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PreprintCC BY-NC-NDChemRxiv

Predictive Model for Acid-Catalyzed SN1 Solvolysis Racemization of Chiral Alcohols in Water

  • Fabian Sievert1,2
  • Per-Ola Norrby3
  • Arseny Kovyrshin3
  • Christoph Bauer3
  • Elliot H. E. Farrar4,5
  • David Buttar6,7
  • Mårten Ahlquist1,2
7 affiliations
  1. 1Department of Chemistry, School of Chemistry, Biotechnology and Health
  2. 2KTH Royal Institute of Technology
  3. 3Predictive Science, Digital and Automation, Pharmaceutical Sciences, R&D, AstraZeneca, Pepparedsleden 1, Mölndal, Sweden, SE-431 83
  4. 4Chemical Development, Pharmaceutical Technology & Development, Operations
  5. 5AstraZeneca
  6. 6Predictive Science, Digital and Automation, Pharmaceutical Sciences
  7. 7R&D, AstraZeneca
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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.

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Cite

BibTeXRIS
BibTeX
@misc{sievert2026predictive,
  title = {{Predictive Model for Acid-Catalyzed SN1 Solvolysis Racemization of Chiral Alcohols in Water}},
  author = {Fabian Sievert and Per-Ola Norrby and Arseny Kovyrshin and Christoph Bauer and Elliot H. E. Farrar and David Buttar and Mårten Ahlquist},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010137/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010137/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Predictive Model for Acid-Catalyzed SN1 Solvolysis Racemization of Chiral Alcohols in Water
AU  - Fabian Sievert
AU  - Per-Ola Norrby
AU  - Arseny Kovyrshin
AU  - Christoph Bauer
AU  - Elliot H. E. Farrar
AU  - David Buttar
AU  - Mårten Ahlquist
PY  - 2026
DA  - 2026/10/09
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010137/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010137/v1
AB  - 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.
ER  -