Graton Jerome, Compain Guillaume, Besseau Francois, Bogdan Elena, Watts Joseph M, Mtashobya Lewis, Wang Zhong, Weymouth-Wilson Alex, Galland Nicolas, Le Questel Jean-Yves, Linclau Bruno
CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
Chemistry. 2017 Feb 24;23(12):2811-2819. doi: 10.1002/chem.201604940. Epub 2016 Dec 27.
Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pK ) when OH⋅⋅⋅F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pK due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic β-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pK between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH⋅⋅⋅F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical V (r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH⋅⋅⋅F IMHB in the modulation of alcohol H-bond donating capacity.
分子相互作用的合理调控在化合物性质优化中具有重要意义。我们之前已经表明，当发生OH⋅⋅⋅F分子内氢键（IMHB）相互作用时，构象刚性环己醇的氟化会导致其氢键（H键）供体能力（由pK表示）减弱，这与由于氟的电负性导致pK增加的情况相反。现在这项工作已扩展到具有不同程度构象灵活性的更广泛的脂肪族β-氟醇。我们表明，密切相关的非对映异构体之间观察到的pK差异可以通过能够参与OH⋅⋅⋅F IMHB的构象体数量的细微变化以及这些IMHB的强度来完全合理化。我们还表明，氢键酸度Kenny理论V（r）描述符准确反映了观察到的变化，并提出了扩展到氟醇的校准方程。这项工作清楚地强调了弱OH⋅⋅⋅F IMHB在调节醇氢键供体能力中的重要性。
