Temperature-Induced Reversible First-Order Single Crystal to Single Crystal Phase Transition in Boc‑γ⁴(<i>R</i>)Val-Val-OH: Interplay of Enthalpy and Entropy

Abstract

Crystals of Boc-γ⁴(<i>R</i>)­Val-Val-OH undergo a reversible first-order single crystal to single crystal phase transition at <i>T</i>_c ≈ 205 K from the orthorhombic space group <i>P</i>22₁2₁ (<i>Z</i>′ = 1) to the monoclinic space group <i>P</i>2₁ (<i>Z</i>′ = 2) with a hysteresis of ∼2.1 K. The low-temperature monoclinic form is best described as a nonmerohedral twin with ∼50% contributions from its two components. The thermal behavior of the dipeptide crystals was characterized by differential scanning calorimetry experiments. Visual changes in birefringence of the sample during heating and cooling cycles on a hot-stage microscope with polarized light supported the phase transition. Variable-temperature unit cell check measurements from 300 to 100 K showed discontinuity in the volume and cell parameters near the transition temperature, supporting the first-order behavior. A detailed comparison of the room-temperature orthorhombic form with the low-temperature (100 K) monoclinic form revealed that the strong hydrogen-bonding motif is retained in both crystal systems, whereas the non-covalent interactions involving side chains of the dipeptide differ significantly, leading to a small change in molecular conformation in the monoclinic form as well as a small reorientation of the molecules along the <i>ac</i> plane. A rigid-body thermal motion analysis (translation, libration, screw; correlation of translation and libration) was performed to study the crystal entropy. The reversible nature of the phase transition is probably the result of an interplay between enthalpy and entropy: the low-temperature monoclinic form is enthalpically favored, whereas the room-temperature orthorhombic form is entropically favored