Quantum chemistry calculations and chemical kinetic studies on the tautomeric mechanism of creatinine

Abstract

Context

Thermal processing of meat typically leads to the formation of heterocyclic aromatic amines (HAAs), a class of highly toxic compounds. Although extensive research has been conducted on HAAs, the precise formation mechanisms of individual HAAs remain incompletely understood, with many critical details yet to be elucidated. Several unresolved aspects concern the number of tautomers of creatinine—the key precursor in HAA formation, the interconversion pathways among these tautomers and the time scales involved, and the equilibrium distribution ratios among the tautomeric forms. Addressing these questions is essential for achieving an accurate understanding of the mechanistic pathways underlying the formation of HAAs.

Methods

All possible tautomers were manually deduced and verified by RDkit, a chemoinformatics toolkit. Geometry optimizations and frequency analyses were performed using density functional theory (DFT). The distribution of various tautomers was evaluated under three different environments—gas phase, ethanol, and water—to simulate real conditions. Calculations were carried out at the B3LYP/def2QZVPP//6-31G(d,p) level of theory, with the polarizable continuum model (PCM) applied for ethanol and water. A similar computational approach to the calculations on distribution was employed to investigate tautomerization mechanisms. Tautomerization kinetics were analyzed within the framework of transition state theory (TST) to determine rate constants for each tautomeric interconversion. Tunneling correction factors (κ) were then calculated to account for quantum mechanical tunneling effects. Subsequently, the corresponding system of differential equations was solved to obtain the time-dependent concentration profiles of each tautomeric species.