title: The profound effect of fluorine substitution on the reactivity and regioselectivity of nucleophilic substitution reactions of strained heterocycles. A study of aziridine and its derivatives.
abstract: Unlike the synthetically exploited oxiranes and thiiranes, aziridines that lack electron-withdrawing substituents, such as acyl or sulfonyl functionalities at nitrogen, are rather unreactive. As expected, three-membered aziridine 6 was calculated to be significantly more reactive than azetidine 7 in nucleophilic cleavage by ammonia, a typical nucleophile. The reactivity of 7 was about the same as that of an acyclic model compound, 8, when release of ring strain in the transition state was taken into account. Fluorine due to its similar size but vastly different electronegativity has been substituted for hydrogen as a means of modifying chemical properties for varied applications. In the present investigation, the effect of fluorine substitution at aziridine positions other than nitrogen was studied. Computations at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level found a vast preference for attack by ammonia at the 3-position of 2-fluoroaziridine in the gas phase at 298 K. When release of ring strain was taken into account, this compound reacted more than 10(11) times faster than 6. The reaction rate with trans-2,3-difluoroaziridine was about twice that of 2-fluoroaziridine, while its diastereomer reacted with ammonia considerably slower. Acyclic fluorinated amine model compounds were employed to assess the generality of the effects produced by fluorine substitution. The results were rationalized by the energy contributions of strain energy releases, stabilization of the leaving group, and the relative electrostatic energies of the heterocycles in the transition states. The more reactive fluoroaziridines underwent nucleophilic attack at rates comparable to those of N-acetylaziridine.
authors.affiliation: U.S. Army Edgewood Chemical Biological Center, APG, Maryland 21010-5424, USA. harold.banks@us.army.mil
authors.forename: Harold D
authors.initials: HD
authors.lastname: Banks
mesh_terms: D005461:Fluorine / Q000737:chemistry*
chemical_list: D005461:Fluorine