Dependence of Intramolecular Hydrogen Bond on Conformational Flexibility in Linear Aminoalcohols

Intramolecular hydrogen bonds (H-bonds) are abundant in physicochemical and biological processes. The strength of such interaction is governed by a subtle balance between conformational flexibility and steric effect that are often hard to predict. Herein, using linear aminoalcohols NH2(CH2)(n)OH (n = 2-5) as a model system, we demonstrated the dependence of intramolecular H-bond on the backbone chain length. With sensitive photoacoustic Raman spectroscopy (PARS), the gas-phase Raman spectra of aminoalcohols were measured in both N-H and O-H stretching regions at 298 and 338 K and explained with the aid of quantum chemistry calculations. For n = 2-4, two conformers corresponding to the O-HN intramolecular H-bond and free OH were identified, whereas for n = 5, only the free-OH conformer was identified. Compared to free OH, a striking spectral dependence was observed for the intramolecular H-bonded conformer. According to the red shift of the OH-bonded band, the strongest intramolecular H-bond yields in n = 4, but the favorable chain length to form an intramolecular hydrogen bond at room temperature was observed in n = 3, which corresponds to a six-membered-ring in 3-aminopropanol. This is in good agreement with statistical analysis from the Cambridge Structural Database (CSD) that the intramolecular hydrogen bond is preferred when the six-membered ring is formed. Furthermore, combined with the calculated thermodynamic data at the MP2/aug-cc-pVTZ//M062X/6-311++G(d,p) level, the origin of decrease in intramolecular hydrogen-bond formation was ascribed to an unfavorable negative entropy contribution when the backbone chain is further getting longer, which results in the calculated Gibbs free energy optimum changing with increasing temperature from n = 4 (0-200 K) to n = 3 (200-400 K) and to n = 2 (above 400 K). These results will provide new insight into the nature of intramolecular hydrogen bonds at the molecular level and the application of intramolecular hydrogen bonds in rational drug design and supramolecular assembly.

Automated summary

In this study, the dependence of intramolecular hydrogen bonds on the backbone chain length was demonstrated using linear aminoalcohols as a model system. It was found that the most favorable chain length for intramolecular hydrogen bond formation at room temperature is 3. These findings provide new insights into the nature of intramolecular hydrogen bonds and their potential applications in rational drug design and supramolecular assembly.