The S_N2 Transition State. 6: Breakdown of the Reactivity–Selectivity Principle in the S_N2 Reaction of α‐Halocarbonyl Compounds. A Molecular Orbital Analysis [1]

Abstract

Abstract. A molecular orbital (MO) analysis of the SN2 transition state (TS) of o-carbonyl derivatives is described with various nucleophile leaving group pairs. On the basis of this analysis it is shown that the enhanced selectivity toward nucleophiles observed in e-halocarbonyl compounds is directly associated with SN2 rate enhancement. Both observations result from a stabilizing frontier orbital interaction between a high lying ,..-type three center orbital along the reaction coordinate axis and the carbonyl a-system. The magnitude of interaction is greater for more powerful nucleophiles, resulting in both greater reactivity as well as additional selectivity relative to simple alkyl halides.*Author to whom correspondence should be addressed.was optimized separately. and kept tetrahedral in 4aand 4b. (d) The NH 3 groups were assumed to be equal and The geometries have been extensively optimized with respect to minimum energy, with the following constraints: (a) T8 structures were located by imposing equal C-X bond lengths as well as equal X-C-C angles, (b) The X-C-C-Odihedral angle was held fixed at 0°a nd 90°, respectively, corresponding to conformations of minimum ("off', la4a) and maximum ("on", overlap between the carbonyl 1r system and tpe lI'·type three-center orbital associated with the X-C-X (reaction coordinate) axis (Fig. 1). (c) The borohydride anionThe reactivity-selectivity principle (RSP) has long been a cornerstone in intuitive mechanistic chemical thinking [2,3 J. Despite its wide scope and application, however, many failures of the RSP have been recorded [2][3][4] .up to the point where its very existence has been cast in doubt [4]. It is therefore of interest to investigate each system which violates the RSP, in order to arrive at a conclusion whether special circumstances present at that particular system, or whether failure of the principle as a whole, are responsible for its observed breakdown. In this article, we wish to report on a study of one such system, the SN2 reaction ofo-halocarbonyl compounds, in which a breakdown in RSP is observed.It has been common knowledge for decades that acarbonyl substituents enhance SN2 reactivity of alkyl halides [5]. However, more recent studies have demonstrated that this is not generally true, and that the extent of rate enhancement strongly depends on the nature of the nucleophile [6,7J. Thus, in the phenacyl bromide (CJi sCOCH2Br) system rate enhancement relative to simple alkyl halides is associated with increased selectivity toward nucleophiles, in clear violation of the RSP. Halvorsen and Songstad [6b] have shown that the ratio between rates of the reactions of a nucleophile with CJi sCOCH2Br and CH;J, respectively, decreases when the nucleophile strength decreases from powerful anionic toward weak neutral nucleophiles.Increased selectivity of o-halocarbonyl compounds toward nucleophiles is also evident from the Hammet p values for the reactions of substituted pyridines with phenacyl bromide (p = -1.87) [6a] and a simple alkyl bromide (p =--{)....

Correlation of the Rates of Solvolysis of 2-Phenyl-2-ketoethyl Bromide and Tosylate

“…Almost a century ago, it was shown that reactions, much later designated as S N 2, can have an enhanced rate in the presence of the substituent. , Later, it was shown that this was not a general phenomenon and weak nucleophiles do not have their rates of attack significantly enhanced. , This represents an apparent breakdown of the reactivity−selectivity principle . Amolecular-orbital analysis has shown that the increases in both selectivity and reactivity result from a stabilizing frontier orbital interaction between the carbonyl π system and a high-energy π-type three-center orbital situated along the reaction coordinate axis.…”

The 18F‐Difluoromethyl Group: Challenges, Impact and Outlook

“…The benzoyl group served to direct a C−H bromination with N ‐bromophthalimide ( 20 ) of α ‐aryl‐ α ‐fluoroacetophenone ( 21 ) to yield an α ‐bromo intermediate ( 22 ) that was reactive towards [ 18 F]fluoride. As a carbonyl functionality, the benzoyl group could also assist nucleophilic substitution at the α ‐carbon, in contrast to the detrimental effects of α ‐fluorine substitution [22] . Cleavage of the auxiliary from [ 18 F] 23 with aqueous KOH, gave the desired 18 F‐difluoromethylarene ([ 18 F] 24 ) in a one‐pot protocol (Scheme 6b).…”

“…the α-carbon, in contrast to the detrimental effects of αfluorine substitution. [22] Cleavage of the auxiliary from [ 18 F]23 with aqueous KOH, gave the desired 18 Gouverneur and co-workers disclosed an approach to 18 F-difluoromethoxy derivatives exploiting the halex reactivity of α-bromo-carbonyl compounds in 2017 (Scheme 7a). [23] Ethyl α-bromo-α-fluoro(aryloxy)acetates were prepared from the relevant phenol in two steps, and these materials were radiofluorinated with [ 18 A third halex strategy was disclosed by Liang and coworkers in 2017 (Scheme 8a).…”

The 18F‐Difluoromethyl Group: Challenges, Impact and Outlook

“…As a carbonyl functionality, the benzoyl group could also assist nucleophilic substitution at the α-carbon, in contrast to the detrimental effects of αfluorine substitution. [22] Cleavage of the auxiliary from [ 18 F]23 with aqueous KOH, gave the desired 18 Gouverneur and co-workers disclosed an approach to 18 F-difluoromethoxy derivatives exploiting the halex reactivity of α-bromo-carbonyl compounds in 2017 (Scheme 7a). [23] Ethyl α-bromo-α-fluoro(aryloxy)acetates were prepared from the relevant phenol in two steps, and these materials were radiofluorinated with [ 18 A third halex strategy was disclosed by Liang and coworkers in 2017 (Scheme 8a).…”