Thermodynamic Insight into Donor–Acceptor Cyclopropane Reactions with 1-Methylindole
- 1Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, 28 Westhampton Way, Richmond, VA 23173, USA
Abstract
Computational and experimental approaches were used to study the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 1-methylindole. In these reactions, the cyclopropane ring is activated for heterolytic cleavage by the electron-withdrawing properties of the methyl esters at C1 and the electron-donating behavior of the phenyl group at C2. The reaction with 1-methylindole produces a diastereomeric zwitterionic intermediate that can either abstract hydrogen from the indole C4 to form a Friedel–Crafts addition product or proceed via electrophilic addition and intramolecular cycloaddition to form a cyclopenta-fused indole. Density functional theory calculations with the B3LYP functional and the 6-31G** basis set were used, in a variety of solvent environments, to determine the energies and conformations of the zwitterionic intermediate as well as the Friedel–Crafts and annulated products. Three stable conformations were identified for each diastereomeric zwitterionic intermediate. The lowest energy conformer contained a geometry pre-optimized for hydrogen abstraction from C4 leading to the Friedel–Crafts product. The second most stable zwitterionic conformer placed the C1 enolate within 3.7 Å of C5, facilitating the formation of the annulation product. Barriers between all species were determined. The Friedel–Crafts product was 5–11 kcal/mol more stable than the annulation product, depending on the solvent environment. To verify these findings, we monitored the disappearance of reactant and formation of products using NMR. Initially, annulation proceeded faster than Friedel–Crafts product formation; however, as the reaction proceeded, a full conversion of cyclopropyl reactant to Friedel–Crafts product was observed, in agreement with the computational results suggesting that the Friedel–Crafts product was enthalpically favored.
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BibTeX
@article{biaku2026thermodynamic,
title = {{Thermodynamic Insight into Donor–Acceptor Cyclopropane Reactions with 1-Methylindole}},
author = {Charles Biaku and Boyi Zhang and Parker Maloney and Malik Bell and Kristine Nolin and Carol A. Parish},
journal = {Molecules},
year = {2026},
month = nov,
doi = {10.3390/molecules31214023},
url = {https://www.mdpi.com/1420-3049/31/21/4023},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Thermodynamic Insight into Donor–Acceptor Cyclopropane Reactions with 1-Methylindole
AU - Charles Biaku
AU - Boyi Zhang
AU - Parker Maloney
AU - Malik Bell
AU - Kristine Nolin
AU - Carol A. Parish
PY - 2026
DA - 2026/11/08
JO - Molecules
DO - 10.3390/molecules31214023
UR - https://www.mdpi.com/1420-3049/31/21/4023
AB - Computational and experimental approaches were used to study the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 1-methylindole. In these reactions, the cyclopropane ring is activated for heterolytic cleavage by the electron-withdrawing properties of the methyl esters at C1 and the electron-donating behavior of the phenyl group at C2. The reaction with 1-methylindole produces a diastereomeric zwitterionic intermediate that can either abstract hydrogen from the indole C4 to form a Friedel–Crafts addition product or proceed via electrophilic addition and intramolecular cycloaddition to form a cyclopenta-fused indole. Density functional theory calculations with the B3LYP functional and the 6-31G** basis set were used, in a variety of solvent environments, to determine the energies and conformations of the zwitterionic intermediate as well as the Friedel–Crafts and annulated products. Three stable conformations were identified for each diastereomeric zwitterionic intermediate. The lowest energy conformer contained a geometry pre-optimized for hydrogen abstraction from C4 leading to the Friedel–Crafts product. The second most stable zwitterionic conformer placed the C1 enolate within 3.7 Å of C5, facilitating the formation of the annulation product. Barriers between all species were determined. The Friedel–Crafts product was 5–11 kcal/mol more stable than the annulation product, depending on the solvent environment. To verify these findings, we monitored the disappearance of reactant and formation of products using NMR. Initially, annulation proceeded faster than Friedel–Crafts product formation; however, as the reaction proceeded, a full conversion of cyclopropyl reactant to Friedel–Crafts product was observed, in agreement with the computational results suggesting that the Friedel–Crafts product was enthalpically favored.
SN - 1420-3049
ER -