Mechanistic insights into amination via nucleophilic aromatic substitution?

Reaction Chemistry & Engineering Pub Date: 2023-05-19 DOI: 10.1039/D3RE00215B

Abstract

Extensive kinetic investigations were performed to identify novel reaction pathways and assess their feasibility to resolve contradictions in the reported understanding of an amination reaction via nucleophilic aromatic substitution. The use of different bases in a reaction system resulted in distinct concentration profiles, such as sigmoidal profiles in both the starting material and the product. The generated profiles could be rationalized by the evolution of a species during the reaction working as a catalyst, suggesting that the mechanism of the reaction changes depending on the specific base. The kinetic studies using confidence intervals narrowed down the window of investigation by assessing the feasibility of different reaction pathways. This study presents novel identification of reaction conditions and additives leading to a change in mechanism, while elucidating the catalytic effect of a newly discovered species formed during the reaction. The findings resolve the previously conflicting explanation of the reaction pathways. The insights gained in this study can have significant implications for planning synthesis strategies for the SNAr reaction towards greener processes with higher yields. Furthermore, the finding of the new catalytic effect opens up new possibilities for optimizing reaction conditions and designing chemical processes in a broader context beyond the specific reaction studied. The approach can be also advantageous for conducting further detailed reaction mechanism analysis in cases where the intermediates are difficult to detect and where the reactions involve larger sized molecules of small molecule drugs. This approach can facilitate application of quantum chemistry calculation by speeding up the process of generating initial chemical structures for larger sized molecules with reduced time and computational cost.

Graphical abstract: Mechanistic insights into amination via nucleophilic aromatic substitution
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