Theoretical Calculations of β‐Lactam Antibiotics. Part VI. AM1 calculations of alkaline hydrolysis of clavulanic acid

Frau, Juan; Donoso, Josefa; Muñoz, Francisco; Blanco, Francisco Garcı́a

doi:10.1002/hlca.19940770611

Cited by 23 publications

(18 citation statements)

References 44 publications

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“…1 the reaction of any carbonyl with methanolate to give a tetrahedric complex is exothermic. According to our results the formation of tetrahedric intermediates proceeds with no activation energy (E a ) which is also confirmed by other authors 13) . Therefore, the initiation will produce a number of intermediates shown in Scheme 3.…”

Section: Anionic Polymerisationsupporting

confidence: 94%

Molecular modelling of ring-opening polymerisation of lactamimide-containing macrocyclic esters

Ponce

Fomina

Rivera

et al. 2000

Macromol. Theory Simul.

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The molecular modelling of anionic (MeO– initiated) and cationic (H+ initiated) polymerisation of lactamimide‐containing macrocyclic esters has been carried out at PM3 and HF/3‐21G levels of theory. It was found that it is strain release that drives the polymerisation of these macrocycles. Most likely that entropy gain on the ring‐opening can not compensate entropy loss on polymer formation due to the relative rigidity of cyclic molecules. Methanolate initiated anionic polymerisation will not lead to high molecular weight product due to the side reactions involving the attack of growing anionic species at carbonyls of lactamimide moiety, while the cationic polymerisation should proceed smoothly provided that polymerisation temperature is less than ceiling temperature.

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Section: Anionic Polymerisationsupporting

confidence: 94%

Molecular modelling of ring-opening polymerisation of lactamimide-containing macrocyclic esters

Ponce

Fomina

Rivera

et al. 2000

Macromol. Theory Simul.

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“…The activation energy for the formation of h is very small (0.26 kcal/mol with RHF). A similar process takes place in the alkaline hydrolysis of clavulanic acid, also with a very low activation energy (3.9 kcal/mol with AM1 semiempirical calculations).…”

Section: Resultsmentioning

confidence: 72%

“…The nucleophilic attack on the carbonyl group was only examined on the α side of the ring, which was the energetically more favorable choice . As in the alkaline hydrolysis of most β-lactams in the gas phase, the process was found to be subject to no activation energy. ,, The result of the nucleophilic attack is tetrahedral intermediate b (Figure , Tables and ), which is much more stable than the reactants (−42.83 kcal/mol with RHF and −47.02 kcal/mol with MP2). These values are greater in absolute terms than those for the azethidin-2-one ring 30 (−20.61 kcal/mol) provided by RHF/6-31+G*//RHF/6-31+G* calculations, which suggests an increased reactivity in the oxo-β-lactam structure.…”

Section: Resultsmentioning

confidence: 99%

Theoretical Study of the Alkaline Hydrolysis of an Oxo-β-Lactam Structure

et al. 1999

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Various potential mechanisms for the alkaline hydrolysis of an oxo-β-lactam in the gas phase (Scheme ) were examined in the light of ab initio data obtained at the RHF/6-31+G*//RHF/6-31+G* and MP2/6-31+G*//MP2/6-31+G* levels. The influence of the solvent was also examined from IPCM (isodensity polarizable continuum model) computations at the RHF/6-31+G* level. In penicillins and cephalosporins, alkaline hydrolysis begins with a nucleophilic attack on the carbonyl group of the β-lactam ring, which is followed by cleavage of the C7−N4 bond. In the oxo-β-lactam studied, the process additionally involves cleavage of the C7−O6 bond in the ring. In fact, this cleavage is subject to a very small activation energy, as little as 0.21 kcal/mol versus the 14.15 kcal/mol for the typical cleavage energy (based on MP2/6-31+G*//MP2/6-31+G* calculations) for the C7−N4 bond. In addition, the hydrolysis end products are more stable than those resulting from the typical cleavage. Consequently, the alkaline hydrolysis involving cleavage of the C7−O6 bonds is kinetically and thermodynamically more favorable than the classical hydrolysis mechanism for penicillins and cephalosporins. This suggests that oxo-β-lactams might act as β-lactamase inhibitors.

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“…Ab initio calculations were recently used to determine structural parameters for various β-lactam compounds [4][5][6][7][8]. On the other hand, the chemical reactivity (basically alkaline hydrolysis) of β-lactam antibiotics has been studied by using semi-empirical methods preferentially [9][10][11][12][13], with the exception of the early investigations of Petrongolo and coworkers [14,15] and more recent studies with a high-quality basis set [16].…”

Section: Introductionmentioning

confidence: 99%

Alkaline and acidic hydrolysis of the β‐lactam ring

Frau¹,

Coll²,

Donoso³

et al. 1997

Elect J Theoret Chem

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SUMMARYA complete study of the alkaline and acidic hydrolysis of the β-lactam ring of azetidin-2-one was carried out using ab initio molecular orbital calculations at the RHF/6-31+G* and RHF/6-31G** levels, respectively. Alkaline hydrolysis has been studied through a BAC2 mechanism characterized by a nucleophilic attack on the β-lactam carbonyl group, formation of the tetrahedral intermediate and cleavage of the C-N bond until the formation of the final product of the reaction, this being the limiting step of the reaction. On the other hand, the acidic hydrolysis has been studied by means of a A-1 type unimolecular mechanism, characterized by a nitrogen-protonation followed by an opening of the ring and further addition of water to the carbonyl group. The system involving the azetidin-2-one ring, the H3O + ion and a water molecule has been considered. Three transition states have been identified; the barriers corresponding to the addition of H + to the nitrogen and the addition of water to the carbonyl group are practically negligible (first and third reaction steps, respectively).

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Theoretical Calculations of β‐Lactam Antibiotics. Part VI. AM1 calculations of alkaline hydrolysis of clavulanic acid

Cited by 23 publications

References 44 publications

Molecular modelling of ring-opening polymerisation of lactamimide-containing macrocyclic esters

Molecular modelling of ring-opening polymerisation of lactamimide-containing macrocyclic esters

Theoretical Study of the Alkaline Hydrolysis of an Oxo-β-Lactam Structure

Alkaline and acidic hydrolysis of the β‐lactam ring

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