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Stereoelectronic Substituent Effects in Polyhydroxylated Piperidines and Hexahydropyridazines
Author(s) -
Jensen Henrik Helligsø,
Lyngbye Laila,
Jensen Astrid,
Bols Mikael
Publication year - 2002
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20020301)8:5<1218::aid-chem1218>3.0.co;2-x
Subject(s) - substituent , chemistry , protonation , conformational isomerism , amine gas treating , stereochemistry , medicinal chemistry , molecule , organic chemistry , ion
From the p K a values of the conjugate acids of a large series of hydroxylated piperidines and hexahydropyridazines, a consistent difference in basicity was found between stereoisomers having an axial or equatorial hydroxyl (OH) group either β or γ to the amine. Compounds with an equatorial OH group in the 3‐position were 0.8 pH units more acidic than otherwise identical compounds with an axial OH group, whilst compounds with an equatorial OH group in the 4‐position relative to the amine were 0.4 pH units more acidic than the corresponding compound with an axial OH. A similar effect was observed for the COOMe substituent. The difference in electron‐withdrawing power of axial and equatorial substituents was explained by a difference in charge–dipole interactions in the two systems. Since this stereoelectronic substituent effect causes differences in basicity in different conformers, certain piperidines and hexahydropyridazines were found to change conformation upon protonation. A method for predicting the p K a of piperidines which takes stereochemistry into account is described.