Water-Soluble Organocatalysts
for Hydrazone and Oxime
Formation
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Abstract
The formation of oximes and hydrazones is widely used
in chemistry
and biology as a molecular conjugation strategy for achieving ligation,
attachment, and bioconjugation. However, the relatively slow rate
of reaction has hindered its utility. Here, we report that simple,
commercially available anthranilic acids and aminobenzoic acids act
as superior catalysts for hydrazone and oxime formation, speeding
the reaction considerably over the traditional aniline-catalyzed reaction
at neutral pH. This efficient nucleophilic catalysis, involving catalyst–imine
intermediates, allows rapid hydrazone/oxime formation even with relatively
low concentrations of the two reactants. The most efficient catalysts
are found to be 5-methoxyanthranilic acid and 3,5-diaminobenzoic acid;
we find that they can enhance rates by factors of as much as 1–2
orders of magnitude over the aniline-catalyzed reaction. Evidence
based on a range of differently substituted arylamines suggests that
the <i>ortho</i>-carboxylate group in the anthranilate catalysts
serves to aid in intramolecular proton transfer during imine and hydrazone
formation