Mechanisms of the Gewald Synthesis of 2-Aminothiophenes from Elemental Sulfur

Document Type

Article

Publication Date

7-5-2024

Abstract

The Gewald reaction is a well-established one-pot method to access 2-aminothiophenes from carbonyl compounds, activated acetonitriles, and elemental sulfur. To elucidate the reaction’s poorly understood mechanism, with regard to the decomposition of sulfur and polysulfide intermediates, we have performed a comprehensive computational study using density functional theory (DFT) calculations at the M06-2X (or ωB97X-D)/aug-cc-pV(T + d)Z/SMD(C2H5OH) level of theory. The results show that the reaction is initiated by a Knoevenagel-Cope condensation, followed by opening of the elemental sulfur, leading to polysulfide formation. The polysulfide intermediates can interconvert and decompose using various mechanisms including unimolecular cyclization, nucleophilic degradation, and scrambling. Protonation of the polysulfides changes their electrophilic behavior and provides a kinetically favorable pathway for their decomposition. This protonation-induced intermolecular degradation is feasible for polysulfides of all lengths, but unimolecular decomposition is kinetically favored for long polysulfides (≥6 sulfur atoms). None of the pathways provide any thermodynamic benefit due to the lack of resonance-stabilized leaving group, and a complex equilibrium of polysulfides of all lengths is expected in solution. Cyclization of the monosulfide with aromatization to the thiophene product is the only driving force behind the reaction, funneling all of the various intermediates into the observed product in a thermodynamically controlled process.

Identifier

85197895262 (Scopus)

Publication Title

Journal of Organic Chemistry

External Full Text Location

https://doi.org/10.1021/acs.joc.4c01189

e-ISSN

15206904

ISSN

00223263

First Page

9609

Last Page

9619

Issue

13

Volume

89

Grant

61891-DNI4

Fund Ref

American Chemical Society Petroleum Research Fund

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