A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed-bed microreactor

We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO catalyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leaving the organic product separate from the aqueous by-products. Furthermore, the microreactor oxidized a wide range of alcohols and remained active in excess of 100 trials without showing any loss of catalytic activity.


Introduction
Microreactors have gained attention because they can help run chemical transformations more efficiently, more selectively, and with a higher degree of safety [1][2][3][4][5][6][7][8][9][10][11][12]. Alcohol oxidations are well suited for microreactors due to high by-product formation, catalyst contamination and safety concerns often associated with scale-up in batch reactors [13]. Recent developments in microreactor technology and solid-supported catalysis have aimed to solve these issues. Numerous flow oxidations have been presented in the literature [13][14][15][16], however many rely on stoichiometric reagents [17,18], suffer from catalyst deactivation [19,20], or rely on soluble catalysts [21], all of which limit their potential as continuous flow processes. Realizing this, we developed a catalytic packed-bed microreactor that could be used for the continuous flow oxidation of alcohols to aldehydes or ketones.
We recently reported the development of an effective solid support for use in packed-bed microreactors [39], AMBERZYME ® Oxirane (AO, 1), a commercially available resin with pendant epoxide functionalities designed for enzyme immobilization. AO is readily functionalized with a range of catalysts and works well as packing material for flow chemistry [39]. In this report, we demonstrate the immobilization of TEMPO and its use in a flow system using the Anelli-Montanari protocol for the oxidation of primary and secondary alcohols [30,40]. Our simplified reactor is advantageous because the reactions not only run continuously, but since the microreactor is made of cheap, disposable fluoroelastomeric tubing, wall oxidation that is commonplace with metal microchannels is not observed [21]. The narrow dimensions of the microreactor also allow excellent heat transfer, increasing the safety of large-scale oxidations. Furthermore, it was determined that the use of a packed-bed microreactor facilitates efficient mixing of a biphasic system without destroying the solid support, a common problem with stirred systems [4].
Using a simplified procedure developed by ourselves and others [39,[46][47][48][49], flow reactions were performed by packing fluoroelastomeric tubing (60 cm, 1.6 mm i.d.) with the AO-TEMPO resin. The tubing was subsequently woven between metal bars, to improve mixing and to enable facile microreactor cooling ( Figure 1). A Y-junction placed at the inlet of the microreactor allowed the immiscible bleach (adjusted to pH 9.1 using NaHCO 3 ) and organic alcohol solutions to form plugs before reaching the packed bed ( Figure 2A). When passing through the AO-TEMPO catalyst bed, the plugs emulsified, as indicated by visual inspection and by the plug coalescence at the microchannel outlet ( Figure 2B). The effective mixing was later supported by the high yields and conversions that were achieved for this biphasic reaction.
Preliminary reactions were performed using benzyl alcohol as the test substrate in order to establish the optimal flow conditions (Scheme 3). A solution of benzyl alcohol in CH 2 Cl 2 (0.2 M), an aqueous NaOCl solution (0.25 M, adjusted to pH 9.1 using NaHCO 3 ), and an aqueous KBr solution (0.5 M) were prepared. The organic phase was loaded into one syringe and a mixture of NaOCl and KBr (30 μL KBr solution per mL NaOCl solution) was added to another. The syringes were placed on separate syringe pumps and the flow rates were regulated such that 1.0 equiv alcohol min −1 , 1.5 equiv NaOCl min −1 , and 0.10 equiv KBr min −1 were delivered to the packed bed. Various flow rates were examined to determine the optimal flow conditions for the oxidation. For data relating flow rate to residence time, see Supporting Information File 1. During our optimization studies, it was shown that a total flow rate of 100 µL min −1 (aqueous flow rate 56 µL min −1 and organic flow rate 44 µL min −1 , approximately 4.8 min residence time) afforded quantitative conversion of benzyl alcohol to benzaldehyde, indicating that efficient mixing was occurring in the column at this flow rate. Faster flow rates (200 or 400 μL min −1 ) could also be used to obtain higher outputs of benzaldehyde, however these reaction conditions did not provide complete conversion of starting material.
Using these optimized flow conditions for the benzyl alcohol oxidation, a number of different substrates were examined to test the generality of the AO-TEMPO packed-bed microreactor. High conversions were achieved when using both aromatic and aliphatic alcohols ( Table 1, Entries 1-6). Secondary alcohols, which are known to be oxidized at a slower rate than primary alcohols, could effectively be oxidized to ketones by increasing the equivalents of NaOCl with respect to the alcohol concentration (Table 1, Entries 7-9). Primary alcohols were shown to be oxidized selectively over secondary alcohols (Table 1, Entry 10). Interestingly, it was also demonstrated that ethyl acetate was almost as effective a solvent as methylene chloride, opening the possibility of making this process "green" (Table 1, Entry 11). While reactions range from modest to high yields, systems that do not perform as efficiently could readily be optimized to afford higher conversions and yields. For the purposes of this paper however, we were solely testing the generality of the method and, therefore, did not optimize every  substrate. Similar to our previous packed-bed systems, these AO-TEMPO microchannels showed a high degree of recyclability, in some cases being used in excess of 100 trials without any apparent loss of catalytic activity. Channels also maintained a high activity after three months of not being used.
To test the long-term activity of the AO-TEMPO packed beds, the oxidation of 4-chlorobenzyl alcohol to 4-chlorobenzaldehyde was run continuously and sampled periodically to monitor its activity. As seen in Figure 3, the activity of the catalyst bed remained high even after hours of use. Furthermore, the workup of this simplified oxidation scale-up comprised only of phase separation followed by concentration, yielding a white crystalline solid with greater than 95% purity by 1 H NMR.

Conclusion
We have demonstrated that using supported TEMPO is an efficient method to oxidize alcohols using a simplified packed-bed microreactor. A biphasic mixture was thoroughly mixed by passing the immiscible liquids through the catalytic packed-bed, leading to no disruptions or degradation of the packing material. Thus, the AO-TEMPO resins are recyclable, showing no loss of catalytic activity and a substrate scope that encompasses many primary and secondary alcohols. The devices presented are predicted to be readily scaled-up to achieve the desired output of a reaction and is of higher throughput than other reported packed-bed microreactors.

Experimental General
Solvents were purified by standard procedures. All other reagents were used as received, unless otherwise noted. Sodium hypochlorite solution (reagent grade, available chlorine 10-15%) was purchased from Aldrich and titrated before use. 1