Activation of the S_N2 Reaction by Adjacent π Systems: The Critical Role of Electrostatic Interactions and of Dissociative Character

Abstract

The activation of the SN2 reaction by π systems is well documented in textbooks. It has been shown previously that this is not primarily due to classical (hyper)conjugative effects. Instead, π-conjugated substituents enhance favorable substrate-nucleophile electrostatic interactions, with electron-withdrawing groups (EWG) on the sp(2) system leading to even stronger activation. Herein we report computational and experimental results which show that this activation by sp(2) EWG-substitution only occurs in a fairly limited number of cases, when the nucleophile involves strong electrostatic interactions (usually strongly basic negatively charged nucleophiles). In other cases, where bond breaking is more advanced than bond making at the transition state, electrophile-nucleophile electrostatic interactions are less important. In such cases, (hyper)conjugative electronic effects determine the reactivity, and EWG-substitution leads to decreased reactivity. The basicity of the nucleophile as well as solvent effects can help to determine which of these two regimes occurs for a given electrophile.

Nucleophilic Influences and Origin of the SN2 Allylic Effect

“…For comparison with a saturated substrate, we conducted analogous computations for the S N 2 reactions of propyl chloride with the same series of nucleophiles. In a recent study, Robiette et al . studied the S N 2 reactivities of selected benzylic systems by using DFT computations, which was supplemented with some competitive yield experiments.…”

“…The reactions between highly basic, negatively charged nucleophiles and the substrate were confirmed to be dominated by electrostatic interactions. However, for reactions that involved neutral or delocalized anionic nucleophiles, the reactivity was less affected by the electrophile–nucleophile electrostatic interactions, whereas the type and degrees of bond formation/bond breaking at the transition state may influence the reactivity …”

Asymmetric Synthesis of 2,3‐Dihydrobenzofurans by a [4+1] Annulation Between Ammonium Ylides and In Situ Generated o‐Quinone Methides

“…As a result of a lower stabilisation of the ylide, addition should be more favoured, and more exothermic, in these cases in comparison with ketone‐based ylides. However, for the elimination step, the reverse is the case as the free‐energy barrier is expected to increase with the ester and amide derivatives . In addition, the isomerisation of betaine by deprotonation/protonation should also be less favoured and the poor yields in these cases can thus probably be explained by a longer lifetime of betaine intermediates that favours side‐reactions.…”

Catalytic Reductive Pinacol‐Type Rearrangement of Unactivated 1,2‐Diols through a Concerted, Stereoinvertive Mechanism

“…[14] It benefits from electron delocalization, [15] as indicated by short C2 À C3 and C2 À Ob onds (1.40 and 1.37 in I-TSB versus 1.53 and 1.43 in I-TSA and in the cyclic siloxane intermediate,respectively) and by natural bond orbital (NBO) analysis (see the Supporting Information). I-TSA is an intermolecular S N 2T S, which is stabilized by electrostatic interactions of the C3 atom with the approaching nucleophile HB(C 6 F 5 ) 3 À and the leaving group.…”

“…In the internal diol, II-TSB is stabilized by the hyperconjugative effect of the ethyl substituent, [14] which shortens the C3 À C4 bond (1.46 vs.1 .52 in the cyclic siloxane intermediate);N BO analysis indicates that the hyperconjugative stabilization is larger in II-TSB than in II-TSA by 3.9 kcal mol À1 (see the Supporting Information). Furthermore,t he presence of the ethyl substituent increases the distance between C3 and the nucleophile as well as the leaving group in II-TSA,w hich weakens the electrostatic interactions.T herefore,i ti sacombination of the hyperconjugative and steric effects of the ethyl substituent that leads to apreference for alkyl migration over deoxygenation in the internal diol.…”