Stereochemical substituent effects: investigation of the cyano, amide and carboxylate group

Three pairs of diastereomeric piperidines, cis- and trans-2-methylpiperidine-3-carboxylate ( and ), cis- and trans-2-methylpiperidine-3-carboxylamide ( and ) and cis- and trans-2-methyl-3-cyanopiperidine ( and ), were synthesised for the purpose of investigating the effect of the axial versus equatorial carboxylate, carboxamide and cyano group on piperidine base strength. The pKa values of the six compounds were determined to be 11.0 (), 10.4 (), 9.5 (), 9.3 (), 7.8 () and 8.0 (). This shows that the strong electron-withdrawing effect of the cyano group and the effect of the amide group are relatively independent of spacial orientation. The carboxylate, on the other hand is considerably less electron-withdrawing when axial.