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

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.