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Synthesis, Characterization, and Application of Ultrasmall Nanoparticles Byung Hyo Kim, Michael J. Hackett, Jongnam Park, and Taeghwan Hyeon Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/cm402225z • Publication Date (Web): 07 Oct 2013 Downloaded from http://pubs.acs.org on October 9, 2013

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Chemistry of Materials

Synthesis, Characterization, and Application of Ultrasmall Nanoparticles Byung Hyo Kim,†,‡ Michael J. Hackett,†,‡ Jongnam Park,§,* Taeghwan Hyeon*,†,‡ †

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Korea School of Chemical and Biological Engineering, Seoul National University, Seoul 151-742, Korea § Interdisciplinary School of Green Energy, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea KEYWORDS ultrasmall nanoparticles, surface to volume ratio, spin canting effect, magic-sized nanocrystals, mass spectrometry ‡

ABSTRACT: Nanomaterials in the size range of 3–50 nm have received increased attention in the last few decades because they exhibit physical properties that are intermediate to those of individual molecules and bulk materials. Similarly, ultrasmall nanoparticles (USNPs), with sizes in the 1–3 nm range, exhibit unique properties distinct from those of free molecules and larger-sized nanoparticles. These properties are greatly sensitive to both the composition and size of the particle, thus the ability to control the synthesis for both of these variables is of paramount importance. This review summarizes various synthetic methods of USNPs of metals, metal oxides and metal chalcogenides as well as the recent advances in the development of unique characterization methods for these USNPs. Lastly is a discussion of several novel applications of USNPs in biomedical imaging, catalysis and semiconductor development, all of which benefit from the large surface to volume ratio and/or other characteristic properties inherent in USNPs.

been developed, and conventional techniques, such as transmission electron microscopy (TEM), are notably insufficient.10

1. Introduction Nanoparticles (NPs) of 3–50 nm have garnered a great deal of attention from the perspective of both basic and developmental science in a vast range of fields. This is due to the fact these NPs exhibit size-dependent electrical, optical, magnetic and catalytic phenomena that cannot be realized by their bulk counterparts. Iron oxide NPs, as an example, exhibit superparamagnetism at room temperature while semiconductor "quantum dots" exhibit the quantum confinement effect.1–4 For spherical particles, the surface area / volume ratio is inversely proportional to the radius so a substantial reduction in particle size leads to a dramatic increase in surface area. This increased surface / volume ratio is what gives rise to the specific physical properties.5–7 USNPs lie in between complete molecular 0dispersions and larger-sized NPs, and consequently exhibit intermediate structural, optical, electrical, catalytic, and magnetic properties. In this size range iron oxide USNPs become nearly paramagnetic7 and some noble metals, like gold USNPs, become fluorescent.8 Some of these unique properties are summarized in Figure 1. The extremely narrow size range of USNPs necessitates nearly monodisperse size distributions and precise characterization techniques to utilize these physical phenomena. Consequently, a firm understanding of the NP formation mechanism is critical to ensure NPs with the desired structures and characteristics can be obtained without the need for extensive sizedependent purification.9 Given the nascent nature of nanomaterials, specifically ultrasmall nanoparticles, new techniques to accurately measure the size of USNPs have not yet

Figure 1. Schematic diagram juxtaposing the differences in the size of particles and their resultant properties.

Since myriad excellent research has been reported in the field of nanotechnology, this review will focus specifically on ultrasmall nanoparticles. Sub-nm aggregates consisting of less than 20 atoms are better defined as clusters than particles or crystals. These clusters require different synthetic methods, characterization methods and result in different physicochemical properties.11 Thus clusters will not be categorized as USNPs for the purpose of this review. Instead, this review will mainly focus on the uniqueness of USNPs of 1-3 nm. USNPs

1 Environment ACS Paragon Plus


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have been thoroughly examined and reviewed in many scientific disciplines,5,6,12–18 so this review will attempt to unify the results across the scientific gamut. Specifically, this review will summarize USNPs of noble metals, magnetic materials and semiconductors in terms of their extremely large surface area and ultrasmall volume. These USNPs will be examined individually, detailing both the inherent attributes of specific elements followed by a discussion of the recent developments in synthetic methodologies. Subsequently this review will examine the advances in characterization methods and conclude with a discussion on the various technological applications being explored in this emerging field.

2. Properties of USNPs When the size of a material decreases to 1-3 nm, the number of atoms constituting the material falls to less than 500. Consequently USNPs can be regarded as large molecules where the majority of the component atoms are located at the interface with the solvent.18 This means a greater number of the constituent atoms of USNPs are exposed to the outer environment. This tendency is shown in Figure 2 where the smallest USNPs are almost entirely exposed to the solvent thus there is essentially no true core. When considering the range of USNP sizes, the percentage of atoms on the surface of a 1.2 nm particle is 96% while a 3.1 nm particle exposes only 31%.19 Below 1 nm, the particles are almost complete molecular dispersions, which is a partial reason for the differences in the macroscopic properties of USNPs compared to clusters. Additionally, as many properties are derived from interfacial interactions of the surface atoms with the solvent, it is easy to see why USNPs accentuate these properties compared to their bulk counterparts. Dominant surface states and the surrounding environment in USNPs can also lead to unique physical properties. For example, when iron oxide USNPs become nearly paramagnetic, it is due to the disordered surface spin. Additionally the surrounding matter, such as surface ligands, can have a dramatic effect on the overall properties of these particles. Au USNPs can exhibit ferromagnetism when the surface atoms are coated with thiol ligand. In addition, CdSe USNPs modulate their emission spectra based on attached ligand as well. Additionally, USNPs have different quantum states compared to larger NPs due to their small volume and small number of atoms.17,20 The controlled energy state modulates the reactivity compared to larger NPs.21 Noble metal USNPs show attenuated surface plasmon resonance and exhibit molecular-like optical properties due to loss of their metallic properties.22 Then the generation of an energy gap near the Fermi energy induces the unique optical properties of metal USNPs. Similarly, iron oxide USNPs possess quantized spin states while larger iron oxide NPs follow a continuum. This section will briefly introduce the unique properties of USNPs originating from the extremely large surface area and ultrasmall volume. The first 4 properties are derived from the surface effect, and the last 2 properties are derived from the small volume effect. However, these two effects can be difficult to differentiate. For instance, catalysis is modulated through surface effects but the selectivity is tuned by the reformed structure and energy state.

Figure 2. The percentage of atoms on the surface of Pd NPs. Reprinted with permission from ref 19. Copyright 2000 Springer.

2.1 Ferromagnetism of Noble Metal USNPs Kubo developed the theory of paramagnetism of small particle of group 11 metals,23 although those metals (Au, Ag, and Cu) are well-known diamagnetic materials. He hypothesized if a metal NP has an odd number of atoms, one electron in the particle must exist as an unpaired electron in the highest occupied state. When the number of atoms in a metal is small enough, the odd number effect becomes significant and the particles begin exhibiting paramagnetism instead of diamagnetism as a result. In fact, this effect has been observed in both metal and semiconductor USNPs.24

Figure 3. (a, c) TEM images and (b, d) field-dependent magnetization curves of (a, b) amine and (c, d) thiol-capped Au USNPs. Reprinted with permission from ref 27. Copyright 2004 the American Physical Society.

However, ferromagnetic behavior was observed for thiolcapped Au USNPs (Figure 3d)25–27 with similar results for USNPs of Ag and Cu.28 The Kubo theory then cannot explain these ferromagnetic properties because it is hard to say only one spin per particle induces exchange coupling. According to Crespo et al., this is a ligand dependent phenomenon as 1.4 nm Au NPs stabilized by weakly interacting amine ligands


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exhibited diamagnetism whereas those stabilized by thiol ligands exhibited ferromagnetism (Figure 3).27 The aforementioned thiol ligands on the Au surface can induce 5d localized holes. These holes cause localized frozen magnetic moments due to the symmetry reduction from the two types of bonding (Au-Au and Au-S) and strong spin-orbit coupling. Consequently, the local structure of the Au-S bond can account for the observed ferromagnetism. Because of the extremely large surface area of metal USNPs, the ferromagnetic properties originating from the surface become more dominant than the diamagnetic properties originating from the greatly diminished metal core. 2.2 Paramagnetism in Magnetic USNPs Iron oxide NPs typically show size-dependent superparamagnetic properties by the Neel and Brown relaxation effect induced by thermal fluctuation. This occurs when the thermal energy exceeds the anisotropic energy.3,4,29,30 However, the spins of surface atoms are disordered because of the differences between the states of the surface atoms and the bulk atoms. This is called the "spin canting effect," and the thickness at which the effect occurs in maghemite is ~ 0.5 - 0.9

core/shell structures composed of a magnetic core and a magnetically disordered shell.7 The magnetically disordered shell is considered as a paramagnetic compound so the total magnetization (M) of NPs is represented as a function of magnetic field (H) by equation 1. (Eq. 1) M (H )  Ms   H In this equation, Ms represents the saturation magnetization originated from magnetic core and χH is the magnetization from the paramagnetic shell. The magnetic susceptibility (χ) is obtained by extrapolation of the difference of the magnetization (M) - magnetic field (H) curves at high field. Because the magnetic core fraction of magnetic USNPs is small, the particles exhibit a smaller saturation magnetization than largersized NPs. In the case of iron oxide, USNPs which have an exceptionally large surface area also have significant paramagnetic activity. Assuming the thickness of the spin canted layer is 0.9 nm,32 iron oxide USNPs of < 1.8 nm become almost paramagnetic since almost all the spins are disordered. Kim et al. has demonstrated this by showing maghemite NPs of 1.5, 2.2 and 3 nm show only weak magnetic properties (Figure 4b, c).7 In particular, the 1.5 nm particles showed paramagnetism at room temperature.

nm.31–34 Therefore, magnetic NPs can be considered as

Figure 4. (a) TEM image of 3 nm iron oxide NPs. (b) Field dependent magnetization curves for various sized NPs. The iron oxide USNPs were nearly paramagnetic. (c) Schematic illustration for the spin canting effect. The spin canted surface layers are assumed to be 0.9 nm. (d) Size-dependent magnetic resonance (MR) properties of iron oxide NPs. (e) USNP enhanced T1-weighted blood pool MR image. Reprinted with permission from ref 7. Copyright 2011 American Chemical Society.



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2.3 Pinned Emission In the case of semiconductors, USNPs have a larger band gap than larger NPs because of their low density of states. 1 In addition, dominant surface states and the surrounding environment also induce changes in the electronic structures. 5 This is observed when CdSe USNPs exhibit a unique broad emission covering the entire visible spectrum ranging from 400 nm to 800 nm, including a blue emission at 445 nm.35 The spectrum is too broad to be explained by quantum confinement alone, nor is it likely due to a lack of uniformity in the USNP population. The blue emission (445 nm) is not from the band gap considering the size-independent wavelength of the peak and the large Stokes shift.36 Additionally, the wavelength and intensity of this peak can be manipulated following the coordination of different surface ligands, suggesting the blue peak likely originated from the particle-ligand interaction. Surface ligands on the NP can act as a trap and consequently pin the emission while the excitation remains variable with respect to particle size.37 This phenomenon of pinned emission has also been confirmed by studying the decay kinetics using ultrafast spectroscopy.38 2.4. Chemical Properties USNPs often exhibit unusual chemical properties and their reactivity is distinctly related to their size due to a combination of their large surface area and reformed structure.13b,39–43 One example is the ability of Au USNPs to oxidize CO well below room temperature.40 Tsunoyama et al. reported that Au USNPs of < 1.5 nm stabilized by poly(N-vinyl-2-pyrrolidone) (PVP) presented higher reactivity for the aerobic oxidation of alcohols than larger sized Au NPs.41 This enhanced catalytic activity was explained by the negatively charged Au cores resulting from electron donation from PVP. Additionally, the crystal structures of USNPs are often markedly different from their bulk counterparts. While bulk Au and Au NPs > 3 nm exhibit a face centered cubic (FCC) structure, Au USNPs often have non-FCC atomic packing structures.13b For USNPs, even minor atomic changes in particle size can lead to dramatic property differences. For instance, Au38 is smaller than Au40 by only 2 atoms, however they show completely different Lewis acidities in the chelation of bidentate thiol ligands.44–46

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In this equation δ is the energy level spacing near the Fermi energy, EF is the Fermi energy, N is the number of metal atoms in the particle and z is the valency. An Au USNP less than 400 atoms (D < 2.5 nm) shows large energy level spacing which exceeds the thermal energy at room temperature.48 As a result Au USNPs absorb light in the wavelength range of 350–400 nm and emit fluorescence, demonstrating these USNPs act as fluorescent centers.21,49 According to Zheng et al., Au USNPs exhibit bright fluorescence throughout the visible and nearinfrared regions and the emission wavelength is tunable with respect to particle size.8 In a similar approach, Ag USNPs also showed luminescent properties.50 Further, Ramakrishna et al. found Au USNPs can be utilized as two-photon absorption materials with a large absorption cross-section in the nearinfrared region.51 A similar observation was made by Patel et al. who reported two-photon emission by water soluble Ag USNPs.52 This ability to fine tune the fluorescent properties of noble metal USNPs can lead to the generation of highly efficient optical probes that could replace organic dyes as well as highly toxic quantum dots. The luminescent properties of these particles have been improved by various approaches because as-synthesized USNPs often shows very poor optical properties. 50,53,54 Nonluminescent as-synthesized Ag USNPs became highly luminescent after purification through a desalting column.50 Additionally, highly fluorescent Au USNPs have been prepared by ligand-induced etching.53 Au NPs were etched via a ligand exchange reaction using polyethyleneimine (PEI), leading to Au USNPs that emitted intense green light. Ying et al. reported a simple, one-pot synthesis of luminescent USNPs with high quantum yield based using bovine serum albumin (BSA).54 BSA molecules sequestered, entrapped, and reduced Au ions in the basic solution, consequently forming Au USNPs which were highly fluorescent.

2.5 Fluorescence of Noble Metal USNPs Noble metal (Au, Ag) USNPs exhibit fluorescence instead of surface plasmon resonance. Surface plasmon resonance occurs when the conduction band electrons absorb a photon generating a very slight charge at the surface which is not felt by the core. This disparity allows the conduction band electrons to oscillate coherently which can be relieved by the emission of a photon. The minimization of a core in Au USNPs precludes this ability instead promoting electrons to a higher energy state which can then be emitted as fluorescence due to the generation of a discrete electronic state. When the size of a metal particle reduces to a few nanometers, close to the Fermi wavelength of conduction electrons of noble metals (1 nm), the energy levels become quantized, leading to the formation of energy gaps.15 The energy level spacing near the Fermi level of a NP can be estimated by Kubo's statistical formula given by equation 2.47 

EF Nz

(Eq. 2)

Figure 5. The comparison between magnetic nanoparticles (MNP) and molecular nanomagnets (MNM) regarding the barriers to the magnetization re-orientation. Magnetic USNPs have quantized spin state like the molecular nanomagnets. Reprinted with permission from ref 17. Copyright 2012 Wiley−VCH Verlag GmbH & Co. KGaA.

2.6 Spin Quantum Effect Recently, it was reported magnetic USNPs have discrete spin quantum numbers whereas larger-sized particles exhibit a continuum of energy states. At low temperatures, iron oxide USNPs exhibit blocked magnetization and stepped magnetic hysteresis, a property often observed in molecular magnets such as Fe8O2 oxo clusters.55 The stepped magnetic hysteresis is derived from the quantization of spin states in the iron oxide particles due to their extremely small volume (Figure 5).17,55 The spin quantum effect was confirmed by electron magnetic


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resonance (EMR) studies.56–58 In a study by Fittipaldi et al., iron oxide clusters were synthesized in the cavity of a ferritintype protein which both constrains the size and reduces solvent interactions.56 The EMR spectra of these clusters showed a unique temperature behavior which was very similar to that of solution synthesized iron-oxo clusters.17,59 As the temperature decreased, the width of the main resonance increased due to reduced thermal averaging. Interestingly, a half-field signal rises in the EMR spectrum clearly demonstrating the spin quantum effect in USNPs.

3. Synthetic Methods The size-dependent properties of USNPs are more prominent than those of larger-sized NPs. Simply adding a single Au atom into Au USNPs can induce changes in the structural, optical, and electrical properties.60 Consequently, the reproducibility and monodispersity are critical considerations in the synthesis of sub-3 nm USNPs. One method for the synthesis of USNPs is the cluster beam method which involves ablating a material with plasma and dispersing the droplets under very high pressure. After Smalley et al. discovered fullerene derivatives could be synthesized via this method,61 many researchers began to synthesize USNPs, such as magic-sized Au clusters, via the method.60 Theoretical calculations predicted several energetic minima where Au could form stable cluster sizes; the calculated sizes matched the experimental results well.62,63 However, the cluster beam method itself is not efficiently sizeselective as it usually produces a very small quantity of polydisperse clusters which may require a subsequent laborious purification step. Because of this, solution-phase colloidal methods have been the most intensively studied due to their simplicity and reproducibility in the synthesis of uniform NPs with controllable sizes, shapes, and compositions.64,65 Colloidal methods involve several techniques including reduction, thermal decomposition, and sol-gel processes. These processes follow LaMer's crystallization theory where particles are formed by nucleation and subsequent growth.64,66 Based on the theory, several strategies could be implemented to reduce the NP size. In the nucleation process, increasing the supersaturation level could induce a higher rate of nucleation. If more nuclei are generated, given a constant mass of monomers, a larger number of smaller particles will result. To achieve this, labile precursors or strong reducing agents have been used.67,68 When isolated in the early stage of the NP formation, USNPs were often found.69 From this observation, it is possible to synthesize USNPs by precluding further growth beyond this point. Magic-sized CdSe NPs (section 3.3) were commonly obtained by lowering the aging temperature to slow the growth rate.70 Strong binding ligands, such as thiol on Au, also limit the growth of NPs, leading to the formation of small-sized NPs.71 Inorganic precursors have even been crystalized in the small pores of macromolecules to achieve the desired ultrasmall size.72 3.1 Synthesis of Noble Metal USNPs Au USNPs have been synthesized by many different methods. Bare Au clusters with closed shell structures such as Au13 (n = 2), Au55 (n = 3), and Au147 (n = 4) were obtained by the cluster beam method.73 Schmid et al. developed one of the first synthetic methods for phosphine-stabilized Au USNPs which resulted in moderately uniform, 1.4 nm-sized NPs by the re-

duction of Ph3PAuCl with diborane in benzene.74 However, this synthetic process requires rigorously inert conditions and utilizes highly toxic diborane gas as the reducing agent. To make the conditions more mild, the process was modified to use NaBH4 for the reduction and triphenylphosphine to passivate the particles, resulting in similar 1.5 nm particles.75 In 1994, Brust and Schiffrin developed a more convenient and scalable synthetic method for thiol-stabilized Au NPs where the Au precursor (HAuCl4) is reduced by NaBH4 in the presence of dodecanethiol ligand resulting in relatively uniformsized Au NPs of < 5 nm.71 Since this seminal work, a tremendous amount of research has been conducted with regard to thiol-stabilized Au USNPs. Au25,76,77 Au38,78,79, Au40,44,80 Au68,81 Au102,82–84 Au144,85 and Au33386 were obtained through modified protocols of the Brust-Schiffrin method. Thiolstabilized Au NPs were also obtained by exchanging phosphine-stabilized Au particles with thiols.87 Recently, various synthetic procedures for preparing Au USNPs using other ligands have been reported. Highly water soluble nucleotidecapped Au USNPs were obtained by reducing HAuCl4 in the presence of adenosine 5'-triphosphate.88 In addition to small molecules, polymers have also been used as stabilizing agents.89 Au USNPs have also been obtained using imidazolium-based ionic liquids as solvents when the ionic liquids were amino-modified.90 The neat reduction of HAuCl4 in the ionic liquid (amino-modified methylimidazolium) resulted in 1.7 nm particles capped by the ionic liquid solvent molecules. Another method to obtain nearly monodisperse Au USNPs reported by Kim et al. involves using a dendrimer as a template.91 The dendrimer-encapsulated Au NPs of 1.3 or 1.6 nm in size were prepared within G4, G6, and G8 poly(amidoamine) (PAMAM) dendrimers. The dendrimers were hydroxyterminated and thus uncharged although synthesis of the AuNPs was also done in cationic G8 dendrimers resulting in greater polydispersity. Briefly, Au ions interact within the dendrimer core and are reduced by NaBH4. The particles are then coated with hydrophobic alkanethiol and extracted from the dendrimer. Using similar chemistries to Au, several synthetic methods have also been developed to synthesize Ag USNPs. Ag USNPs were stabilized by 3-mercaptophenylboronic acid (3MPB) following the reduction of AgNO3 by NaBH4.92 As opposed to NaBH4, highly fluorescent Ag USNPs were also synthesized via the reduction of Ag ions by photogenerated ketyl radicals which were optimized to require a minimum exposure time to prevent quenching by the formed nanoparticles.93 Park et al. also reported a synthetic method of uniform Ag USNPs by reducing AgNO3 in the presence of oleylamine and oleic acid.94 The process is greatly simplified compared to the previously reported accounts involving mild oleylamine as a reductant. This simple procedure could easily be scaled to achieve gram quantities. Platinum group metals of ultrasmall size have also been reported. Teranish et al. reported a simple synthetic method for obtaining Pt USNPs.95 Their method involved the reduction of simple alcohols in the presence of PVP as a protective polymer in a refluxing aqueous system. The size of the NPs could then be controlled from 1.9 to 3.3 nm by changing the alcohol or the concentration of the reagents. Specifically, smaller NPs could be synthesized by increasing the concentration of alcohol in water or increasing the amount of PVP. Li et al. reported the synthesis of monodisperse Pt USNPs stabilized with peptides in aqueous solution at room temperature.96 The specifically selected peptide molecule, P7A, was able to bind to



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the surface of the Pt NPs and regulate the nucleation and growth rates to obtain monodisperse Pt NPs with sizes in the 1.7–3.5 nm range. Pt nanoparticles have also been synthesized with hydrophobic ligands. Uniform 2 nm-sized Pt NPs were obtained by the decomposition of platinum dibenzylideneacetone under mild conditions in the presence of n-octylsilane.97 Pd USNPs containing 7–8 atom shells have been synthesized by hydrogen reduction of Pd(II) acetate in acetic acid in the presence of imidazolium functionalized bipyridines.98 By using a simple redox-controlled method, 2.0–2.5 nm sized Pd NPs have also been obtained.99 3.2 Ultrasmall Magnetic USNPs Nanoparticles of ferromagnetic (Fe, Co, Ni) or ferrimagnetic (iron oxide, ferrites) materials have widely been investigated because of their superparamagnetic properties. Many synthetic methods for producing iron oxide nanoparticles have been reported, but the sizes are usually larger than 3 nm.7,58,67,72,100–103 To reduce the size of iron oxide nanoparticles below 3 nm, nanoparticles must be synthesized within systems that can constrain the size. Bonacchi et al. synthesized 1.8 nmsized maghemite NPs by precipitation in small constrained media.72 Briefly this method entails the formation of iron oxide USNPs within a cyclodextrin host. Due to the uniform size of the cyclodextrin, the resulting particle size could also be controlled. High resolution TEM images showed nearly monodisperse NPs with an average diameter of 1.8 nm. Ultrasmall iron oxide nanoparticles were also prepared by mineralization inside the cavity of proteins.58 Ultrasmall iron oxide nanoparticles have been obtained by thermal decomposition of an iron complex under reducing environment; this process tends to produce smaller-sized particles than other methods. Kim et al. reported a synthetic method for the large-scale production of monodisperse iron oxide USNPs by thermal decomposition of iron-oleate complexes in the presence of oleyl alcohol at a relatively low temperature of about 250 °C (Figure 4a).7 Ex-situ sampling experiments revealed that oleyl alcohol acted as a mild reductant and lowered the reaction temperature producing a large number of nuclei. The large number of nuclei coupled with the limited amount of reduced iron leads to a controlled growth process resulting in uniform USNPs. Glaria et al. reported the synthesis of reasonably monodisperse maghemite NPs with a diameter of ~2.8 nm following the hydrolysis and oxidation of an organometallic precursor, [Fe{N(SiMe3)2}2], in the presence of amine ligand as stabilizing agent.67 The precursor readily decomposes exothermically at room temperature, leading to small-sized particles. The polyol method has also been used to synthesize iron oxide USNPs. Park et al. reported the synthesis of nearly monodisperse and highly water dispersible 1.7 nm sized iron oxide NPs by refluxing Fe3+ ions in tripropylene glycol under O2.100 The same group also synthesized paramagnetic ~ 1 nm-sized gadolinium oxide (Gd2O3) NPs using a similar method.101 Co NPs of 2–3 nm were obtained from organometallic precursors such as Co(η3C8H13), (η4C8H12) and Co[N(SiMe3)2]2 in the presence of diisobutyl aluminum hydride and PVP.68,104 Similar to other syntheses presented, Co USNPs were synthesized within the size-constrained nanopores of zeolites.105 These particles demonstrated a ferromagnetic-paramagnetic transition when the temperature increased from 10 to 20 K due to the strong finite size effect.

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Monodisperse 2 nm-sized Ni USNPs were synthesized by the thermal decomposition of nickel acetylacetonateoleylamine complexes in a phosphine solvent.106 The strong reducing environment of the solvent leads to rapid nucleation which generates small particles. When trioctylphospine was used, the particle size was smallest due to their bulkiness. The initially formed Ni NPs were then easily oxidized to form NiO USNPs. Monodisperse Ni USNPs of < 1.2 nm have also been prepared using hydrophobic dendrimers as templates.107 3.3 Ultrasmall Semiconductor USNPs Semiconductor USNPs have various unique optical properties. These particles are usually synthesized using colloidal methods.36,108–114 Trioctylphosphine-capped CdSe USNPs with a size of 1.6 nm were synthesized in a concentrated butylamine solution.108 Cossairt and Owen isolated a variety of CdSe USNPs by the reaction of Cd carboxylate with phosphine selenide.112 The size and size distibution of USNPs was affected by the reaction temperature. Conducting the reaction at 50 oC generated particles with an absorption that extends to only 380 nm, whereas particles synthesized at 115 oC showed absorption maxima extending to 560 nm, the typical absorption wavelength for CdSe quantum dots. InP USNPs ranging in size from 1.5 to 2.3 nm were synthesized by reacting indium salts and P(SiMe3)3 in a protic solvent.113 Interparticle distance between InP USNPs was adjusted by varying the length of the linear alkylamine ligand. Electronic coupling between InP particles was observed for small NPs with a shorter interparticle distance. USNPs were observed during the growth of anisotropic nanomaterials.115–119 Ithuria et al. found that 10 sec after the onset of the reaction between Cd acetate and trioctylphosphine selenide, 2 nm-sized CdSe USNPs were visible on the TEM images which showed broad fluorescence by deep trap pinned emission.118 As the synthesis progressed, the USNPs selfassembled by lateral extension forming nanoplatelets with large lateral dimensions. Cademartiri et al. synthesized Bi2S3 necklace nanowire consisting of spherical USNPs.119 The cluster to nanocrystal transition of these Bi2S3 were intensively studied using X-ray absorption spectroscopy (XAS), X-ray photoelectron spectroscopy (XPS), and nuclear magnetic resonance (NMR) spectroscopy.120 A coordination model based on the measurement included a Bi2S3 core that resemble the bulk crystal structure with 75% of Bi atoms accessible to the oleylamine ligands. A special case of semiconductor USNPs is magic-sized nanoclusters.6 USNPs with thermodynamically stable structures are referred to as "magic-sized nanoclusters" which is adopted from metal cluster having an exceptionally stable closed shell structure.6 Magic-sized nanoclusters and other ultrasmall nanocrystals have similar compositions and sizes but differ in terms of band width and growth mechanism. Because the sizes of semiconductor nanoparticles are precisely determined by their absorption and luminescent properties, optical data was used to investigate the most stable particle sizes. The magic-sized nanoclusters have a narrow band width of about 20 - 30 nm because they contain only one particle size. These magic-sized nanoclusters showed quantized growth during the early stage of the quantum dot formation.6,70,121–124 Figure 5 shows the synthetic progress of magic-sized CdSe nanoclusters formed by reacting a mixture of CdO in dodecylamine and nonanoic acid with Se in trioctylphosphine.70 The reaction temperature was kept low to


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ensure slow nucleation and the optical spectra of reaction aliquots showed well-defined discrete absorption peaks of 330, 360, 384, 406, 431, and 447 nm (Figure 6). During the crystal growth, absorption peaks of each aliquot were shifted to next sized peak indicating a discrete growth pattern. Magic-sized nanoclusters are a commonly observed phenomenon in various synthetic systems. Magic-sized nanoclusters of CdTe, PbSe and CdS have also been observed by ex situ optical spectroscopy during the slow nucleation processes.104,106,107,121–123 The precise composition of magic-sized nanoclusters was identified by mass spectrometry.125 Mass spectra of dodecylamine capped (CdSe)n nanocrystals prepared in reverse micelles exhibited dominant (CdSe)13, (CdSe)33, and (CdSe)34. Wang et al. isolated discrete, magic-sized (CdSe)13 nanoclusters which were generated by the reaction of cadmium acetate with selenourea in oleylamine.126 The (CdSe)13 nanoclusters were well characterized by optical spectra, Rutherford backscattering, CHN analysis and LDI mass spectrometry. These magic-sized clusters often form lamellar structures, consequently leading to growth in two dimensional CdSe nanosheets. Free (CdSe)13 nanoclusters were successfully isolated by sonication of a mixture of (CdSe)13-(oleylamine)13 with an excess of oleylamine.

4.1. Microscopy TEM is the most popularly employed technique to measure the size of NPs because it provides information on the morphology of particles in direct way. TEM images of metal USNPs of high atomic mass can be clearly obtained, even 0.8 nm sized nanoparticles have been measured.38,92 On the other hand, TEM images of 3d metal oxide USNPs were often vague due to the low contrast of low mass 3d atoms and oxygen atoms. It is very difficult to obtain high-quality TEM images of sub-2 nm NPs, especially for particles composed of elements with lower atomic numbers because the resolution is dependent on the contrast which is low for small-sized particles.127 Moreover, USNPs are readily damaged or melted by the electron beam.128 To increase the resolution of microscopy, scanning transmission electron microscopy (STEM) has been used.129-132 Palmer and co-workers determined the size of thiol-capped Au USNPs via quantitative high angle annular dark field scanning transmission electron microscopy (HAADF-STEM).130 Pennycook et al. took high-resolution images of sub-2 nm sized CdSe USNPs by using aberration-corrected STEM.131 The resolution of these STEM images were so high even atomic arrangements were obtained. The STEM images and combined density functional theory simulations showed the predominance of surface atoms were destabilized in NPs leading to a disordered structure. Three dimensional atomic scale structure of Au USNPs were constructed by STEM images coupled with simple imaging simulation.132 The Au USNPs were identified as Au309 with either Ino-decahedral, cuboctahedral or icosahedral geometries (Figure 7). Scanning probe microscopy (SPM), which includes scanning tunneling microscopy (STM) and atomic force microscopy (AFM), can provide a spatial resolution as high as 0.1 nm.133 These technologies are still not suitable for USNPs characterization though because SPM techniques generally have strict requirements such as extremely stable and clean surfaces, stringent vibration control and sharp tips.

Figure 7. High-resolution STEM images of Au USNPs. Reprinted with permission from ref 132. Copyright 2008 Nature Publishing Group. Figure 6. Absorption spectra of the reaction of CdO and Se over time shows different populations of magic-sized NPs. Reprinted with permission from ref 70. Copyright 2007 Wiley−VCH Verlag GmbH & Co. KGaA.

4. Size Characterization Precise measurement of NP size and distributions is paramount for both characterizing fundamental size-dependent properties and for many technological applications. The accurate characterization of USNPs is extremely challenging because it requires a spatial resolution on the angstrom scale. Consequently, there are only few reports on the accurate size characterization of USNPs.

Recently, in situ microscopic techniques for NPs were developed to characterize temporal changes. The dynamic morphology of USNPs which appeared on the early stage of NP growth was characterized in situ by TEM. Yuk et al. introduced a new type of liquid cell for in situ TEM examination based on the entrapment of a solution between two graphene layers.134,135 The graphene liquid cell facilitated imaging by enabling atomic resolution. The liquid cell has also been employed to track the growth mechanism of Pt NPs. A combination of these analytical techniques has also been reported. Coalescence in the thermal annealing of FePt alloy USNPs was detected by high-resolution STEM coupled with an in situ stage.136



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4.2. Mass Spectrometry Mass spectrometry (MS) is widely used for measuring molecular mass by ionizing the sample and sorting species by the mass-to-charge ratios. Because the particle size is proportional to the cube root of mass, the size can be calculated from the mass measured with MS. To obtain the masses of NPs, the particles must not decompose during ionization or detection and the range of measurement should be large in order to quantitate higher mass NPs. Matrix-assisted laser desorption ionization (MALDI), laser desorption ionization (LDI), and electro-spray ionization (ESI) techniques are mild enough to prevent NP fragmentation during ionization. In addition, a time-of-flight (TOF) analyzer can detect heavy masses over 300,000 Da. Combining the advantages of MALDI or ESI for ionization and TOF for detection, MALDI-TOF or ESI-TOF MS are the most appropriate methods for characterizing USNPs by mass spectrometry. Whetten et al. first used LDI-MS to identify the smallest fraction of Au NPs synthesized by the Brust-Schiffrin method.137 After this pioneering work,137 various sized USNPs of Au and Pt have been characterized by MALDI-TOF,138–140 LDI-TOF,87 and ESI-TOF141 MS. Khitrov et al. obtained a mass spectrum of n-hexadecylamine-capped ZnS NPs with sizes of 2.5-3.7 nm by MALDI-TOF MS.142 The mass peaks were well correlated with the size distributions obtained by TEM and absorption spectroscopy. The obtained results sug-

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gested the mass spectrum of ZnS nanoparticles had a double charge and most of the stabilizing ligands were removed. The authors attributed the doubly charged spectrum to the high ionic character of the ZnS compound. MS on its own is difficult to use as a quantitative characterization technique, usually requiring standard curves of known pure materials. To this effect, Kim et al. devised a way to use MALDI-TOF MS to characterize both the size and distributions of iron oxide USNPs (Figure 8).10 The MS spectra could be readily converted to a size distribution plot using a simple size-to-mass conversion equation. This method efficiently allows the calculation of particle size to a resolution of only a few angstroms. As such, MS has enabled the investigation of the nucleation process of iron oxide NPs which is extremely difficult to monitor via any other method. MS has another advantage on the size measurement of USNPs compared with other methods. While microscopic techniques involve calculating and averaging data of very small subsets, MS data quickly analyzes an extremely large population, thus the obtained results more accurately describe the entire population. In addition, the limits of detection for MS range from molecular species to several nanometer-sized particles. The resolution of MS is so high that 0.1 nm differences can be distinguished, which is exceedingly difficult to achieve using other characterization methods for < 2 nm particles, especially TEM.10

Figure 8. (a) A curve relating the mass detected from MALDI-TOF mass spectra to the diameter of the nanoparticle. The solid blue curve represents the mass-diameter relationship from the derived equation for D. The position of each red dot indicates the mass spectra peak position (x-axis) and the average diameter measured from TEM image (y axis) for iron oxide USNPs synthesized from a single batch. (b) Six representative mass spectra and TEM data sets used in (a). Scale bars are 10 nm. (c) Counting 3 nm-sized iron oxide NPs in a TEM image for obtaining precise size distribution. (d) Size distributions of iron oxide NPs obtained from the TEM image in (c) (red bars) and from the mass spectrum (blue line). (e) MALDI-TOF mass spectra of 1 and 3 nm iron oxide NPs and their 4:1, 2:1, 1:1, 1:2, and 1:4 mixtures. Reprinted with permission from ref 10. Copyright 2013 American Chemical Society.


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4.3. Other Characterization Methods As shown in Figure 6, UV-VIS absorption spectroscopy is the most powerful technique to characterize semiconductor NPs. Because the band gap of semiconductor NPs varies with size, the size of the particles can be easily determined by the absorption and emission wavelengths.143 Size distribution is can also be estimated by absorption spectra.144 Interestingly, noble metal USNPs absorb visible light not by the surface plasmon but by their semiconducting characteristics.21,22,48 Wilcoxon et al. reported the use of high-performance liquid chromatography (HPLC) using a size exclusion column to study the size distribution of Au USNPs. This method is sensitive enough to distinguish changes in the hydrodynamic diameter corresponding to metal core size changes of less than 0.4 nm.128,145 The use of analytical size exclusion chromatography is also scalable and has been demonstrated on the semipreparative scale.146 While reverse phase HPLC has also been successfully used to separate Au USNPs, it is only capable of purifying analytical quantities and the columns are easily clogged by retained particles.147 Lastly, HPLC has been applied to chiral column chromatography. By passivating the surface of a gold USNP with achiral molecule, 2phenylethylthiol, it was found the particles began to act as a racemate as observed by CD analysis. The particles were subjected to a chiral HPLC setup which was successful in separating the particles as if they were enantiomers.148

5. Applications 5.1. Utilizing the High Surface Area of USNPs USNPs are effective catalysts because of their enormously large surface area.43 Many studies have revealed remarkably enhanced catalytic activities of metal NPs of < 3 nm.13 Au USNPs showed outstanding electrocatalytic activity in the electroreduction of oxygen while their bulk counterparts exhibited poor catalytic performance.42 In addition to their large surface area, their unique electronic structures have proven advantageous for catalytic applications such as CO oxidation.149 High levels of selectivity have been achieved by precisely altering the electronic structures of noble metal USNPs.42,150–152 This selectivity can be seen in the oxidation of styrene to benzaldehyde in the presence of 1.4 nm-sized Au USNPs.151 Zhu et al. also reported the use of Au USNP catalysts for selective oxidation reactions, but interestingly they are also effective reducing agents for hydrogenation.152,153 USNPs were utilized as therapeutic agents due to their catalytic effect. Ce4+ ions are able to reversely bind the anionic oxygen species and reduce them. Recently, ceria USNPs were examined for their ability to scavenge reactive oxygen species for the prevention of ischemic stroke.154 The therapeutic effect is attributed to a high catalytic efficiency due to the large surface area of ceria USNPs. Paramagnetic USNPs have recently been investigated as magnetic resonance imaging (MRI) contrast agents due to their high fraction of surface paramagnetic ions.7,100,101 MRI contrast agents are categorized into longitudinal (T1) and transversal (T2) agents.155 T1 relaxation makes the local MR signal brighter whereas T2 relaxation is observed as a darkening of the signal thus T1 agents are preferred for their increased clarity.156 The T1 signal can be enhanced by contrast agents through spin-lattice relaxation which occurs by the interaction between the protons on water molecules and the nearby elec-

tron spins of the paramagnetic center. Thus chelates of paramagnetic ions such as Gd3+, Mn2+, and Fe3+, all of which possess a large number of unpaired electrons, are typically used as MRI contrast agents.157 Paramagnetic nanoparticles have also been used for T1 MRI contrast for the purpose of endowing various functionalities and increasing circulation time.158 As the particles become smaller they exhibit stronger inner-sphere relaxation because the T1 relaxation is enhanced by surface paramagnetic ions.158 Gadolinium oxide USNPs of 1 nm in size exhibited high r1 relaxivity of 9.9 mM-1s-1, which is higher than that of commercial Gd complexes.101 Similarly, manganese oxide USNPs coated with biocompatible ligands showed bright MR images.100 Johnson et al. prepared ultrasmall NaGdF4 nanoparticles and characterized their MR and optical properties.159 The r1 relaxivity increased from 3.0 mM-1s-1 to 7.2 mM-1s-1 with the decrease of particle size, and the 2.5 nm sized nanoparticles showed the highest relaxivity. The luminescent ultrasmall β-NaGdF4:Yb3+/Tm3+ nanoparticles can be applied as potential bimodal probes in optical and MR imaging. 5.2. Utilizing Unique Properties of USNPs The paramagnetic properties of iron oxide USNPs (section 2.2) were adopted toward the development of new MRI contrast agents. Mn, and especially Gd, can be toxic so new, better-tolerated contrast agents had to be developed.160 Iron oxide is more biologically compatible and has also demonstrated its potential to be used as a T1 MRI contrast agent. However, the intrinsically high magnetic moment of the iron oxide NPs hindered their adoption as T1 MRI contrast agents. Recently, Kim et al. found iron oxide USNPs could in fact be applied as T1 contrast agents because they show very low magnetization due to the spin canting effect.7 Iron oxide USNPs synthesized by thermal decomposition of iron oleate complexes in the presence of oleyl alcohol exhibited nearly paramagnetic properties. This resulted in a high r1 relaxivity of 4.78 mM-1s-1 and a low r2/r1 ratios of 3.67 (Figure 4d). High-resolution MR blood pool imaging enhanced by iron oxide USNPs enabled clear observation of blood vessels with sizes down to 0.2 mm (Figure 4e), demonstrating the potential of the iron oxide USNPs as T1 MRI contrast agents.

Figure 9. (a) Photographs under UV light and (b) relative fluorescence (I/I0) at λex = 470 nm of aqueous Au USNP solutions (20 mM) in the presence of 50 mM of various metal ion. Reprinted with permission from ref 161. Copyright 2010 Royal Chemical Society.

The luminescent properties of metal USNPs (section 2.5) have been applied to biosensing materials.49,150,161–164 Au USNPs capped with 11-mercaptoundecanoic acid combined with 2,5-pyridinedicarboxylic acid were applied for sensing of Hg2+



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ions.49 Additionally, bare Au USNPs could also act as specific sensors for Hg2+ ions because of the strong Hg2+ - Au+ interaction.161 The high specificity of this interaction provided excellent selectivity toward the detection of Hg2+ compared to other relevant metal ions (Figure 9b).161 The selectivity could even be visualized with the naked eye (Figure 9a). The luminescent metal USNPs have also been used as optical imaging agents.163,164 Lin et al. prepared water-soluble Au USNPs by reacting hydrophobic Au NPs with dihydrolipoic acid. 163 The resulting product exhibited photoluminescence with a quantum yield of 1–3 % as well as no acute toxic response in vitro. Broad emission from pinned emission of CdSe USNPs (section 2.4) can be applied to white light emission device (LED).165,166 Schreuder et al. demonstrated that CdSe USNPs showed pure white-light electroluminescence.166 These CdSe USNP LEDs provided excellent CIE (Commission Internationale de L'Eclairage) color coordinate (0.333, 0.333) and high color rendering index, indicating the LEDs were high quality light sources mimicking sunlight. 5.3. Utilizing Small Volume of USNPs The ultrasmall dimensions of USNPs were used to reduce the toxicity of inorganic particles. Semiconductor USNPs have been pursued as optical imaging probes but their high toxicity has greatly slowed their translation. Only very small semiconductor NPs which can easily be renally excreted are recommended for in vivo imaging applications.167,168 A hydrodynamic diameter of 4.36 nm was achieved by capping 3 nm-sized CdSe NPs with a zwitterionic cysteine ligand.168,169 Biodistribution data showed the cysteine-capped CdSe NPs were fully excreted through the kidney within 4 h. Similarly, InAs/InP/ZnSe USNPs coated by mercapto-propionic acid exhibited near infra-red emission and showed good renal clearance.162 The strong quantum confinement of the electronic wave function within semiconductor USNPs leads to a greatly enhanced energy efficiency of these materials. Ma et al. synthesized various sized PbSe USNPs of 1.1 - 2.9 nm and investigated the size-effect of Schottky solar cells.170 PbS particles of 2.3 nm size exhibited the highest efficiency due to the relatively large band gap, large absorption and reduced charge recombination. Strong carrier-carrier interactions from the strong spatial confinement of semiconductor USNPs enables them to generate multiple excitons.171,172

6. Summary and Conclusions In recent years, a tremendous amount of research has been published on USNPs. The boom in this subset of nanotechnology is attributable to the discovery of the myriad new physicochemical properties displayed by these particles and their potential utility in the fields of optics, catalysis and theranostics. After the first USNPs were synthesized and isolated, the intrinsic properties were examined categorically in terms of size, composition, and the microenvironment around the particle such as bound ligand. Currently these properties are being optimized including the development of new and better methods to control the size, shape, and composition of USNPs. However, if USNPs are ever expected to move from the benchside into a commercial environment, cost-effective and large-scale methods of synthesis will need to be developed without sacrificing the integrity of the material. This has been

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a daunting task for nanotechnology in general and is expected to be even more difficult for USNPs considering the difference of only a few atoms per particle means the difference between a functional and failed product.46 There is an abundance of excitement regarding the emergence of nanomedicine with many expecting it to replace chemical-based medicine. However as mentioned, NP synthesis and analysis is not nearly as well-defined as organic chemical synthesis. Nor does there exist a large infrastructure for the manufacture of NPs; unlike chemical manufacture. Consequently, the process to bring a sufficient quantity of welldefined USNPs to clinical trials is already very difficult. In addition, there are still many concerns to be investigated regarding how long the particles stay in the body and whether or not the more toxic heavy metals that constitute the inorganic particles, such as in quantum dots, can be leached over time. While the clinical outlook for USNPs in the near-term is unlikely, the non-clinical potential is certainly apparent. As presented in this review, new techniques are being developed to facilitate the rapid analysis of USNPs and even wellestablished analytical tools such as MS have been repurposed quite impressively to this effect. Additionally, the rapid release of new synthetic methods for USNPs coupled with the recent successes demonstrated in the scale-up of nanoparticles to kilogram batches augur well for the future of USNPs.3 The basic science investigating the optical and catalytic properties of USNPs also suggest a bright future in the production of optical devices,165,166 solar cells170 as well as ex vivo biosensing and diagnostics.161 Likely these will be the areas that initially realize the potential of nanotechnology in the very near future.

AUTHOR INFORMATION Corresponding Author * E-mail: (T. H.) [email protected]; (J. P.) [email protected]

Notes The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENT T.H. acknowledges the financial support by Korean Ministry of Science, ITC and Future Planning through Institute for Basic Science (IBS). J. P. acknowledges financial support by the National Research Foundation (NRF) of Korea grant funded by the Korean government (No. 2010-002864).

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