A MOLECULAR MECHANICAL MODEL THAT REPRODUCES THE RELATIVE ENERGIES FOR CHAIR AND TWIST-BOAT CONFORMATIONS OF 1,3-DIOXANES

We present molecular mechanics calculations on the conformational ener gies of several 2,2-dimethyl-trans-4,6-disubstituted-1,3-dioxanes. Pre vious studies by Rychnovsky et al. have suggested that the relative co nformational energies of chair and twist-boat forms of these 1,3-dioxa nes were poorly represented by the molecular mechanical models MM2 an d MM3 (MacroModel implementations of MM2 and MM3) both when compared to experiment and to high-level quantum mechanical calculations. We ha ve studied these molecules with a molecular mechanical force field whi ch features electrostatic-potential-based atomic charges. This model d oes an excellent job of reproducing the relative conformational energi es of the highest level of theory (MP2/6-31G) applied to the problem. Furthermore, when empirically corrected using the MP2/6-31G relative conformational energies of the unsubstituted compound 2,2,4-trimethyl -1,3-dioxane, the absolute energy differences calculated with this new model between the chair and twist-boat conformers for five substitute d compounds are within an average of 0.30 kcal/mol of the MP2/6-31G v alues. The correlation with experiment is also very good. One can, how ever, modify the initial molecular mechanical model with a single V-1( -O-C-O-C-) torsional potential and do an excellent job in reproducing the absolute conformational energies of the dioxanes as well, with an average error in conformational energies of 0.45 kcal/mol. This same t orsional potential was independently developed by comparing ab initio and molecular mechanical energies of the molecule 1,1-dimethoxymethane . Thus, we have succeeded in developing a general molecular mechanical model for 1,3-dioxoalkanes. In addition, we have compared the standar d MM2 and MM3 models with MM2 and MM3* (ref. 2) and have found some s ignificant differences in relative conformational energies between MM2 and MM2. MM2 has an improved correlation with the best ab initio dat a compared to MM2 but is still significantly worse than that found wi th lower-level ab initio or AM1 semiempirical quantum mechanics or the new molecular mechanical model presented here. MM3 leads to conformat ional energies very similar to MM3. Energy component analysis suggest s that the single most important element in reproducing the conformati onal equilibrium is the electrostatic energy. This fact rationalizes t he success of AMBER models, whose fundamental tenet is the accurate re presentation of quantum mechanically calculated molecular electrostati c effects. (C) 1995 by John Wiley and Sons, Inc.