title: Are the Crystal Structures of Enantiopure and Racemic Mandelic Acids Determined by Kinetics or Thermodynamics?
abstract: Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood.
authors.affiliation: Department of Chemistry, University College London , 20 Gordon Street, London WC1H 0AJ, U.K.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Hylton
authors.affiliation: Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton , Highfield, Southampton SO17 1BJ, U.K.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Tizzard
authors.affiliation: Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton , Highfield, Southampton SO17 1BJ, U.K.
authors.forename: Terence L
authors.initials: TL
authors.lastname: Threlfall
authors.affiliation: Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton , Highfield, Southampton SO17 1BJ, U.K.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Ellis
authors.affiliation: Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton , Highfield, Southampton SO17 1BJ, U.K.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Coles
authors.affiliation: School of Chemical Engineering and Analytical Science, University of Manchester , The Mill, Oxford Road, Manchester M13 9PL, U.K.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Seaton
authors.affiliation: Max-Planck-Institut für Dynamik Komplexer Technischer Systeme , D-39106 Magdeburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze
authors.affiliation: Max-Planck-Institut für Dynamik Komplexer Technischer Systeme , D-39106 Magdeburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Lorenz
authors.affiliation: Max-Planck-Institut für Dynamik Komplexer Technischer Systeme , D-39106 Magdeburg, Germany.|Otto-von-Guericke-Universität , Chemische Verfahrenstechnik, D-39106 Magdeburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Seidel-Morgenstern
authors.affiliation: Max-Planck-Institut für Dynamik Komplexer Technischer Systeme , D-39106 Magdeburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stein
authors.affiliation: Department of Chemistry, University College London , 20 Gordon Street, London WC1H 0AJ, U.K.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Price
mesh_terms: D007700:Kinetics; D008333:Mandelic Acids / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D008333:Mandelic Acids