An electrochemical flow cell for the convenient oxidation of Furfuryl alcohols
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Effecting oxidation reactions electrochemically dispenses with the need for reactive and potentially toxic reagents but barriers remain towards wide adoption of the technique, in part because of negative prior experiences with batch-mode reactions. Electrochemical flow set-ups fix the electrodes to maintain a uniformly narrow gap, and can operate continuously until a desired quantity of substrate has been processed. We describe the fabrication of an electrochemical flow cell and its application in the transformation of furfuryl alcohols into hydroxypyrones. The cell is simple to operate with inexpensive equipment under a constant current regime, flow rate being controlled by a standard laboratory syringe pump. With the addition of a trace of NaClO4 as electrolyte to provide a stable current flow, the oxidations proceed routinely with a current efficiency of around 60%.
KeywordsElectrochemistry Anodic oxidation Furans Achmatowicz reaction Hydroxypyrones
Advances in reaction technology have made electrochemical synthetic methodologies more accessible, and recent high-profile reviews will help the approach to gain traction among mainstream synthetic chemists [27, 28, 29, 30, 31]. In this context, flow chemistry has emerged as a major enabling technology in organic synthesis , and the construction of electrochemical flow cells [33, 34, 35, 36, 37] allows the reactions to be performed in the absence of an added electrolyte by virtue of the very close proximity of the two electrodes [38, 39, 40]. Furthermore, reactions may be performed using simple equipment under a constant current regime, without the need for a considerably more expensive potentiostat. Synthetic electrochemical transformations have been reported in which the power source is a lantern battery , a D-cell battery , a mobile phone charger , or a photovoltaic cell [44, 45], among others.
Our group has worked extensively on oxidative dearomatisation reactions of furan derivatives en route to mostly spirocyclic natural products. Of most relevance is a method based on stepwise electron- and proton-transfer steps mediated by DDQ . The extended alkylidene spiroacetals generated in this reaction were found to be poorly stable in the presence of the oxidant and acceptable results could only be obtained by running the reaction at −90 °C and keeping the reaction time short; the reactions were then clean but incomplete. An electrochemical flow variant of this process could, in principle, achieve complete oxidation by fine control of the flow rate / residence time. In related work , we described the formation of butenolide spiroacetals from 2-(4-hydroxybutyl)furan derivatives either directly, using an excess of MCPBA, or in two steps, using sequential oxidations with MCPBA and PDC, with overall yields of 60–65%. Again, an electrochemical variant of this reaction would remove the need to employ reactive chemical oxidants and then separate the spent reagent from the desired product. This paper describes a preliminary project to fabricate a suitable device, that could be deployed in any organic chemistry laboratory, and illustrate its effectiveness in a transformation of value to synthetic chemists. The aim was to develop a flow method for the anodic oxidation of furfuryl alcohol derivatives under constant current conditions, employing a commercial power supply, and then determine the synthetic potential of the approach for accessing side-chain functionalised hydroxypyrone derivatives.
Results and discussion
Cell design and construction
Electrical connection to the electrodes was achieved using three spring-loaded pins (Preci-dip) with a standard pitch separation of 2.54 mm, and hidden in a straight socket (Fig. 1f) to facilitate the attachment of a cable. The upper mount also includes fluidic threaded ports (Fig. 1g) to match M660 1/16″ super flangeless fittings (Upchurch Scientific). Solutions were driven in and out the cell through 1/16″ outer diameter PTFE tubing (Cole Parmer). Inside the cell, the inlet and outlet are 1 mm in diameter (Fig. 1h). Suitable gaskets (Fig. 1i) were manufactured in thin sheets (25–100 μm) from a variety of materials – including PEEK, PTFE, FEP, and Kapton – using a Roland GX-24 CAMM cutter plotter (Roland DG). For operation, the cell is held together by ten M3 screws. Detailed 2D and 3D diagrams are available as Supporting Information, and the original Vectorworks file will be provided by the authors upon request.
Cell testing and optimisation
Optimisation of electrolysis parameters (25 μm Kapton gasket)
Application to substituted furfuryl alcohols
Substrate screening for the flow anodic oxidation of furfuryl alcohols (25 μm Kapton gasket)
In general, separate oxidations were conducted back-to-back over the course of a day without the need to disassemble the cell and clean the electrodes. To begin, the electrodes were wiped in a figure-of-eight motion with a paper towel, the cell was assembled and the various substrates were oxidised sequentially, typically in two runs of 20 min for each substrate. For cleaning between substrates, methanol was flowed through the cell via syringe. No drop in performance of the cell was noted during these daily runs, which required 2.0–2.5 h in total. At the end of a set of oxidations, the cell was disassembled, the electrodes were wiped over with methanol, and the cell assembled with a blank gasket (no channel) between the electrodes for storage. All the oxidations described in this article were performed without the need to re-polish the electrode surfaces and no passivation was observed by adhering to this regime.
The current efficiency of the process is calculated to be ~60%, based on substrate conversion measured by GC analysis of the crude product solution. Loss of efficiency may result from methanol oxidation to form formaldehyde and/or formic acid; for comparison, Atobe’s flow oxidation method demonstrated an efficiency of <10% due to solvent oxidation .
Synthesis of hydroxypyrones (3) by anodic oxidation then hydrolysis
In conclusion, an electrochemical flow cell has been constructed and its utility demonstrated by the anodic oxidation of furfuryl alcohols 1, with the resulting compounds affording hydroxypyrones 3 following acidic treatment. This method works well when the substrates lack features that promote fragmentation (cf. Scheme 3). Applications of the cell to oxidations more broadly are being trialled within the group.
The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no 316955.
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