Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins.
The effect of replacing the beta-lactam carbonyl oxygen in cephalosporins by sulfur on their reactivity has been investigated. The second-order rate constant for alkaline hydrolysis of the sulfur analogue is 2-fold less than that for the natural cephalosporin. The thioxo derivative of cephalexin, wi...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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2004
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| _version_ | 1797072563110674432 |
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| author | Tsang, W Dhanda, A Schofield, C Page, M Dhanda, A |
| author_facet | Tsang, W Dhanda, A Schofield, C Page, M Dhanda, A |
| author_sort | Tsang, W |
| collection | OXFORD |
| description | The effect of replacing the beta-lactam carbonyl oxygen in cephalosporins by sulfur on their reactivity has been investigated. The second-order rate constant for alkaline hydrolysis of the sulfur analogue is 2-fold less than that for the natural cephalosporin. The thioxo derivative of cephalexin, with an amino group in the C7 side chain, undergoes beta-lactam ring opening with intramolecular aminolysis by a reaction similar to that for cephalexin itself. However, the rate of intramolecular aminolysis for the S-analogue is 3 orders of magnitude greater than that for cephalexin. Furthermore, unlike cephalexin, intramolecular aminolysis in the S-analogue occurs up to pH 14 with no competitive hydrolysis. The rate of intermolecular aminolysis of natural cephalosporins is dominated by a second-order dependence on amine concentration, whereas that for thioxocephalosporins shows only a first-order term in amine. The Bronsted beta(nuc) for the aminolysis of thioxo-cephalosporin is +0.39, indicative of rate-limiting formation of the tetrahedral intermediate with an early transition state with relatively little C-N bond formation. |
| first_indexed | 2024-03-06T23:09:31Z |
| format | Journal article |
| id | oxford-uuid:64f818a0-07b1-4c27-ad66-5b31b8ee7c27 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:09:31Z |
| publishDate | 2004 |
| record_format | dspace |
| spelling | oxford-uuid:64f818a0-07b1-4c27-ad66-5b31b8ee7c272022-03-26T18:22:30ZKinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:64f818a0-07b1-4c27-ad66-5b31b8ee7c27EnglishSymplectic Elements at Oxford2004Tsang, WDhanda, ASchofield, CPage, MDhanda, AThe effect of replacing the beta-lactam carbonyl oxygen in cephalosporins by sulfur on their reactivity has been investigated. The second-order rate constant for alkaline hydrolysis of the sulfur analogue is 2-fold less than that for the natural cephalosporin. The thioxo derivative of cephalexin, with an amino group in the C7 side chain, undergoes beta-lactam ring opening with intramolecular aminolysis by a reaction similar to that for cephalexin itself. However, the rate of intramolecular aminolysis for the S-analogue is 3 orders of magnitude greater than that for cephalexin. Furthermore, unlike cephalexin, intramolecular aminolysis in the S-analogue occurs up to pH 14 with no competitive hydrolysis. The rate of intermolecular aminolysis of natural cephalosporins is dominated by a second-order dependence on amine concentration, whereas that for thioxocephalosporins shows only a first-order term in amine. The Bronsted beta(nuc) for the aminolysis of thioxo-cephalosporin is +0.39, indicative of rate-limiting formation of the tetrahedral intermediate with an early transition state with relatively little C-N bond formation. |
| spellingShingle | Tsang, W Dhanda, A Schofield, C Page, M Dhanda, A Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. |
| title | Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. |
| title_full | Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. |
| title_fullStr | Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. |
| title_full_unstemmed | Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. |
| title_short | Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. |
| title_sort | kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins |
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