Stereoelectronic Substituent Effects in Polyhydroxylated Piperidines and Hexahydropyridazines

From the pKa 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 i...

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Veröffentlicht in:Chemistry : a European journal 2002-03, Vol.8 (5), p.1218-1226
Hauptverfasser: Jensen, Henrik Helligsø, Lyngbye, Laila, Jensen, Astrid, Bols, Mikael
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Sprache:eng
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Zusammenfassung:From the pKa 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 pKa of piperidines which takes stereochemistry into account is described. Whether an electronegative substituent is equatorial or axial has been found to affect its electron‐withdrawing power in the title compounds; those with equatorial OH or COOMe were consistently less basic than the isomers with the corresponding axial substituent. This effect influences the conformational equilibrium of these molecules. For example, the conformer B (see scheme) is a weaker acid than the conformer A, which makes it more favored at acidic pH.
ISSN:0947-6539
1521-3765
DOI:10.1002/1521-3765(20020301)8:5<1218::AID-CHEM1218>3.0.CO;2-X