# Aqueous-Phase Multicomponent Reaction Mechanism for the Synthesis of Pyrido[2,3‑d]pyrimidines: A Theoretical Perspective

## TL;DR

This paper uses theoretical methods to study how pyrido[2,3-d]pyrimidines form in water, focusing on reaction steps and temperature effects.

## Contribution

The study provides a detailed theoretical mechanism for a multicomponent reaction in aqueous phase, identifying the rate-determining step.

## Key findings

- Carbon–carbon bond formation between benzaldehyde and Meldrum’s acid is the rate-determining step.
- Temperature increases the reaction rate but does not significantly enhance pyrido[2,3-d]pyrimidine formation beyond trace amounts.
- The theoretical model aligns with experimental results and explains the reaction mechanism in detail.

## Abstract

A theoretical investigation of the reaction among benzaldehyde,
Meldrum’s acid, and 6-aminouracil in aqueous solution is presented
in this study, incorporating the impact of temperature on both the
thermodynamic and kinetic aspects of the reaction. Five free energy
profiles are presented, concerning the Knoevenagel condensation, Michael
addition, cyclization, propanone, and CO2 release. We have
also performed a simple kinetic analysis and a detailed microkinetic
analysis. According to our results, the carbon–carbon bond
formation between benzaldehyde and Meldrum’s acid is the rate-determining
step. The temperature increases the reaction rate; however, it is
still insufficient for the formation of pyrido­[2,3-d]­pyrimidines beyond trace amounts, in good agreement with experimental
results. This explanation provides a thorough understanding of the
multicomponent reaction mechanism that leads to the formation of pyrido­[2,3-d]­pyrimidines, thereby opening new possibilities for further
exploration and optimization of the catalyzed process.