DOI: 10.1002/chem.201405117

Review

& Gold Nanoparticles

Nonfunctionalized Gold Nanoparticles: Synthetic Routes and Synthesis Condition Dependence Aila Jimenez-Ruiz, Pilar Perez-Tejeda, Elia Grueso, Paula M. Castillo,* and Rafael PradoGotor*[a] Dedicated to Professor Francisco Sanchez in the event of his 70th birthday

Chem. Eur. J. 2015, 21, 9596 – 9609

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Review Abstract: Since Faraday first described gold sol synthesis, synthetic routes to nanoparticles, as well as their applications, have experienced a huge growth. Variations in synthesis conditions such as pH, temperature, reduction, and the stabilizing agent used will determine the morphology, size, monodispersity, and stability of nanoparticles obtained, allowing for modulation of their physical and chemical properties. Although many studies have been made about the synthesis and characterization of individual nanosystems of in-

Introduction Gold nanoparticles are a very promising tool for multidisciplinary applications in both environmental and medical fields[1, 2] as well as in the field of electronic device design, owing to their unique properties, such as quantum size effects or fluorescence quenching.[3–8] The extent of these properties depends strongly on the size, morphology, and nanoparticle stabilization, and is therefore linked to the nanoparticles’ synthesis conditions. The most relevant fact about gold nanoparticles that makes them stand out against both other metallic and organic nanoparticles is the characteristic band in the absorption spectra caused by the oscillation of the valence electrons by interaction with an electromagnetic field,[9] that is, the surface plasmon resonance band (SPR), which is characteristic of noble metal nanoparticles. The great advantage afforded by this SPR band to these nanosystems, and which makes them fitting for a great number of applications, resides in the fact that any external change that affects the nanoparticle’s electronic density—for example, variations of the dielectric constant of the solvent or interactions with ligands or absorbed molecules, or aggregation processes—will induce a change in the SPR band. Those changes can usually be observed by UV/Vis spectroscopy, or even by the naked eye. By using the SPR band for sensing the state of the nanoparticles, these can also be employed as molecular markers in transmission and light-scattering spectroscopy,[10, 11] giving rise to surface-enhanced spectroscopy techniques[12, 13] such as SERS (surface enhanced Raman),[14, 15] SEIR (IR increased surface), and surface-enhanced fluorescence.[11, 16] Moreover, nanoparticles in general, due to their small diameter, have a high surface area, and so they are very appropriate for catalytic applications.[5, 17, 18] Particularly, noble metal nanoparticles have shown a good reactivity to some functional groups contained in biomolecules (with which they can react by means of, for example, direct incubation), opening the way to a myriad of medical applications in both the sensor-building

[a] A. Jimenez-Ruiz, Prof. P. Perez-Tejeda, Prof. E. Grueso, Dr. P. M. Castillo, Prof. R. Prado-Gotor Physical Chemistry Department, University of Seville C/Prof. Garc†a Gonz‚lez, s/n, 41012 Sevilla (Spain) E-mail: [email protected] [email protected] Chem. Eur. J. 2015, 21, 9596 – 9609

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terest, to our knowledge the common, general traits that all those synthesis share have not been previously compiled. In this review, we aim to offer a global vision of some of the most relevant synthetic procedures reported up to date, with a special focus on nonfunctionalized gold nanoparticle synthetic routes in aqueous media, and to display a broad overview of the influence that synthesis conditions have on the shape, stability, and reactivity of nanoparticle systems.

field and for drug-delivery processes.[4, 6, 19–23] For those kinds of applications, it is important to take into consideration the size of the nanosystems. Particularly, for clinical applications the diameter of the nanoparticles used is usually restricted to a range of between 5 to 100 nm; this is due to bigger nanoparticles showing risks of occlusion of the cardiovascular system and smaller ones being phagocytosed before reaching target cells.[24] Moreover, toxicity studies have shown that apart from their size, both the shape and the ionic character of the surface are also of special relevance when designing nanosystems for medical purposes.[4] At this point, it is important to remember that nanosystems are characterized not only by the properties of the metal cluster core (as it happens when working with non-nanometrical scale metal particles or common semiconductors), but also by those of the organic molecules that constitute the monolayer which contributes to cluster stabilization. Geometry, that is, the shape of the nanoparticles, also has a good degree of influence—specifically, there is a strong distinction between spherical and non-spherical nanoparticles. In spherical gold nanoparticles, uniform radiation interaction creates only one plasmon band, which is located in the UV/Vis region and gives nanoparticle solutions their characteristic intense colors. In non-spherical nanoparticles, such as nanocylinders or nanorods, longitudinal and transversal axis create not only one, but two dipolar resonance frequencies, and therefore two plasmon bands are observed.[25] For this reason, nanorods absorb not only in UV/ Vis, but also in the near infrared (NIR) spectrum region (Figure 1). Thanks to this broad absorption, NIR absorbing nanoparticles can be used both for medical and environmental purposes with greater efficiency than spherical ones. Gold nanorods are the most popular non-spherical gold nanoparticles; while their properties are quite similar to spherical ones, nanorods can be used for cancer cell destruction by photothermal treatments with IR light.[8, 26] Outside the clinical field, many sensor applications of gold nanoparticles make use of their excellent quenching properties, and are therefore limited to smaller nanoparticles, since the quenching efficiency increases both with a smaller size and a closer distance between nanoparticle and dye.[5, 27] Investigations on fluorescence quenching efficiency phenomena have proved that AuNPs can provide complete quenching of fluorophore systems for nanoparticles up to a diameter of 25 nm, and show a decreasing quenching rate beyond this limit.[27]

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Review When designing a synthetic route for a given nanoparticle system of interest, it is important to take into account that the chemical growth of nanometer-sized particles always involves a solid-phase precipitation in a solution. Since the supersaturation conditions necessary to induce nanoparticle precipitation are the result of a chemical reaction, parameters such as stirring rate, temperature, or addition rate and order all have influence in the size and morphology particle size distribution of the resulting nanoparticle suspension. We should not lose sight either of the fact that the stability of those colloidal solutions strongly depends on the valency of the counterions in the solution. For example, for negatively charged gold colloids, the flocculation value is about 20 mmol L¢1 for monovalent cations, about 0.4 mmol L¢1 for divalent cations, and in the range of 10¢6 mmol L¢1 for trivalent cations.[28] Although nucleation is the key process step of the synthesis, Ostwald ripening and aggregation are also important for the determination of the size, morphology, and properties of the resulting nanosystem.[29] Precipitation can be induced by several methods, such as chemical reduction, photoreduction, oxidation, or hydrolysis. Alternatively, it can also be induced by altering other parameters related to the solubility of the reactants, such as pH, concentration, or addition order of the reactants. By controlling these factors it becomes possible to guide nucleation kinetics and growth, thereby allowing for the generation of well-defined, stable, and monodisperse nanoparticle solutions.[30, 31] Taking into account all of these facts, it is clear that synthetic routes can be designed in terms of controlling nucleationgrowth kinetics taking into account the wide range of possibilities that directly affect not only the size and shape of gold nanoparticles obtained, but also the final colloid stability. From here on, we review the main parameters that need to be taken into account in order to obtain stable syntheses that show defined, reproducible traits. Special focus is placed on the influence of both reducing and stabilizing agents, pH, temperature, and other synthesis factors. Five of the most studied methods for obtaining gold nanoparticles discussed throughout the work are also summarized in the Supporting Information; these methods are single-phase synthesis, two-phase synthesis, seeding approaches, and laser ablation and solvated metal atom dispersion (SMAD) techniques.

Reducing Agent Influence of direct reduction in synthetic procedures The first nanoparticle synthesis was described in 1857 by Michael Faraday in his impressive Bakerian Lecture “Experimental Relations of Gold (and other metals) to Light”.[1] Faraday had achieved stable gold colloids by using phosphorus as a gold chloride reducing agent and carbon sulfide as the stabilizer. He noticed that the optical properties in the ruby-red stable suspensions were not the same than those observed neither in the bulk nor in the violet or green unstable state, and described the importance of maintaining a proper phosphorus– gold relation and a controlled sulfide addition in order to obtain the ruby-red stable colloids. When using H2 instead of Chem. Eur. J. 2015, 21, 9596 – 9609

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phosphorus as the gold salt reducing agent, Faraday reported a blue solution, probably due to non-spherical nanoparticle formation. He also described other now well-known effects, such as salt addition causing the coagulation of the colloid.[1] Some gold colloids synthesized by Faraday remained stable and are still on display in Faraday’s original laboratory in the Faraday Museum at The Royal Institution of Great Britain (UK).[1, 2] Gold precursor salts used have not experienced a great change since Faraday’s studies; still mainly either HAuCl4 or KAuCl4 are used. In contrast, nowadays there is a wide spectrum of known suitable reduction agents, such as carbohydrates, aldehydes, alcohols, or diamines, which in addition to their reducing power can provide steric and/or electrostatic stabilization, thus helping improve the stability of the resulting synthesis. Amongst all known nanoparticle syntheses, Turkevich’s stands out for its simplicity and proven good results; it describes, in a direct, single-phase and easy method, how to obtain spherical gold nanoparticles by using, for the first time, trisodium citrate as a gold salt reducing agent. In a one-step synthesis, trisodium citrate solution is added to a boiling solution of aqueous gold salt, while maintaining vigorous stirring;

Paula M. Castillo obtained her degree in Chemical Sciences at the University of Seville (Spain). As a Ph.D. student in Nanotechnology and Molecular Spectroscopy, at University Pablo de Olavide (Seville, Spain), Paula worked with several research projects related to medical and environmental nanoparticle applications. Her Diploma Thesis dissertation was based on the synthesis and characterization of noble metal nanoparticles for biomedical applications. In 2012, she attained her Ph.D. with “Cum Laude” distinction for her dissertation entitled “Vectorisation of nanoparticles formulated with the anti-tumoral agent camptothecin”. She has written several papers, book chapters and five patents, the last two obtained as a postdoctoral researcher at University of Seville (Spain), focusing her studies on the synthesis and characterization of new gold nanobiosensors, their structure, kinetics and reactivity studies. Raafel Prado-Gotor received a B.Sc. in Chemistry from the University of Seville (Spain). In 1999, he received his Ph.D. from the same university. He carried out postdoctoral research for two years (2000–2001) under Prof. M. Kochoyan and C. Roumestand at the Centre of Biochemie Structural (C.N.R.S., Montpellier, France) on the development of the use of NMR to study DNA and proteins in solution. Since 2000 he has been a Research Professor at the department of Physical Chemistry in the University of Seville (Spain). In 2003 he worked with Prof. Soledad Penades in the new Research Centre of La Isla de la Cartuja (CICIC). From this moment on his research has focused on the study of the interactions of proteins and DNA with nanoparticles and on the optimization of these interactions from a thermodynamic and kinetic point. He has over sixty publications, including four book chapters and two patents in the field of nanoparticles with biomedical applications.

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Figure 1. Transmission electron micrographs, spectra and photographs of different aspect ratio nanoparticle solutions. (Reprinted with permission from reference [45]. Copyright (2005) American Chemical Society.)

after several minutes, solutions show a marked change in color from grey to ruby red, due to nanoparticle formation.[32, 33] Based on this citrate synthesis, and on previous works (Mie, Maxwell, Shulttze-Hardy, Smoluchowsky, Derjaguin, Overbeek and others), Turkevich and Enìstìn studied in a later work the colloidal behavior of nanoparticles. They assumed that citrate had a dual behavior, in which it acted both as a stabilizer and as a reducing agent.[34] Their studies focused in the variation found in the stabilization potential when adding electrolytes such as NaClO4 ; they calculated the Hamaker constant (A) and concluded that the morphology of aggregates formed after coagulation of the nanoparticles had taken place was dependent on the electrolyte concentration in the electric double layer (EDL). They stated that at moderate electrolyte concentration, coagulation rate was slow, and two-dimensional aggregates were formed. At high electrolyte concentrations, the coagulation rate was faster, leading to three-dimensional aggregates due to the influence of the attractive potential. At both slow coagulation rate and low ionic strength, the electric double layer was big enough for it to mitigate interparticle attraction, and one-dimensional aggregates could be formed under suitable synthesis conditions.[34] Turkevich and Enìstìn also determined the existence of an electrolyte critical concentration (W), which is the limit of stability at which aggregation occurs. When the attraction potential is high, both the Hamaker constant and the coagulation rate are also high, and therefore the electrolyte concentration that can be added while maintaining the stability (W) is lower.[34] More recently, Turkevich authored an extensive review in which the three basic mechanistic steps of a nanoparticle synChem. Eur. J. 2015, 21, 9596 – 9609

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thesis were explored in great detail. A complete set of experimental data which included novel (at the time it was published) techniques like high-resolution electronic microscopy (HRTEM), which was used for characterization of the crystalline faces of gold in the studied colloids.[35] Turkevich cites two main approaches to gold nanoparticle generation: the disintegration of macroscopic gold pieces by way of an electric arc and the direct reduction of gold salts in solution by either chemical or physical methods, the latter of which included ultrasonic radiation and laser radiolysis. Amongst them, he makes a strong defense of the results obtained by employing citrate reduction in boiling aqueous solutions, conditions which allow for the obtainment of monodisperse and stable 20 nm gold nanoparticles. Upon characterization of the colloids that were obtained by this technique, it was found that synthesis parameters, such as temperature, concentration of reactants or reactant ratio, played a key role into determining the monodispersity of the samples; indeed, any changes to those properties meant a different size distribution being found for the colloid. Based on those observations, Turkevich defends a chemical process with three main steps (nucleation, growth, and coagulation) as the cause of the nanoparticle formation in solution. The nucleation step was first explored by Turkevich in an early work[32] using a seeded approach with a solution of gold salts and hydroxylamine hydrochloride; the solution did not show spontaneous gold reduction, but when small presynthesized gold nuclei were added they acted as a catalyst. By controlling both initial Au3 + and added gold seed concentrations, nanoparticles could be easily made to grow to a controlled, monodisperse size. This effect was then expressed as a mathe-

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Review matical relation [Eq. (1)], in which Df refers to the final diameter of the particle; Dn is the seed diameter and Aun and Aug are the amount of gold in the seed and the growth medium respectively. By controlling these parameters, Turkevich et al. were able to synthesize monodisperse gold colloid solutions ranging from 20 to 120 nm in diameter. Df ¼ Dn ð

Aun þ Aug 1=3 Þ Aun

ð1Þ

For nucleation, Turkevich observed that nucleation kinetics presented a three-step curve: an induction period in which almost no nucleation took place, followed by a self-catalyzed growth in the number of nuclei up until a stable zone at which no additional nuclei were formed. These observations were interpreted as a nucleation processes not being immediate upon addition of the reductant, but rather preceded by a polymerization step in which gold salts associate to form either an organic or hydroxide gold polymer, depending on pH. When these polymers grow to a size at which the stabilizing lattice energy of the resulting particle surpasses its surface energy, reduction of the gold ions takes place in a simultaneous way: all ions reduce at the same time to give rise to a gold nucleus. The diameters of such gold nuclei were estimated to be around 1 to 2 nm by Uyeda et al.[36] who also identified twin particle crystalline structures that resulted from coalescing gold nuclei. As exposed by Turkevich, this coalescence step precedes nanoparticle growth: the first step in nucleus enlargement is not the direct reduction of the citrate gold salts over gold nuclei surfaces, but the coalescence of those gold nuclei to form 20 nm particles with multiple twinned faces. Further aggregation of these particles is prevented by the citrate adsorption on their faces: from this point on, growth takes place essentially by direct reduction. Turkevich’s work in this field is remarkable not only by his procedural descriptions, which are still a standard on gold nanoparticle synthesis, but also by his characterization work which helped establish the three main steps of nanoparticle formation: his mathematical relations are still being cited by first-line research groups more than fifty years after they were first formulated. The formation mechanism of gold nanoparticles obtained by using Turkevich’s method of reduction with sodium citrate was studied in 1994 by Chow et al. By measuring dynamic light scattering (DLS), UV/Vis spectroscopy, transmission electron microscopy (TEM) and the zeta potential of a number of samples, they concluded that nanoparticle formation in those conditions involves a size reduction step, from bigger to smaller nanoparticles, during the aforementioned reduction process in which the solution changes in color from purple to red. This change was found to be dependent on the Au3 + and Au0 ionic concentration.[37] Gold nanoparticles obtained by reduction with sodium citrate are nowadays one of the most studied[37–40] and used synthesis for all kind of applications, in particular in the biomedical field, with remarkable examples such as antibody conjugation[41] or light-triggered release of NO.[42] This is partially due to the ease of obtaining size-controlled, stable nanoparticles Chem. Eur. J. 2015, 21, 9596 – 9609

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with this synthetic route, and to the low toxicity of all reactants used, amongst other facts. Due to the excellent optical properties of the surface plasmon band, the grade of success when carrying out the functionalization of gold nanoparticles with biomolecules can be easily controlled by UV/Vis spectroscopy, as described for example by Kah for anti-EGFR.[43] The synthesis used by Kah is based on a previous work by Hayat’s group,[19] who achieved monodisperse 20 nm spherical nanoparticles in a fast and single-phase method by using citrate to carry out gold salt reduction in aqueous media. The nanoparticles’ extinction spectra, which shows a sharp plasmon band centered at 520 nm following nanoparticle synthesis, changes to longer wavelengths and show a decreased absorbance intensity after antibody linkage, a fact that serves to prove that conjugation has taken place. As we mentioned earlier, apart from sodium citrate, there is an ample spectrum of suitable reducing agents, which allow chemists to modulate the chemical properties of the resulting nanosystems. As an example, Sau and Murphy make use of two reducing agents[44] for obtaining CTAB (cetyltrimethylammonium bromide) protected gold nanorods. The process takes place in a three-step synthesis, which involves both a seed and a stock solution that are then mixed. For the seed solution, which contains spherical nanoparticles, they use a strong reducing agent, NaBH4, which is added upon an initial CTAB– gold salt solution; the stock solution is prepared by using ascorbic acid as a weak reducing agent upon a gold–silver salt solution containing CTAB. Finally, the seed solution is added upon an aliquot of the stock one to obtain the blue nanorods suspension. In order to stop nanorods’ growth when the desired size has been reached, the surfactant needs to be removed with sodium sulfide. TEM measurements confirm that greater nanorod lengths are obtained when smaller seed concentrations are used and when a greater time is elapsed before sodium sulfide addition.[45] (Figure 1) When silver is used along with gold, the less positive silver nitrate reduction potential makes gold reduction slower, and therefore generates more homogeneous rod sizes, minimizing anisotropic shapes.[40, 46, 47] Xia et al showed by TEM analysis that the nanoparticles obtained became more spherical and monodisperse when Ag + trace ions were added to a gold–citrate solution. As shown in the figure, the size of nanoparticles also decreases with growing sodium citrate concentrations, in accordance with other researchers’ observations[40] (Figure 2). Gold as a catalyst—the seeding growth approach The influence of seeds into nanoparticle monodispersity was studied by Natan et al., who carried out a comparative study between citrate-capped nanoparticles’ growth when synthesized by direct reduction at room temperature with sodium borohydride and when two different sized seeds (2.6 and 12 nm) were used. In their work, the seeding approach greatly improved sample monodispersity; for the same final particle size, it was observed that 12 nm seeds gave rise to less polydisperse colloids, a fact that was attributed to the larger seeds

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Figure 2. TEM images of Au NPs with Ag at different citrate concentrations. (Reprinted with permission from reference [40]. Copyright (2009) American Chemical Society.)

being themselves less polydisperse than the smaller ones. In the same work, they also perfected a novel seeded synthetic procedure that had been previously explored in a preliminary way.[48] A series of nanoparticle syntheses was carried out by using hydroxylamine (NH4OH) as a reductant of gold salts at room temperature. When no seeds were added, hydroxylamine was unable to reduce the gold salts by itself and so no particle growth took place; however, the addition of 12 nm gold seeds caused gold salts to immediately start reducing over the seeds’ surface, which was evidenced by a rapid growth on the intensity of their plasmon band. This growth continued until the gold salts were fully consumed; by successive addition of HAuCl3 aliquots, particles could be easily made to grow into the desired size without any complex procedures and while maintaining an excellent monodispersity in at least a range of 13 to 115 nm. As a side effect, a small population of thin, elongated rods was also found in some of the final synthesis, with a major axis ranging from 90 to 200 nm; those rods were not found to be formed from fused nanoparticles. Also, it is remarkable to note that no intermediate shapes between particles and rods were found, suggesting that the rods are independent structures that are not derived from irregular growing of spherical nanoparticles. Murphy et al.[49] determined in a series of simple experiments the influence of seed concentration, reducing agent, ionic strength, and addition speed into nanoparticle size and stability. Citrate seeds of 12 nm diameter were used to test the method, at constant gold atom (seed plus added gold salt) concentrations and fast, slow and step-by-step reducing agent addition speeds; in these experiments, reduction was carried out by using ascorbic acid as reductant. The results showed that when using slow or step-by-step addition, nanoparticle diameter was fully dependent in the seed-to-gold salt ratio: higher seed concentrations gave rise to bigger nanoparticle sizes. When the reducing agent was added in a single, fast step, no correlation existed between seed size and nanoparticle size; some citrate-to-seed ratios even gave rise to particles whose average diameter was smaller than that of the starting Chem. Eur. J. 2015, 21, 9596 – 9609

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gold seeds. It is important to note that ascorbic acid is a weak reducing agent that cannot reduce gold salts by itself; however, added gold nuclei favor this reduction by acting as a mediator for electron transfer from ascorbic acid to gold atoms. Slower reductant addition rates favor growth of existent nuclei in detriment of nucleation, while faster rates cause a sharp rise in the number of nuclei which grow to smaller final sizes. Alternate reducing agents were explored by using the 12 nm seed fast addition rate method: for citrate, aggregated nanoparticles were formed with estimated diameters between 2 and 10 nm; hydrazine with SDS gave 2–5 nm nanoparticles when seeded and 5–10 nm when not seeded, demonstrating that increased nucleation rates also happened when reducing with this agent; and for sodium borohydride, bigger particles were found for the seeded approach that for the unseeded one, which implied predominant growth over nucleation effects. The influence of the ionic strength was explored by varying the concentration of NaCl used. For faster addition rates, no changes were observed, and the nanoparticle size distribution was the same as that obtained without NaCl. Meanwhile, for fast addition rates, non-spherical rodlike and multifaceted particles formed alongside the spherical ones. To minimize this effect, AgNO3 was added in the absence of any rod-forming surfactants: while Ag + ions favor rod formation when coupled with these surfactants, in this case rod formation was minimized when AgNO3 was added in a proportion of 1:50 silver to gold atom concentration. The authors attribute this effect to the possible formation of AgCl salts of microscopic size that could act as nuclei to favor spherical particle formation; it is also remarkable to note that no metallic silver particles were found in solution. Murphy’s group also published that same year a simple approach to seeded nanoparticle synthesis in which gold nanoparticles were prepared by a step-by-step growing method from citrate-protected gold seeds of around 3.5 nm in diameter.[50] A “growing solution” containing HAuCl4 and CTAB was also employed. Ascorbic acid was used as a reductant; again, it was chosen for its inability to reduce gold salts at room temperature, which ensured that no spontaneous, uncontrolled growth of particles would take place. By using varying concentrations of seed, two initial sets of 5.5 and 8 nm were grown; the latter were used as seeds by yet again mixing them with growing solution and reductant. The resulting nanoparticles were spherical with a diameter of 17 nm; by repeating the cycle, a final set of 37.5 nm spherical particles plus some 200 Õ 17 nm rod-sized particles were obtained. All the sets were capped with dodecanethiol by using a toluene extraction. Results showed good monodispersity of the samples (less than 15 % dispersion) and a great concordance of their experimental results with Turkevich’s theoretical equations was found, which suggested that no additional nucleation took place when using this approach; this fact allows for a closer particle size control that most other classical, widely-used synthetic procedures. By varying both gold seed and surfactant concentration, multiple more complex shapes such as triangles or stars can

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Review be achieved.[46, 51] In a recent study, Takenaka and co-workers showed that nanorod elongation with hexadecyltrimethylammonium bromide (HTAB) occurs in dense solutions, and at higher surfactant concentrations, due to the decrease of the Au3 + free ions concentration.[52] Once HTAB has directed NP growth and the desired shape has been obtained, it can be removed by adding thiols such as mercaptopropionic acid; these kinds of compounds not only provide stability but also add carboxylic acid end groups that are available for further functionalization.[53] Reduction of metals other than gold that show highly negative reduction potentials require stronger reducing agents, with a greater reductive capacity than that provided by most of the amines, alcohols, or hydroxycarboxylic acids. In these cases, some reducing agents commonly used are H2 gas,[54] hydrazine (N2H4), or ABH4 type compounds (in which A is Na or another alkali metal) such as NaBH4. Sodium borohydride is a strong reducing agent frequently used both in organic and aqueous media nanoparticle synthesis, especially for medical applications.[55] A good example of a gold synthesis that also makes use of NaBH4 as a reductant is the Brust–Shiffrin method, which uses it to allow for the obtainment of small-sized nanoparticles covered with dodecanethiol. The starting gold salt is reduced with NaBH4 in toluene using tetraoctylammonium bromide (TOAB) as both a stabilizing agent and phase-transfer catalyst in a biphasic method.[56] In this way, stable spherical thiol gold nanoparticles between 1–3 nm in diameter are obtained. As thoroughly described by Brust,[56] nanoparticle synthesis that use alkanethiols, sodium borohydride, and surfactants are directly affected not only by the nature of the seeds, but also by the addition order of the reactants. They explored an industrial approach to dodecanethiol-coated nanoparticle synthesis that employs annealing procedures to improve sample polydispersity. Seeds were prepared by mixing solutions of gold salts in aqueous media with tetradecylammonium bromide (DTAB) dissolved in toluene; upon mixing, the aqueous phase turned colorless and was removed. Two distinct procedures with inverse addition orders were then used to obtain seeds. In procedure I dodecanethiol was added, and the resulting mixture was then reduced with borohydride, giving rise to 1.5 nm single-crystal seeds. For procedure II the first step was the borohydride-induced reduction; the solution was then stirred from three hours, and finally dodecanethiol was added; this procedure led to the generation of 3.5 nm multitwinned seeds. Both sets of nanoparticles were then subjected to annealing: heating to 463 K caused the toluene to evaporate and gave a black precipitate inside an orange matrix composed of melted DTAB, dodecanethiol, and borohydride salts. The solutions were then cooled to room temperature and resuspended in toluene. Smaller seeds gave a bimodal nanoparticle distribution with maxima at 25 and 35 nm, while larger ones gave a unimodal distribution of particles with a medium diameter of 5.8 nm. When both seeds were mixed, no large particles formed and the size distribution resembled that found for 3.5 nm seeds (5.3 to 8 nm). The marked difference in seed behavior is then attributed to the physical properties of seeds Chem. Eur. J. 2015, 21, 9596 – 9609

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themselves: smaller seeds have a calculated melting point of 500 K, while larger ones melt at 900 K. Thus, by heating to 463 K the 1.5 nm seeds melt almost completely, and then recrystallize slowly as the solution is cooled to room temperature, giving rise to polydisperse large particles; 3.5 nm seeds do not fully melt, and grow slightly due to atom migration from one particle to another. Since no new gold salts are added after the seeds form, actual growth of the particles is heavily impaired by the reaction media; this way, small nanoparticles of about 5 nm in diameter can be industrially synthesized. Based in Brust’s studies, the Martin synthesis also uses sodium borohydride as a strong gold reducing agent, but is done in aqueous instead of organic media.[57] As this synthesis is carried out without any further stabilizing agent, HAuCl4 and NaBH4 need to be previously stabilized in HCl (3 weeks) and NaOH (3 months), respectively. In this time-consuming synthesis, stable spherical gold nanoparticles ranging from 3 to 5 nm in diameter can be generated.[57] Some other Brust method variations using phosphines, amines, or carboxylate ligands have also been described;[58] in addtion, nanoparticle synthesis may also be carried out in other organic solvents such as dimethylformamide (DFM) and formamide (FM) that, like TOAB in Brust’s method, are also reducing agents.[59] Ratio Au/reducing agent The gold/reducing agent ratio determines the nanoparticles’ final size even more so than their absolute concentrations.[39] In an earlier work, Frens observed that variations in citrate concentration in relation to gold lead to several different nanoparticle size distributions.[60] This is due to reducing agents (such as trisodium citrate or ascorbate) being physisorbed on the NPs surface and forming a passivation layer that has a strong influence on the coarsening process and therefore in particle aggregation. The existence of this passivation process justifies larger particles being obtained at lower citrate concentrations, and causes reductant concentration to be of special interest in the stabilization processes carried out at lower gold concentrations. As described by Kimling, the best size distribution and colloid stability for gold citrate nanoparticles are obtained for those synthesized at 100 8C and with a gold concentration below 0.8 mm (Figure 3). At higher concentrations, nanoparticles become larger and the obtained suspension is less stable. They established a gold concentration upper limit of around 1–2 mm for obtaining colloidal nanoparticles that were stable for at least one month.[39]

Stabilizing Agents Both the electrostatic and steric effects provided by the stabilizing agent can help avoid the nanoparticle aggregation processes, thus improving their stability. The stabilizing or capping agent can be added during or post nanoparticle synthesis; those that are added post-synthesis are done so by using

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Figure 3. Peak wavelength of the SPR as a function of the concentration ratio of gold ions versus reductant citrate preparation at 100 8C. (Reprinted with permission from reference [39]. Copyright 2006 American Chemical Society.)

direct incubation or by chemical reaction with the nanoparticles’ added functional groups. Here we describe reactants that act both as reducing agents and as stabilizers, therefore having a double role in nanoparticle synthesis (Figure 4). Since Turkevich’s method was published, sodium citrate has become the most used reducing agent for gold nanoparticle synthesis. As explained before, trisodium citrate (SC) can act both as a gold salt reducing agent from Au3 + to metallic state and as a stabilizing agent due to its anionic character, thus both generating nanoparticles and helping avoid their aggregation in one single step.[32, 39] SC also has a third role in nanoparticle synthesis, since by changing the relation between gold salts and SC added, the pH of the solution can be modulated.[38] Aminoacids such as l-lysine could also act as electrostatic stabilizers in NaBH4-reduced gold nanoparticles[61] . Surfactants such as CTAB used in nanorods synthesis also show those two functions, acting as shape forming agents and preventing aggregation.[46] Although nanorod formation mechanisms are not clearly defined, authors agree that since the adsorption of CTAB bilayers on solution occurs in a preferred direction, crystal growth at that face is hindered and an elongation pattern is generated in the other direction, giving rise to

rodlike structures.[25, 44, 62] Other authors have described gold nanorod synthesis from spherical nanoparticles by using antibodies as templates.[63] CTAB can also be used as a stabilizing agent on spherical nanoparticle synthesis, under conditions that do not promote rod growth. An example of this use was described by Murphy[50] in a work in which CTAB-protected seeds are used for further nanoparticle growth; no rods were found in synthesis of particles under 17 nm, while larger ones showed a small fraction of nonspherical forms. This surfactant-protected seed approach is also used by Brust on his industrial-scale synthetic routes;[64] in this case, DTAB-protected seeds are made to grow into spherical, dodecanethiol-protected nanoparticles. Polymers such as poly(N-vinylpyrrolidone) (PVP) or branched polyethyleneimine (BPEI), which are more bulky and structurally complex than SC, can also be used as reducing agents and fill the role of capping and stabilizing agents. In this case, the stabilization is achieved by hindering interparticle approach by steric effects.[65–67] Moreover, some of those polymers, such as poly(ethylene glycol) (PEG), can also add functional groups suitable for further nanoparticle functionalizations.[15] As is the case with SC, the molar ratio between gold salt and some diblock copolymers such as poly[2(dimethylamino)ethylmethacrylate] (PDMA) or poly(ethylene oxide) (PEO) can be also used in synthesis to regulate nanoparticle size, with the longer blocks yielding the smallest nanoparticles as a result.[68–70] On the topic of stabilization by steric effects, we also have to take into account proteins such as BSA, which are easily adsorbed onto gold surfaces and are commonly used for enhancing colloid stability,[71] and another reducing/stabilizing agent that doubles as a size regulator agent: chitosan, a cationic polysaccharide. Depending on both its molecular weight and the concentration used, a wide range of chitosan–nanoparticle sizes can be obtained. When the concentration of chitosan is low (up to 0.01 %) larger nanoparticles are formed; at higher chitosan concentrations, a narrower size distribution is obtained.[72] Other compounds that can play this double role are thiol/ thiolated and other sulfur-containing ligands such as N-(2-mercaptopropionyl)glycine (tiopronin), which are added during synthesis. They also provide carboxylic acid groups available for further functionalizations.[73, 74] Thiol nanoparticles can also be obtained by the Brust–Schiffrin method, which takes place in organic solvents.[56] Going a step further, gold nanoparticles that have been synthesized by using conducting nanofiber polymers (such as polyaniline) as reducing agents have shown a huge potential for the development of memory data storage devices. The Kaner group found that the best results were obtained for 2 nm gold nanoparticles, and reported that the higher conductivity results were achieved with smaller nanoparticle sizes and higher particle densities.[75] Other reducing/capping agents, such as oleyl amine (OLA), hyperbranched polyethyleneimine, or piperazine derivatives, have been reviewed by Saha.[65]

Figure 4. Quick overview of some commonly used nanoparticle stabilizing agents. Chem. Eur. J. 2015, 21, 9596 – 9609

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Review Influence of pH The pH influence in gold nanoparticle synthesis has not been traditionally explored in as much depth as other more direct factors, although Turkevich himself pointed out the formation of various AuIII–hydroxide complexes when using direct gold salts reduction in a basic reaction media.[35] In fact, pH control plays a key role, if not as direct or intuitive as the nature of reductant or capping agent, in the final size of a given nanoparticle synthesis. In this sense, Goia et al.[76] carried out an extensive study in which gold nanoparticles were synthesized in aqueous media and the pH was varied between ¢1.25 and 12.9; the chosen synthesis procedure was the classic procedure of direct reduction of gold salts by ascorbic acid, and arabic gum was used as a stabilizer. In this way, large gold colloids were formed, with final diameters ranging from 90 to 4600 nm in diameter; by using SEM measurements, it was found that these particles were formed by coagulation of smaller gold nanoparticles of 16 to 29 nm in diameter. Larger colloids and particles formed at lower pH values. In order to explain this phenomenon, up to six gold complexes were identified; at neutral pH, the chloride complex AuCl4¢ is the predominant form, and increasing pH values causes the Cl¢ atoms to be successively substituted by OH¢ , while lower pH values cause HCl–salt complexes to form. The small variation that was found in DE values (defined as the difference between the redox potential of gold salts and that of the ascorbic acid) at different pH was cited as the cause of the slight variation in nanoparticle size, from 29 to 16 nm, as the final pH of the solutions increased. However, the great difference between final colloids’ size cannot be attributed solely to this factor. Instead, the researchers found that the zeta potential of the formed particles was around ¢30 mV for pH media of 4 and higher, but rose drastically (up to near 0) for pH < 4. It was also found that the final pH of the particle solutions was much higher than the starting salt ones, due to the generation of free Cl¢ ions upon reduction of AuClx complexes; for all solutions but one (which did not contain chloride complexes, but instead Au(OH)4¢) the final pH was acidic. The drastic reduction in the negative charge of the nanosized particles (zeta potential values) caused by the drop in pH values led to coagulation of the smaller nanoparticles to nanometer-sized ones; in the solution in which the pH remained basic aggregation was prevented by repulsive forces, and the colloid showed a final size in the nanometric range. In a recent work, Patungwasa[77] et al. studied pH influence in size, polydispersity and morphology for AuTSC nanoparticles (Figure 5). They demonstrated by TEM micrograph analysis that the coagulation rate is pH dependent, and that the greater the pH, the lower width distribution and mean particle diameter that is obtained. At low pH values (5 or lower) a wide size distribution of polyhedral nanoparticles, formed by slow coagulation rates and enlarged by deposition, is observed. If the pH is between 5 and 6 a mixture of ellipsoidal and other nanoparticles appear, and finally, when pH is between 6 and 8, Patungwasa et al. observed a narrow size distribution of spherical nanoparticles. They suggested that the observed morpholChem. Eur. J. 2015, 21, 9596 – 9609

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Figure 5. TEM micrographs of gold nanoparticles obtained by citrate reduction at the following pH values: a) 4.0, b) 4.5, c) 5, d) 5.5, e) 6.0, and (f) 6.5. (Reprinted from reference [77], with permission from Elsevier.)

ogy changes are related to the nucleation and growth mechanisms that involve both variations in the reduction potential AuCl4¢/Au0 with pH due to the formation of hydroxo–chloro complexes (¢59 mV per pH unit) and in the interparticle potential due to changes in the citrate concentration. They also concluded that there is a limit in the surface charge density, since the surface interaction potential is high enough (50 mV) to avoid aggregation and maintain kinetic stability between AuTSC nanoparticles.[77] Following on from the research by Goia and Patungwasa, and based on the Turkevich method, Muangnapoh stated that zeta potential is also pH dependent, ranging from ¢40 to ¢60 mV in a stable red colloid dispersion when the pH is between 5 and 9 units.[78] When the pH is adjusted to values below 5, the suspension stability decreased and a lower intensity in the absorption of the surface plasmon resonance band is observed (Figure 6).

Figure 6. UV/Vis spectra of gold nanoparticles synthesized at different pH. (Reprinted from reference [78], with permission from Elsevier).

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Review As an example of the great influence that pH has on the characterization and reactivity of gold nanosystems, two representative examples will be briefly discussed. It is known that both fluorescence quenching and catalytic activity of gold nanoparticles are size dependent, becoming enhanced or faster, respectively, with smaller size.[5] As smaller size causes more unstable nanoparticles, and the fluorescent agents added can affect both the final stability and the size of the nanoparticles, any variation in the synthetic process needs to be carefully monitored to assure the stability of the resulting nanosystem. On the subject of fluorescence quenching effects, luminol(3aminophthalhydrazide) and ferricyanide were bound to both citrate- and borohydride-reduced gold nanoparticles in a pH dependent way by Duan, who concluded that chemiluminescence was inhibited by nanoparticles smaller than 5 nm, and enhanced by those larger than 10 nm, but not than 25 nm. This upper limit is due to larger sizes implying smaller superficial areas, which cause both catalytic activity and fluorescence quenching to reduce.[5] When Au nanoparticles were studied as catalysts in CO oxidation, the best efficiency was obtained with TiO2-covered gold nanoparticles. By using a deposition–precipitation method, commercial TiO2 nanoparticles were added to a solution of HAuCl4 at both pH 8.5 and 6. Higher catalytic activity was observed for nanoparticles that were synthesized at pH 8.5; this effect was attributed to their mean diameter being lower (2 nm) compared with that of nanoparticles for which the synthesis was carried out at pH 6 (10 nm).[79]

Other Synthesis Factors Temperature Reaction temperature is probably the most important factor to consider in nanoparticle synthesis, because as we previously stated, slight variations in temperature conditions can greatly affect synthesis reproducibility. Nanoparticles can be obtained at a wide range of working temperatures, but it needs to be carefully controlled, or both the size and the stability of the resulting solutions can be compromised. Based on previous work from Hauser and Lynn,[80] Turkevich studied the role of temperature in gold sols obtained by reduction with sodium citrate.[32] He concluded that for a lower reaction temperature, the time required to complete the reduction process was increased and the mean particle size of sols obtained was decreased in comparison with faster reduction processes.[32] Proper control of temperature and time consumed in each nanoparticle synthesis will help to obtain the desired size and shape. The reaction temperature can be achieved by several means of heating, for example, boiling or irradiation (UV,[39] g,[81] or laser ablation).[82] In a thermal reduction reaction, a lower temperature leads to irregular shapes and a larger diameter of the nanoparticles produced. Insufficient temperature or the temperature gradients that tend to appear in reflux experiments tend to cause irChem. Eur. J. 2015, 21, 9596 – 9609

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regular heating, and therefore shape and size of nanoparticles obtained are also irregular.[39] A better size distribution at several temperatures can be obtained by controlling pH during the nanoparticle growth phase and when mixing solutions. By adding proper amounts of sodium hydroxide, and using trisodium citrate as a reducing agent, monodisperse gold nanoparticles can be obtained from 25 to 100 8C.[83] Klabunde’s group described a nanoparticle synthesis method which used complex thiols (sodium 3-mercapto-1-propanesulfonate, the sodium salt of the 1-mercapto-5-tetrazoleacetic acid and 3-mercapto-1,2-propanediol) in an industrialscale procedure known as solvated metal atom dispersion (SMAD).[84] Since thiolate groups adsorb on the surface of gold nanoparticles, they are extensively used in synthesis. We have already covered their use in both Brust’s method and when citing tiopronin as a capping agent. However, the focus of this work is not to analyze functionalization of nanoparticles, even if it is done at the time of their synthesis, and therefore no further insights into tiopronin nanoparticles will be exposed. For Klabunde’s method, complex equipment is used in order to vaporize metallic gold rods and ketones under vacuum conditions and in a vessel cooled with liquid nitrogen; these conditions were kept for 3–4 h. Frozen Au and acetone vapors were then allowed to condense, by removing liquid nitrogen cooling and vacuum, into a solution containing the thiol in water, in which nanoparticle formation took place. Finally, the ketone was evaporated by using milder vacuum conditions to obtain the thiolated colloid in water. In this way, colloids made using sodium 3-mercapto-1-propanesulfonate had a diameter of around 4.2 nm; those made with the sodium salt of the 1mercapto-5-tetrazoleacetic acid were 3.4 nm and those capped with 3-mercapto-1,2-propanediol were of around 6.6 nm in diameter. A digestive procedure (Ostwald ripening), which consisted of heating the solution under reflux for 90 min, was tried for the three colloids. The first two, the capping agents of which were ionic, were unstable; the third experienced a clear growth and sharpening of its plasmon band, and its color shifted from brown to purple. This effect was interpreted as a clear improvement in both particle size and monodispersity from the unripened colloid. In a previous work, Klabunde et al. had proposed a quite similar industrial synthesis procedure that used toluene instead of water and had dodecanethiol as a capping agent. In this work, a drastic change in size, from 5–40 nm in the original mix to 1–6 nm, was observed following vacuum evaporation of ketone. Those observations were justified in the light of ketone molecules being substituted by thiol molecules as capping agents, due to dodecanethiol being more soluble in toluene than in ketone; this procedure could be accompanied by a slight ripening of the nanoparticles. After digestive ripening, the final diameter of the colloid is 4 nm. Changes in size of the carbonated chain of the thiol were noted to not produce appreciable variations in the final product. As for laser methods, size polydispersity in nanoparticles obtained with laser ablation has been found to be higher than that observed when using other heating methods. When surfactants, such as sodium dodecyl sulfate, are used in laser syn-

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Review thesis of Au nanoparticles, not only is the stability enhanced, but also nanoparticle size can be decreased.[85] Other synthetic routes can be achieved at room temperature, while still obtaining stable nanoparticle suspensions. For example, plasma discharges can be applied against a gold solution, producing highly dispersed gold nanoparticles without the use of any further reducing agent.[86] Also, tannic acid is often used in gold nanoparticles synthesis at room temperature;[87] it acts both as reducing and stabilizing agent, and by controlling pH, size-controlled 2 to 10 nm nanoparticles can be achieved.[88] Yet another way relies on the use of ionic liquids, such as 1-butyl-3-methylimidazolium hexafluorophosphate, by using a sputtering deposition method at room temperature; this way, 2 nm stable and photoluminescent NPs have been obtained.[89] Stirring and addition order Besides the accurate control of reactant concentration, pH, temperature, and time that has been described above, there are many other factors to be taken into account in order to achieve stable and reproducible nanoparticle synthesis. As explained before, a faster nucleation and a lower growing rate both lead to monodisperse nanoparticles; so it is logical to infer that size, shape, and monodispersity of nanoparticles obtained can vary as a function of stirring parameters, such as the rate, time, temperature, or even the nature of the magnetic or mechanic stirring method. Stirring parameters can also affect both the homogeneity of the precursor mixing and the rate of solvent evaporation. Similarly, Murphy and co-workers amongst many others demonstrated that time employed and mixing speed during the precursor addition both affect the resulting rate of reaction, which causes those factors to have a great impact in the morphology of the NPs obtained, even going as far as to not to allow for the obtainment of a stable nanoparticle system if they are not properly controlled. For citrate gold capped nanoparticles (Turkevich’s method) the addition order of the reactants has also been studied. When comparing a direct method in which sodium citrate is added to a solution of gold with the reverse method (gold salts added to a previously prepared solution of sodium citrate), it was found that the oxidation induced by sodium citrate increased in the latter method, which lead to a narrower size distribution of stable nanoparticles.[92] Brust’s studies on thiol-capped nanoparticles[64] show that addition order’s influence is not restricted to traditional procedures, but instead is a core factor to be controlled on any synthesis route with independence of the nature of the reaction media or the reactants employed. Working with fresh solutions, taking into account the noble metal sensitivity to light and high temperatures, using a suitable purification (centrifugation, filtration, dialysis) and drying (rate, lyophilisation, evaporation) method, maintaining a clean equipment and having controlled and appropriate final storage conditions are all factors that can highly influence the formation and therefore the long-term stability of synthesized nanoChem. Eur. J. 2015, 21, 9596 – 9609

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particles, and as such are worth of being taken into account for every nanoparticle synthesis we wish to accomplish.

Conclusion and Perspective Due to their unique optical properties, noble metal nanoparticles, and specifically those made of gold, are one of the most studied and synthesized nanoparticles. There are two main reasons that explain this particular usefulness; one is the presence of a characteristic well-defined surface plasmon band that gives these nanoparticles a distinctive intense color and can be used both for synthesis control and for the characterization of the final products. The other is their ease of functionalization by direct incubation with several very common functional groups, amongst them thiols (both simple and complex) or carboxylic groups. This leads to a broad range of applications, and noble metal nanoparticles are nowadays the most studied and synthesized on a worldwide basis. In this review we have focused on gold nanoparticle synthesis, in particular those derived from the classical protocols described by Faraday and Turkevich, due to their special importance and ubiquity. Since these protocols were described, a lot of effort has been made to achieve control of the geometry and improve the stability and homogeneity of the particles obtained; much of this work has been accomplished by modifying and controlling the parameters listed above. In the last few decades, synthetic procedures have experienced a natural evolution towards more complex shapes that can be adapted to an ever growing number of specific applications, thus earning a relevant place on such diverse fields as medicine, biotechnology, or materials science and engineering. Synthesis of gold nanoparticles can be achieved by several methods that depend on the desired properties of the final product (mainly the size, shape, and functionalization) and on varied external factors, such as the funds and the technology available for a specific research project. Stability is a key factor to take into consideration and because of this suitable reducing and stabilizing agents must be studied in detail prior to each synthesis. Moreover, changes on the synthetic parameters, some of them previously explored in this review (pH, temperature or addition order) can also heavily impact the outcome of different synthesis that make use of exactly the same reagents. This impact is due to those parameters affecting different factors on the nucleation, growth and Ostwald ripening processes of the particles, which in turn lead to different size and shape formation being more or less favored. Table 1 offers a quick overview of the most important methods and approaches divided in five groups: single, double, seeded, laser ablation and SMAD. Detailed information about those methods that pose a special importance can be found in the Supporting Information. Even though more than sixty years have passed since it was first described, the classical gold reduction in a single-phase method using citrate as both reducing and stabilizing agent remains the faster, easier, and most used synthesis leading to stable and spherical NPs. Thiol or surfactants added during synthesis can lead to NPs that show increased stability and better shelf lifetimes, non-spherical shapes, or new functional

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Review Table 1. Most common synthesis procedures ordered by group and publication year. An asterisk * denotes synthetic procedures that are described in more depth in the accompanying Supporting Information. Publication year

Reducing agent

Stabilizing agent

Method

Diameter [nm]

Shape

Faraday[1]

1857

phosphorus H2

carbon sulfide carbon sulfide

gold reduction

ruby red (probably spherical) blue (probably rods)

Turkevich[32]

1951

sodium citrate hydroxylamine hydrochloride

thermal single-phase gold reduction RT seeding approach

20 20–120

spherical spherical

Frens[60]

1973

sodium citrate

thermal single-phase gold reduction

16–150

spherical

*Brust-Schiffrin[56]

1994

NaBH4

TOAB and CH3(CH2)11SH[a]

water–toluene biphasic method with alkanethiol

1–3

spherical

Goia[76]

1999

ascorbic acid

arabic gum

room temperature reduction

90–4600

spherical

Natan[90]

2000

sodium citrate NH2OH

RT seeding approach iterative RT seeding approach

20–100 12.7 Õ 11.7–116 Õ 112 13.7 Õ 11.2–233.6 Õ 74.2

spherical spherical rods

Jana and Murphy[49]

2001

ascorbic acid

RT reduction

22

spherical

ascorbic acid NaBH4 NaBH4/citrate hydrazine hydrazine

citrate SDS SDS SDS

seeding approach reduction seeding approach reduction seeding approach

20 3–4 5–30 5–10 2–5

spherical spherical spherical spherical spherical

Jana and Murphy[50]

2001

citrate

CTAB

seeding approach (iterative)

37 200 Õ 17

spherical rods

Mafun¦[85]

2001



SDS

laser ablation

1–5

spherical

*Klabunde[91]

2002



CH3(CH2)11SH[a]

vacuum vaporization and reflux (SMAD[e])

4

spherical

*Sau and Murphy[44]

2004

NaBH4/ ascorbic acid

CTAB

RT seeding approach

20-100 (2–4 aspect ratio)

rods

Kimling[39]

2006

sodium citrate (or ascorbic acid)

thermal, UV irradiation or RT gold reduction

9-120

spherical

Klabunde[84]

2007



vacum vaporization and reflux (SMAD[e])

4.2 3.4 6.6

spherical spherical spherical

*Kah[43]

2008

sodium citrate

thermal single phased gold reduction

20

spherical

Patungwasa[77]

2008

potassium citrate

thermal single phased gold reduction at various pH

18–100

spherical to polyhedral

*Brust[64]

2009

NaBH4

DTAB and CH3(CH2)11SH[a]

seeding approach in organic media

25 and 35 (1.5 seeds) 5–8 (3.5 seeds)

spherical

Martin[57]

2010

NaBH4

HCl and NaOH

slow gold reduction

3–5

spherical

Sivaraman[88]

2010

tannic acid

pH adjusted room RT

2–10

spherical

Kaner[75]

2011

polyaniline nanofibers

gold autoreduction at several temperatures

< 1– > 10000

spherical to microsheets

HSCH2CH2CH2SO3Na[b] C3H3N4NaO2S[c] HSCH2CH(OH)CH2OH[d]

[a] Dodecanethiol. [b] Sodium 3-mercapto-1-propanesulfonate. [c] Sodium salt of 1-mercapto-5-tetrazoleacetic acid. [d] 3-Mercapto-1,2-propanediol. [e] SMAD = Solvated metal atom dispersion.

groups that can be available for further applications. Seedmediated synthesis involve more laborious protocols, but Chem. Eur. J. 2015, 21, 9596 – 9609

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show improved monodispersity and open up a whole new area in the field of nanoparticle size control. Seeded ap-

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Review proaches can and are widely used for the synthesis of gold nanorods, nanoparticles with a wide range of new applications due to presenting a second plasmon band in the NIR region in addition to that characteristic of spherical particles. From the first spherical nanoparticles described by Turkevich, to the anisotropic nanorods or the more complex nanoshells, the synthesis of nanosystems is experiencing a huge interest, which is reflecting in more and more specific synthetic procedures being researched, patented, and published every year. Geometry of the resulting nanoparticles is a key factor, since the anisotropy of the nanosystem greatly affects its physical and optical properties. Nowadays, efforts on the development of new nanosystems are focused in three basic directions: 1) finetuning the surface plasmon resonances of such particles, 2) providing biomimetic materials, and 3) providing anisotropic crystals, that are expected to play a crucial role on the development of printed electronics. On this topic, many studies about specific synthetic routes have been developed and published in the past years, and despite a large variety of geometries having been produced from a wide assortment of materials, the influence of key parameters (such as temperature or nature of the reactants used) involved on those synthesis have not yet been clearly discerned for the major part. In this review, we have aimed to offer a global vision of the most important factors that can affect the outcome of those synthetic routes.

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Nonfunctionalized Gold Nanoparticles: Synthetic Routes and Synthesis Condition Dependence.

Since Faraday first described gold sol synthesis, synthetic routes to nanoparticles, as well as their applications, have experienced a huge growth. Va...
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