title: 1,3-Dipolar [3 + 2] cycloaddition reactions ofN,C,C-trisubstituted nitrones with ring-acceptor methylenecyclopropanes: a computational study.
abstract: BACKGROUND
  1,3-Dipolar [3 + 2]-cycloaddition of nitrones to the carbon-carbon double bonds of methylenecyclopropanes yields a mixture of regioisomeric 4- and 5-isoxazolidines. The mechanisms of the reactions ofN,C,C-trisubstituted nitrones with ring acceptor substituted dimethyl methylenecyclopropanes-1,2-dicarboxylate and aryl methylidene cyclopropanes-1,1-dicarboxylate have been investigated with the Becke 3-Parameter Lee-Yang-Par exchange-correlation functional, a Hartree-Fock DFT hybrid functional, to delineate the factors responsible for the regioselectivity of these class of reactions.
  
  
  RESULTS
  The energetics of the reaction of the phenyl-substituted nitrone with unsubstituted methylenecyclopropane indicate that the formation of the 5-spirocyclopropane is favored over the 4-spirocyclopropane kinetically and thermodynamically. However, the energetics of the reaction of the same phenyl nitrone with vicinal ester (-CO2CH3)-substituted methylenecyclopropane show an inversion in the regioselectivity favoring the formation of the 4-regioisomer over the 5-regioisomer. For the reactions ofN,C,C-trisubstituted nitrone with vicinal ester (-CO2CH3)-substituted methylenecyclopropane (-R1=H, -R2=Ph and -R1=CH3and -R2=CO2CH3) and geminal ester (-CO2CH3)-substituted methylenecyclopropane (R3=H, R4=H; R3=OCH3, R4=CH3; and R3=H, R4=Cl), the energetics indicate that the 5-spirocyclopropane is favored over the 4-spirocyclopropane. The calculations also indicate that electron-donating groups increase regioselectivity of the 5-regioisomers over the 4-regioisomers.
  
  
  CONCLUSIONS
  The regioselectivity of these reactions is determined by both electronic and steric factors. The pathways with the lower activation barrier leads to the more stable regioisomer in all cases, implying that the pathways that are kinetically favored are also thermodynamically favored. However, it is also clear from the energetics that these reactions are not reversible and are therefore under kinetic control. Therefore the selectivity of the reactions is governed solely by the difference in activation barriers leading to the two isomers and not in any way by the thermodynamic stability of the isomers formed.
authors.affiliation: Department of Chemistry, Kwame Nkrumah University of Science and Technology, PMB University Post Office, Kumasi, Ghana.
authors.forename: Mary
authors.initials: M
authors.lastname: Mensah
authors.affiliation: Department of Chemistry, Kwame Nkrumah University of Science and Technology, PMB University Post Office, Kumasi, Ghana.
authors.forename: Evans Elikem
authors.initials: EE
authors.lastname: Amepetey
authors.affiliation: Department of Chemistry, Kwame Nkrumah University of Science and Technology, PMB University Post Office, Kumasi, Ghana.
authors.forename: Richard
authors.initials: R
authors.lastname: Tia
authors.affiliation: Department of Chemistry, Kwame Nkrumah University of Science and Technology, PMB University Post Office, Kumasi, Ghana.
authors.forename: Evans
authors.initials: E
authors.lastname: Adei
keywords: Density functional theory; Methylenecyclopropanes; Nitrones; Regioselectivity; Spirocyclopropanes