Fungicide Precursor Racemization Kinetics for Deracemization in Complex Systems. Issue 3 (22nd December 2020)

• Record Type: Journal Article
• Authors: Guillot, Michael; de Meester, Josephine; ter Horst, Joop H.; Riant, Olivier; Leyssens, Tom
• Is Part Of: European journal of organic chemistry. Issue 3(2021)
• Page Start: 473
• Page End: 482
• Publication Date: 2020-12-22
• Subjects: Co-crystallization -- Deracemization -- Kinetics -- Polarimeter -- Racemization; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.202001402
• Languages: English
• ISSNs: 1434-193X

Abstract

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. Abstract : The kinetics of racemization of a fungicide precursor compound were studied in the presence of a base, varying its concentration, the solvent or by adding an acid in the system. Kinetics are first order with respect to the enantiomeric excess and base concentration without the acid. When the acid is present, a decrease in the overall speed of racemization is observed alongside a more complex mechanism.