Theoretical calculations of β-lactam antibiotics. V. AM1 calculations of hydrolysis of cephalothin in gaseous phase and influence of the solvent

A comprehensive study on the gas-phase alkaline hydrolysis of cephalosporins by using the semiempirical AM1 method was carried out. Cephalothin was the model compound used on account of the presence of a good leaving group at C(3′). According to the results obtained, the hydrolysis process takes place via a twostep reaction mechanism that involves the formation of an intermediate with a fully open β-lactam ring that still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the β-lactam carbonyl group of cephalosporins containing a good leaving group at C(3′). On the other hand, the alternative mechanism involving hydrolysis of the ester function in the side chain at 3′ and subsequent hydrolysis of the resulting β-lactam yieds essentially the corresponding enamine. The presence of a first solvation layer consisting of five water molecules showed that, even though some potential barriers are slightly increased, the mechanism involved is identical to that of the gas-phase hydrolysis of this antibiotic. © John Wiley & Sons, Inc.     

Numerical sensitivity of trajectories across conformational energy hypersurfaces from geometry optimized molecular orbital calculations: AM1, MNDO,and MINDO/3

The monocyclic β-lactam [[4(S)-methyl-2-oxo-1-azetidinyl]thia]acetic acid was studied by the semiempirical molecular orbital methods AM1, MNDO, and MINDO/3. Using the reaction coordinate option in the program MOPAC on VAX and Cray X-MP computers, the potential energy curve was calculated for rotation of the C2-N1-S-C torsional angle in the conformationally flexible side chain while optimizing all other geometrical variables in the molecule. The trajectory taken during geometry optimization was found to be sensitive to the computer, the program version, the convergence criteria, and the degree of code optimization used in the calculation. In order to reduce the likelihood of spurious results, conformational or reaction energy hypersurfaces need to be calculated with the more precise SCF convergence and minimization criteria available in programs for MINDO/3, MNDO, and AM1 calculations. The nitrogen in the model β-lactam antibiotic is predicted to invert periodically as the dihedral angle to the exocyclic N-substituent sweeps through 360°.     

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

The gas-phase basic hydrolysis of clavulanic acid ( a ) was studied by using the AM1 semi-empirical method. The results obtained show that the hydroxyethylidene side chain at C(2) is pivotal to the stability of the different reaction products involved. The products with an open oxazolidine ring are more stable than those with a closed ring fused to the β-lactam ring. This behaviour differs from that of penicillins and cephalosporins where the most stable degradation products are those with an intact thiazolidine or dihydrothiazine ring, respectively, fused to the β-lactam ring. The different chemical reactivity of clavulanic acid relative to penicillins and cephalosporins could explain the disparate behaviour of the latter two types of compound towards β-lactamases. Once the acyl-enzyme intermediate of clavulanic acid has been formed, it can evolve with cleavage of the oxazolidine ring to form a difficult to deacylate compound.     

Comparison of semiempirical calculations for silicon compounds

A comparison is made of the performance of the MINDO/3, MNDO, AM1, and PM3 methods in calculating the nature of the dimer reconstruction observed on the silicon (100) crystal surface. Based on this case study we conclude that MINDO/3 gives the most realistic results, with PM3 calculations being quite similar but both MNDO and AM1 missing some key features of this system and giving rather unrealistic charge distributions. Hence use of PM3 is recommended for Si containing molecules where a lack of parameters or other restrictions prevent the use of MINDO/3.     

Modeling β-lactam interactions in aqueous solution through combined quantum mechanics–molecular mechanics methods

In this article, we have carried out a series of theoretical computations intended to analyze the interactions of β-lactam compounds in aqueous solution. The final aim is to rationalize the influence of the medium on β-lactam antibiotics reactivity. In particular, the hydrolysis reaction has been studied because of the considerable interest due to its relationship with resistance mechanisms developed by bacteria. The study is extended to the simplest β-lactam molecule, propiolactam or 2-azetidinone, and to the corresponding hydroxylated complex (resulting from the addition of a hydroxyl anion to the carbonyl group) that plays a crucial role in hydrolysis processes. Molecular Dynamics simulations have been carried out using a hybrid quantum mechanics–molecular mechanics potential: the solute is described using the density functional theory, whereas water solvent molecules are treated classically. This represents a sophisticated computational level which, compared to usual force-field simulations, has the advantage of allowing a detailed analysis of solute's electronic properties. The discussion of results is focused on the role played by solute–solvent hydrogen bonds and solvent fluctuations on solute's structure. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1401–1411, 1999     

Theoretical Calculations of β-Lactam Antibiotics. Part VII. Influence of the solvent on the basic hydrolysis of the β-lactam ring

We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OH^? ion on the β-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OH^? ion in approaching the β-lactam carbonyl group. Using the supermolecular approach and a H₂O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).     

Correlation of singlet-triplet gaps for aryl carbenes calculated by MINDO/3, MNDO,AM1, and PM3 with Hammett-type substituent constants

Heats of formation, atomic charges, and geometries of some 110 structures involving substituted singlet and triplet phenyl and 4,4-dimethyl-1,4-dihydronaphthalene carbenes and the corresponding diazomethanes were calculated by MINDO/3, MNDO, AM1, and PM3 semiempirical molecular orbital methods. The singlet-triplet gaps for AM1 and PM3 calculations for the para derivatives in both systems have been successfully correlated with Brown σ⁺ constants. Good correlations with σ⁺ were found for the charges on the carbenic centers of the singlets as well as with the energy barrier for rotation of the aryl group about the C-C single bond in substituted singlet phenylcarbenes. Comparisons of these results with experimental data indicate that AM1 and PM3 are much better than MNDO and MINDO/3 in predicting the intrinsic substituent effects in singlet carbenes.     

Theoretical study of the proton affinities of 2-, 3-, and 4-monosubstituted pyridines in the gas phase by means of MINDO/3, MNDO,and AM1

Proton affinities (PAs) of 2-, 3-, and 4-monosubstituted pyridines in the gas phase are calculated using the MINDO/3, MNDO, and AM1 methods. The following substituents are considered: F, Cl, CN, CH₃, CF₃, CHO, NO₂, NH₂, N(CH₃)₂, OCH₃, and SCH₃. The results are compared with experimental values. It is found that all MINDO/3 PAs are ca. 6% too high (mean value) compared to the experimental results; on the other hand, the MNDO values are ca. 7% too low (mean value). However, a much better agreement has been observed for the AM1 method where the theoretical values are only ca. 2.4% too low (mean value). Correlations between the calculated proton affinities on one hand and the charges on the acid H atom and Hammett constants on the other hand are studied. Particularly good linear relationships are found for the 4-monosubstituted compounds within the AM1 formalism.     

Hydrocarbon acidities calculated with MINDO/3, MNDO,and AM1

Acidities of 32 hydrocarbons have been calculated using MINDO/3, MNDO, and AM1. All three semiempirical procedures have systematic errors and reproduce experimental acidities poorly. A linear correlation, however, does exist between the calculated and experimental results. Correction of the AM1 or MNDO acidities leads to good agreement with literature values even for acids, such as methane and ethylene, whose conjugate bases are small localized anions. Predictions for several hydrocarbons are given.     

Semiempirical and ab initio calculations on the alkaline hydrolysis of the β-lactam ring Influence of the solvent

We used semiempirical and ab initio calculations to investigate the nucleophilic attack of the hydroxyl ion on the β-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions. We also used ab initio calculations and the PM3 semiempirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential energy barrier of 20.7 kcal mol⁻¹ due to the desolvation of the hydroxyl ion in approaching the β-lactam carbonyl group. Using the supermolecular approach and a water solvation sphere of 20 molecules around the solute, the potential energy barrier is lowered to 17.5 kcal mol⁻¹. Ab initio calculations using the SCRF method predict a potential energy barrier of 13.6 kcal mol⁻¹. These three values, especially the last two, are very close to the experimental value of 16.7 kcal mol⁻¹.     

The azomethine ylid strategy for β-lactam synthesis

A summary of the development, mechanistic features, and scope of the azomethine ylid strategy for the synthesis of a variety of bicyclic β-lactam derivatives, including carbapenams, carbapenems as well as heteroatom substituted variants, is presented.     

Intermolecular interactions of methyl acetate, β-propiolactone,ethyl acetate,and γ-butyrolactone: An AM1 semiempirical study

Closely related structures, like esters and lactones, have vastly different physical properties. This is apparently due to differences in the intermolecular interactions. The intermolecular interactions of methyl acetate, β-propiolactone, ethyl acetate, and γ-butyrolactone have been studied using the AM1 semiempirical method. Some of the “arranged clusters” were also compared to possible covalently bound trimers and tetramers of β-propiolactone and γ-butyrolactone. © 1992 John Wiley & Sons, Inc.     

PM3, AM1, MNDO and MINDO3 semi-empirical IR spectra simulations for compounds of interest for Titan's chemistry: diazomethane, methyl azide, methyl isocyanide, diacetylene and triacetylene

Four semi-empirical methods (PM3, AM1, MNDO and MINDO3) have been tested to find the best auxiliary tool for the gas chromatography/Fourier transform IR spectroscopy/mass spectrometry (GC/FTIR/MS) identification of five compounds of interest for Titan's atmospheric chemistry as test compounds: diacetylene, triacetylene, diazomethane, methyl azide, methyl isocyanide. Of the four methods, MINDO3 can be considered as the most appropriate method to facilitate the identification of such and similar compounds, since (1) the simulated IR spectra best match the experimental spectra for four compounds of five studied; and (2) MINDO3 provides the best linearity between the calculated and experimental frequencies (correlation coefficient of 0.995; a scaling factor of 0.84 can be applied to afford better correspondence between the calculated and experimental wavenumbers). None of the semi-empirical methods tested is able to predict (even approximately) infrared band intensities, and therefore a spectral intensity pattern.     

IR spectra simulation as auxiliary tool for gas chromatography/Fourier transform IR spectroscopy/mass spectrometry identification of unknown compounds. 2. PM3, AM1, MNDO and MINDO3 simulations for simple nitriles

A set of the semi-empirical methods (PM3, AM1, MNDO and MINDO3) supplied by the HyperChem™ package has been tested to find the best auxiliary tool for the gas chromatography/Fourier transform IR spectroscopy/mass spectrometry identification of nitriles, taking 23 relatively simple nitriles as test compounds. Of the four methods, MNDO can be considered as the most advantageous since: (1) for 17 compounds of 23 tested, the IR spectra simulated by this method best match the experimental spectra (and in additional 3 cases, the results are as good as those obtained by AM1 method); (2) within the range of experimental wavenumbers of 900–3100 cm⁻¹, MNDO provides the best linearity between the calculated and experimental values (with a correlation coefficient of 0.989). A scaling factor of 0.85 can be used to afford better correspondence between the calculated and experimental wavenumbers. A disadvantage of the MINDO simulations is underestimation of ν_CN (and sometimes ν_CH) band intensities.     

硝酸酯化合物生成热的分子轨道研究

用MINDO/3, MNDO和AM1三种SCF-MO方法, 在全优化分子几何构型的基础上, 系统地计算研究了32个硝酸酯化合物的生成热, 与实验值相比, MNDO计算结果偏大很多; MINDO/3计算值与凝聚相实验值符合较好, 由于克服了MNDO法过高地估算原子之间Van der Waals核排斥能的缺点, AM1法给出了较满意的结果: 与七个气态实验值之间存在良好的线性关系(相关系数为0.992), 其间的平均绝对差值和平均差值分别只有10.28和-1.01kJ/mol。     

Calculations of molecular vibrational frequencies using semiempirical methods

MINDO/3, MNDO, AM1, and PM3 calculations of molecular vibrational frequencies are reported for 61 molecules. All techniques were applied to both well-behaved and badly behaved systems. Overall, MINDO/3 and MNDO were found to contain rather large errors whereas AM1 and PM3 were relatively accurate. Since no technique does well for all molecules, the technique used should be chosen based on the molecular vibration of interest. In general, AM1 and PM3 together provide fairly accurate results.     

Mindo/3 and mndo calculations of closed- and open-shell cations containing C,H, N,and O

Heats of formation of 119 closed- and open-shell carbocations calculated by the semiempirical quantum chemical methods MINDO/3 and MNDO are reported and compared with experimental data. With proper consideration of failures in specific areas, both methods can be used for the thermodynamics of carbocations containing C, H, N, and O. MINDO/3 predicts unrealistic values for nitrogen containing cations with nitrogen multiple bonds and is not suited for closed-shell cations containing oxygen. Saturated acyclic hydrocarbon radical cations often are computed with abnormally long CC bonds by MNDO. Otherwise, the standard deviation of the two methods is not very different, being in the range of ±13 kcal/mol. MINDO/3 tends to overestimate the cation stabilities, whereas MNDO calculates cations usually too high in energy. Some of the errors which were found in the calculations of the ions are related to the computed values for the parent neutral structures, but others are not.     

A convenient route to α-amido-β-lactams

Dedicated to Professor John C. Sheehan on the occasion of his sixty-fifth birthday. A method for the synthesis of α-amido-β-lactams without the intermediacy of an α-amino-β-lactam is described. The appropriate β-keto ester is used for preparing a vinylamino β-lactam via a “Dane salt” by a previously reported method. Oxidation with ruthenium tetroxide and periodic acid of this product leads directly to the desired “V”, or “G” or analogous α-amido side chain.     

Rearrangements of bicyclo[n.1.1]alkylium cations

In accord with experimental observations, AM1, MNDO and MINDO/3 calculations suggest facile rearrangement pathways available to bicyclo[n.1.1]alkylium cations (n=1,2,3).     

PM3, AM1, MINDO3 semi-empirical IR spectra simulations for some nitriles of interest for Titan's chemistry

A set of the semi-empirical methods (PM3, AM1, MNDO and MINDO3) has been tested to find the best auxiliary tool for the identification of nitriles by gas chromatography/Fourier transform IR spectroscopy/mass spectrometry, considering five nitriles of interest for Titan's chemistry as test compounds: acetonitrile, acrylonitrile, cyanoacetylene, 2-butynenitrile and dicyanoacetylene. Of the four semi-empirical methods, MNDO can be considered as the most advantageous auxiliary tool for the gas chromatography/Fourier transform IR spectroscopy/mass spectrometry (GC/FTIR/MS) identification of nitriles of interest for Titan's atmospheric chemistry, since (1) the simulated IR spectra best match the experimental (in some cases AM1 gives comparable results); (2) it provides the best linearity between the calculated and experimental frequencies (correlation coefficient of 0.990); a scaling factor of 0.90 can be applied to afford better correspondence between the calculated and experimental wavenumbers. At the same time, none of the methods is able to predict infrared intensities and a spectral intensity pattern.