Predictive Model for Acid-Catalyzed SN1 Solvolysis Racemization of Chiral Alcohols in Water
Year: 2026
Type: preprint
Abstract: We have developed a predictive model for assessing the racemization risk of drug candidates featuring chiral alcohol motifs, addressing an important concern in drug discovery and development. Specifically, it predicts the activation free energy of stereoisomerization through the acid-catalyzed SN1 solvolysis mechanism based on the calculated electronic reaction energy associated with carbocation formation, the assumed rate-determining step. At the core of the framework is a linear regression model relating the calculated electronic reaction energy difference between the chiral alcohol and the carbocation intermediate to the activation free energy derived from experimental racemization kinetics. The resulting model showed a strong correlation and high statistical significance (R2=0.92, p=1.9 ∗ 10−8), reproducing the activation free energy with a root-mean-square error of 4.1 kJ/mol. Thus, the model has the potential to enable high-throughput assessment of racemization risk in drug candidates, supporting the development of safer pharmaceuticals and more efficient drug development pipelines.
Source: ChemRxiv
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7221120420