Fluorine‐Induced Pseudo‐Anomeric Effects in Methoxycyclohexanes through Electrostatic 1, 3‐Diaxial Interactions. Issue 52 (18th August 2020)

• Record Type: Journal Article
• Authors: Piscelli, Bruno A.; Sanders, William; Yu, Cihang; Al Maharik, Nawaf; Lebl, Thomas; Cormanich, Rodrigo A.; O'Hagan, David
• Is Part Of: Chemistry. Volume 26:Issue 52(2020)
• Page Start: 11989
• Page End: 11994
• Publication Date: 2020-08-18
• Subjects: anomeric effects -- computational chemistry -- conformational analysis -- fluorination -- medicinal chemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202003058
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: We report counter‐intuitive axial preferences in non‐stereochemically biased, selectively fluorinated methoxycyclohexanes. These pseudo‐anomeric effects are apparent when electronegative CF2 groups are placed at the C‐2, C‐4 and C‐6 positions of the cyclohexane ring to render the C‐3/5 axial hydrogen atoms electropositive. The electrostatic interaction between these axial hydrogen atoms and the ‐OMe oxygen is stabilising. The effect is explored using high‐level ab initio and DFT calculations in the framework of NBO, QTAIM and NCI analysis across a range of derivatives, and experimentally ( 19 F{ 1 H}‐NMR at −80 °C) for some illustrative examples. The effect is significant in energy terms for a weak interaction, and illustrates a new stereoelectronic aspect attributed to selective fluorine substitution in organic chemistry. Abstract : Fluorine chemistry : Selective fluorination in methoxycyclohexanes induces an electrostatic 1, 3‐diaxial interaction favouring a counter‐intuitive axial preference.