Diffusion-NMR Meets Hybrid Chiral Micelles: A New Route to Enantiomeric Differentiation

Enantiomers are chiral molecules that exist as non-superimposable mirror images of
each other. These compounds are of great importance in fields such as
pharmaceuticals, food, and materials science due to their unique interactions with other
chiral entities, which can result in distinct biological or physicochemical properties.
Differentiating enantiomeric mixtures is crucial for the development and application of
these compounds, but it remains a significant challenge in analytical and
physicochemical sciences. Matrix-assisted DOSY (MAD) using chiral resolving agents
(CRAs) is a promising approach for evaluating enantiomeric mixtures through diffusion-
NMR. However, current implementations face limitations, including high CRA costs,
limited availability, and subtle diffusion separation, often within the experimental error
margin. [1,2] To overcome these issues, this study investigates a hybrid chiral matrix
composed of reverse micelles formed by the cationic surfactant (-)-DMEB in
combination with either (R)-BINOL or (S)-BINOL to enhance enantiomeric discrimination
of mandelic acid (MA). Samples containing 40 mM of MA, varying concentrations of
BINOL and 150 mM of DMEB in 500 µL of CDCl₃ were prepared. ¹H diffusion-NMR
experiments were performed using the Oneshot pulse sequence on a 600 MHz
spectrometer at 25 °C. Overall, the results revealed that systems containing only BINOL
or DMEB exhibited enantiomeric differentiation in the frequency domain but no diffusion
separation. Interestingly, the hybrid system containing (S)-BINOL and (-)-DMEB
enabled both frequency and diffusion separation of the MA enantiomers, exhibiting
stereoselectivity for the (R)-MA enantiomer. In contrast, the combination of (R)-BINOL
and DMEB failed to achieve such separation, indicating that the enantiodiscrimination
ability of the hybrid matrix depends strongly on the BINOL configuration. Titration
experiments revealed stronger interactions between (R)-BINOL and DMEB and confirmed
BINOL's localization in the micelle's polar region. In the presence of MA, (S)-BINOL
consistently enhanced enantiomer frequency separation in all studied concentrations,
whereas (R)-BINOL displayed a competition effect with DMEB, preventing efficient
separation for some range of BINOL amounts. Overall, this study demonstrates that
tuning the matrix composition in hybrid chiral micellar systems can significantly impact
enantiodiscrimination performance. These findings highlight a promising, cost-effective,
and adaptable strategy for probing chiral interactions and enhancing stereochemical
analysis using diffusion-NMR.

1. Cabral, TLG, et al. Angew. Chem., 137, 5, e202418508, 2025.
2. Cabral, TLG, et al. Chem. Eur. J., 31, 25, e202404694, 2025.

Acknowledgments: FAPESP grant #2020/10246-0, #2021/05081-5, and #2023/07116-6.