Mechanistic analysis and kinetic profiling of Soai’s asymmetric autocatalysis for pyridyl and pyrimidyl substrates

Abstract

Abstract Nonlinear effects in chemical reactions, coupled with amplifying catalysis, can lead to remarkable phenomena like spontaneous symmetry breaking, central to the origin of biological homochirality. Soai’s asymmetric autocatalysis is a prototypical reaction for this, where the enantiomeric excess of the product alcohol is amplified during alkylation of pyridyl and pyrimidyl carbaldehydes by diisopropylzinc. However, the complex equilibria and elusive intermediates make the mechanism difficult to clarify. Here we unravel the intricate dynamics of this reaction by in situ high-resolution mass spectrometry, kinetic analysis, and reaction profile simulations. We identify for both the pyrimidyl and the pyridyl systems transient hemiacetalate isopropyl zinc complexes, formed by the addition of the alcoholate product to the aldehyde, as key catalytic intermediates. These diastereomeric complexes enable dual stereocontrol, explaining the observed enantioselectivity. Our analysis confirms the structures of all intermediates and validates the autocatalytic cycle, offering insights into how substituent and structural variations influence reaction performance. This understanding guides the design of new, efficient asymmetric autocatalytic systems.