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Controlling nanomaterial synthesis, chemical reactions and self assembly in dynamic thin films Xianjue Chen,a Nicole M. Smith,b K. Swaminathan Iyerb and Colin L. Raston*a Recent advances in continuous-flow processors, which integrate sustainability metrics including scalability, have established their utility in materials and chemical processing. In this review the spinning disc processor (SDP) and the related rotating tube processor (RTP), are highlighted in the use of highly sheared and micro-mixed dynamic thin films in gaining control over such processing for a wide range of applications. Both SDP and RTP have a number of control parameters beyond traditional batch processing which are effective in (i) manipulating the size, shape, defects, agglomeration, and

Received 10th July 2013

precipitation of nanoparticles, as well as decorating preformed nano-structures, for a variety of

DOI: 10.1039/c3cs60247h

inorganic and organic compounds, (ii) controlling chemical reactivity and selectivity including the formation of polymers, and (iii) disassembling self organised nano-structures, as a tool for probing

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macromolecular structure under shear conditions.

Introduction In a fundamental and unified understanding of the processing– structure–property–performance relationships for a wide range of materials and chemical science, processing plays an essential role in the follow-up materials design and applications. Traditional batch processing methods have dominated chemical synthesis,

a

Centre for Nanoscale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Bedford Park SA 5042, Australia. E-mail: [email protected]; Tel: +61 88201 7958 b School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia

Xianjue Chen

Xianjue Chen completed BEng and MEng at Harbin Institute of Technology, China, and upon achievement of a China Scholarship, joined Professor Raston’s research group at the University of Western Australia as a PhD candidate. His PhD thesis is mainly focused on the fabrication of novel inorganic twodimensional materials by using microfluidic devices, decoration of graphene with noble metal nanoparticles, and their applications.

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but they have limitations in terms of environmental and economical sustainability, product scalability, and selectivity. In recent years, they have been facing even more challenges with the diversity of emerging fields in nanotechnology. The ability to precisely control the formation of functional materials within nano-scale dimensions requires novel synthetic methods integrated with scalability and variable control parameters. This has led to the development of innovative processing platforms which offer alternative pathways over traditional batch processing for gaining such control. Process intensification (PI) concerns the development of novel equipment and methods for substantially decreasing the size, energy consumption and waste production, and was

Nicole M. Smith

Nicole Smith is a Research Associate at UWA, School of Chemistry and Biochemistry/Experimental and Regenerative Neurosciences – School of Animal Biology. She has previously held an Agence Nationale de la Recherche (ANR) Postdoctoral position at INSERM, U869, Institut Europe´en de Chimie – Biologie (IECB) in Bordeaux, France under the guidance of Prof. Jean-Louis Mergny (2010–2011), followed by a second postdoctoral position at The Australian National University (ANU) (2012) with Prof. Christopher Easton.

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Fig. 1

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An overview of the components of process intensification (PI).4

defined as such to describe the strategy of reducing the size of footprint needed to achieve a specific chemical transformation. C. Ramshaw was a pioneer in PI,1–3 especially in developing spinning disc processing (SDP) technology. An overview of the components of PI is given in Fig. 1 which is based on a review by Stankiewicz and Moulijn.4 Scalability and economical sustainability are built into the reactor or processor, as the major advantages of PI. Incorporating scalability at the inception of the science, and other aspects of sustainability can facilitate transfer of the science to the market place, potentially making it both environmentally and economically feasible. Overall, more

environmentally benign processing is important in minimising energy usage, reducing the generation of waste and the use of toxic substances, and providing a safer working environment. In addition, improvements in reactor technology can also lead to enhanced reaction specificity and selectivity, thereby avoiding by-products, and contributes to a significantly lower cost of subsequent product processing. The SDP and also the rotating tube processor (RTP) are leading processing platforms of PI technology in industry, and are gradually gaining prominence in academia as viable alternatives to conventional chemical processing methods.5

K. Swaminathan Iyer is an Australian Research Council (ARC) research fellow in the School of Chemistry and Biochemistry, The University of Western Australia. He completed a PhD in Materials Chemistry under the guidance of Prof. Igor Luzinov from Clemson University, South Carolina (2004) and followed it by postdoctoral training under Prof. Igor Sokolov, Clarkson University, New York (2005). He moved to the University of Western Australia in 2006 where he heads the research in Bionanotechnology.

Colin Raston is SA Premier’s Professorial Research Fellow in Clean Technology at Flinders University, and is recipient of an Australian Research Council Professorial Fellowship. He completed a PhD under the guidance of Professor Allan White, and after postdoctoral studies with Professor Michael Lappert at the University of Sussex, he was appointed a Lecturer at The University of Colin L. Raston Western Australia (UWA) (1981) then to a Chair of Chemistry at Griffith University (1988), being awarded a DSc there in 1993, Monash University (1995), Leeds (2001) and UWA (2003), before moving to Flinders University in 2013. He is a recipient of the Burrows Award, Green Chemistry Challenge Award, HG Smith Award and the Leighton Memorial Award from the RACI, and is a former President of the RACI. His research cover aspects of nano-chemistry and green chemistry.

K. Swaminathan Iyer

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These processors share a similarity in the utilization of centrifugal fields for achieving continuous-flow processing, high mass and heat transfer rate, and enhanced surface interactions, which determine their utility in controlling chemical reactivity and selectivity. Some research groups have been exploring the use of these continuous-flow processors, in establishing their utility in manipulating the fabrication of nanoparticles, controlling inorganic and organic reactions, controlling polymer and polymer related reactions, controlling chemical reactivity and selectivity, and probing macromolecular structures, which are inherently difficult using traditional processing strategies. We have been investigating the use of SDP and RTP, which had their origins in chemical engineering, to readdress the fabrication of nanomaterials under continuous flow, and similarly carrying out chemical synthesis. In addition, we have developed the use of the SDP and RTP to control the dis-assembly and re-assembly of self organised systems. There have been a number of earlier relevant critical literature reviews,4–8 and the focus of the review herein is to provide a comprehensive overview of the latest advances in the application of SDP and RTP, in potentially taking the focus from industry driven targets to the research arena. While different descriptors of SDP and RTP have appeared in the literature, for example, spinning disc reactor for SDR, we will consistently use the terms SDP and RTP to avoid any confusion.

Continuous-flow processors SDP is a form of process intensification which has many practical advantages beyond scalability when compared to traditional batch processing. These include safety, rapid micro-mixing with well controlled engineered path lengths, and lower energy consumption associated with high inertia discs relative to other continuous flow mixing devices such as tubular mixers, with the ability to precisely control the processing temperature and deal with highly exothermic reactions because of efficient mass and heat transfer.5 A schematic view of a typical SDP is shown in Fig. 2, with the key components including: (i) a rotating disc with controllable heating and speed, (ii) feed jets with controllable feed rates directing reagents onto the disc, or delivering gas over the thin film as reactive gases and/or providing an inert atmosphere. Thin highly sheared films (25–200 mm) are generated on the rapidly rotating disc surface contributing to many influential chemical processing characteristics. This includes high surface area to volume ratio between the film and the disc surface which results in more favorable interactions between the film and its surroundings, very high heat and mass transfer rates associated with the thin film, and uniform heating throughout the entire reaction mixture, in contrast to limited heat conduction and convection in a batch reactor. Strong shear rates, as high as 13 000 s1, create turbulence with waves and ripples, enhancing the micro-mixing and breaking down the surface tension of the film. The rapid rotation of the disc results in a short residence time for the liquid film on the surface which is typically less than 1 s for a 10 cm diameter disc. Increased residence time can be obtained via multiple passes of the reaction mixture

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Fig. 2 A schematic view of an SDP and a photograph of a 20 cm diameter spinning disc housed in such a unit.

onto the disc or by having several discs operating in sequence or parallel under identical conditions.9 The RTP, Fig. 3, has been developed as a variance of SDP with the ability to control the residence time for reactions on the rotating surface. Here a thin film of liquid will reside in the tube with the thickness governed by its viscosity, the height of a ridge at the end of the tube, and the rotational speed. Adding more liquid to one end of the tube will slowly force some liquid out the opposite end, and thus by controlling the rate of addition it is possible to control the residence time. It also allows multiple

Fig. 3 Schematic of an RTP showing high mass and heat transfer, and a photograph of an RTP which has a rotating tube 30 cm in length and 6 cm in diameter.

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Fig. 4 Overall characteristics and control parameters for SDP and RTP.

processing in a single pass using additional feed jets along the tube. Such processing is not possible using SDP where there would be an incomplete coverage of a reagent on the surface of the disc if it is directed at a point away from the centre of the disc. The overall characteristics and control parameters for SDP and RTP are shown in Fig. 4.

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into account water evaporation from the liquid film surface.33 Measurements of the thickness and stability of thin films of liquid (1–150 mm) on a rotating horizontal disc covered a range of viscosity and surface tension involving the use of various alcohols and water.34 Work on bi-layered films formed over a rotating disc established that viscous force dominates over centrifugal force, and the upper layer thin film moves faster than the lower layer.35 Infrared (IR) thermal imaging readily establish the temperature profiles and flow characteristics of thin liquid films on a rotating surface.36 Theoretical and experimental studies have established that thin films formed under high acceleration fields in the SDP generate intense surface ripples which play an important role in improving the efficiency, selectivity, yield, and quality of products in many mixing-dependent chemical reactions. Whether a chemical reaction is influenced by the mixing process or not, is dependent on the relative time scales of mixing and reaction rates. Therefore, a faster microfluidic mixer can provide appropriate micro-mixing conditions when performing fast competitive reactions. The short diffusion and conduction path length offered by the very thin films is the basis for the very high transport rates within the film.37 The high sheared thin liquid films associated with the SDP (and RTP), which have excellent heat and mass transfer properties, offer the ability to control very fast chemical reactions such as polymerization, crystallization, and competing fast chemical reactions.

Synthesis and processing of Dynamic thin films on rotating surfaces nanoparticles Fluid dynamics on horizontal rotating surfaces along with theoretical simulation have been investigated by a number of research groups. It is clear that in many practical applications the fluid is forced outward by the centrifugal force, and the motion of the fluid can be retarded by its viscous resistance. Therefore, the most basic model must balance these two forces, which was first introduced in a mathematical model by Emslie et al. for the formation of a uniform layer of a Newtonian liquid.10 In the following work, different physical factors of the process were considered, such as gravity, evaporation, surface topography, air shear, surface tension, cooling/heating, thermocapillarity, presence of a magnetic field and pH control.11–29 Experimental performance of thin films in conducting heat and mass transfer to the disc and the surrounding gas was studied by Ramshaw et al., establishing that very high transfer coefficients are achieved at modest disc speeds with water-like liquids.30,31 However, the heat transfer performance is significantly reduced at higher viscosities. The practical transfer coefficients are much higher than those predicted by a simple analysis based upon the film or by penetration theory, which may be attributed to the micro-mixing within the film. Wagner derived an expression for calculating the heat transfer coefficient for a rotating disc in ambient air for a laminar boundary layer.32 Heat transfer from a horizontal heated rotating disc to a thin water film flowing over it was investigated by Quinn and Cetegen, taking

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Nanoparticles, as a subset of nanomaterials, are fabricated to take on distinct physical, chemical and biological properties relative to the bulk form of the same materials, and are at the forefront of breakthrough developments in many areas of nanotechnology. Beyond the need to address scalability of the processing, a key to their applications is the ability to manipulate their size over a very narrow size distribution, along with controlling their shape and surface characteristics. These properties are also important in nano-toxicology, as are the level of dispersion of the particles and any leaching out of toxic species. Nanoparticles of a particular diameter are likely to have significantly different nano-toxicity relative to those of a different diameter, or indeed of different shapes.38 Therefore, there is a pressing need for precisely fabricating nanoparticles with control over their size, i.e. a narrow size distribution, and their shape, agglomeration, and surface characteristics. Super-saturation is a prerequisite for fabricating nanoparticles in solution as a ‘bottom up’ process, offering the kinetic driving force for homogenous nucleation, with the critical nucleus being generated through random collisions of solute clusters moving in solution. Many procedures for preparing nanoparticles rely on batch processing which has potential in small niche production of nanoparticles. Nevertheless, controlling the size and size distribution, and shape of the particles, requires specific conditions, and batch processing is not necessarily adaptable to

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Fig. 5 Cartoon of nano-structures that have been fabricated via ‘bottom up’ processes using an SDP or RTP.

fine tuning such properties. Traditional batch processing also suffers from low micro-mixing efficiency. Micro-mixing is defined as the efficiency of two or more reagents mixing at the molecular level, and is enhanced when the mixing time is shorter than the induction time, which is the time required for the reaction, nucleation and growth of nanoparticles. Fast ‘flash’ generation of nanoparticles surmounting the obstacles of batch production is required. SDP and RTP have the potential to effectively control the local super-saturation by intense micro-mixing of the reagents, resulting in rapid throughput of nanoparticles. Given that the gradient force of the homogeneous nucleation process in SDP and RTP is local super-saturation, the intensity of micro-mixing determines the growth mechanism and therefore the nature of the particles. The systems can be easily cleaned, and devised for noninvasive real time monitoring of reactions.39 Fig. 5 summarises the types of nanomaterials that have been prepared using SDP and/or RTP, with specific details highlighted below. Metal nanoparticles SDP has been used to prepare silver nanoparticles with remarkable control in size from 5 to 200 nm.40 This involves the use of silver nitrate in water in one jet feed, and ascorbic acid as the reducing agent in the other, in the presence of starch as the stabilizing agent, which turns out to also be effective in controlling the shape of the particles. Both ascorbic acid and starch are reagents, with water as the reaction medium, thereby adding green chemistry credentials to the processing. At high disc speed, the strong shear forces result in homogeneous concentration fields, so that after nucleation all particles have the same growing conditions and therefore have sizes within a very narrow size distribution. Controlling the concentration and speed is effective in determining the particle size. At low disc speeds, the concentration and temperature fields become less uniform and the driving force for Ostwald ripening becomes more dominant, resulting in a broad size distribution of particles. The shape and agglomeration of the silver particles can be controlled by changing the surfactant, with acicular particles formed using polyethylene glycol (PEG), and agglomerate rosettes formed using poly(4-vinylpyridine). Thus in the case of using SDP to control the formation of nanoparticles of silver, and presumably of other systems, the choice of surfactant is essentially another control parameter, and clearly the surfactant controls nucleation and growth of the particles. In this context the palindromic

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Fig. 6 Controlling the size, phase and defects in silver nanoparticles: (a) size as a function of concentration and speed (standard deviation vary from 1.3 nm for 5 nm particles to 8.6 nm for 250 nm particles). High resolution TEM of (b) defect free silver nanoparticles showing the corresponding hexagonal phase FFT pattern, (c) cubic phase silver nanoparticles with multiple twins.40

DNA dodecamer d(CGTAGATCTACG) has been employed as a scaffold/surfactant to fabricate silver nano-structures using SDP.41 The DNA dodecamer self-assembles into closed pack monolayers, controlling the formation of silver nano-plates, including silver triangles inside larger silver triangles. As shown in Fig. 6, defects can be engineered into particles >10 nm in diameter by the enhanced mixing and thus faster kinetics and crystal growth using a grooved rather than a smooth disc for the SDP. To achieve the same size particle using a smooth disc requires lower concentrations of the reagents, and the particles are less likely to have defects. Defect free particles o10 nm in diameter take on the hexagonal phase of silver rather than the usual cubic phase for larger particles. These results establish that the many parameters of the SDP, beyond conventional batch processing, can be varied to control the nature of silver nanoparticles generated, and to establish the parameters for a particular material, care needs to be taken in systematically varying the parameters, one at a time, which is readily mapped out given the high throughput capabilities of SDP. In doing so, nanoparticles with tuneable properties are accessible by simply changing the shear, rather than changing the choice of reagents (reducing agent and surfactant) in batch processing, where controlling such properties is inherently more difficult. Surfactant free reduction of aqueous dihydrogentetrachloropalladate (H2PdCl4) using hydrogen gas as the reducing agent at ambient pressure for the same 10 cm diameter SDP results in nano-rosettes of palladium built of 6 nm particles.42 In the presence of polyvinylpyrrolidone (PVP), regular nano-spheres can be generated, depending on the conditions.43,44 The reaction occurs in an atmosphere of hydrogen gas on a rotating surface with solutions of H2PdCl4 experiencing shear forces and viscous drag between the moving fluid layer and the disc surface resulting in turbulence and ripples which give rise to highly efficient micromixing within the dynamic thin fluid layer. The flow is accompanied by non-linear waves, which strongly influence the diffusion

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Fig. 8 (A) RTP-NCP synthesis of gold nano-rods, with representative high resolution TEM, (B) and (C).45 Fig. 7 (a) SEM image of palladium nano-spheres in a dielectric scaffold of PVP (scale bar: 200 nm), (b) cross-section TEM image of a single palladium nano-sphere, (c) HRTEM image of the palladium nano-sphere showing inter-particle separation, and (d) a schematic representation of such a 3D palladium nano-sphere.43

boundary that develops beneath the surface of the film over the rotational speed of the disc (10 cm diameter with 80 concentric grooves 0.6 mm in depth, spinning at ca. 2400 rpm) which enhances the gas absorption into the liquid. These progressive waves generated in the region of active micro-mixing offer the important control necessary to prepare palladium nano-spheres of uniform composition and overall structure, which are shown in Fig. 7. The cross-section TEM image and high resolution TEM image show that the self assembled structure in each nano-sphere is a composite comprised of 5 nm palladium nano-crystals bound with the PVP in B150 nm nano-spheres. The PVP acts as a scaffold holding the nano-crystals together in a three-dimensional dielectric environment, as represented in Fig. 7. In comparison, batch processing using the same reagents result in nano-sphere composites from several hundred nanometres in dimension to several microns.44 A direct seedless method for the high yield synthesis of single crystal gold nano-rods has been developed using a sequential combination of a RTP and a narrow channel processor (NCP). The key feature of this work is the use of the RTP to grow nano-clusters of gold for then the growth of the gold nano-rods under laminar flow conditions in the NCP, using stable stock feed solutions of chloroauric acid (HAuCl4)/cetyl trimethylammonium bromide (CTAB)/acetylacetone and silver nitrate (AgNO3)/CTAB/carbonate buffer.45 The processing time on the RTP (30 cm in length, tube 6 cm in diameter) is insufficient for the controlled growth of the rods, but is essential in the nano-cluster formation. This work highlights a potential limitation of the RTP, namely that the residence time in the tube may not be enough, and this can even be more of an issue for SDP. It also highlights the power of

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sequential use of microfluidic platforms, and that no one processor will solve all processing requirements. The gold nano-rods generated using the sequential processing have average dimensions of 6.6 nm by 24.2 nm, with standard deviations of ca. 25%, Fig. 8, and is a first in continuous processing of the material. Inorganic nanoparticles Controlled synthesis of mono-dispersed zinc oxide (ZnO) nanoparticles has been achieved using a 10 cm SDP.46 This involves two jet feeds, one delivering zinc nitrate hexahydrate dissolved in ethanol along with PVP as a capping agent, and the other sodium hydroxide (NaOH). Here the choice of temperature, surface texture, flow rates, and rotational speed of the disc controls the intense mixing of solutions, acceleration of nucleation and growth of ZnO nanoparticles, and subsequently the size of the resulting nanoparticles. Mono-dispersed ZnO nanoparticles down to 1.3 nm in diameter, with poly-dispersities of approximately 10%, are the main product, the other being sub-nanometre clusters which slowly undergo ripening post-SDP. Size selective synthesis of super-paramagnetic magnetite (Fe3O4) nanoparticles is effective using a 10 cm disc SDP. However this requires the use of ammonia (NH3) gas at ambient pressure as a source of base over the dynamic aqueous thin film of Fe2+/3+ precursors on the surface of the SDP, with the liquid delivered through a jet feed at room temperature.47,48 The size of Fe3O4 nanoparticles is controlled with a narrow size distribution over the range 5 nm to 10 nm, and the material has very high saturation magnetizations, in the range 68–78 emu g1, in accordance with super-paramagnetic behaviour. Here the size, size distribution and morphology of Fe3O4 nanoparticles can be controlled by varying the operating parameters of the SDP, including concentrations, disc rotation speed, surface texture (grooved or smooth), and the use of NH3 as the base. Using aqueous ammonium hydroxide (NH4OH) or NaOH in a second

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jet is not effective in gaining control over the very fast kinetics of nucleation and growth of Fe3O4 nanoparticles, but this is overcome using NH3 gas as the base with controllable mass transfer to the dynamic thin film. The formation of barium sulfate particles in aqueous media at 25 1C has been established for a smooth 0.5 m diameter SDP.48–50 At rotational speeds higher than 900 rpm, spontaneous precipitation occurs with crystals B0.7 mm in size. At a super-saturation ratio of 2000, the number of generated crystals is comparable with those generated using a T-mixer, but with much higher energy efficiency. A facile control over the particle morphology is also described using the example of the precipitation of calcium carbonate from calcium hydroxide solutions with gaseous carbon dioxide in SDP.39,50–52 Simply changing the speed of rotation of the disc (1100–1650 rpm) results in the formation of either ‘cubic’ or ‘spherical’ particles of calcium carbonate. A range of parameters were investigated in forming calcium carbonate, including rotational speed, liquid flow rate, and gas flow ratio which was increased to be in the same molar proportion as the liquid. The SDP is capable of generating higher rates of mass transfer than batch processing, with mass transfer rates being strongly dependent on the liquid flow rate. The rotational speed affects the average particle size due to the higher rate of mixing imparted by the disc to the fluid as the speed is increased. A light-driven large-area spinning disc processor (HTSDP) has been developed for continuous-flow preparation of nanomaterials at high temperatures.53 For temperatures r550 1C, nanoparticles of TiO2 exclusively as the anatase phase and B5 nm in size are accessible for a single pass over the disc. The reaction medium of choice here was PEG 200 which was unaffected by the high temperatures for a very short residence time on the disc, r1 s. The HTSDP surmounts the limitation that conventional methods for heating the disc have been proven incapable of, i.e. exceeding a reactor disc temperature of B200 1C. Both SDP and RTP have been used to fabricate ultrathin single-crystalline rhabdophane lanthanide phosphate (LnPO4) nanowires at room temperature, using water as a benign reaction medium.54 Both the continuous flow microfluidic platforms are effective in tuning the aspect ratios of the LnPO4 nanowires to enhance their thermodynamically favoured one-dimensional growth along the c axis. This is associated with the suppression of the Ostwald ripening phenomenon during the nucleation and growth of nanowires in the spin-up zones, Fig. 9. The difference in outcome for SDP versus RTP relates to different micro-mixing, with the SDP having nucleation of particles in the spin-up zone followed by growth of the nanoparticles, whereas the RTP has spontaneous nucleation and growth of the nano-wires on mixing. The results here show that not only can the choice of SDP versus RTP control the residence time, it can also affect the outcome of the nature of the material generated. One-dimensional crystalline cerium phosphate (CePO4) nano-rods decorated with cadmium telluride (CdTe) quantum dots (QDs) have been synthesized in a sequential, aqueous procedure under continuous flow using an RTP (30 cm long

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Fig. 9 TEM of LnPO4 nano-wires, formed using the RTP (a and b) and SDP (c and d), for different concentrations.54

tube, 6 cm diameter) followed by a narrow channel processor (NCP).55 The reaction time for the preparation is dramatically shortened relative to traditional batch processing, and the resulting QDs have strong fluorescent emission at tunable wavelengths which can be enhanced by simply adjusting the precursor feed rates. The CePO4 nanorods B3–5 nm in diameter and 200–300 nm in length, can be coated with QDs of different sizes using the NCP. This is another example of combining dynamic thin film processing (using an RTP) with another continuous flow precursor, as in the aforementioned synthesis of gold nano-rods.45 Organic nanoparticles Nanoparticles of trans-b-carotene are accessible using SDP with fine tuning of their size by varying the reaction conditions and the choice of surfactants, a-, b-cyclodextrins and amphiphilic sulfonato-calix[n]arenes, n = 4, 5, 6, 8,56 with the surfactant dissolved in water in one jet feed, the other as a tetrahydrofuran solution of the nutraceutical. Several parameters affect the particle size and colloidal stability of the dispersions. Increasing the feed rate of the aqueous phase containing the surfactant affords smaller particles, as expected with limited supply of carotene particle size growth at lower concentrations. The mean particle sizes, derived from hydrodynamic diameters using dynamic light scattering (DLS) can be optimised at 40(2) nm for sulfonato-calix[5]arene, whereas a-, b-cyclodextrins result in nanoparticles with a mean diameter of 71(1) and 68.5(6) nm, respectively. This also establishes that the choice of surfactant is an important control parameter in the ‘bottom up’ synthesis of nutraceutical nanoparticles using the SDP, and the same applies to RTP (see below). The particles are comprised of H-aggregates and amorphous carotenoid, rather than single nano-crystals, which relates to the fast nucleation and growth of the particles under intense micro-mixing, and is consistent with the lack of control over particle shape. The particle size distribution depends on the feed rate of the solution, rotational speed of the disc, and head size of the feed

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injector. At a higher feed rate of the aqueous phase with higher disc rotation speed, the particle size has broader distribution. Using a large feed injector, 2.1 mm diameter, the range of size of particles was narrow with polydispersity index (PDI) decreasing from 0.243 to 0.175 when the feed rate of the aqueous phase was 3.0 mL s1. In contrast the mean size of the particles was larger using a smaller feed injector (0.7 mm diameter). Here the high feed rate through the small diameter of the feed injector together with a high rotational rate leads to splashing of the solution and break down of the liquid film on the rotating disc into rivulets. This results in a loss of the mixing efficiency and loss of control of particle size. Water-soluble calix[4]arenes bearing p-substituted phosphonic acid groups, 1, X = PO3H2, n = 4, form nanoparticles in solution using SDP.57 The crystallization process involves a NaOH (1.0 M) solution containing the p-phosphonic acid calix[4]arene being delivered through one jet feed, and aqueous hydrochloric acid (HCl) solution at different concentrations (1.0, 1.5, 3.0, and 6.0 M) delivered through a second jet feed to ensure an acidic solution upon mixing (1 mL s1 flow rate for a 10 cm diameter disc with 80 grooves, 0.6 mm in depth, 1500 rpm disc rotation). Rapid crystallization occurs which is dependent on the molarity of the acid used, and affords micron-sized particles. However, the use of HCl solutions containing 10% acetonitrile results in the formation of specifically 3.0(3) or 20(2) nm particles depending on the concentration of the acid. Here the use of a mixture of solvents, and variation in the processing parameters is important in generating material at the nano-scale. Importantly the phase of the material is different to that formed using batch processing, and the use of the SDP, and most likely the RTP, can afford different phases, and this has implications in the pharmaceutical industry in controlling the formation of polymorphs of drugs. Spherical chitosan nanoparticles were successfully produced using SDP, with acetic acid and tartaric acid as solvents for the chitosan polymer.58 The results established that it was possible to produce discrete nanoparticles of mean diameter below 100 nm with a narrow size range. Nanoparticle size distribution was not affected by variation in the speed of the SDP within 1000–3000 rpm, suggesting optimized mixing of reagents was realized which can contribute towards a robust manufacturing capability. However, the size distribution was readily modulated by defining the concentration and type of acid employed as the solvent for the feed solution containing the chitosan. Curcumin nanoparticles of less than 50 nm in diameter are accessible at room temperature using a RTP (30 cm horizontal tube, 6 cm in diameter).59 Here a mixture of surfactants, didodecyl-dimethylammonium bromide (DDAB) and pluronic F127 polymers, spontaneously render high stability of the produced hydrophobic curcumin nanoparticles at physiological pH 7.4 for up to eight hours, Fig. 10. Bulk curcumin is only sparingly soluble in aqueous media, which is an issue for bioavailability. This can now be overcome by generating curcumin nanoparticles, noting that curcumin has anti-cancer activity, and in this context the nanoparticles generated using the RTP have enhanced cytotoxicity in oestrogen receptor negative

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Fig. 10 Schematic of curcumin nanoparticle fabrication using an RTP, highlighting a narrow particle size distribution (DLS).59

and positive breast cancer cell lines compared with free curcumin.59 The formation of curcumin nanoparticles involves acid base processing with curcumin being soluble in base, ensuring that the solution on mixing is acidic. This organic solvent free processing is also highlighted by the formation of a narrow size distribution of the nanoparticles (o100 nm in diameter) of the drug meloxicam, which is one of the most effective nonsteroidal anti-inflammatory drugs (NSAIDs).60 This also involves in situ stabilization of the nanoparticles by surfactants. Alternatively the nanoparticles can be stabilised post RTP processing, using a layer-by-layer encapsulation of polyelectrolytes of polyallylamine hydrochloride (PAH) and polyprotamine sulfate (PSS).61 Failing to stabilize them as such results in the spheroidal particles, with evidence for significant defects arising from the very fast kinetics associated with nucleation and growth of the particles under intense shear, undergoing Ostwald ripening post SDP with the growth of micron-sized needles, of the same phase, but now seemingly defect free. The anti-solvent approach can also be used for organic molecules, highlighted by the formation of meloxicam nanoparticles stabilised in situ. Here the drug is dissolved in an organic solvent and delivered to the RTP in one jet feed, and an aqueous solution of the surfactant delivered through the other jet feed.60 Coating nanoparticles and nano-layers Nano-fibers of fullerene C60 approximately 5–8 nm in cross section, and 250–350 nm in length, formed on treating the starch–iodine complex with C60 in water followed by ascorbic acid to remove the iodine, can be coated with elemental silver in a controlled way using SDP, Fig. 11.62 This involves the addition of aqueous silver nitrate in one jet feed and the nanofibres in another along with ascorbic acid as the reducing agent. The uniformity of the coating, established using TEM, exemplifies the ability of the SDP to coat preformed nanoparticles with another material. Replacing C60 by fullerene C70 results in a toroidal structure of fullerenes shrouded by starch, and using the same SDP (10 cm diameter) under similar conditions results in the silver metal nucleating and growing into 8 to 12 nm particles inside

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Fig. 11 Formation of a silver–C60 hybrid nano-structure showing a TEM of a single filament, and a microtomed cross-section of the silver–C60 hybrid nano-structure.62

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Ultrafine (2–3 nm) superparamagnetic magnetite (Fe3O4) nanoparticles can be uniformly coated on SWCNTs by modified chemical precipitation methods using SDP in aqueous media at room temperature.65 The resulting decorated SWCNTs are superparamagnetic with specific saturated magnetization of 30 emu g1. Here the SWCNTs are first pre-functionalised with carboxylic acid groups using microwave radiation, which dramatically reduces the reaction time and minimizes damage to the SWCNTs. The modified SWCNTs are readily dispersed in water, and applied directly for decoration with Fe3O4 nanoparticles using the SDP. The ability to effectively decorate the SWCNTs with Fe3O4 nanoparticles relates to the functionalization with carboxylate (COO) moieties which can bind directly to Fe2+/3+ ions. Moreover, the strong shear forces and intense micromixing using SDP result in an extremely rapid induction time for nucleation and growth of nanoparticles, giving ultrafine nanoparticles with narrow size distribution. In contrast, the same chemistry via traditional batch processing results in much larger Fe3O4 nanoparticles (8–10 nm) with random aggregation.

Exfoliation and scrolling of layerstructured compounds

Fig. 12 A schematic of a C70 nano-ring and its utility as a nano-reactor to nucleate particle growth within the central cavity using an SDP, showing SPM topography images and representative line scans across the AFM image.63

the toroidal structure, rather than silver completely coating the fullerenes, Fig. 12.63 This selective control of the growth of silver particles, as established using scanning probe microscopy imaging as well as TEM, was not possible using batch processing. SDP can be used to efficiently decorate noble metals (Au, Pt, and Ag) nanoparticles on single wall carbon nanotubes (SWCNTs) stabilized using starch, or indeed plating the SWCNT with a layer of the metal, depending on the concentrations of the metal salt precursors.64 The SWCNTs shrouded by a layer of metal are significantly shortened, down to a few hundred nanometres, as established using TEM. This lateral slicing occurs at points of discontinuity of the metal, and arises from the high shear with the dynamic thin films on the disc, although the impact of the liquid leaving the disc with the collecting walls cannot be ruled out as being responsible for some of the slicing. Indeed, the high impact velocity may be an issue in some applications of the SDP, but this would be minimal using the RTP.

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‘‘Top down’’ exfoliation and scrolling of the two-dimensional materials, graphite and hexagonal boron nitride (h-BN) flakes, occurs in thin films of N-methyl-2-pyrrolidone (NMP) generated in the SDP.66 In a typical experiment, suspensions of graphite and h-BN flakes in NMP are directed close to the centre of a 20 cm disc rotating at 2500 rpm, giving a thin film (r200 mm in thickness) with high surface area-to-volume ratio, as a continuous flow process, with a 200 mL solution recycled over 20 hours using a flow rate of B60 mL min1. The recycling overcomes the short residence time (typically o1 s) for a finite volume of liquid on the rapidly rotating disc. The proposed mechanism of exfoliation and scrolling of graphite and h-BN is depicted in Fig. 13. The flakes accelerated by the centrifugal effect move along with the liquid in the thin film, and contact periodically with the surface of the disc, where they experience shear forces arising from the friction from the grooved disc, as

Fig. 13 Proposed mechanism of exfoliation and scrolling of graphite and h-BN flakes using an SDP, with supporting SEM images.66

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well as the viscous drag of the liquid. The shear forces provide the energy for exfoliation and scrolling process, with three possible subsequent events. Lift from the shear force on the upper layers of the flakes may facilitate exfoliation of the bottom layers with different degrees of folding. Another scenario is that the edge of the flakes can curve to eventually form scrolls. Apparent reduction in the thickness of the flakes and formation of carbon and h-BN scrolls is evident. The method has potential for exfoliating other inorganic layer compounds, with or without scroll formation.

Controlling chemical reactivity and selectivity A major challenge in organic synthesis is gaining control of reactivity and selectivity. Traditionally, this is done in organic solvents using batch processing. Advances have been made in carrying out reactions in organic solvents, and in alternative reaction media, under continuous flow. It is possible to control competing condensation reactions using SDP, with dramatic enhancement in rates of reactions. Moreover, given that for SDP all reagents are treated in the same way, it is possible to optimise the control parameters to approach 100% conversion. It is also noteworthy that the rapid throughput possible using SDP, can allow access to libraries of compounds for drug discovery, as well as minimizing solvent usage, or indeed the ability to carry out solventless reactions, and sequential reactions. A novel approach involving the use of SDP for the synthesis of a 2,4,6-triarylpyridine, 4-( p-dimethylaminophenyl)-2,6-bis(4aminophenyl)pyridine, has been developed, overcoming a series

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of competing reactions.67 This compound is part of a series of 2,4,6-triarylpyridines that have been shown to interact with and stabilize G-quadruplex DNA.68 However, the direct synthesis of this target is not accessible using traditional batch methodology due to thermodynamic and kinetic constraints. The active micro-mixing in the dynamic thin film generated by the SDP at elevated temperatures overcomes the energy barrier for the formation of 4-(p-dimethylaminophenyl)-2,6-bis(4-aminophenyl)pyridine, effectively controlling chemical reactivity and selectivity, as summarised in Fig. 14. The SDP has distinct advantages over batch processing techniques in the manufacturing of pharmaceuticals, with a test reaction achieving a phase-transfer-catalyzed (ptc) Darzen’s reaction for preparing a drug intermediate and the recrystallization of an active pharmaceutical ingredient.69 In comparison to reported batch processes, the ptc reaction using SDP resulted in 99.9% reduction in reaction time, 99% reduction in inventory, and 93% reduction in impurity levels. Free-radical photo-polymerization of n-butyl acrylate with >90% conversion has been achieved in a 400 mm thick film using an SDP, with an exposure time of 40 s at a radiation intensity of 175 mW cm2.70 Four main variables of film thickness, UV intensity, initiator concentration, and exposure time, have been investigated under static film conditions. There is a linear increase in conversion with exposure time at low to moderate UV intensities (5–50 mW cm2) for any film thickness, whereas conversion increases in a logarithmic manner at higher UV intensities. Additionally, a decrease in conversion occurs in thicker films with UV intensities r125 mW cm2. However, the conversion increases with the film thickness at 170 mW cm2,

Fig. 14 Consecutive and concurrent reactions leading to the formation of the dimethylamino functionalised 4 0 -aryl-2,6-bis(4-aminophenyl)pyridine, 6; k1 and k2 represent the rate constants for the formation of the Schiff base adduct of the Claisen Schmidt condensation product, 4, and the 1,5-diketone, 5, respectively.67

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presumably due to the adiabatic conditions. Moreover, a linear increase in conversion with the UV intensity is obtained in a low intensity range (5–50 mW cm2).70 Poly-condensations using an SDP are possible using neat monomer for accessing high molecular weight product.71 Such reactions are usually carried out using batch processing with reaction times B15–20 h. The SDP allows much higher reaction temperatures and thus considerably shorter reaction times. Acceleration of the polymerization of styrene without compromising either molecular weight or polydispersity is possible using a SDP.72 Increase in monomer conversion as high as 20% is possible for a single pass across the disc surface, which corresponds to a residence time of approximately five seconds. The increased conversion is associated with the hydrodynamic conditions generated on the SDP surface, such as high mixing intensities, shear rates and viscous flow characteristics. For example, shear forces may lead to disentanglement of preformed inactive coiled chains and thus bring about a reduction in the viscosity of the pre-polymer mix by shear thinning. The degree of extension of polymer chains is influenced by the centrifugal force as the polymerizing film travels radially outward through the disc, and is also dependent on the rotational speed, which affects the translational and segmental diffusion of active chains. Classical carbon-cationic polymerization of styrene has been studied in a SDP and the results compared to those for a conventional stirred tank reactor (STR).73 Addition of styrene to the slurry of silica-supported boron trifluoride (BF3/SiO2) in 1,2-dichloroethane results in uncontrolled reaction in the STR at monomer concentrations >25% w/w and initial temperatures of 20–25 1C. Monomer concentrations of 75% w/w allow safe and controllable polymerization in the SDP at 40 1C, affording molecular weights comparable to those reported in the literature for polymer prepared at 60 1C. Exceptional heat transfer rates achieved in the SDP are sufficient to deal with the heat evolved when styrene is polymerized at concentrations as high as 75% w/w, the reaction proceeding under essentially isothermal conditions. The study also shows the effects of monomer/solvent feed rates, monomer concentrations, disc size, and disc rotational speed on monomer conversions, polymer molecular weights, and polydispersities. SDP can provide a useful module for catalytic reactions by immobilizing the catalyst on the surface, demonstrated by the rearrangement of a-pinene using an immobilized catalyst system.74 The high shear rates between the reaction medium and the catalyst result in faster reaction rates allowing the reaction to achieve near completion in less than one second (residence time on the disc). In addition, the selectivity of the process using SDP may be influenced by controlling the residence time of the reaction which minimizes possible side reactions.75 More importantly, this study also highlights that the immobilized catalyst remains active over a considerable period of time, for the continuous processing rather than the batch mode of operation. An RTP has been used for continuous production and separation of biodiesel with conversions in excess of 98% for residence times o1 min at atmospheric pressure and moderate operating temperatures (40–65 1C).76 Canola oil and methanol

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are mixed and pumped into the RTP with NaOH as a catalyst. The centrifugal forces are generated on the rotating tube surface, producing shear thin films 700–1400 mm thick. The hydrodynamic condition inside the RTP results in faster conversions by enhancing the high heat- and mass-transfer rate. The choice of operating parameters, including rotating speed, flow rate, temperature, and catalyst concentration affect the conversion of the trans-esterification reaction.

Probing the structure of self organised systems The ability to disassemble self organized systems using SDP is a new application of the shear forces associated with the dynamic thin films. Beyond the disc disassembly of molecular capsules held together by hydrogen bonds, the technology has exciting possibilities in loading cargoes of active molecules and enzymes for drug delivery within the confines of the capsules, for example, as well as probing the structure of macromolecules such as DNA and viruses. The high shear rates coupled with the turbulent micromixing across the thin film provide a mechanism to disassemble the hexameric capsules based on C-alkylpyrogallol[4]arenes in a chloroform solution, followed by spontaneous reassembly of the C-alkylpyrogallol[4]arenes to the parent hexameric state as the solution leaves the disc, Fig. 15.77,78 DLS data on solutions initially containing two different capsules establish the disassembly of the hexameric capsules into solvated monomers or lower order oligomers, on the disc, with instantaneous reassembly into mixed hetero-hexameric capsules post-SDP. At the same time, this flash disassembly–reassembly process can be used to load a range of molecular cargos within the capsules. Waves generated in a fluid film over a moderately spinning disc enhance the absorption of gas molecules into a liquid. The flow is accompanied by nonlinear waves, which strongly influence the diffusion boundary that develops beneath the surface of the film. The progressive waves generated in the region of active micro-mixing in the film of solution in the present study provides a method of dramatically increasing the concentration of hydrogen in solution, and thus reassembling capsules are able to entrap molecular hydrogen, which can be determined using NMR spectroscopy, with the concentration inside the capsules at 30 mole percent.77

Fig. 15 Schematic of the SDP shear induced disassembly of molecular capsules based on C-alkylpyrogallol[4]arenes, for uptake of hydrogen gas post SDP.77

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Conclusion and outlook The SDP and RTP are attractive and viable technologies for manipulating and controlling the organisation of matter, in forming nanomaterials, controlling chemical synthesis, and probing self-assembled structures in a continuous operation mode. The centrifugal force induced high micro-mixing, enhanced heat transfer rates for the thin films, high mass transfer rates arising from the breakdown in surface tension of the liquids by the waves and ripples, and high shear force arising from the viscous drag, offer unique capabilities in a wide range of applications. The scalability and sustainability metrics of these systems in general contribute to benefits in both academic and industrial fields. As the advantages, and any limitations, of these continuous flow processors evolve, their potential for replacing traditional batch processors will become more apparent, depending of specific types of reactions and applications. Finer control of uniformity of metal nanoparticles, for example, is destined to improve the outcome of transition metal catalysed reactions. Major advances have been made in flow chemistry in general, using tubes or micro-structured systems with etched channels,79 where scalability can also come from arrays of such devices without compromising the outcome of the reactions. However, the use of such microfluidic systems for fabricating nano-materials can suffer from clogging of the narrow channels, unlike for SDP or RTP. Further developments on the fluid dynamics of the continuousflow processing systems and advanced design of novel continuousflow processors,80 hold promise in expanding the applications, for example in gaining control over kinetic versus thermodynamic products, that is not possible, or of limited practical convenience or low yielding, using traditional batch processing.

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