Mechanistic Analysis and Kinetic Profiling of Soai’s Asymmetric Autocatalysis for Pyridyl and Pyrimidyl Substrates

Nonlinear effects in chemical reactions, ¹ coupled with amplifying catalysis, give rise to remarkable phenomena such as spontaneous symmetry breaking, ² a process associated with the emergence of a homochiral world at the origin of life. ^3,4 Soai's asymmetric autocatalysis ⁵ serves as a prototypical reaction that intrinsically integrates these properties. In this reaction, the enantiomeric excess of the added product alcohol is not only preserved during the alkylation of pyridyl and pyrimidyl carbaldehydes with diisopropylzinc but is also amplified. However, elucidating the underlying mechanism is challenging due to complex reaction equilibria, elusive intermediates, and highly sensitive, structure-dependent kinetics. In this study, we utilize in situ high-resolution mass spectrometry (HRMS), kinetic analysis, and reaction profile simulations to unravel the intricate dynamics of these systems. We demonstrate that both the pyrimidyl and pyridyl reaction pathways involve the formation of catalytically active transient hemiacetalate isopropyl zinc complexes via the addition of the alcoholate product to the carbaldehyde reactant. These diastereomeric complexes enable dual stereocontrol, which accounts for the pronounced positive nonlinear effects observed. Furthermore, our comprehensive analysis provides unambiguous structural identification of all reaction intermediates, delivering experimental validation of the proposed autocatalytic cycle. The quantitative insights gained also reveal the impact of substituent variations and system-specific differences on reaction efficiency and enantioselectivity. This mechanistic understanding paves the way for the rational design of novel, highly efficient autocatalytic processes.