Crystallographic and Spectroscopic Evidence of High-Pressure Phase Transition of l -Histidine Methyl Ester Dihydrochloride

Abstract We investigate the dependence of the structural and vibrational properties of l-histidine methyl ester dihydrochloride (LHMED) on high-pressure conditions in the range of 0.0–8.2 GPa. Combining single-crystal X-ray diffraction (SCXRD) and Raman spectroscopy, we found a reversible pressure-induced phase transition between 1.05 and 1.8 GPa, from monoclinic (P21) to triclinic (P1). XRD analysis reveals an abrupt unit cell volume reduction of approximately 5.50%, indicating a significant structural reorganization to accommodate the applied stress. High-pressure Raman spectra corroborate these findings, exhibiting discontinuities in the ω(P) slopes, the emergence of a new lattice mode, and various other bands associated with internal modes at 1.8 GPa, reflecting the symmetry reduction. Density Functional Theory (DFT) calculations using the Generalized Gradient Approximation-Tkatchenko-Scheffler (GGA-TS) functional were employed to obtain accurate vibrational assignments and validate the experimental lattice parameters. Furthermore, Hirshfeld surface and crystal void analyses demonstrate that the transition is driven by a redistribution of intermolecular contacts and the strengthening of the hydrogen-bond network, particularly N–H···Cl and C–H···Cl interactions. The data analysis yields a bulk modulus (K0 = 14.68 GPa), which indicates that LHMED is a soft molecular crystal. Our results show that the presence of a methyl ester group increases structural flexibility compared to nonmethylated l-histidine, leading to a conformational transition at lower pressure. Upon decompression, SCXRD showed that the original monoclinic phase is mostly recovered, highlighting remarkable crystalline memory and structural reversibility; however, Raman spectroscopy measurements during the pressure-release process, down to 0.7 GPa, revealed slight hysteresis, as indicated by subtle variations in some vibrational modes.