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Title:Stereoelectronic effects at carboxylate: Synthesis and study of a syn oriented model for the histidine-aspartate couple in enzymes
Author(s):Cramer, Katherine D.
Doctoral Committee Chair(s):Zimmerman, Steven C.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Abstract:The synthesis of 3,6,13,16-tetraoxa-9,23-diazatricyclo(,11) -tricosa-1(22),8,10,18,20-pentaene-22-carboxylic acid, a model for the histidine-aspartate couple found in enzymes, is detailed. The model contains a syn oriented carboxylate and the effect of this orientation on the proximate imidazole is described.
Two methods were developed to obtain the key synthetic precursor, 1-((N,N-dimethylamino)sulfonyl) -2,4-bis((2-hydroxyethoxy)methyl) -imidazole. The first route began with 1-benzylimidazole-2,5-dimethanol. The second route involved a novel oxidation of an imidazoline to an imidazole under Swern conditions. Structurally similar model compounds were also prepared using the described methods.
The effect of the syn oriented carboxylate on the basicity of the proximate imidazolium ion as determined by titration are described. The increase in pK$\sb{\rm a}$ value is larger than for any previously reported imidazolium ion-carboxylate model and may be attributable to the syn orientation of the carboxylate.
The kinetic behavior of the model was evaluated relative to structurally similar imidazole compounds by observing the nucleophilic hydrolysis of 4-nitrophenyl acetate and the general base catalyzed hydrolysis of 2-nitrophenyl diphenylphosphinate. The compounds fit a Bronsted plot (k$\sb2\sp{\rm max}$ vs. pK$\sb{\rm a}$) for both hydrolysis reactions. Deuterium solvent isotope effects were consistent with the indicated mechanisms. The syn oriented carboxylate provides only a small rate enhancement: a result which is consistent with an increase in basicity of the imidazole. The kinetic results do not support a role for the carboxylate in proton transfer; instead they support an electrostatic role in stabilization of the imidazole.
Issue Date:1990
Rights Information:Copyright 1990 Cramer, Katherine D.
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9026163
OCLC Identifier:(UMI)AAI9026163

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