This paper reviews recent developments on the synthesis of noble metal nanoparticles in micro and millifluidic devices and their catalytic application in organic flow synthesis. A variety of synthesis methods using microfluidics is presented for gold, silver, palladium, platinum, and copper nanoparticles, including the formation in single-phase flows and multiphase flows. In the field of organic chemistry, metal nanoparticles can be used as catalysts. This can lead to remarkably improved reaction performance in terms of minimizing the reaction time and higher yields. In this context, various applications of those metal nanoparticles as catalysts in microfluidic devices are highlighted at selected examples. As a new direction and operational window, nanocatalysts may be synthesized in situ in flow and directly utilized in an organic synthesis. This allows making use of highly active, yet instable catalyst species, which may only have a very short life of a few seconds – a type of flashed nanocatalyst organic synthesis.
Recently, nanoparticles, of spherical and non-spherical shape, are widely used in many different areas such as electronics, energy, textiles, biotechnology, etc. [1–6]. Such expanding applications have resulted in an increased focus on studying the method of synthesis of nanoparticles. Conventionally, nanoparticles are produced with methods such as liquid-phase synthesis, for example, the co-precipitation of soluble products, sol-gel process, microemulsion, etc. [7–10], which are applied mostly in traditional batch processes. One of the drawbacks of conventional methods is the lack of suitable control over mixing. Poor mixing creates particles with wide size distribution, irreproducibility of size, and morphology. Besides, it is difficult to obtain the same result when scaling up the batch process, that is, to achieve process reliability.
Currently, microfluidic technology introduces a new method to overcome conventional process limitations [11–14]. The high surface area to volume ratio and reduced diffusional dimensions characterize microfluidic devices and enable, among other advantages, more controlled transport such as mass and heat transfer as well as reducing chemical reaction time. The advantages from the increased heat transfer rates can be very important, for instance, in multiphase reactors, where the improved heat transfer in microreactors diminishes the chance of the formation of the so-called local “hot spots”, compared to batch reactors. Accordingly, product selectivity is improved by performing exothermic, multiphase reactions in a microreactor. Furthermore, small-sized microreactors have safety advantages in the use of toxic, harmful, or expensive chemicals. Besides, microfluidic synthesis techniques operate at steady state and give superior control over reaction conditions, such as reagent addition, mixing, and temperature. Also, scaling up is more efficient than for a batch process [15, 16]. Regarding the scale up and flow pattern, mixing in flow systems is relatively well characterized in comparison to batch vessels. Therefore, scaling up the flow reactors is easier and faster. Another interesting feature is that online monitoring can be implemented, allowing quick parameter space study for kinetic studies and can yield optimization [17, 18]. These advantages are key for producing a wide range of nanoparticles with more uniform size distribution and desired shape, morphology, (super-)structure, and crystallinity of nanoparticles  (Table 1 presents a summary of the comparison of the main features of the nanoparticle synthesis for batch and flow).
|Minimal particle size||Small||Very small|
|Particle size distribution||Large||Small|
|Reproducibility||Poor to moderate||Good to very good|
|Operational stability (e.g., fouling)||Very good||Good|
|Mixing quality||Good||Very good|
|Surface area to volume ratio||Small||High|
|Mass and heat transfer||Moderate||Very good|
|Scale-up efficiency||Good||Very good|
As mentioned, frequently, all types of nanoparticles including inorganic , organic , and polymeric  nanoparticles with well-defined composition can be synthesized within microreactors. Inorganic nanoparticles are classified into three categories: dielectric [22, 23], semiconductor [24, 25], and metal [26, 27] nanoparticles. Considering metal nanoparticles, they can be applied as a catalyst in catalytic reactions.
The complexity of the nanoparticle synthesis with its cascade of elemental reaction steps (e.g., reduction, seed formation, growth, and stabilization) is increasingly reflected in a complexity of the microfluidic system. Separate feeds for the respective reactants/stabilizers are given; each elementary step has its own reaction channel and is operated at the best process conditions for the given step. Thus, the microfluidic architecture is characterized by a series of mixing injections and reaction channels (Figure 1). Some of these devices shown in Figure 1 were used in the examples described in this review.
Therefore, in this paper, our aim is to briefly review recent research on the synthesis of selected metal nanoparticles (gold, silver, palladium, platinum, copper) and their catalytic applications in organic reactions in microfluidic devices. The most recent progress on the synthesis of some more industrially important noble metal nanoparticles is discussed, providing some examples from each one.
2 Metal nanoparticles in a microfluidic reactor
Metal nanoparticle formation involves at least two steps: the initial nucleation and subsequent particle growth (sometimes followed by polymer stabilization). In most conventional methods, both processes take place simultaneously in a one-pot process under reaction conditions which are often not optimal for both. These processes also take place under mixing-masked conditions due to the fastness of this elementary process. Therefore, synthesized particles in batch often suffer from broad size distribution . To obtain uniform nanoparticles, all nucleation processes should take place in a short period of time (no longer than needed) and separately (each process under optimal conditions). Materials should be supplied slowly not to reach the concentration level at which nucleation would occur. The goal is rather to prepare many nucleation centers so that small particles are produced. Because of the better control of the reaction kinetic parameters, such as better mixing and efficient heat and mass transfer, microfluidic reactors have been widely designed and applied to produce uniform metal nanoparticles. For metal nanoparticle synthesis, the benefits of using microreactors over conventional methods rely on very fast mixing, the capability to control the temperature along the flow, and the potential to combine separated reaction steps in a one-flow .
Gold nanoparticles have attracted significant attention due to their wide range of applications. For a more detailed overview of gold nanoparticle applications in chemistry and bioscience, the reader is referred to a comprehensive review about this topic .
As one of the first works, the synthesis of gold nanoparticles in microfluidic was reported by Wagner et al. . Single-phase flow  is applied to synthesize gold nanoparticles (5–50 nm) in a glass-silicon microreactor directly from a gold salt (HAuCl4) and a reducing agent (ascorbic acid). By optimizing the experimental parameters such as flow rate, pH, and excess of reducing agent, a narrow size distribution is achieved, which is two times narrower than in a conventional synthesis. Moreover, by elevation of pH during reaction and hydrophobization of internal reactor surfaces, reactor fouling was decreased . The higher the pH, the smaller mean diameter was obtained (at pH=2.8 the mean diameter=21 nm, and at pH=9.5 the mean diameter=8 nm). The same author used a microfluidic chip, a three-step static micromixer (by IPHT Jena, Jena, Germany). This device contains four fluid inlet ports and one outlet port. In the first step, the first two inlets are premixed. Then in the second step, the third inlet is premixed with the mixture of the first inlets. Finally, the last inlet is mixed with the mixture stream of previous inlets. For a single mixing step in the chip device, the residence time was varied from approximately 1 s to 1 min. This leads to the formation of Au nanoparticles in single and cluster forms with different shapes such as hexagonal nanocrystallites or tetrahedron-like cluster of nanoparticles (Figure 2) .
Luty-Błocho et al.  investigated gold nanoparticle synthesis in continuous flow using a fast reducing agent, sodium borohydride, which needed even faster mixing. The whole idea was to chemically impact the nucleation and growth processes in order to obtain smaller and better defined nanoparticles (this was seen under the umbrella of the “Novel Process Windows” concept). A slow reducing agent, ascorbic acid, was investigated to compare to the fast one. In this regard, the impact of process conditions on each elementary step such as mixing and reaction was varied, for example, using two polymers of known fast and slow particle absorption. A multi-lamination micromixer was utilized, which can mix in some 10 ms, depending on flow rates. When slowly reducing the gold particle precursor HAuCl4 with ascorbic acid, the smallest nanoparticles (0.8–4 nm) are obtained for the highest applied flow rate of 7.5 ml/min (Figure 3A). Using the fast reducer, sodium borohydride, even smaller nanoparticles (0.6–3 nm) are achieved for the flow rate of 10.0 ml/min. In the batch process, the average size and particle size distribution is broader (1.5 nm to 2 μm) (Figure 3B). Thus, when comparing two reducers, the gold nanoparticles, which were synthesized through sodium borohydride, are smaller and more uniform. This demonstrates that mastered chemical conditions supported by microfluidic engineering can allow a certain nanomaterial shaping control.
Pacławski et al.  produced gold nanoparticles by reduction of gold(III) chloride complex ions using glucose as a reducing agent in a microreactor. This process includes a series of elementary steps: (i) reduction of gold(III) and gold(I) complex ions ([AuCl3(OH)]-) to metallic gold; (ii) nucleation; and (iii) growth of gold nanoparticles. The synthesis was performed in the presence of different amounts of polyvinylpyrrolidone (PVP) as a stabilizing agent. In these studies, the rate constant is determined from experiments done in a batch system. Then, on the basis of information obtained from experiments in the batch reactor (the rate law as well as the optimal PVP concentration), gold nanoparticles were synthesized at different flow rates of the stabilizer solution (0.05–1.45 ml/min) and of the gold precursor and glucose mixture (3.0 ml/min) (Figure 4). In the studied system, glucose also acts as a capping agent. However, because of the high rate of the nanoparticle formation, glucose is not found to be an efficient stabilizer. The addition of PVP into the reaction mixture increases the stability of gold nanoparticles and enables to obtain smaller nanoparticles. In this system, the diameter of synthesized spherical gold nanoparticles can be controlled from 10 to 50 nm.
By using the segmented flow technique  in microflow reactors instead of single-phase flow, gold nanoparticles of even better defined properties are produced . In the segmented flow technique, an immiscible fluid is introduced to divide the reagent phase into discrete slugs or droplets. The key advantages of segmented flow contain the reducing of the axial dispersion and the susceptibility to reactor fouling . On the basis of the analysis of flow fields and the resulting particle size distribution, Cabeza et al. illustrated that the slip velocity between the two fluids and the internal mixing in the continuous-phase slugs determines the particle size distribution . The reduction in the axial dispersion has less impact on the particle growth and hence on the particle size distribution. Gold nanoparticles are synthesized from HAuCl4 with rapid reduction by NaBH4 (Figure 5). In this way, gold nuclei are obtained, which grow by agglomeration, and it is controlled by the interaction of the nuclei with local flow. Therefore, the difference in the physical properties of the two phases, such as density, viscosity, and surface tension, and the inlet flow rates finally control the particle growth. Hence, a careful choice of continuous and dispersed phases is necessary to control the nanoparticle size and size distribution.
By increasing the residence time, the particle size distribution widened independent of the inert fluid dispersed in the aqueous phase. For instance, with toluene as the inert fluid, particle sizes of 3.8±0.3, 4.6±2.1, and 4.9±3.0 nm are achieved at residence times of 10, 20, and 40 s, respectively .
In addition to spherical nanoparticles, anisotropic metal nanocrystals such as nanorods have been synthesized using microfluidics [39–41]. As one of the early works, Boleininger et al.  presented a continuous flow synthesis of gold and silver nanorods with specific shapes. They used small, spherical gold seeds in a growth solution containing the gold salt (HAuCl4) in millimolar concentrations, a mild reducing agent (ascorbic acid), and a high concentration of a surfactant molecule (cetyltrimethylammonium bromide, CTAB), which produces a rod-shaped anisotropic particle growth solution. The seeds and growth solution are injected to a microreactor. The effects of the concentration in the mixture of growth-to-seeds solution and of the growth temperature on particle shape were tested. Fewer seeds generate particles of higher aspect ratio and also a higher growth temperature produced smaller aspect ratio (fatter rods) (Figure 6).
Bullen et al.  presented a direct seedless approach to synthesize gold nanorods in continuous microfluidic. Two different solutions (HAuCl4/CTAB/acetylacetone and AgNO3/CTAB/carbonate buffer) at room temperature are introduced to a rotating tube processor followed by a narrow channel processing microfluid. The rotating tube processing provides a good mixing of two solutions and therefore with the aid of centrifugal force gold nanocrystals were formed. Thereafter, the gold nanocrystal solution continuously entered the narrow channel processor for growth of the gold nanorods (Figure 7).
In addition to single-phase flow, droplet-based flow has been used to synthesize anisotropic gold nanocrystals. Duraiswamy and Khan  used presynthesized gold nanoparticle seeds and growth reagents. A first reagent solution contained a premixed Au3+, Ag+, and CTAB solution; a second reagent solution contained an aqueous solution of ascorbic acid. These are dispensed into monodisperse picoliter droplets which are produced by a microfluidic T-junction (Figure 8). From the other arm of the T-junction silicon oil was continuously introduced into the microchannel. Creating the mixtures in a droplet prevents the contact between the growing nanocrystals and the microchannel walls.
The effects of the reagent concentrations and of the flow rate ratio of the oil to aqueous reagent streams. By varying those critical factors, nanocrystals with desired shape and size with tunable optical resonances are achieved (Figure 9).
One of the recent applications of gold nanoparticles in flow chemistry is catalyzing the aminoalkylation reaction . Abahmane et al. studied the A3-coupling (alkyne, aldehyde, amine) reaction under heterogeneous catalysis in a two-step microfluidic system . The A3 reaction mechanism includes two reaction steps that require different catalytic supports. Montmorillonite K-10 (MM K-10) is applied to promote the initial condensation reaction and Au nanoparticles on an alumina support are used to catalyze the second aminoalkylation step.
Three different reaction regimes A–C were realized by operating at one temperature or using a two-temperature ramp, as well as having a different reactant insertion scheme along the reaction pathway (Figure 10). Applying reaction regime C and MM K-10 as a catalyst for the first reaction at 25°C and 2.5% gold nanoparticles supported on Al2O3 as a catalyst for the second reaction at 80°C, a conversion of 97% could be obtained. The flow chemistry approach considerably improved the reaction performance of the A3-coupling reaction in terms of shortened reaction time and higher yields compared with conventional batch reactors.
Homogeneous and heterogeneous catalysis have their own advantages and a combination of those advantages could develop sustainable catalysts with novel reactivity and selectivity. Heterogeneous catalysts are recycled more easily than homogeneous ones, but it is difficult to apply them in traditional organic reactions. As a solution out of this dilemma, Gross et al.  replaced homogeneous AuCl3 with a dendrimer encapsulated Au nanoparticle, heterogeneous catalyst, to catalyze olefin cyclopropanation reactions. The diastereoselectivity of Au-catalyzed cyclopropanation reactions can be considerably improved (Scheme 1). The same heterogeneous catalyst was also applied in a fixed-bed flow reactor. By adjusting the residence time of reactants, the catalytic reactivity and product selectivity of secondary reactions can be well controlled in a way that is not easily available for homogeneous catalysts (Scheme 2).
One of the earlier methods to synthesize silver nanoparticles in a microflow reactor was based on thermal reduction . Lin et al.  synthesized silver nanoparticles by thermal reduction of silver pentafluoropropionate using trioctylamine (TOA) as a surfactant in isoamyl ether in a continuous flow tubular microreactor. A narrow particle size dispersion is obtained.
The reaction mixture is introduced into a tubular coil made of a stainless steel needle (0.84 mm i.d.) heated to a temperature of between 100°C and 140°C using an oil bath. The ratio of TOA/silver pentafluoropropionate, the flow rate, the temperature versus time profiles, and the reaction temperature were varied to investigate their effects on the average size and distribution range of the silver nanoparticles. The flow rate has a major influence on the size of the nanoparticles and their polydispersity. At a flow rate of 0.08 ml/min, the average diameter of the Ag nanoparticles was 8.7±0.9 nm. As the flow rate is increased to 0.6 ml/min, the synthesized particles become polydisperse and the average diameter of nanoparticles is reduced to 5.6±1.3 nm (Figure 11). In contrast to this, a change in the TOA concentration did not make any substantial difference in either the size or size distribution of the nanoparticles. Changing TOA/silver pentafluoropropionate molar ratios from 3, 6, to 12, silver nanoparticles are synthesized with an average diameter of 8.7±0.9, 8.6±0.9, and 8.6±1.0, respectively (flow rate: 0.08 ml/min; temperature: 100°C).
He et al.  investigated the effect of the interior wall of the capillary tube on the synthesis of silver nanoparticles and found that the well-dispersed silver nanoparticles were synthesized continuously in a polytetrafluoroethylene microcapillary reactor. A relation between the particles and the interior wall of the tube results in a broader size distribution and a lower yield.
To observe the effect of segmented flow on the nanoparticle size distribution, Ravi Kumar et al.  applied a unidirectional expanding spiral microreactor. Stearic acid sophorolipid reduced/capped Ag nanoparticles were synthesized in the aqueous phase and air or kerosene was utilized as inert phase to produce the gas-liquid and liquid-liquid segmented flow, respectively. Whereas in one case the reactant phase is in the form of dispersed phase slugs, in the other case it is in the form of continuous phase. The particle sizes were much smaller when generated by gas-liquid flow than by liquid-liquid flow (Figure 12). This effect is strengthened by the unidirectionally expanding spiral geometry of the channel, inducing transverse flows.
The effect of segmentation, which is determined by the slug sizes and the slip velocity, controlled the nanoparticle size distribution. The micromixer having a smaller orifice diameter yields smaller slugs and also a narrow particle size distribution.
Knauer et al.  presented a two-step microflow technique for colloidal dispersion synthesis of noble metal core/shell (Au/Ag) and multishell nanoparticles (Au/Ag/Au) in aqueous solute ions in the presence of CTAB.
Binary metal nanoparticles of silver and gold can have optically fine-tuned absorption in the visible spectrum, the so-called plasmonic absorption. The shift of the plasmonic band is influenced by the ratio between silver and gold, the shape and the size of the binary particles, and the distribution of the two metals inside the particle. For example, when forming silver or gold as a shell or core, a different plasmon absorption is found. Likewise for other nanoparticle applications (such as catalysts or surface enhanced Raman spectroscopy), the surface conditions of the metal shell/core particles are of major importance [47, 48].
The synthesis is based on the reduction of a gold salt, HAuCl4, and a silver salt, AgNO3, at the surface of seed particles by ascorbic acid . In order to improve mixing in the microfluidic system, the segmented flow principle was applied. Whereas the synthesis of Au/Ag core/shell nanoparticles is carried out at 80°C, the Au/Ag/Au core/double shell nanoparticle is synthesized at room temperature. The obtained size distribution of the Au/Ag core/shell and also multishell nanoparticles synthesized by the microfluidic technique is very narrow. In the case of Au/Ag core/shell nanoparticles, an average diameter of 20 nm with a distribution half width of 3.8 nm, and for Au/Ag/Au multishell nanoparticles an average diameter of 46 nm with a distribution half width of 7.4 nm are achieved (Figure 13). The optical spectra of the particle solutions exhibited extreme changes with the deposition of each additional metal shell (Figure 14). Owing to the changes in their optical properties, the prepared particles are very useful for future sensing applications as well as for labeling in bioanalytics or as nonlinear optical devices.
As one spotlight of the increasing interest in biosynthesis of nanoparticles, the microfluidic biosynthesis of Ag nanoparticles in tubular microreactors in the presence of Cacumen Platycladi (C. Platycladi) extract was developed by Liu et al. . The effect of technical parameters (volumetric flow rate, the concentration of the C. Platycladi extract, the inlet mixing pattern) and reactor parameters (reactor materials and inner diameter) on the size distribution of the silver nanoparticles were studied. To simulate the profile evolution of the velocity, biomass concentration and temperature within the microreactors, computational fluid dynamics was applied. It was found that, unlike in conventional batch reactors, the interfacial effect between the solid surface and bulk solutions cannot be ignored in microreactors and has an important influence on the particle size distribution. Reactor materials with more intense interfacial interaction (coarser surface and larger friction coefficient) with the bulk solutions yield silver nanoparticles with larger average size and wider size distribution. They stated that the relatively coarse surface of the reactor material can provide more sites for nucleation due to its larger superficial area. Nanoparticle deposition on the wall surface increases friction by improving the roughness of the surface. Therefore, materials with rough surface are capable of producing a stronger interfacial effect, which then leads to particle formation with larger average size and wider size distribution of the nanoparticles. In addition, Ag nanoparticles were synthesized with larger average size and wider size distribution. The research unraveled the influence of process parameters on the size distribution of Ag nanoparticles in the microfluidic biosynthesis.
Xu et al.  reported on the fabrication of silver microstructures inserted in a catalytic microreactor (Figure 15). Silver nanostructures were produced by photoreduction (using a femtosecond laser) of upright nanoplates and attached nanoparticles and were fabricated inside the microfluidic channel as catalytic active sites for the reduction of 4-nitrophenol to 4-aminophenol. On-chip catalytic reduction achieved silver microstructures with high catalytic activity. This was monitored by in situ surface-enhanced Raman scattering.
Palladium nanoparticles play a key role as a catalyst in many reactions such as the formation of C-C bonds. Song et al.  used a polymeric microfluidic device to produce palladium nanoparticles. The device was fabricated by developing the photoresist SU-8 on a polyetherketone (PEEK) substrate. Five parallel channels were fabricated to scale up the production yield and minimize the mixing volume and dead time. The Pd nanoparticles, when obtained from conventional batch process, had a mean diameter of 3.2 nm with 35% relative standard deviation. The Pd nanoparticles that were produced in a microreactor had a lower relative standard deviation of 10% at almost the same mean diameter of 3.0 nm.
A glass capillary microflow reactor system has been used to synthesize palladium nanoparticles by thermal decomposition of palladium acetate (Pd(OAc)2) in diphenyl ether in the presence of poly(benzyl ether) dendron ligands (PBED GnNH2, n=1–3) as a stabilizer . The effects of the hydrodynamic parameter (capillary diameter, velocity, volume flow rate, and reaction temperature) and concentration (precursor and stabilizer) on the particle size were investigated. The particle size can be controlled by optimizing the velocity and temperature as well as the ligand/precursor concentration ratio. The particle size is not influenced by the volume flow rate but by the velocity. The reason is that the reaction time is defined by the latter. Unlike batch processes, smaller Pd particles are produced in the microreactor system at low ligand concentrations when the molar ratio of the ligand to metal precursor is kept in the range of 1–5. As another characteristic of the microreactor synthesis, the concentration of the Pd precursor can be increased (up to 27 mm) with keeping a constant particle size (3.1±0.2 nm) and a good monodispersity, which is an advantage compared with batch processes (Figure 16).
One of the most important applications of palladium nanoparticles is catalyzing the cross-coupling reactions . Ceylan et al. applied magnetic silica-coated nanoparticles in an electromagnetic field as heatable media to perform chemical synthesis [54, 55] (Figure 17). Palladium particles obtained by reductive precipitation of ammonium-bound tetrachloropalladate salts give nanoparticles which can be used as good catalysts for different Pd-catalytic cross-coupling reactions. Only a slight amount of palladium leaching is observed (34 ppm for Suzuki-Miyaura reactions and 100 ppm for Heck reactions).
Lee et al.  demonstrated a microfluidic approach to synthesize platinum nanoparticles, which were applied to create a hierarchical catalyst containing metal-decorated nanoparticles that were assembled into porous microparticles (Figure 18). Applying a spiral silicon-Pyrex microreactor, platinum nanoparticles were produced continuously and coated onto the surface of the magnetic silica nanospheres. The reactants were: amine grafted magnetic core-shell silica suspension, Pt precursor [dipotassium tetrachloroplatinate(II)] and the reducing agents. To ensure a single liquid phase reaction, the microreactor is kept at a high pressure of 10 bar and high temperature. At 160°C with a residence time of 90°s and using ethylene glycol as reducing agent, Pt nanoparticles of approximately 2.4±0.2 nm are produced and attached to the surface of the magnetic silica nanospheres. These Pt-decorated silica nanospheres are assembled into micron-sized particles by using emulsion templates generated with a microfluidic drop generator. Lastly, in order to study the catalytic reactivity, the assembled particles are introduced into a packed-bed microreactor.
One of the applications of Pt nanoparticles is to catalyze the hydrogenation of nitrobenzene to aniline. Kataoka et al.  applied immobilized platinum nanoparticles inside a microreactor in order to catalyze the hydrogenation of nitrobenzene. To improve the adsorption and catalytic activity of the nanoparticles, catalytic support layers are offered as a film on the inner wall of the microreactor. Applying an immobilization technique, Pt nanocatalysts demonstrated a good catalytic activity and can be easily regenerated. During 14 h of continuous experiment and for 50 mm initial nitrobenzene concentration, aniline yields of 92% can be achieved. Table 2 presents a comparison of catalyst activity in microreactor and batch experiments.
|Catalyst||t, h||Yields (%)||TOF, h-1|
aBatch experiment, nitrobenzene: 50 mm, 5 wt% Pt/TiO2 or 5% Pt/C 1 mg; IPA: 30 ml; H2: 0.1 MPa, 40°C, 600 rpm.
TOF, turnover frequency.
The study and comparison of the copper nanoparticle formation between microfluidic and conventional batch processes was reported by Song et al. . Compared with results from the conventional batch process, Cu nanoparticles synthesized from microfluidic devices are smaller (8.9 nm vs. 22.5 nm) with narrower size distribution, along with more stable to oxidation (Figure 19).
Zhang et al. reported on chemically synthesized copper nanofluids using home-made microfluidic reactors and by using a boiling three-necked flask . The effects of the flow rate of reactants, reactants concentrations, and surfactant concentration on the copper particle size and size distribution were studied. Neither of them had much impact on the particle size and size distribution of copper nanoparticles synthesized in microfluidic reactors because of the fast mass diffusion in the microscale dimension. The copper nanoparticle average size was approximately 3.4 nm with a coefficient of variation of approximately 22%, whereas the average size distribution of copper nanoparticles formed by batch is 2.7–4.9 nm with a coefficient of variation larger than 30% (Figure 20). The synthesis time of copper nanofluids in the microreactor can be reduced as much as one order of magnitude, from approximately 10 min to approximately 28 s.
Compared with Au and Pt, the application of heterogenized Cu catalysts is limited due to their oxidative instability and limited catalyst activity. Cu nanocatalysts were used in the Ullmann-type C-O coupling  of potassium phenolate and 4-chloropyridine in a combined microwave (MW) and microflow process.
Benaskar et al.  developed a process using a supported Cu nanocatalyst in an Ullmann etherification reaction. With the combination of microwave and microflow in one process, the Ullmann-type C-O coupling of potassium phenolate and 4-chloropyridine is performed (Figure 21). Taking advantage of the selective absorption of the microwave energy on the catalyst (by use of non-absorbing solvents), yields of up to 80% are attained without substantial catalyst deactivation. The microreactor was packed with beads coated with Cu/TiO2 and CuZn/TiO2 catalysts in different segments. By increasing the number of catalyst segments to four, the product yield improves up to 75% in 80 min.
3 Metal nanoparticles in a millifluidic reactor
Recently, in addition to microfluidic devices, the concept of applying millifluidic devices has been introduced in order to synthesize nanoparticles [62–66]. In general, millifluidic devices are referred to as devices which have an internal, transversal scale larger than one millimeter. Millifluidics are easier to fabricate compared with microfluidics and are therefore cheaper. Another benefit of using milliflow reactors is that the flow volume is larger than that of microflow reactors, while both microfluidics and millifluidics share main advantages such as precisely defined flow patterns, short residence times, and good mass/heat transfer, yet with different individual quality. Besides, millifluidic devices can better resist fouling and are easier to interface with typical laboratory devices. Investigating the benefits of applying millifluidics in nanoparticle synthesis, researchers have begun to focus more and more attention to them [62–66].
Lately, metal nanoparticles such as gold, silver, and copper have been synthesized, applying millifluidics. Li et al. studied the size evolution of gold nanoparticles in a millifluidic reactor and they also used numerical simulations to support the experimental data . According to the results, they found that particle size can be better controlled compared with batch reactors. However, the synthesized nanoparticles within the millifluidic channels demonstrated a broad size distribution even at the shortest measured residence time (3.53 s), specifying that both surface growth and reaction kinetic are important in controlling the size and size distribution of nanoparticles .
Moreover, Krishna et al.  employed a millifluidic chip for an in situ real-time analysis of morphology and dimension-controlled growth of gold nanostructures with a time resolution of 5 ms (Figure 22). Those gold nanoparticles were catalytically active and in order to provide a good application of them, they were applied for the reaction of 4-nitrophenol to 4-aminophenol. For this reaction, applying the gold nanoparticle catalysts with the flow rate of 5 ml/h at T=298°C, they could achieve the conversion of 90.5%. Whereas, without using the gold catalyst, conversion was approximately 20% .
Jun et al.  applied a millifluidic mixer to synthesize biocompatible gold nanoparticles (Figure 23). Using a millifluidic setup enabled them to control the mixing step between a gold salt solution and an ascorbic acid solution at different initial pH, which allows controlling the final gold nanoparticle sizes (from 3 to 25 nm) with a low polydispersity formed in an aqueous surfactant-free solution .
Gottesman et al. synthesized silver nanowires and nanoparticles by a polyol method in a millifluidic reactor and optimized the reaction conditions to obtain higher yield of producing nanowires . Besides, they compared their results with the corresponding standard batch reaction. The nanowires that they synthesized in 30 min reaction time and at a temperature of 198°C had as best yield (92% of nanowires) with the average diameter of 71±2 nm. The batch process yield that they obtained was similar as compared to that from the millifluidic process with the average nanowire diameter of 53±7 nm (Figure 24) .
Biswas et al.  developed a millifluidic platform to synthesize ultra-small copper nanoclusters. Accordingly, by using the millifluid setup, they could achieve low residence time. They also applied numerical simulation and according to those simulation results they demonstrated that high flow rates can be produced within the millifluidic reactor owing to the possibility of creating low pressure drops which leads to a decrease in residence times. The low residence times coupled with the use of an effective stabilizing agent such as a bidentate PEGylated surfactant, MPEG, results in a highly stable colloid (stable for more than 3 months) composed of ultra-small Cu nanoclusters. They also showed that by increasing the flow rate (lowering the residence time), smaller nanoparticles could be produced, due to better control of the growth process at higher flow rates  (Figure 25).
During the past 2 years, millifluidic devices have become attractive for the synthesis of nanomaterials because they present a growing potential and the possibility of future applications in the field. Nevertheless, there is still much room open for thorough investigations for applications in nanomaterial synthesis.
4 Outlook: metal nanoparticles generated in flow and used in situ
The application of flow chemistry techniques can offer the possibility for the in situ generation of nanomaterials. Owing to the short residence time scales of microfluidics, the unstable intermediates can be generated in flow. In this context, Yoshida applied the flash chemistry concept , which utilizes in-flow generated high-energy intermediates for ultrafast reaction, towards the making of new generations of unstable catalysts. These unstable reactive catalysts are generated fast and consumed in a later reaction before they decompose. With such an approach, Nagaki et al.  prepared a new generation of a highly reactive Pd catalyst for Suzuki-Miyaura coupling  by using a flow microreactor (Figure 26). As there are hardly any available examples of in situ generated heterogeneous nanocatalysts in microfluidics, the work of Nagaki et al.  is presented in this section, although their reactive catalyst is homogeneous. This catalyst species was generated from fast mixing of the precursors [Pd(OAc)2] (1 mol%) and tBu3P (1 mol%) in a micromixer. The outcoming flow mixture is then directly injected into a reaction section in which the Suzuki-Miyaura reaction mixture flows (residence time: 0.65 s).
This processing, named the flash method, is compared with three alternative injection schemes (methods A–C) which introduce the two catalyst precursors separately, either in serial or parallel fashion, directly into the reaction mixture. Accordingly, such injected catalysts exhibit a much slower reaction performance than the unstable, highly active flash catalyst.
The difference in reaching reaction completion ranges from approximately 3 min (flash) to approximately 15 min (method A) to approximately 30 min (method B). This homogeneous catalytic reaction example with an unstable catalytic intermediate has a heterogeneous counterpart. Jamal et al.  combined the synthesis of gold nanoparticles with their immobilization in a microreactor in order to apply in a catalytic organic reaction. Such produced gold nanoparticles have very narrow size distribution (1–3 nm) and are immobilized into the inner volume of functionalized silica microcapillaries, which then constitutes the catalytic microreactor (Figure 27). This example can be considered as an outlook of a promising process that combines the advantages of microfluidic devices to synthesize nanoparticles and using them in situ as catalysts in organic reactions.
This review aims to cover recent achievements on metal nanoparticles, which are produced in continuous flow (micro and millifluidics) devices and their catalytic application in organic synthesis. The significantly reduced diffusion distance in microfluidic systems provides strongly improved mixing and heat transfer. In combination with reduced and kinetically matched residence times and decoupling of elementary processes (each under optimal conditions) by serial injection of reactants, this allows metal nanoparticles to be synthesized with controlled size, shape, and size distribution. In the field of organic chemistry, metal nanoparticles can be applied as catalysts. The joined benefits of the microflow and the catalytic nanoparticles can remarkably enhance the reaction performance, for example, in terms of minimizing the reaction time and improving the yield.
We kindly acknowledge the European Research Council for the Advanced Grant on “Novel Process Windows” No. 267443.
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