Role of Racemization Kinetics in the Deracemization Process via Temperature Cycles

Abstract

A suspension of crystals of both enantiomers of a conglomerate forming chiral compound can be deracemized by applying temperature cycles in the presence of a racemizing catalyst that enables in solution the conversion of the undesired enantiomer into the desired one. We aim at showing through experiments that, seemingly paradoxically, accelerating the racemization reaction by increasing the catalyst concentration speeds up the deracemization process if all the other parameters are left unchanged. We prove this by deracemizing, via temperature cycles, crystals of N-(2-methyl-benzylidene)-phenylglycine amide (NMPA) suspended in either pure acetonitrile (ACN) or a mixture of isopropanol/ACN (95:5 w/w) in the presence of different concentrations of the base catalyst 1,8-diazabicyclo-[5.4.0]­undec-7-ene (DBU). The applied periodic temperature cycles follow a rather standard protocol. Prior to that, we have fully characterized the racemization reaction rate, as a function of enantiomers’ concentration, catalyst concentration, and temperature, thus proving that the reaction is second order in NMPA and DBU, and estimating the Arrhenius parameters for the two solvent systems.

Fungicide Precursor Racemization Kinetics for Deracemization in Complex Systems

“…Overall racemization kinetics of our system seem therefore enhanced when using protic solvents with dielectric constant ɛ > 18, contrary to the system studied by Breveglieri et al [31] that showed a strong enhancement of the kinetics when using acetonitrile compared to isopropanol (which has a similar dielectric constant as propan-1-ol). In comparison, the rate constant in propan-1-ol is significantly higher than in acetonitrile.…”

“…Brevegleri et al measured a rate constant of the same order (9.44 L.mol À 1 .min À 1 at 25°C in acetonitrile) for a similar compound, N-(2-methyl-benzylidene)-phenylglycine amide (NMPA) in a more polar solvent. [31] Thus, the kinetic model we propose for the racemization reaction of BnFTP in presence of DBU is confirmed by the experimental data. It is a first-order kinetic model similar to the one developed and validated by Brevegleri et al and in accordance with the literature.…”

“…Brevegleri et al. measured a rate constant of the same order (9.44 L.mol −1 .min −1 at 25 °C in acetonitrile) for a similar compound, N‐(2‐methyl‐benzylidene)‐phenylglycine amide (NMPA) in a more polar solvent [31] …”

“…Furthermore, out of these two effects, the Formation of hydrogen bonding seems to have a stronger effect, as the rate constants for isopropanol compared to acetone, though similar in polarity, show a four‐fold increase while for propanol a three‐fold increase is observed compared to acetonitrile. In the case of Breveglieri et al., the non‐stabilizing effect of hydrogen bonding when using NMPA, [31] could be explained by a disruption in the mesomeric effect of the imine group, in the β position of the carbonyl, caused by hydrogen bonding of its nitrogen atom with the alcohol group of the solvent. Resulting in its lone pair no longer being available in the resonance.…”

Designing Isothermal Batch Deracemization Processes with Optimal Productivity: 1. Parametric Analysis Using a Population Balance Equation Model

“…Comparing Figure 6(c) and (d) one can also see that a faster racemization reaction (higher R) leads to higher dimensionless productivities if the other parameters are equivalent. This is in agreement with recent literature on polythermal deracemization processes where the racemization kinetics were quantitatively investigated 41,42 . The authors of both studies concluded that a higher racemization rate leads to faster deracemization if the racemization reaction is rate-limiting.…”