Synthetic pepsin

24 July 2015 - Sensational headlines

Hie amide hydrolysis 2015.PNGThe one reaction missing on the amide Wikipedia page: amide hydrolysis. Better leave that one to nature's proteases. Their grandpa (called pepsin) was discovered as early as 1836. The amide bond is simple too strong (resonance stabilised) and will resist any nucleophile. Good to know then that in one particular synthetic chemical configuration featuring nickel, amide bond cleavage is indeed possible with many thanks to Hie et al. (DOI) of the Kendall Houk laboratory who report about it in the journal Nature.

Here is a typical batting order: substrate N-methyl-N-phenyl-benzamide, solvent toluene (110°C), catalyst bis(cyclooctadiene)nickel(0), carbene ligand SIMes (both 0.1 eq.) , methanol (1.2 eq.) and product methyl benzoate in a 88% reported yield. Not strictly a hydrolysis more like a amide to ester conversion. Naturally, success critically depends on the type of substrate. The Weinreb amide N-methoxy-N-methyl-benzamide (differs from substrate 1 by a single oxygen) yields only 22% of product. Luckily the report is able to trace the substrate's fortunes to a single parameter: the computed Gibbs free energy. With respect to reaction mechanism the reaction is a classic oxidative addition - ligand exchange - reductive elimination.