Substituent effects in saturated systems. Preparation, stereochemistry, and acidity of pipecolic (piperidine-2-carboxylic) acid derivatives

Abstract

The preparation and properties of cis- and trans-4-substituted pipecolic (piperidine-2-carboxylic) acids are described, the substituents being methyl and t-butyl. Their stereochemistry has been assigned according to the method of preparation and confirmed by ¹H n.m.r. spectroscopy and epimersation experiments. The epimerisation experiments show that in the corresponding isomeric ethyl pipecolates the conformational preference of the ethoxy-carbonyl group is less than would be expected from comparison with cyclohexanecarboxylates. The difference is attributed to dipolar repulsions involving the axial ethoxycarbonyl group and the nitrogen lone pair. Using the hydrochlorides of the substituted pipecolic acids, measurements of the acidity of the ammonium group (pK_a²) and the carboxy-group (pK_a¹) reveal a significant dependence upon conformation which may be rationalised in terms of hindrance to internal hydrogen bonding (‘hydrogen chelation’).