Research Projects

Organic compounds containing methyl and fluoromethyl groups are essential in the field of organic chemistry due to their profound biological significance. The humble methyl group, with its unique characteristics – being monovalent and lipophilic – holds immense versatility in the design and optimization of bioactive compounds. This magic methyl effect is exploited by pharmaceutical scientists to significantly enhance drug potency. Similarly, fluorinated alkyl groups also play a crucial role in fine-tuning the biological and physical properties of molecules. Despite these advancements, the synthesis of certain methyl- and fluoromethyl-containing pharmaceutical building blocks and active agrochemical intermediates remains a significant challenge. In this context, cross-coupling methylation reactions involving alkenes and arenes often rely heavily on specific coupling partners such as methyl halides, peroxides, redox-active esters, and boronates. Additionally, these reactions necessitate stoichiometric quantities of sacrificial oxidants and reductants, thereby limiting their broad applicability. We propose to demonstrate the potential of acetic acid, a non-toxic, stable, inexpensive, and readily available sustainable alternative methyl source, for electrooxidative reactions. The Kolbe decarboxylation, a century-old reaction, involves the electrochemical oxidation of carboxylates to generate reactive radicals. While methyl radicals (Me•) are valuable intermediates, their uncontrolled reactivity and tendency for dimerization limit their utility. Despite extensive research, intermolecular radical cross-coupling involving Me• or alkyl radicals has been challenging. We envision that a shielding strategy using the structured Helmholtz layer, combined with careful electrode engineering, could help steer the chemoselectivity of a specific reaction, even though these approaches are seldom implemented in electrocatalysis. The synergistic effect of the photoanode and the mass transfer limitations of acetates through the outer Helmholtz layer is expected to mitigate the Kolbe dimerization issues and will enable the formation of R-Me products. Upon successful implementation of all the three processes, we aim to apply this concept to synthetic transformations such as direct C-H functionalization or cross-coupling reactions with alkenes and arenes. Also, the Me• radicals can add across unsaturated bonds to deliver difunctionalized products. Next, we aim to extend this process to access various methylated derivatives through cross-coupling reactions with aryl or vinyl halides. Overall, our decarboxylative methylation approach aims to achieve three primary objectives: (a) utilizing acetic acid as the methylating reagent, (b) enabling late-stage modifications of bioactive molecules, and (c) facilitating electrochemical oxidation of organic molecules (fluoroacetic acid derivatives) at lower overpotentials through the use of photoanodes.