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Synthesis and Characterization of para ‐Substituted N , N′‐ Dihydroxybenzamidines and Their Derivatives as Model Compounds for a Class of Prodrugs
Author(s) -
Schwarz Laura,
Girreser Ulrich,
Clement Bernd
Publication year - 2014
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201301622
Subject(s) - chemistry , dehydrohalogenation , nitrile , hydroxamic acid , oxime , prodrug , hydroxylamine , taft equation , stereochemistry , computational chemistry , substrate (aquarium) , medicinal chemistry , chemical shift , density functional theory , molecule , organic chemistry , substituent , catalysis , biochemistry , oceanography , geology
A synthetic strategy for previously unknown para ‐substituted N , N′ ‐dihydroxybenzamidines and their O ‐monosubstituted and O , O′ ‐disubstituted methyl, benzyl, and tetrahydropyranyl derivatives is described. The procedure starts with the corresponding hydroxamic acid chlorides, which after dehydrohalogenation give nitrile oxides. These intermediates in turn react with O ‐substituted hydroxylamines to afford the desired N , N′ ‐dihydroxybenzamidines after workup. This new class of potential prodrugs was characterized by 15 N NMR spectroscopy. The chemical shifts show significant correlations with Hammett σ values, especially for the oxime‐type nitrogen with r 2 > 0.99. The Hammett σ parameter reliably correlates with electron density in molecules. The presented results thus allow predictions relating to π‐electron density and basicity in this functional group, and these are important parameters for the discussion of substrate enzyme interactions.