Fluorine‐InducedPseudo‐Anomeric Effects in Methoxycyclohexanes through Electrostatic 1,3‐Diaxial Interactions

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 (19F{1H}‐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.

Fluorinated Rings: Conformation and Application

“…[74] Remarkably, by the introduction of fluorine atoms at C-2 position, the axial methoxy conformer 39 ax becomes more stable (39 ax is favored by 1.34 kcal mol À1 in the gas phase). [73] Experimentally, the axial conformer (less polar) 39 ax predominates in nonpolar solvents, unlike the equatorial conformer (more polar) 39 eq which is favored in polar solvents (Figure 10). In the same manner, when fluorine atoms are introduced at C-4 position of methoxycyclohexane, the axial methoxy conformer 40 ax is observed in the gas phase (DG eqÀax = 0.79 kcal mol À1 ).…”

“…This extraordinary challenge has been addressed recently through the unusual axial preferentiality of the methoxy group in fluorinated methoxycyclohexanes. [73] Typically, the equatorial conformer of methoxycyclohexane 38 is favored by 0.4 kcal mol À1 in the gas phase over the axial conformer (Figure 10). [74] Remarkably, by the introduction of fluorine atoms at C-2 position, the axial methoxy conformer 39 ax becomes more stable (39 ax is favored by 1.34 kcal mol À1 in the gas phase).…”

“…These interactions are also responsible for the axial methoxy preference in the tetrafluoro-(41) and hexafluoro-methoxycyclohex-ane (42) which are favored by 1.96 and 3.32 kcal mol À1 , respectively, over the corresponding equatorial conformers. [73] On the other hand, when the oxygen atom in methoxycyclohexane is replaced with difluoromethylene (ÀCF 2 ), the local electrostatic stabilizing interactions (CÀF dÀ ••• d + H ax ÀC) in 43 become weaker and hence the equatorial conformer 43 eq is dominant. The same equatorial preference is also observed when the fluorine substitutes are located at C-3 and/or C-5 positions in methoxycyclohexane 44 and 45.…”

“…In these particular cases, strong CÀ F ax dÀ ••• dÀ O ax destabilizing electrostatic interactions shift the equilibria towards the equatorial conformers (Figure 10). [73] In the same manner to carbocycles, the conformational behavior of heterocyclic cyclohexane is of tremendous interest, particularly for pharma applications. [3] Piperidine for instance, a component that is frequently present in bioactive compounds, [75] exhibits unique conformational preference when incorporated with fluorine atoms.…”

“…All values are given in kcal mol À1 . [73,74] (Figure 11). In more polar solvent (DMSO), the F-axial conformation become more favored both experimentally and computationally.…”