Optimising a vortex fluidic device for controlling chemical reactivity and selectivity

A vortex fluidic device (VFD) involving a rapidly rotating tube open at one end forms dynamic thin films at high rotational speed for finite sub-millilitre volumes of liquid, with shear within the films depending on the speed and orientation of the tube. Continuous flow operation of the VFD where jet feeds of solutions are directed to the closed end of the tube provide additional tuneable shear from the viscous drag as the liquid whirls along the tube. The versatility of this simple, low cost microfluidic device, which can operate under confined mode or continuous flow is demonstrated in accelerating organic reactions, for model Diels-Alder dimerization of cyclopentadienes, and sequential aldol and Michael addition reactions, in accessing unusual 2,4,6-triarylpyridines. Residence times are controllable for continuous flow processing with the viscous drag dominating the shear for flow rates >0.1 mL/min in a 10 mm diameter tube rotating at >2000 rpm.

of dynamic thin films in SDP and RTP break down surface tension resulting in high mass transfer 14,15 , and the thinness of the films ensures rapid heat transfer between the liquid and rotating surface 10,16 . SDP has feed jets directed close to the centre of a rapidly rotating disc where there is intense micro-mixing, with residence times of typically less than a second, depending on the size of the disc, spinning speed, surface texture of the disc itself, viscosity of liquid and flow rates 10 . With respect to applications in organic synthesis, the SDP has been used to isomerize a-pinene 7 , control polymerization reactions 3,6,8 , and prepare 1,5-diketones as an entry to 2,4,6-triaryl pyridines 9 . Intriguingly, for the latter, several passes are required to move beyond the chalcone intermediate to form significant quantities of the desired 1,5-diketone 9 . The RTP has jet feeds delivering solutions intensely mixed at one end to go through the rapidly rotating tube, with the product collected at the other end [18][19][20][21][22][23][24] . Here the residence times can be minutes, depending on flow rates and the length of the tube.
To overcome limitations in these devices and introduce more flexibility in parameters, the new vortex fluidic device (VFD) was designed to operate in the same horizontal position as the RTP, as well as being able to operate at different angles, defined by the tilt angle, h, with a closed end of the tube and jet feeds for delivering liquids and any gases from the other end, which is where the resulting processed liquid departs under continuous flow operation ( Figure 1a). Shear in the thin films formed in the VFD arise from the viscous drag as for the SDP and RTP, as well as a contribution from a combination of centrifugal force with gravity, for operating at tilt angles .0u, as an additional advantage beyond the SDP and RTP, along with the ability to use smaller volumes of liquid, and a much lower cost of construction. Another advantage of VFD is that it can also operate in a so-called confined mode for a finite volume of liquid, for extending the shearing time, where the instability of the thin films arises exclusively from a combination of centrifugal force and gravity 25 .

Results
The prototype of the VFD presented herein operates with a 10 mm diameter tube, for speeds up to 10,000 rpm and temperatures up to 200uC. Overall the device has several reproducible operating parameters including rotating speed, tilt angle h, and flow rates, along with operating parameters for traditional batch operated reactions, such as varying the temperature and concentration of reactants.
To gain insight into the average film thickness for steady state conditions, we determined the height of the thin film in the tube, and thus the internal area of liquid coverage, for a fixed volume of liquid ( Figure 1b). For example, the average thickness of the liquid film for 1 mL of water in the 10 mm tube inclined at 45u and rotating speed at 7000 rpm is ,230 mm. We found that the shape of the film is quasi-parabolic and where the vortex extends to the base of the tube for high rotating speeds, it approximates to a uniform film  To understand the effect of the VFD on molecular reactions, we investigated the dimerization of neat cyclopentadiene and methylcyclopentadiene for different rotating speeds and tilt angles, at room temperature, under confined mode ( Figure 2) and continuous flow mode (Figure 3), respectively. In confined mode, fixing the speed at 7000 rpm, the processing time at 1 hour and varying the tilt angle for 0.2 mL of cyclopentadiene results in an increase in percent conversion to the dimer, for h . 0 ( Figure 2a). As h increases the percent dimerization increases to a plateau at ca 45u then decreases before increasing again as h reaches 90u. Given the practical inconvenience of operating at this angle, especially when operating under continuous flow, the optimum shear for confined mode was set at h 5 45u, which corresponds to the optimum angle for exfoliation of graphite and h-BN, and also for continuous flow dimerization conditions at low flow rates (see below) 25 . For 7000 rpm and h 5 45u, for the same volume of liquid, there is an increase in percent dimerization over time relative to the static control and for h 5 0u (Figure 2b). At h 5 0u the liquid will rotate close to the same speed as the tube, with no shear, and consistent with this is that the outcome is the same as the static control sample, with 2.5% conversion after 3 hours, compared with 6.8% conversion in the VFD. For comparison, agitation using conventional rapid magnetic stirring results in some additional dimerization, increasing from 2.5% to 3.6% conversion for the same period. For h 5 45u, the percent dimerization increases for increasing speed, for 1 hour processing, from ca 2000 rpm to 10,000 rpm ( Figure 2c). Operating speeds $2000 rpm under this confined mode ensures that the resulting vortex is maintained to the base of the tube, for a more uniform shear present in the thin film, which is consistent with our initial observations ( Figure 1b).
To investigate VFD under continuous flow we used methylcyclopentadiene to overcome the evaporative loss of cyclopentadiene at room temperature, and found that the percent dimerization increases dramatically relative to the confined mode. For example, 0.2 mL of methylcyclopentadiene at room temperature for 1 hour with h 5 45u for the tube rotating at 7000 rpm results in 0.75% dimerization (compared with 0.34% for the static control) whereas for a single pass under continuous flow conditions for the 15 cm long tube, with h 5 45u for a flow rate of 0.1 mL/min, there is 1.9% dimerization, for which the residence time on the tube is approximately 12 minutes. For a low constant flow rate of 0.1 mL/min with the tube rotating at 7000 rpm, the percent dimerization increases for increasing speed, although this is small for h 5 0u (Figure 3a). As h increases the dimerization increases up to 45u, then decreases up to 60u, followed by progressive increases at 75 and 90u, which is consistent with the variation in dimerization observed in the confined mode.
Dimerization of methylcyclopentadiene under different flow rates, with the tube rotating at 7000 rpm, varies dramatically for lower flow rates (Figure 3b). At the maximum flow rate (1.0 mL/min) there is essentially no difference in the percent conversion with variation in h, but significant differences develop in tracking to the lowest flow  rate (0.1 mL/min) where the conversion increases as h increases to 45u, decreases as it approaches 60u then increases again towards 90u. For h 5 45u there is a four-fold increase in dimerization relative to h 5 0u, and effectively establishes the contribution from the shear associated with viscous drag as the liquid moves along the horizontal tube (h 5 0u), and the additional contribution to shear established in the confined mode (see above) for h . 0u. At low flow rates the film thickness is expected to be smaller than at high flow rates for the same speed, and with thicker films the overall contribution of the shear from the viscous drag will be reduced. The increase in percent conversion at high h ($75u) then establishes a different shear regime, albeit of less practical convenience where the mass of the liquid has to move up the side of the tube against gravity. The low conversions observed at low speeds for higher h values relates to these thicker films and the resultant less shear as the liquid moves along and up the tube in overcoming the effect of gravity.
We have translated the optimised conditions of these dimerization reactions to investigate confined and continuous flow synthesis of 2,4,6-triarylpyridines (Figure 4a). These are formed via an aldol condensation reaction to give 3a-d, followed by a Michael addition to give 4a-c (Figure 4). In some cases there is a need to gain control over competing reactions, as in the undesirable Schiff base condensation coupled with aldol condensation (compound 6a), which is a favoured product using batch processing in attempting to prepare the 1,5diketone 4a via the chalcone 3a. This unwanted product arises from poor heat and mass transfer which is overcome using SDP, but requires multiple passes because of the short residence time (,1 second for a 10 cm disc) 9 . A single pass, under continuous flow conditions, on the VFD now allows direct access to 4a, albeit with low amounts of chalcone formation, depending on the choice of control parameters (Figure 4b). At low flow rate (0.1 mL/min) the percent yield is higher than at corresponding high flow rates (1 mL/ min) which is expected due to the longer residence time, but high flow rate reduces the relative amount of chalcone being formed. The amount of chalcone is minimal for h 5 0 and 90u, whereas at 45u there is a larger amount of the compound, especially at a low flow rate. This again reflects a different shear regime at this angle, consistent with what has been identified in the dimerization of methyl cyclopentadiene. However, the confined mode operation of the VFD is effective in preparing the chalcones 3a-d in high yield. Thus the choice of continuous flow versus confined mode is another parameter in gaining control over the outcome of the reactions. Interestingly the 2,4,6-triarylpyridines 5a-d can also be formed in the VFD under continuous flow conditions in a single pass in the presence of NH 4 OAc (Figure 4a, reaction iv). This is particularly important for 5d given that it was not possible to make the 1,5diketone precursor, 4d, using methods (ii) and (iii) (Figure 4a). 2,4,6-Triarylpyridines are accessible using SDP but the short residence time necessitates several passes through the microfluidic device, with less control over the product distribution 9 . They are also accessible in a one step process in the presence of NH 4 OAc using microwave irradiation 33 , but this is not immediately scalable processing, and the energy usage using microwave heating is questionable 34 .

Discussion
The VFD has different shear regimes in the thin films. For the confined mode of operation, the shear depends on the tilt angle h of the rapidly rotating tube, which is greatest at 45u and 90u, and the speed of the tube. This was established by the increase in dimerization of cyclopentadiene relative to controls (h 5 0u, no agitation or stirring of the liquid). For the continuous flow mode, the viscous drag dominates the shear for flow rates at 1.0 mL/min, and for flow rates approaching 0.1 mL/min the different shear established for the confined mode also become important, which has been established by the increase in dimerization of methylcyclopentadiene relative to the same controls.
The increase in shear, as judged by the increase in dimerization of the cyclopentadienes, for h up to 45u, then a decrease before an increase as h approaches 90u, defines different shear regimes corresponding to different orientations of the centrifugal force relative to gravity, for which the fluid dynamics is presumably complex. The findings provide a basis for understanding the outcome of recent applications of the VFD operating under confined mode, where the optimum tilt angle approximated to 45u. This includes the 'top down' exfoliation of laminar material 25,26 , the 'bottom up' growth of nano-particles 27,28 , disassembly of self organised systems 14,29 , and entrapping microalgal cells 30,31 . The results for the continuous flow synthesis are consistent with the synthesis of superparamagnetic nanoparticles for h at 0u for a flow rate of 1 mL/min 30 , noting that the tilt angle under continuous flow becomes important for much slower flow rates, especially approaching 0.1 mL/min.
The shear in the confined and continuous flow modes is effective in enhancing the chemical reactions, in providing a 'soft' form of energy to increase molecular collisions for reactions under diffusion control. The increase in percent conversion of the cyclopentadienes is possible without heating the samples, and for the formation of the 2,4,6-triarylpyridines the ability to circumvent the formation of the Schiff base, compound 6a, establishes the ability to gain control over kinetic verses thermodynamic product. Intense micromixing and associated shear here also allows direct access to amine substituted chalcones and 1,5-diketones, without the need to prepare the corresponding nitro-compounds 35 , for then reduction of the functional groups post-aldol and Michael addition reactions, and also formation of the 2,4,6-trialylpyridine.
The above cyclopentadiene Diels-Alder reactions and the ability to use the VFD to control reactivity and selectivity in the formation of 2,4,6-triarylpyridines, establishes the utility of using the inexpensive microfluidic device for improving the outcome of chemical reactions. This coupled with the ability to scale down to sub-millilitre volumes in the confined mode or scale up under continuous flow mode while maintaining intense shear allows for controlled chemical reaction conditions to be achieved. There is potential for application of the VFD in a myriad of functional group transformations, with hierarchical control, including reactions of gases with liquids, in taking advantage of the high mass transfer of gases at the dynamic interface between the two states. A potential limitation of the VFD is continuous flow operation for highly viscous liquids and/or where the product gelates which may clog the outlet system.
The VFD is modular and can be readily modified, in changing the nature of the tube, with surface texture features for increasing the intensity of micro-mixing, and covalent attachment, in controlling the contact angle of the surface (hydrophobic/hydrophilic balance) to change the viscous drag and thus the shear intensity. The VFD can also incorporate field effects, including standard light sources and lasers, and has high throughput processing capabilities for developing libraries of nanomaterials and organic compounds. Several reactions can potentially be telescoped within a single platform, or sequential platforms, with the ability to carry out reactions in an inert atmosphere using a gas feed or by placing the small unit in a controlled atmosphere glove box, and properties of liquids under intense shear can also be studied for small volumes.
www.nature.com/scientificreports SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 Australia, and all experiments used a 10 mm NMR tube, 15 cm in length, which was capped in the confine mode dimerization studies of 0.2 mL of freshly distilled cyclopentadiene. For dimerization studies of under continuous flow mode, freshly distilled methylcyclopentadiene was kept in an ice bath prior to use, and the liquid was collected after steady state flow from the tube. The percent conversions for both studies were determined using 1 H NMR. For the confined mode synthesis of the chalcones (3), a mixture of p-aminoacetophenone (1) (1 mmol), sodium hydroxide (1 mmol) and benzaldehyde (2) (1 mmol) in 2 mL PEG was spun in a capped tube at 7000 rpm, 45u degree tilt angle at 80uC (for 3a and 3d) or ambient temperature (for 3b and 3c) for 30 minutes. Water (25 mL) was then added and the resulting yellow precipitate collected and dried in vacuo. For continuous flow synthesis of 1,5-diones (4), p-aminoacetophenone (1) (1 mmol) and hydroxide (2 mmol) in PEG 300 (1 mL) was directed through one jet feed, with the other a solution of benzaldehyde (2) (1 mmol) in PEG 300 (1 mL). Both solutions were then passed through the VFD using continuous flow mode; 80uC, 7000 rpm, 0 degree tilt angle and 0.1 mL/min flow rate. Water was added to the processed liquid affording a yellow precipitate as mixture of 1,5-diketone (4) and chalcone (3). Similarly excess NH 4 OAc (400 mg) was used in place of NaOH, to afford the 2,4,6-triarylpyridine (5) directly.