title: Reactivity of activated versus nonactivated 2-(bromomethyl)aziridines with respect to sodium methoxide: a combined computational and experimental study.
abstract: The difference in reactivity between the activated 2-bromomethyl-1-tosylaziridine and the nonactivated 1-benzyl-2-(bromomethyl)aziridine with respect to sodium methoxide was analyzed by means of DFT calculations within the supermolecule approach, taking into account explicit solvent molecules. In addition, the reactivity of epibromohydrin with regard to sodium methoxide was assessed as well. The barriers for direct displacement of bromide by methoxide in methanol are comparable for all three heterocyclic species under study. However, ring opening was found to be only feasible for the epoxide and the activated aziridine, and not for the nonactivated aziridine. According to these computational analyses, the synthesis of chiral 2-substituted 1-tosylaziridines can take place with inversion (through ring opening/ring closure) or retention (through direct bromide displacement) of configuration upon treatment of the corresponding 2-(bromomethyl)aziridines with 1 equiv of a nucleophile, whereas chiral 2-substituted 1-benzylaziridines are selectively obtained with retention of configuration (via direct bromide displacement). Furthermore, the computational results showed that explicit accounting for solvent molecules is required to describe the free energy profile correctly. To verify the computational findings experimentally, chiral 1-benzyl-2-(bromomethyl)aziridines and 2-bromomethyl-1-tosylaziridines were treated with sodium methoxide in methanol. The presented work concerning the reactivity of 2-bromomethyl-1-tosylaziridine stands in contrast to the behavior of the corresponding 1-tosyl-2-(tosyloxymethyl)aziridine with respect to nucleophiles, which undergoes a clean ring-opening/ring-closure process with inversion of configuration at the asymmetric aziridine carbon atom.
authors.affiliation: Center for Molecular Modeling, Ghent University, Member of QCMM-Alliance Ghent-Brussels, Technologiepark 903, B-9052 Zwijnaarde, Belgium.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Goossens
authors.forename: Karel
authors.initials: K
authors.lastname: Vervisch
authors.forename: Saron
authors.initials: S
authors.lastname: Catak
authors.forename: Sonja
authors.initials: S
authors.lastname: Stanković
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
authors.forename: Frank
authors.initials: F
authors.lastname: De Proft
authors.forename: Paul
authors.initials: P
authors.lastname: Geerlings
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
authors.forename: Michel
authors.initials: M
authors.lastname: Waroquier
authors.forename: Veronique
authors.initials: V
authors.lastname: Van Speybroeck
mesh_terms: D001388:Aziridines / Q000737:chemistry*; D007477:Ions / Q000737:chemistry; D000432:Methanol / Q000737:chemistry*; D015394:Molecular Structure; D011789:Quantum Theory; D012997:Solvents; D013237:Stereoisomerism
chemical_list: C570462:2-(bromomethyl)aziridine; D001388:Aziridines; D007477:Ions; D012997:Solvents; D000432:Methanol