Electrochemical Approaches to Organic Synthesis Eugene E. Kwan and Andrei K. Yudin August 2002

Electrochemistry Role in Synthesis: Electrochemical steps are the same as traditional reagent-based steps, only electrons and electrogenerated species are used as the reagents. Why Electrochemistry? - reactions are cheap and do not produce toxic byproducts. - transformations not available via traditional techniques can be carried out. - specialized electrodes and conditions allow for high selectivity. - readily available analytical techniques like cyclic voltammetry allow systematic predictions of selectivity and investigation of kinetics.

Anodic Aromatic FluorinationCyclopropylphosphonate Synthesis Oxidation of Sulfides Examples of Electrochemical Reactions

Electrochemical Apparatus Cells Cells control the flow of electricity and reactants. They can be divided or undivided: Undivided Divided Electrodes Electrodes deliver the electrons. Different electrodes may have different surface characteristics and overpotentials. Examples include platinum, graphite, nickel, and magnesium.

- only works on Pt electrodes - thought to occur through nitrene intermediate - better than traditional method, which relies on Pb(OAc) 4, a toxic oxidant - no toxic byproducts - the N-N bond remains difficult to cleave Siu, T. and Yudin, A. K. "Practical Electrochemical Olefin Aziridination with a Broad Substrate Scope," JACS. 2002, 124, 530. Electrochemical Aziridination

ReactIR Characterization Real-time attenuated total reflectance (ATR) FTIR spectra were taken with a ReactIR 1000 spectrometer using a liquid nitrogen cooled mercury cadmium telluride detector. Principal components analysis (PCA) of the mid-infrared region allowed determination of concentration profiles. diamond tipped ATR detector nitrogen purge line probe made of inert alloy adjustable joints internal mirrors direct beam The probe is dipped into the reaction and scans are periodically performed and averaged by the computer. A “waterfall” profile is generated and then analyzed. With internal standards, quantitative kinetic data can be extracted. The PCA algorithm does not require any internal standards or knowledge of the reaction.

ReactIR Data a preliminary “waterfall” profile of an aziridination reaction a PCA-generated set of spectra region used for analysis noise generated by water and gas impurities PCA-calculated concentration profiles for the reaction The PCA algorithm assumes the data (above) can be represented by a linear combination (bottom right) of eigenvector spectra (top right). It searches for peaks which change at the same rate and assumes they belong to the same component. It looks for a minimum number of eigenvectors which can reproduce the data within a set margin of error. Further experiments are needed to determine the identity of the eigenvectors.

Electrochemical Alkoxylation Intermolecular Intramolecular Cyclizationa potentiostat This is a convenient technique for generating alkoxylated piperidine and pyrrolidine style structures. It works on a wide variety of substrates and electrode surfaces and can be carried out quickly. It is highly selective and gives good to excellent yields. Siu, T., Li, W., and Yudin, A. K. J. Comb. Chem. 2000, 2, Shono, T. Matsumura, Y., Tsubata, K. Organic Syntheses. CV 7, 307.

Characterization 1 H NMR shows two rotamers: axial alpha proton ReactIR is unable to follow this reaction probably because the reactant and product have very similar IR spectra. GC shows no significant reaction after four electron equivalents have been passed because the starting material has been completely bis-methoxylated. GC was unable to resolve mono- and bis- methoxylated product or bismethoxylated diastereomers. starting material various products

Alkoxylation in Synthesis We attempted the above synthesis, however the methoxylation step failed because the S=O bond was preferentially oxidized over the alpha position on the piperidine ring. One possible way to get around this may be to run the reaction completely dry so there is no oxygen source. The products of this synthesis are useful precursors to a number of important pharmaceuticals. The CVs in degassed 1:1 MeCN/MeOH on glassy carbon show similar profiles with significant anodic currents which means the methoxylation should be possible. The two anodic peaks probably result from the stepwise generation of radical cations and cations.

Acknowledgements - Yudin Group: Sacha Bhinder, Leslie Fradkin, Larissa Krasnova, Tung Siu, and Shahla Yekta. - Lautens Group: Wooseok Han and the use of their ReactIR. - NMR: Tim Burrow. - U of T Department of Chemistry - NSERC