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19F NMR-Guided Chiral Analysis and Machine Learning for Absolute Configuration Prediction of Carboxylic Acids
Shuyi Lu1,2,3, Qian Wu1,3, Shanshan Wang1,2,3
1Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, P. R. China.
Analytical Chemistry
|October 7, 2025
Summary
An aromatic 19F probe (P1) shows superior enantiomeric recognition of chiral carboxylic acids compared to an aliphatic probe (P2). P1 enables accurate absolute configuration assignment and pharmaceutical quality control, aided by a new online predictive tool.
Area of Science:
- * Organic Chemistry
- * Analytical Chemistry
- * Computational Chemistry
Background:
- * Chiral analysis is crucial in pharmaceuticals and synthesis, requiring accurate absolute configuration assignment.
- * 19F-labeled molecular probes offer advantages in chiral analysis, with stereochemistry being key for enantiodiscrimination.
- * Chiral derivatizing agents (CDAs) are used to differentiate enantiomers via NMR.
Purpose of the Study:
- * To comparatively evaluate two 19F-labeled probes, aromatic P1 and aliphatic P2, as CDAs for chiral carboxylic acids.
- * To elucidate the mechanisms behind their enantiomeric recognition capabilities.
- * To introduce a novel online platform for automated absolute configuration prediction.
Main Methods:
- * Synthesis and application of two 19F-labeled chiral derivatizing agents: (S)-1-(2-fluorophenyl)ethylamine (P1) and trans-2-fluorocyclohexanamine (P2).
- * Comparative enantiomeric recognition studies of chiral carboxylic acids using 19F NMR.
- * Density Functional Theory (DFT) calculations to investigate probe-analyte interactions and energy differences.
- * Application of P1 for determining enantiomeric excess (ee) values in pharmaceutical samples (ibuprofen).
- * Development of an online platform integrating P1-guided 19F NMR with machine learning for automated configuration prediction.
Main Results:
- * The aromatic probe P1 demonstrated superior enantiomeric recognition compared to the aliphatic probe P2, especially for analytes with distant chiral centers or multiple chiral centers.
- * DFT calculations revealed that P1's higher efficiency stems from a greater energy difference between diastereomers and favorable hydrogen bonding interactions.
- * P1 was successfully applied to determine ee values and analyze pharmaceutical formulations of ibuprofen.
- * A novel online platform was developed for automated absolute configuration prediction using P1 and machine learning.
Conclusions:
- * Aromatic 19F-labeled probes like P1 are more effective than aliphatic ones for enantiorecognition, highlighting the importance of probe-analyte interactions.
- * P1 is a versatile tool for pharmaceutical quality control and chiral analysis.
- * The developed online platform offers a rapid and automated method for assigning absolute configurations, advancing chiral analysis techniques.
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