title: Exploring phase-transfer catalysis with molecular dynamics and 3D/4D quantitative structure-selectivity relationships.
abstract: Quantitative Structure-Selectivity Relationships (QSSR) are developed for a library of 40 phase-transfer asymmetric catalysts, based around quaternary ammonium salts, using Comparative Molecular Field Analysis (CoMFA) and closely related variants. Due to the flexibility of these catalysts, we use molecular dynamics (MD) with an implicit Generalized Born solvent model to explore their conformational space. Comparison with crystal data indicates that relevant conformations are obtained and that, furthermore, the correct biphenyl twist conformation is predicted, as illustrated by the superiority of the resulting model (leave-one-out q(2) = 0.78) compared to a random choice of low-energy conformations for each catalyst (average q(2) = 0.22). We extend this model by incorporating the MD trajectory directly into a 4D QSSR and by Boltzmann-weighting the contribution of selected minimized conformations, which we refer to as '3.5D' QSSR. The latter method improves on the predictive ability of the 3D QSSR (leave-one-out q(2) = 0.83), as confirmed by repeated training/test splits.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: James L
authors.initials: JL
authors.lastname: Melville
authors.forename: Kevin R J
authors.initials: KR
authors.lastname: Lovelock
authors.forename: Claire
authors.initials: C
authors.lastname: Wilson
authors.forename: Bryan
authors.initials: B
authors.lastname: Allbutt
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Burke
authors.forename: Barry
authors.initials: B
authors.lastname: Lygo
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hirst
mesh_terms: D002384:Catalysis; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D044367:Phase Transition; D021281:Quantitative Structure-Activity Relationship