The Elusive High Temperature Solid-State Structure of d,l-Norleucine

Abstract

D,L-Norleucine (2-aminohexanoic acid), C 6 H 13 NO 2 , has been the subject of many structural, spectroscopic, and thermoanalytical investigations 1 in the last half century as a result of its remarkable thermal behavior. In fact, D,L-norleucine is used as a reference system for thermal behavior in molecular organic materials, such as pharmaceuticals, and more recently has been a test case for the modeling of concerted phase transitions at the molecular level. 2,3 The interest has centered around the singlecrystal to single-crystal transitions and structures for a low temperature β-form, and a room temperature R-form, which can be found in the Cambridge Structural Database (DLNLUA, DLNUA01, DLNLUA02). [4][5][6] The existence of a high temperature γ-form, based on postulation from Weissenberg photographs, was proposed as long ago as 1953 4 and observed in Laue diffraction patterns 5 over a decade ago, but the structure has remained elusive. Recent work aimed at modeling the high temperature phase transition has also resulted in a prediction of the high temperature form. 2,3,7 Clearly, knowledge of the true high temperature form would enable the most accurate modeling of the transition, and this communication now reports the new experimentally determined single crystal structure of this γ-form.The transition temperature between the low and room temperature forms has not previously been reported. We have found that both the transition temperature and the transition behavior are extraordinarily variable. We have also confirmed the welldefined reversible single-crystal to single-crystal (R to γ) transition at 390-391 K, which is indefinitely repeatable, with a very narrow hysteresis. The range normally observable by differential scanning calorimetry (DSC), variable temperature vibrational spectroscopy, or X-ray diffraction is of the order of a few degrees. The range observable by very slow heating and cooling under a hotstage microscope is only 0.6 K, but the absolute temperatures vary by a few tenths of a degree between crystals, or between parts of the same crystal. We have now succeeded in solving this structure and examining the relationship of all the forms. A single crystal of the R-form was mounted on the diffractometer at room temperature and then subjected to a preliminary analysis of its thermal behavior by systematically raising the temperature and checking the unit cell parameters. A change in unit cell dimensions (full cell data are deposited as Supporting Information), indicating a phase transition and retention of crystalline structure, was observed at 390 K, showing precise agreement with hot stage microscopy results 8 (Figure 1) and also those from DSC 9 (Figure 2). As observed by Anwar 5 and Mnyunkh, 7 the high temperature phase transition causes crystal cracking; however, the degree of cracking can be reduced by slowing down the heating rate.For reliability of comparison, new structures of the βand Rforms were redetermined 10 close to the phase transition (at 198 and 385 K) and are also included a...

Size‐Dependent Phase Stability of a Molecular Nanocrystal: a Proxy for Investigating the Early Stages of Crystallization

“…As the temperature is increased, an increase in structural disorder is observed, particularly the relaxation of the molecules at the surfaces as the nanocrystal attempts to minimize the surface free energy by moving away from the starting idealized structure. The alkyl chains show increasing disorder, but the nanocrystal remains in the b form until 475 K, at which point it transforms to a high-temperature polymorph (exhibiting the characteristic motifs of the g structure as recently identified experimentally) [35] . Interestingly, this particular transformation-unlike the b-to-a transition-does not involve any layer movements, but rather rotations of the alkyl chains to yield a new variation at the van der Waals surface.…”

Solid-state transformations in the β-form of chlorpropamide on cooling to 100 K

“…We can compare the transition in the -polymorph of chlorpropamide with some other transformations related to the changes in the orientation and/or conformation of the alkyl tails (Coles et al, 2009(Coles et al, , 2010Ferrarini et al, 2003;Herbstein, 2006;Naik & Vasudevan, 2009;Sokolov et al, 2008;Takahashi & Ito, 2010). The conformational changes involving the alkyl tails in chlorpropamide occur between 260 and 125 K. Dynamical transitions related to the orientation of the alkyl tails and changes in their conformations (trans versus gauche) in other crystalline and biological systems have been observed in a similar temperature range (180-260 K; Coles et al, 2010;Surovtsev & Dzuba, 2009;Takahashi & Ito, 2010).…”

Crystal structures of amino acids: from bond lengths in glycine to metal complexes and high-pressure polymorphs

“…[161] These structures are divided into layers, and at a specific temperature (which is different on cooling and on heating, i.e. hysteresis occurs) every second molecular bilayer is translated along the two shortest axes to take on a modified type of hydrophobic stacking, while leaving the hydrogen bonding region intact ( Figure 36).…”