Theoretical study of the conformational and electrostatic properties of C4-monosubstituted 2-azetidinones

Abstract

The conformational preferences and electrostatic properties of 2-azetidinone, 4-(S)-methoxycarbonyl-2-azetidinone and 4-(R)-methyl-2-azetidinone have been studied in gas-phase, aqueous solution and CC14 solution using quantum mechanical methods. Gas-phase calculations were performed at the ab initio HF, MP2, and MP4 levels and solvent effects were investigated using a self-consistent reaction-field procedure adapted to the AM I Hamiltonian. An almost planar arrangement was adopted by the/3-1actam ring in the three cases, whereas the alkoxycarbonyl side group was found to display a large conformational flexibility. The effects of the different solvents on the electrostatic properties of the three compounds were investigated by following the changes in both molecular electrostatic potentials and induced dipole moments. The resulting electrostatic parameters were used as static reactivity indices to predict the response of the systems to the attack of nucleophilic reagents. Theoretical results were compared with experimental data available on the structure and properties of/3-1actams. The validity of the method as a predicting tool was critically discussed.

Quantum chemical study of several monocyclic complex β‐lactam C‐3, C‐4, and N‐derivatives, and β‐ring model molecules

“…The reactivity of C‐substituted 2‐azetidinones has been related to the deviation from planarity of the β‐lactam ring caused by the presence of the substituent 25. As a higher single character of the N1C2 bond, higher pyramidal character of the N1 atom, lower degree of polar form, and a higher antibiotic activity of the drug is achieved.…”

“…2‐Azetidinone, by contrast, is almost planar. It is the simplest four‐membered lactam that has been extensively studied by x‐ray 20, 21, by the joined (ED + MW) 22, and by ab initio methods 6, 20, 23–25. Its hydrolysis and the influence of the solvent have been analyzed theoretically 26.…”

FTIR study of five complex β‐lactam molecules

“…Although the molecular structure of 2‐azetidinone was recently investigated using experimental and theoretical methods, very little is known about the structural properties of its substituted derivatives 7. The reactivity of C‐substituted 2‐azetidinones was related to the deviation from planarity of the β‐lactam ring caused by the presence of the substituent 8. Because a weaker CN bond and a lower degree of amide resonance is produced, the antibiotic activity of the drug increases.…”

QSAR study of β‐lactam antibiotic efflux by the bacterial multidrug resistance pump AcrB

“…Furthermore, it has been shown recently by QSAR studies [56,57] that lipophilicity parameters can be treated as a linear combination of suitable steric and electronic molecular properties, which may aid in mechanistic interpretation of pump-drug interactions. On the other hand, -lactam antibiotic molecules interact with polar solvents, so charge transfer [58] and changes of -lactam molecular dipole moment and atomic charges [59] occur. These findings as well as the above results, explain why electronic and HB parameters are important in PLS models.…”