title: Origin of regioselectivity in α-humulene functionalization.
abstract: Humulene is a sesquiterpene with an important biochemical lead structure, consisting of an 11-membered ring, containing three nonconjugated C═C double bonds, two of them being triply substituted and one being doubly substituted. As observed by many groups, one of the two triply substituted C═C double bonds is significantly more reactive. In order to rationalize this peculiar regioselectivity, the conformational space of humulene has been explored computationally using various DFT functionals. Four different conformations were identified. Each conformation is chiral and has two enantiomeric forms, yielding a total of eight conformers. The potential energy surface for the interconversion of these conformers was characterized via intrinsic reaction coordinate analyses. Furthermore, an evaluation of the microcanonical partition functions allowed for a quantification of the entropy contributions and the calculation of the temperature dependent equilibrium composition. The results strongly suggest that the high regioselectivity is related to a strong, hyper-conjugative σ(Cα-Cβ)-π(C═C) orbital overlap in the predominant conformations that discriminates one triply substituted double bond from the other. Furthermore, the order of magnitude of the calculated activation energies for the interconversions of the conformers is supported by NMR measurements at different temperatures.
authors.affiliation: Department of Chemistry and Applied Bio-Sciences, ETH Zurich, Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Neuenschwander
authors.forename: Barbara
authors.initials: B
authors.lastname: Czarniecki
authors.forename: Ive
authors.initials: I
authors.lastname: Hermans
mesh_terms: D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D000081222:Monocyclic Sesquiterpenes; D011789:Quantum Theory; D012717:Sesquiterpenes / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000081222:Monocyclic Sesquiterpenes; D012717:Sesquiterpenes; C042686:humulene