Comparisons of pKa and log P values of some carboxylic and phosphonic acids: synthesis and measurement.
The changes in the physiochemical properties accompanying the substitution of a phosphonic acid group for a carboxylic acid group on various heterocyclic platforms was determined. A series of low molecular weight heterocyclic carboxylic and phosphonic acids was prepared, and the acid dissociation content (pKa) and log P values were measured potentiometrically. These values were compared to those of substituted benzene phosphonic acids, carboxylic acids, sulfonamides, and tetrazoles. The carboxylic acids included 3 pyrazoles, an imidazole, a triazole, 2 pyrimidines, and 6 aryl compounds. The phosphonic acids included a triazole, 2 pyrazoles, 4 pyrimidines, a thiophene, and 6 aryl compounds. Most of the compounds synthesized had adequate water solubility, although a simple methyl substituent in 2 series had a great effect, completely changing the properties. Log P values for the synthesized carboxylic and phosphonic acid compounds were below 2, and pK1 values for the heterocyclic phosphonic acids were generally 2 to 3 log units lower than for the heterocyclic carboxylic acids.
Franz
R D
RD
Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, PO Box 1539, King of Prussia, PA 19406-0939, USA. Robert_G_Franz@GSK.COM
D001393:Azoles / Q000737:chemistry; D001555:Benzene Derivatives / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D008970:Molecular Weight; D063065:Organophosphonates / Q000737:chemistry*; D011199:Potentiometry; D011743:Pyrimidines / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry
D001393:Azoles; D001555:Benzene Derivatives; D002264:Carboxylic Acids; D006573:Heterocyclic Compounds, 1-Ring; D063065:Organophosphonates; D011743:Pyrimidines; D013449:Sulfonamides; D013876:Thiophenes