Protonation Equilibria and Alkaline Hydrolysis of Glycine Ethyl Ester

Robson, Margaret

doi:10.1038/208265a0

Cited by 5 publications

(5 citation statements)

References 11 publications

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“…Following the discovery of the antihypertensive agent, diazoxide, 7-chloro-3-methyl-2//-l,2,4-benzothiadiazine 1,1dioxide (I, R3 = CH3, R7 = Cl, Rs = R6 = Rg = H),1 many fPresented in part at the Medicinal Chemistry Symposium, Chelsea College of Science and Technology, London, England, April 1 [5][6][7][8][9][10][11][12][13][14][15][16][17]1969, organized by The Society for Drug Research. analogs were prepared in order to study structure-activity relationships.2'3 The development and wide application of the substituent constant method to structure-activity problems by Hansch4 prompted us to examine this approach in the antihypertensive benzothiadiazine series.…”

Section: Received June 30 1971mentioning

confidence: 99%

Rates of alkaline hydrolysis and muscarinic activity of some aminoacetates and their quaternary ammonium analogs

Cho¹,

Jenden²,

Lamb³

1972

J. Med. Chem.

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The muscarinic activity and rates of hydrolysis of a series of acetoxyethylamine derivatives were compared in an effort to explain the differences in potencies of the tertiary and quaternary amino esters. The more flexible compounds, like dimethylaminoethyl acetate (1 A), are much weaker muscarinic agents than their corresponding quaternary analogs ( lB), while rigid compounds, like aceclidine (6A), are more potent than their methochlorides. These differences may be rationalized in terms of a cyclic ammonium conformation which could readily be formed by the open chain derivatives, and which may also account for an anchimeric acceleration of the hydrolysis of the tertiary amino ester. Kinetic experiments have also provided evidence for the mechanism of this anchimerically assisted reaction.In a study investigating the effect of pH on the muscarinic activity of some tertiary amines, it was noted that the hydronium ions of oxotremorine, arecoline, and pilocarpine were more potent muscarinic agents than their N-Me quaternary salts.' A similar relationship has been reported for the tertiary amine aceclidine (3-acetoxyquinuclidine)z~3and some arecoline analog^.^ In contrast, the more classical cholinergic agents related to ACh are more active than the hydronium ions of their N-demethyl analogs.'-' In all the compounds whose tertiary derivatives are more effective than their N-Me quaternary analogs, the basic N is contained in a ring while in pairs of compounds in which the reverse is true the N is attached to an aliphatic chain.These differences have been rationalized in terms of the conformations of the 2 types of compounds in aqueous solution.' If interaction with the receptor requires that the C=O group and positively charged N be arranged in either a transoid or open chain conformation, the ease with which the compounds could attain this conformation should be reflected in their potency. Conversely, any molecular feature that opposed this conformation would be expected to decrease potency. In a flexible molecule like dimethylaminoethyl acetate (lA), the attraction between the proton on the charged N and the C=O could favor a large population of conformations in which these 2 groups are close together, while the more rigid cyclic compounds could assume these conformations only with difficulty. Because of their tendency to form cyclic conformations, the flexible tertiary amino esters would be less potent than their quaternary derivatives.that the cyclic ammonium structure (A) of dimethylaminoethyl acetate has an anchimeric effect on its alkaline hydrolysis. No such effect was observed with the alkaline hyThis postulate was based in part on the reports of Hansenstg drolysis of aceclidine because of the inability of this rigid molecule to attain a cyclic ammonium conformation.here, in which a comparison was made of the muscarinic activity and rates of hydrolysis of pairs of acetoxyethylamine derivatives with differing degrees of flexibility about the ethylamine side chain (Figure 1). Each pair consists of a tertiary am...

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Section: Received June 30 1971mentioning

confidence: 99%

Rates of alkaline hydrolysis and muscarinic activity of some aminoacetates and their quaternary ammonium analogs

Cho¹,

Jenden²,

Lamb³

1972

J. Med. Chem.

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“…Formulation and related theoretical background of hydrolysis kinetics for esters with two or more basic side-chain sites cannot be found in the literature. Also, the hydrolysis rate parametrization of monobasic esters needs a unified view for exact evaluation as evidenced by literature data cited above. − …”

Section: Resultsmentioning

confidence: 99%

“…Also, the hydrolysis rate parametrization of monobasic esters needs a unified view for exact evaluation as evidenced by literature data cited above. [12][13][14][15][16][17][18][19][20][21][22] We therefore first provide definition, relationships, feasibility, and methodical description for the microscopic treatment of ester hydrolysis kinetics.…”

Section: Resultsmentioning

confidence: 99%

“…It was observed, for example, that insertion of a permanent cationic moiety into ethyl-acetate causes a 200-fold acceleration of the base-catalyzed hydrolysis − The typical molecules in such studies were amino acid esters, since their amino site is located near the ester moiety, and the amino protonation takes place in the pH range of the hydroxide-catalyzed ester hydrolysis. Thus, the protonated/deprotonated status of the amino site can cause a switching effect on the hydrolysis propensity of the ester.…”

Section: Introductionmentioning

confidence: 99%

“…11 Charge-dependent rate constants have also been reported for a number of compounds, the side-chain of which contains a protonating/deprotonating site near the ester group. [12][13][14][15][16][17][18][19][20][21][22] The typical molecules in such studies were amino acid esters, since their amino site is located near the ester moiety, and the amino protonation takes place in the pH range of the hydroxide-catalyzed ester hydrolysis. Thus, the protonated/deprotonated status of the amino site can cause a switching effect on the hydrolysis propensity of the ester.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Ester Hydrolysis in Terms of Microscopic Rate Constants

2006

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Hydroxide-catalyzed ester hydrolysis for molecules of coexisting species is quantitated in terms of microscopic rate constants, a new, species-specific physicochemical parameter. Relationships between the overall and component reactions, as well as the macroscopic and microscopic rate constants are deduced. Experimental techniques, evaluation methods, and feasibility are discussed. Species-specific, pH-independent rate constants of four coexisting, differently hydrolyzing microspecies are determined for the first time. Protonation of an alpha-amino and beta-imidazolyl site in amino acid esters has been found to accelerate the hydroxide-catalyzed hydrolysis by factors of 120 and 7.5, respectively, whereas they jointly exert a nearly 3000-fold acceleration. A total of 20 microscopic protonation equilibrium constants, as component parameters in the rate equations, have also been determined. The species-specific rate constants have been found to correlate with the site- and species-specific basicity of the leaving group and the NMR chemical shift of an adjacent proton. Individual contributions of the various microforms to the overall hydrolysis rate are depicted in microscopic reaction fraction diagrams.

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Bibliography

Smith

Martell²

1975

Critical Stability Constants

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Protonation Equilibria and Alkaline Hydrolysis of Glycine Ethyl Ester

Cited by 5 publications

References 11 publications

Rates of alkaline hydrolysis and muscarinic activity of some aminoacetates and their quaternary ammonium analogs

Rates of alkaline hydrolysis and muscarinic activity of some aminoacetates and their quaternary ammonium analogs

Characterization of Ester Hydrolysis in Terms of Microscopic Rate Constants

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