Experimental and Theoretical Studies on Stereomutation Through gem‐Difluorocyclopropanylide Intermediates

• Published in: Asian journal of organic chemistry 2024-04, Vol.13 (4), p.n/a
• Main Authors: Akaishi, Dai, Sekine, Keisuke, Ito, Shigekazu
• Format: Article
• Language: English
• Subjects: Ambient temperature; carbanions; chirality; cyclopropanes; fluorine; Isomerization; Isotope effect; Optical activity; Quantum tunnelling; Racemization; tunnel effect
• ISSN: 2193-5807; 2193-5815
• DOI: 10.1002/ajoc.202300566

A desilylation process of optically active silyl‐substituted gem‐difluorocyclopropanes with tetrabutylammonium fluoride (TBAF) showed a substantial reduction of enantiopurity of the resultant gem‐difluorocyclopropanes even at ambient temperatures. The electron‐withdrawing aryl substituent at the 3‐position in the 1‐silyl‐2,2‐difluorocyclopropane system accelerated the racemization, indicating a correlation with the stability of the anionic intermediates. The plausible racemization pathway through homolytic cleavage of the distal bond in gem‐difluorocyclopropane is inconsistent with the experimental results because the high energy of >34 kcal/mol is required for generating the open‐shell 2,2‐difluoropropane‐1,3‐diyl skeleton. The DFT studies using the anionic 2,2‐difluoromethyl‐3‐phenylcyclopropanylide intermediate supported the alternative isomerization pathway through the intramolecular migration of hydrogen and the resultant thermodynamically stable 2,2‐difluoromethyl‐1‐phenylcyclopropanylide anion could facilitate the racemization process at the stereocenter. Although the transition state indicated considerable activation energies, the high frequency of imaginary vibration should correlate with a barrier of a very narrow width enabling quantum tunneling under the H‐migration step. The observed isotope effect is compatible with the proposed mechanism through the intramolecular H‐migration. The desilylation process of optically active silyl‐substituted gem‐difluorocyclopropanes showed considerable reduction of enantiopurity. The DFT studies using the 2,2‐difluoromethyl‐3‐phenylcyclopropanide intermediate supported the intramolecular migration of hydrogen. The high frequency of imaginary vibration in the transition state indicated quantum tunneling under the H‐migration.