An investigation of the kinetics and mechanism of Cu(II)-catalyzed and ligandless CuAAC reactions

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Recent work in the Watson group has challenged the prevailing literature surrounding copper-catalysed, azide alkyne cycloaddition (CuAAC) reactions. This project will aim to tackle three key aims stemming from these findings.1) The role of NaAsc. Prior work by Fokin posited that the Cu(I) catalysed system was 'ligandless', with supporting studies involving CuSO4 and NaAsc. Our group has found evidence, however, that NaAsc enhances the reaction and that it may be a ligand for Cu(I). This project will seek to establish if NaAsC is acting as a ligand and to probe and profile its effect on reaction kinetics.2) Cu(II) based CuAAC. These observations surrounding the effect of NaAsc were made alongside a discovery of a Cu(II)-promoted CuAAC reaction (using 2-ethynyl pyridine). To better understand if there is a greater generality to this mechanistic mode, this project with look at a (similarly) highly conjugated alkyne used by M.G. Finn, as shown below: This project will seek to profile the CuAAC reaction using the Finn alkyne and Cu(II), and, if Cu(II) catalysis seems operational, this reaction will be fully explored and charted.(3) Investigation of alkynyl phosphonates as Cu(II)-based CuAAC reagents. This will aim to build upon any findings within aim 2), with the idea of establishing a general (predictive) design criteria for the development of Cu(II)-based CuAAC reactions.