Structural and energetics aspects of a proposed mechanism for the phosphate-mediated Pictet–Spengler cyclization reaction: A computational study

Abstract

A proposed phosphate-mediated mechanism for the Pictet–Spengler cyclization reaction is systematically examined using DFT and ab initio methods both in vacuum and in acetonitrile solution. In particular, the condensation reaction of either phenethylamine or 3-hydroxyphenethylamine with formaldehyde to yield the corresponding tetrahydroisoquinoline products was investigated. One mechanistic pathway involves a pre-reaction complex between an iminium cation and a phosphate ion (either dihydrogen phosphate or hydrogen phosphate), a post-reaction complex between the tetrahydroisoquinoline product and the protonated phosphate, and a single transition state complex connecting the pre- and post-reaction complexes. Energy barriers for the reaction system to transition from the pre- to the post-reaction complexes are lower with dihydrogen phosphate rather than with hydrogen phosphate, and in solution rather than in vacuum. Accordingly, the MP2/6-31++G(d,p) calculated lowest energy barriers in solution are 20.83kcal/mol (3-hydroxyphenetylamine) and 28.77kcal/mol (phenethylamine). Another mechanistic pathway was also considered for the reaction in acetonitrile solution of the 3-hydroxyphenethylamine substrate. In this case, a third molecule (a solvent molecule, or another phosphate anion) was added to interact with the hydroxy group of the pre- and post-reaction dimer complexes of the iminium cation with the phosphate anion. For all trimer complexes considered, the reaction appears to proceed through a two-step mechanism. The lowest energy path for the reaction occurs when the third molecule added is hydrogen phosphate, with an MP2/6-31++G(d,p) calculated energy barrier of 12.49kcal/mol in the rate determining step.