Conformational preferences of α-fluoroketones may influence their reactivity

Abstract

Fluorine has been shown in many cases to impart specific and predictable effects on molecular conformation. Here it is shown that these conformational effects may have an influence on reactivity through studying the relative reactivity of various α-halogenated ketones towards borohydride reduction. These results demonstrate that the α-fluoro ketones are in fact a little less reactive than the corresponding α-chloro and α-bromo derivatives. It is suggested, supported by computation, that this effect is due to reactive conformations in which the C–X bond is orthogonal to the carbonyl group for good orbital overlap being disfavoured in the case of fluoro ketones.

Fluorohydration of alkynes via I(I)/I(III) catalysis

“…2 ). Interestingly, a study by Pattison has established that α-fluoroketones preferentially adopt a cis -conformation in polar solvents [ 54 ]. In the solid state, a dihedral angle of φ = −3.7° was observed thereby placing the C–F bond in the same plane as the carbonyl group.…”

Fluorine conformational effects characterized by energy decomposition analysis

“…16,18,25 It has been also found that F atoms adjacent to carbonyl groups stabilize the trans/gauche F-C-C=O arrangements in the gas-phase, although this intrinsic preference can be reversed to the alternative cis form in polar solvents as suggested by DFT calculations coupled with a continuum solvent model. [26][27][28] On the other hand, the NBO characterization of the 2-fluoroethanol (F-CH2CH2-OH) conformers has explained the largest stability of a particular gauche structure by the presence of a favorable electrostatic O-H δ+ ••• δ-F interaction, which is termed as a non-classical hydrogen bond. 29 In contrast, a very recent work interprets the 4 JHF couplings in α-fluoro amides as a genuine N-H•••F hydrogen bond.…”

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses

“…The α-fluorination of the methyl ketone functional group profoundly modifies the physicochemical properties of the related substrate and the reactivity of its carbonyl group [ 14 ]. The presence of one or more fluorine atoms in the terminal α position of a methyl ketone moiety enhances the electrophilicity of the carbonyl group, and the resulting fluorinated compound becomes more susceptible to undergo a nucleophilic attack by the catalytic residues of proteolytic enzymes, leading to a slow-binding competitive inhibition of the target by forming hemi(thio)ketal adducts [ 15 , 16 , 17 ]. Among the three-terminal fluoromethyl groups (-CH 2 F, -CHF 2 , and -CF 3 ) next to the carbonyl, -CHF 2 is the most interesting and yet least explored [ 18 ].…”