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Study of Meldrum's Acid Cyclization Reactions.
Cristina Trujillo1, Pilar Goya2, Isabel Rozas1
1School of Chemistry, Trinity Biomedical Sciences Institute , Trinity College Dublin , 152-160 Pearse Street , Dublin 2 , Ireland.
The Journal of Physical Chemistry. A
|February 22, 2018
Summary
Meldrum's acid derivatives undergo cyclization reactions. Computational analysis reveals that methylene analogues are less reactive due to unfavorable conformations and intramolecular hydrogen bonds, explaining the lack of successful cyclization.
Area of Science:
- Organic Chemistry
- Computational Chemistry
Background:
- Cyclization reactions are crucial in organic synthesis.
- Meldrum's acid derivatives have been utilized in various synthetic pathways.
- Previous studies by Danishefsky et al. demonstrated successful cyclizations of ethyl derivatives.
Purpose of the Study:
- To investigate the reasons behind the unsuccessful cyclization of sulfamidomethylene and ureidomethylene Meldrum's acid derivatives.
- To compare the reaction mechanisms of successful (ethyl) and unsuccessful (methylene) cyclizations.
- To understand the influence of conformation and intramolecular interactions on reactivity.
Main Methods:
- Density Functional Theory (DFT) calculations, specifically MP2/6-311+G(d,p) level of theory.
- Simulations conducted in an aqueous environment.
- Conformational analysis and potential energy surface mapping.
- Analysis of electron density to identify intramolecular hydrogen bonds.
Main Results:
- Ethyl derivatives adopt minimum energy conformations conducive to cyclization.
- Methylene analogues exhibit significantly less stable entrance channel conformations compared to their energy minima.
- Intramolecular hydrogen bonds are present in both minimum energy and cyclization-initiating conformations for all studied derivatives.
- Thermodynamic factors, including intramolecular hydrogen bond strength and conformational energy penalties, explain the lack of reactivity in methylene derivatives.
Conclusions:
- The unsuccessful cyclization of methylene Meldrum's acid derivatives is thermodynamically governed.
- The energy penalty to reach the required cyclization conformation and the strength of intramolecular hydrogen bonds are key factors limiting reactivity.
- Computational modeling provides a rational explanation for the observed differences in cyclization success.