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Base‐dependent selectivity of an S N Ar reaction
Author(s) -
Chan Lai C.,
Cox Brian G.,
Jones Ian C.,
Tomasi Simone
Publication year - 2011
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.1820
Subject(s) - chemistry , dabco , selectivity , quinuclidine , octane , intramolecular force , amine gas treating , nucleophilic aromatic substitution , hydrogen bond , medicinal chemistry , nucleophilic substitution , organic chemistry , molecule , catalysis
A detailed kinetic analysis and computational study of an S N Ar reaction between 2,5,6‐trifluoronicotinonitrile, 2 , and the ambident 3‐isopropoxy‐1 H ‐pyrazol‐5‐amine, 3 , is presented. The selectivity with respect to the reaction at the primary amino group of 2 , to give the desired product, 2,5‐difluoro‐6‐[(3‐isopropoxy‐1 H ‐pyrazol‐5‐yl)amino]nicotinonitrile, 1 , is strongly dependent upon reaction conditions. Reaction is found to proceed via both uncatalysed and base catalysed routes, and selectivity towards 1 is strongly enhanced in the presence of the base diazabicyclo[2,2,2]octane (DABCO). Computational studies in tetrahydrofuran solution at the B3LYP/6‐31G* level of theory have provided valuable insight into alternative kinetically indistinguishable reaction pathways. The results suggest that for reaction at the primary amino group, proton removal by DABCO accompanying amine addition allows avoidance of a high‐energy, zwitterionic Meisenheimer intermediate. Reactions at the alternative pyrazole nitrogen atoms are less sensitive to the presence of base because of stabilisation of the Meisenheimer zwitterions by intramolecular hydrogen bonding. Copyright © 2010 John Wiley & Sons, Ltd.