Synthesis of fluoro-analogues of lead compounds can produce desirable changes in properties,  resulting in applications in medicinal chemistry, chemical biology, etc.  (1).  Fluorine is unique in its exceptional electronegativity and similarity in size to hydrogen.  Over the years many exemplary syntheses have made a variety of organofluorine compounds available for research.  Some years ago we reported the results of a computational study that demonstrated that certain mono- and difluoroaziridines gave rise to profound rate accelerations relative to aziridine in substitution reactions with a typical nucleophile, ammonia (2).  These calculations were performed in the gas phase, rather univiting experimental conditions.  When De Kimpe and coworkers (3) investigated this chemistry using methanol as both nucleophile and solvent, the reactions required sealed tubes at elevated temperature, and in one case, a surprising regioselectivity was observed.  In the present study this reaction is revisited computationally  [MP2(Full)/6-311++G(d,p)] in CH3OH solution (IEFPCM.)  To explore the importance of hydrogen bonding donating interactions by CH3OH, a solvent of similar polarity,  CH3CN, for which such interactions are absent was investigated and the DGact values in the two solvents compared .  Reasonable explanations are provided for differences between experiment and computation. (1) See, for example, (a)  Ojima, I.  J. Org. Chem. 2013 , 78, 6358 � 6383.  (b) Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V.  Chem. Soc. Revs. 2008 , 37, 320 � 330.  (c) Hu, X-G.; Hunter. L. Beilstein  J. Org. Chem. 2013 , 9, 2696 � 2708.(2) Banks, H.D. J. Org. Chem. 2006 , 71, 8089.(3) Verniest, G.; Colpaert, F.; Van Hende, E.; De Kimpe, N. J. Org. Chem. 2007 , 72, 8569 � 8572.

Profound effect of fluorine substitution on the rate of nucleophilic substitution of aziridine in solution

248th National Meeting (2014)

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