Stepwise Hydration Reveals Conformational Switching in Chiral Prolinol

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Abstract
Understanding the interactions of chiral molecules with water is crucial, given the central role that water plays in chemical and biological processes. We report the investigation of the amino alcohol prolinol, a widely used chiral catalyst and auxiliary in asymmetric synthesis, and its interactions with one to three water molecules by applying broadband rotational spectroscopy. Bare prolinol adopts two low-energy conformations stabilized by an intramolecular O-H···N hydrogen bond. Upon complexation with a single water molecule, four prolinol-H2O isomers are identified, showing addition and insertion structures, where the original prolinol conformations are conserved. Notably, complexation with two and three water molecules induces prolinol to adopt its highest energy conformations, which lie more than 9.5 kJ mol-1 above the global minimum and feature an intramolecular N-H···O hydrogen bond. In prolinol-(H2O)2,3, water acts as a conformational switch for prolinol, binding to both the amino and hydroxyl groups. Combined NMR studies and molecular dynamics simulations reveal that, in bulk water, prolinol exists as a highly flexible conformational ensemble, with no evidence of a stable intramolecular hydrogen bond, and mainly samples the same conformational space as that displayed in prolinol-(H2O)2,3. Our results illustrate how stepwise hydration proceeds and reveal the profound changes that water can induce in flexible chiral molecules. These findings provide a solid foundation for future experiments and modeling of solvation-induced processes.
Funding Information
  • King's College London
  • Engineering and Physical Sciences Research Council (EP/X039420/1)
  • European Research Council (101124939)
  • Ministerio de Ciencia, Innovaci?n y Universidades (PID2023-147698NB-I00)
  • Agencia Estatal de Investigaci?n (PID2021-127622OB-I00)
  • Agencia Estatal de Investigaci?n (PID2022-141085NB-I00)
  • Agencia Estatal de Investigaci?n (PID2024-161682OB-I00)
  • Eusko Jaurlaritza (IT1491-22)
  • Seventh Framework Programme (PCIG12-GA-2012-334525)
  • CINECA award (2022WKTH9E CUP J53D23008810)

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