10.1021/jo061255j.s001
Harold D. Banks
Harold D.
Banks
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
American Chemical Society
2006
strain energy releases
ammonia
reactive
nucleophilic
transition
MP
acyclic model compound
fluoroaziridine
Fluorine
ring strain
amine model compounds
Nucleophilic Substitution Reactions
fluorine substitution
aziridine
2006-10-13 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/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/3053755
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 <b>6</b> was calculated to be significantly more reactive than azetidine <b>7 </b>in nucleophilic
cleavage by ammonia, a typical nucleophile. The reactivity of <b>7</b> was about the same as that of an acyclic
model compound, <b>8</b>, 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<sup>11</sup> times faster than <b>6</b>. The reaction rate with <i>trans</i>-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 <i>N</i>-acetylaziridine.