Mechanism of Alkoxy Groups Substitution by Grignard Reagents on Aromatic Rings and Experimental Verification of Theoretical Predictions of Anomalous Reactions

Abstract

The mechanism of direct displacement of alkoxy groups in vinylogous and aromatic esters by Grignard reagents, a reaction that is not observed with expectedly better tosyloxy leaving groups, is elucidated computationally. The mechanism of this reaction has been determined to proceed through the inner-sphere attack of nucleophilic alkyl groups from magnesium to the reacting carbons via a metalaoxetane transition state. The formation of a strong magnesium chelate with the reacting alkoxy and carbonyl groups dictates the observed reactivity and selectivity. The influence of ester, ketone and aldehyde substituents was investigated. In some cases, the calculations predicted the formation of products different than those previously reported; these predictions were then verified experimentally. The importance of studying the actual system, and not simplified models as computational systems, is demonstrated.

Direct C–C Bond Construction from Arylzinc Reagents and Aryl Halides without External Catalysts

“…Secondly, electron‐rich aryl iodides could participate in the reaction, even with the electron‐deficient diarylzinc compounds. These results demonstrate that an aromatic nucleophilic substitution (S N Ar) process is less likely here 13. Since an electron‐withdrawing group on both 1 or 2 could enhance the reaction, it is conceivable that some critical anionic intermediates, which could be stabilized by electron‐withdrawing substituents, may be involved in the reaction.…”

How and Why Does Ni0 Promote Smooth Etheric CO Bond Cleavage and CC Bond Formation? A Theoretical Study

“…2h Encouraged by this, we focused on an unprecedented reaction route involving the “Ni 0 ‐ate complex”, which is completely different from the conventional mechanism (Scheme ). First, the reactants form an association complex CP1 with an energy loss (9.9 kcal mol −1 ) 22. At CP1 , PhOMe acted as a bridge for assembly of all the reactants: Ni 0 coordinates to the phenyl π plane, and PhMgBr forms a Lewis acid/base complex with ethereal oxygen.…”

Proximity- and Chelation-Induced SNAr 1,4-Aromatic ortho-Substitution of ortho-Methoxyphenyl 2-Alkyl Ketones

“…That the reaction was energetically feasible in spite of the disruption of aromaticity of the naphthalene moiety was contrasted with its failure in the case of isopropyl o-methoxybenzoate. 4e The mechanism of this unique, albeit long neglected, transformation was recently reported by Houk and Shaw, 7 and clarified based on theoretical calculations. Indeed, they showed that an inner sphere attack of nucleophilic groups from the reagent involved magnesium chelates.…”

“…The reaction profile suggests second order kinetics (Grignard reagent) in agreement with an addition/elimination mechanism. Following the computational studies by Houk and co-workers with o-methoxynaphthyl esters and ketones, 7 the more bulky ketone 12 requires at least a sec-O OMe 3h: X = Br 99% 3i:…”