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Title:Mechanistic studies on the asymmetry amplifying, autocatalytic Soai reaction
Author(s):Athavale, Soumitra Vinayak
Director of Research:Denmark, Scott E
Doctoral Committee Chair(s):Denmark, Scott E
Doctoral Committee Member(s):van der Donk, Wilfred; Sarlah, David; Fout, Alison
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Autocatalysis, Soai Reaction, Mechanism
Abstract:The autocatalytic, asymmetry-amplifying alkylation of pyrimidine-5-carbaldehydes with diisopropylzinc, crowned as the ‘Soai reaction’, occupies a venerable position in organic chemistry. The transformation is peerless in its efficiency for asymmetric autocatalysis and sensitivity to initial chiral imbalances, making it a sui generis example of a reaction predisposed to evolve toward homochirality. Enantiopure products are obtained in three reaction cycles even with calculated autocatalyst e.e. as low as 5 × 10-5 %. In the absence of added catalyst, symmetry breaking can yield non-racemic products, thus categorizing the transformation as an example of absolute asymmetric synthesis. A large variety of chiral additives and even circularly polarized light and isotopic chirality can influence the outcome of the reaction by biasing an initial imbalance toward one of the enantiomers. Soai’s seminal discoveries have received widespread attention in diverse chemical fields and have revived discussions regarding absolute asymmetric synthesis, chiral symmetry breaking, and the origin of biological homochirality. The astonishing and unparalleled characteristics of this transformation pose a set of unique mechanistic questions that have challenged investigators for more than two decades. Principle among these is: (1) an elucidation of the precise identity and modus operandi of the autocatalyst, (2) a transition state structure rationalizing the basis of asymmetric autocatalysis, (3) an explanation for the origin of positive, non-linear (auto)catalysis, and, (4) a justification of the puzzling, restrictive and idiosyncratic substrate requirements that allow successful amplifying autocatalysis. Two decades since Soai’s pioneering publication, a holistic comprehension of the reaction remains an open challenge with fundamental implications on our understanding of chiral symmetry breaking and absolute asymmetric synthesis. Results presented in this dissertation address these questions (vida supra) that lie at the heart of unmasking the mechanism of the Soai reaction. The unprecedented observation of asymmetry amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc was pivotal in deconstructing the Soai system. Comprehensive spectroscopic analysis of phenyl and pyridyl zinc alkoxides revealed the structural rationale for the assembly of the active, square-macrocycle-square (SMS) tetrameric autocatalyst that is formed via a pyridine-assisted cube-escape. Kinetics with a Trojan-horse substrate allowed the interrogation of the crucial alkyl-transfer step in the catalytic pathway. Augmented by computational studies, this approach led to the identification of the floor-to-floor transition model, wherein a two point docking of the substrate to the autocatalyst is followed by alkylation from a preferred arm-bound diisopropylzinc molecule, leading to the homochiral product. The binding mode is inaccessible to the more stable, heterochiral SMS tetramer, thus providing a simple resolution for the origin of non-linearity. The mode of action of the Soai autocatalyst is unveiled for the first time. The paradigm of mixed catalyst-substrate experiments allowed extensive study of structure activity relationships in the pyrimidine and pyridine system. Ensuing results enabled a formulation of the roles played by structural constituents in effecting catalysis and selectivity in the Soai reaction. An exploration of substituted nicotinaldehyde derivatives led to the determination of novel, competent substrates. Among these, the 5-fluoro-6-((trimethylsilyl)ethynyl)nicotinaldehyde system provided an opportunity to carry out a careful comparison between three autocatalytic systems in regard to the Lewis basicity of the aromatic nitrogen. Model kinetic simulations revealed how this factor critically influences the interplay of three steps in the autocatalytic pathway that are determinants reaction progression. The low Lewis basicity of the pyrimidine nitrogen abrogates inhibition effects and results in superlative performance in the Soai reaction. The findings contribute substantially to understanding the mechanism of this extraordinary transformation, which has stood as a longstanding challenge in chemistry and will serve as a platform for further studies and explorations in the fascinating area of asymmetric autocatalysis.
Issue Date:2019-07-08
Rights Information:Copyright 2019 Soumitra Athavale
Date Available in IDEALS:2019-11-26
Date Deposited:2019-08

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