Conformational preferences of α-fluoroketones may influence their reactivity.

Graham Pattison

doi:10.3762/bjoc.13.284

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.

Highlights

Introduction αHalogenated ketones are widely used electrophiles in organic synthesis, being highly reactive in both nucleophilic addition to the carbonyl group and in SN2 nucleophilic displacements [1]
This paper aims to examine some of the effects that α-halogenation can impart on carbonyl reactivity with a particular emphasis on the effects of α-fluorination
The initial focus of this work was on comparing the reactivity of various α-monohalogenated ketones to examine the effects of different halogen atoms on the reactivity

Summary

Introduction

Halogenated ketones are widely used electrophiles in organic synthesis, being highly reactive in both nucleophilic addition to the carbonyl group and in SN2 nucleophilic displacements [1]. Our research group has recently been exploring the synthesis and reactivity of α-fluorinated ketones [2,3,4] and here their reactivity relative to other halogenated ketones is compared. The orbital overlap in α-halogenated ketones provides activation to the carbonyl group, making it more reactive towards nucleophilic addition than nonhalogenated carbonyl compounds [6]. It is well established that the halogen leaving groups in these substrates are highly activated by orbital overlap with the adjacent carbonyl group, making α-halogenated ketones one of the most reactive classes of electrophiles available to synthetic. As the most electronegative element, fluorine is often involved in introducing

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