How Alkyl Halide Structure Affects E2 and S_N2 Reaction Barriers: E2 Reactions Are as Sensitive as S_N2 Reactions

Abstract

High-level electronic structure calculations, including a continuum treatment of solvent, are employed to elucidate and quantify the effects of alkyl halide structure on the barriers of SN2 and E2 reactions. In cases where such comparisons are available, the results of these calculations show close agreement with solution experimental data. Structural factors investigated include α- and β-methylation, adjacency to unsaturated functionality (allyl, benzyl, propargyl, α to carbonyl), ring size, and α-halogenation and cyanation. While the influence of these factors on SN2 reactivity is mostly well-known, the present study attempts to provide a broad comparison of both SN2 and E2 reactivity across many cases using a single methodology, so as to quantify relative reactivity trends. Despite the fact that most organic chemistry textbooks say far more about how structure affects SN2 reactions than about how it affects E2 reactions, the latter are just as sensitive to structural variation as are the former. This sensitivity of E2 reactions to structure is often underappreciated.

Nucleophilic Substitution (SN2): Dependence on Nucleophile, Leaving Group, Central Atom, Substituents, and Solvent

“…Rablen and co‐workers explained and quantified the effects of alkyl halide structure on S N 2 and E2 barriers at the high‐level G4 method. Employing CN − as a nucleophile and Cl − as a leaving group, they investigated substitution patterns on the alkyl halide, including α‐ and β‐methylation, adjacent unsaturated functional groups (allyl, benzyl, propargyl, α to carbonyl), ring size, and α‐halogenation and cyanation.…”

Imaging dynamic fingerprints of competing E2 and SN2 reactions

“…To date, most theoretical predictions about the ratio between elimination and substitution have been indirectly inferred from stationary point electronic structure calculations 25, 26 . In particular, many studies have dealt with the influence of the degree of methyl-substitution on the height of the potential energy barriers for E2 and S N 2 reactions as an indirect estimation of the preference for a specific reaction 27, 28 . However, these calculations cannot account for dynamical effects such as the influence of the impact parameter, the role of reactant reorientation during the collision, the specific atomistic reaction mechanisms, or the energy partitioning 16 .…”

Activation parameter changes as a mechanistic tool in SN2 reactions in solution

“…For instance, αand β-methylation of the substrate increases the ΔG ≠ by 8 and 4 kJ.mol -1 , respectively. Benzyl and carbonyl substituents decrease significantly the reaction barriers of SN2 reactions (up to 20-28 kJ.mol -1 ) [106]. It is noting that the same influence of the substituent variation in α-and β-positions in alkyl halides on the energetic barrier of SN2 reactions revealed in the gas phase [106,107].…”

“…The analysis of the influence of structural changes on the barriers of SN2 reactions of alkyl halides with cyanide ion in acetonitrile revealed quantitatively the contribution of different substituents to the ΔG ≠ value [106]. For instance, αand β-methylation of the substrate increases the ΔG ≠ by 8 and 4 kJ.mol -1 , respectively.…”