Molecular Pharmacology, Vol 3, 307-317, Copyright © 1967 by the American Society for Pharmacology and Experimental Therapeutics

Quantum Mechanical Calculation of Stability in 2-Formyl N-Methyl Pyridinium (Cation) Oxime (2-PAM⁺) Conformers

¹ Medical Research Laboratory, USAEARL, Edgewood Arsenal, Maryland; Chemistry Department, New York University, Washington Square, New York, New York; Physics Department, Research Institute for Advanced Studies (RIAS), Martin Company, Baltimore, Maryland

1. Twelve conformers of 2-formyl N-methyl pyridinium (cation) oxime (2-PAM⁺) were geometrically defined and were subjected to extended Hückel molecular orbital (XHMO) quantum mechanical calculation.

2. The parameter molecular total overlap population (MTOP) was described and was shown to reflect stability and, in this study, to predict expected geometry.

3. By analyzing total energy (TE) and molecular total overlap population (MTOP), within the limitations of the conditions used and the validity of the approximations in the model chosen, the least stable isomers were found to be the two planar oxime-trans pairs (N₁T_ and N₃T_); the most stable planar isomers were found to be those with oxime syn (cis), and of these the proton pair with aldoxime nitrogen vicinal to ring three (N₃S_) was found to be slightly more stable than its ring counterpart (N₁S_); the most stable of all conformers were found to be the aldoxime out of plane (OOP) quartet; for any rotational state the syn (cis) oxime configuration was found to be more stable than its respective anti (trans) analog; for any nonsterically hindered aldoxime-ring rotational and oxime configurational state the proton anti (trans) configurational state was found to be more stable than its proton syn (cis) analog.

4. By evaluating differences in the same parameters used above, barriers to rotation, conformation, and configuration were estimated and the energetic implications suggested were deemed significant to consider that the most stable conformers are likely to retain their identity at room temperature in slightly acidic solution (their protonated states).

5. The feasibility, implicit in an earlier study, of theoretically determining conformational stability, barriers to rotation, conformation, and configurational stereoisomerism of molecules in the free molecular state (and possibly in dilute solution) is partially and tentatively substantiated.

6. Although by using total energy (TE) alone, the expected geometry was not predictable from the three aldoxime-ring bond lengths chosen, molecular total overlap populations (MTOP’s) clearly indicated that maximal stability should occur between 1.40 Å and 1.55 Å for planar conformers and very close to 1.55 Å for OOP conformers. This finding may generally imply that any molecule can have its exact geometry accurately predicted by theoretical calculations alone.

7. The use of structures derived from crystallography in the stereochemical and quantum chemical analysis of chemical reactivity in solution is suggested at least at times to be precarious.

Note:
ACKNOWLEDGMENT Very warm and special thanks are rendered to Professor Bodil Jerslev for kind and illuminating communications. The technical assistance in data compilation of Betty Wallet, Robert Montgomery, Andrew Westling, Margaret Dalton, Lorraine Hensley, Shirley Hinegardener, Betty Manthei, Toni Caron, and Linda Grimm is gratefully appreciated. The work in developing the programs used in these studies was supported in part by the Air Force Office of Scientific Research of the Office of Aerospace Research under contract AF49(638)-1530. These studies were supported in part by Department of the Army Contract Number DA-18-035-AMC-745(A).