Fungicide precursor racemization kinetics for deracemization in complex systems

Guillot, Michael and de Meester, Josephine and ter Horst, Joop H. and Riant, Olivier and Leyssens, Tom (2021) Fungicide precursor racemization kinetics for deracemization in complex systems. European Journal of Organic Chemistry, 2021 (3). pp. 473-482. ISSN 1434-193X (https://doi.org/10.1002/ejoc.202001402)

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Abstract

In the racemization area, the keto-enol equilibrium is a major player when it comes to racemizing α-chiral carbonyl compounds. The racemization kinetics in the co-crystal induced deracemization of a fungicide precursor is complex as next to the racemization catalyst, which is a base, an acidic co-former is used to ensure the crystallization of the co-crystal. Here we show that understanding of the racemization kinetics of the target compound is of key importance for optimization of the co-crystallization based deracemization process. The racemization rates in solution as a function of solvent and base concentration were determined by measuring the decreasing enrichment of the chiral ketone due to racemization over time, using a polarimeter set-up with a continuous recycling loop through the polarimeter cell. The established racemization kinetics model aligns with the experimental data giving access to the intrinsic racemization rate constant. The proposed mechanism is first order with respect to the enantiomeric excess of the target compound and the base-catalyst concentration. The solvent is shown to strongly affect the racemization constant, with protic solvents increasing this rate substantially due to hydrogen-bond stabilization of the enolate. Finally, we observed the presence of the chiral acid co-former to alter the reaction mechanism albeit remaining first order with respect to the enantiomeric excess. Though more complex, the mechanism still followed Arrhenius law, providing key information on the impact of temperature.

ORCID iDs

Guillot, Michael, de Meester, Josephine, ter Horst, Joop H. ORCID logoORCID: https://orcid.org/0000-0003-0118-2160, Riant, Olivier and Leyssens, Tom;
CORE (COnnecting REpositories)