cancer Institute Fellowship modification, and bioconjugation of inorganic (QDs, plasmonic, with Prof. Richard Mathies of the College of Chemistry, University of magnetic, catalytic TiO ) NPs. Since 2018, he is a Senior Medical California, Berkeley, and some industrial experience with Vertex Scientist at Karachi Institute of Radiotherapy and Nuclear Medicine Pharmaceuticals. He began at NRL as a National Research Council (KIRAN), Karachi, Pakistan.. Fellow in 2002 and as a Research Biologist in 2004. He currently serves as the Senior Scientist for Biosensors and Biomaterials with the Maria Francesca Casula received her Ph.D. in Chemistry from the Center for Bio/Molecular Science and Engineering. His research University of Cagliari, where she currently is Associate Professor of interests include how nanoparticles engage in energy transfer and how General and Inorganic Chemistry. She has been a visiting researcher biological processes are altered at a nanoparticle interface. at the University of California, Berkeley, as a postdoctoral fellow. Her research area is focused on the design of functional nanomaterials for Emmanuel Stratakis is a Research Director at the Foundation for biomedical, catalytic, and environmental applications. Synthesis− Research and TechnologyHellas (FORTH). He received his Ph.D. properties relationships of the developed nanomaterials is achieved by in Physics from the University of Crete in 2001, and then he joined a multitechnique textural and structural characterization, and the the University of California, Berkeley, as a visiting researcher. He is corresponding results are reported in 115 scientific papers in peer- currently leading the Ultrafast Laser Micro- and Nano- Processing reviewed journals and two book chapters. group of FORTH (https://www.iesl.forth.gr/ULMNP). He has over 170 SCI publications and more than 6000 citations, and he has Athanasia Kostopoulou received her B.Sc. degree in Physics (2004) coordinated many National and EU grants. Since 2015, he is the and her M.Sc. degree (2006) on Materials Physics & Technology Director of the European Nanoscience Facility of FORTH, part of the from the Physics Department at the Aristotle University of NFFA-Europe EU Infrastructure, where he is a member of the Thessaloniki. In 2012, she received her Ph.D. from the Department General Assembly. He is a National Representative to the High-Level of Chemistry at the University of Crete, and since then she was a Group of EU on Nanosciences, Nanotechnology and Advanced Postdoctoral Fellow in the Institute of Electronic Structure and Laser Materials and a National Expert in the NMBP Program Committee of at FORTH in Heraklion. Since 2016, she is part of the group of the the Horizon 2020. He is a member of the Scientific Committee of Ultrafast Laser Micro and Nano Processing (ULMNP) Laboratory COST, of the Physical Sciences sectoral scientific council of the and she is working on the chemical synthesis and elucidation of the National Council for Research & Innovation of Greece, and national microscopic physical or photoinduced mechanisms involving nano- delegate of the OECD Working Party on Bio-, Nano-, and crystal systems. The last few months she is the coordinator of a Converging Tech (BNCT). project funded from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Wolfgang Parak studied physics at the Technische Universitat Technology (GSRT) related to perovskite nanomaterials for photo- München and obtained his Ph.D. in 1999 at the Ludwig Maximilians voltaic applications. UniversitatM ̈ ünchen. After a postdoctoral stay from 2000−2002 at the Department of Chemistry at the University of California at Eunkeu Oh received an M.Sc in physics from Pohang University of Berkeley, he started his own group in the framework of an Emmy Science and Technology (POSTECH) and worked for Samsung since Noether fellowship at the Ludwig Maximilias UniversitatM ̈ ünchen, 1996. In 2006, she obtained a Ph.D. in biological science from Korean which is equivalent to Assistant Professor. In 2005, he held there a Advanced Institute of Science and Technology (KAIST) on temporary position as Associate Professor for Physical Chemistry. In developing biosensors utilizing the property of energy transfer 2007, he became Full Professor at the Physics Department at the between quantum dots and gold nanoparticles. She subsequently Philipps Universitaẗ Marburg. Since 2013, he is also group leader at joined the Naval Research Laboratory through a postdoctoral CIC Bimagune in San Sebastian, Spain. In 2017 he moved to the fellowship of Johns Hopkins University. Currently, she focuses on the development of nanoparticle-based optical materials and their Universitat Hamburg as a Full Professsor in physics. He is also biological application. Associate Editor of ACS Nano. Kimihiro Susumu is a Research Chemist in the Optical Sciences Antonios G. Kanaras obtained his degree in Chemistry from the Division at the Naval Research Laboratory through KeyW University of Crete, and a Master’s degree in Bioinorganic Chemistry Corporation. His research has focused on the development of from the University of Ioannina. Then he received a Ph.D. degree 4862 DOI: 10.1021/acs.chemrev.8b00733 Chem. Rev. 2019, 119, 4819−4880 Chemical Reviews Review from the Department of Chemistry, University of Liverpool, working DMSO dimethylsulfoxide on the organization of gold nanoparticles using biomolecular tools. DMVC dimethylvinylcarbinol He was a postdoctoral scientist at the Department of Chemistry, DNA deoxyribonucleic acid University of California, Berkeley, and Lawrence Berkeley Lab, DTAB decyltrimethylammonium bromide working on the synthesis and energy applications of semiconductor DTT dithiothreitol nanoparticles. Currently, he is a Professor/Chair at the School of EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Physics and Astronomy, University of Southampton, and the Head of EG ethylene glycol the Laboratory for Inorganic Nanoparticles and Applications. EQE external quantum efficiency Antonios’ research is highly multidisciplinary working at the interface ETL electron transport layer of Physics, Chemistry, Biology, and Materials Science. He is Fellow of FDA Food and Drug Administration the Higher Education Academy, Fellow of the Royal Society of FET field-effect transistor Chemistry, Fellow of the Royal Society of Biology, and Fellow of the GO graphene oxide Institute of Physics. GSH glutathione GTS glutathione S-transferase HDA hexadecylamine ACKNOWLEDGMENTS His histidine A.H-J. was funded by the Leverhulme Trust (ref RPG-2015- HIV human immunodeficiency virus 005). A.M. was supported by HEC/DAAD with a Ph.D. HPA n-hexylphosphonic acid fellowship. I.C. was funded by an Alexander von Humboldt HRTEM high resolution transmission electron microscopy postdoctoral fellowship. N.F. acknowledges funding from the HSA human serum albumin Swedish Governmental Agency for Innovation Systems ICBA indene-C bisadduct (Vinnova). A.F. was funded by DAAD/HEC. W.J.P. acknowl- ID identity document edges funding from the German Research Foundation (DFG ITO indium titatium oxide grant PA 794/28-1). M.F.C. acknowledges funding from LBL layer-by-layer University of Cagliari (under FIR 2018). A.G.K. acknowledges LED light emitting diode funding from BBSRC (BB/N021150/1, BB/P017711/1). A.K. Leu leucine acknowledges funding from the Hellenic Foundation for LNA locked nucleic acid Research and Innovation (HFRI) and the General Secretariat LSPR localized surface plasmon resonance for Research and Technology (GSRT), under grand agreement Lys lysine no. 1179. MBP maltose binding protein mPEG methoxy poylethylene gylcol ABBREVIATIONS USED MRI magnetic resonance imaging NC nanocluster Acac acetlyacetonate NHS N-hydroxysuccinimide Ala alanine NIR near infrared APTS aminopropyl trimethoxysilane NMF n-methylformamide Asn asparagine NMR nuclear magnetic resonance Au NP gold nanoparticle NP nanoparticle Au NR gold nanorod NTA nitriloacetate Ag NP silver nanoparticle OA oleic acid Ag NC silver nanocluster ODA ocatdecylamine Ag Te silver telluride ODE octadecene BHJ bulk heterojunction ODPA octadecylphosphonic acid BPEI branched polyethyleneimine OEG oligoethylene glycol BSA bovine serum albumin OLA oleylamine BSPP bis(p-sulfonatophenyl)phenyl) phosphine dehy- OPA n-octylphosphonic acid drate OPH organophosphate hydrolase CBMT chlorobenzenemethanethiol OPV organic photovoltaic CKD chronic kidney disease OT n-octanethiol Co NP cobalt nanoparticle P3HT poly(3-hexylthiophene-2,5-diyl) CPP cell-penetrating peptide PAA peroxyacetic acid CTAB cetyltrimethylammonium bromide PAMAM polyamidoamine CTAC cetyltrimethylammonium chloride PBS phosphate buffered saline Cu NP copper nanoparticle Pd NP palladium nanoparticle Cys cysteine PDMA polydimethylsiloxane Da Dalton PEDOT poly(3,4-ethylenedioxythiophene) DCB dichlorobenzene PEG polyethylene glycol DDA dodecylamine PEG-MA poly(ethylene glycol) methacrylate DDT 1-dodecane thiol PEG-SH poly(ethylene glycol) thiol DEG diethylene glycol PEI polyethyleneimine DFT density functional theory PEO poly(ethylene oxide) DHJ depleted heterojunction PFH poly(9,9-diheylfluorene) DHLA dihydrolipoic acid PHA polyhydroxyalkanoate DMEC dimethylethynylcarbinol 4863 DOI: 10.1021/acs.chemrev.8b00733 Chem. 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