Ab initio rotational barriers and solvation free energies of fluorinated dimethyl ethers

Abstract

Halogenated ethers are a significant class of inhalation anesthetics, but current molecular mechanics packages have not been parameterized to deal with this class of compounds. Here a first step is made towards the determination of these parameters for halogenated ether anesthetics by calculation of the -CH 3, -CF 3, -CH 2F, and -CHF 2 rotational barriers in a series of ten fluorinated dimethyl ethers. With the 6–31G ∗∗ basis set, the shape and magnitude of the rotational barrier was found to be dependent on the number and location of fluorine substituents. Inceasing the number of fluorine substituents on the opposite methyl group leads to a decrease in the rotational barrier. With zero, one, two, and three fluorines on the opposite methyl group, the -CH 3 rotation barrier was found to be 2.53, 1.76, 1.02, and 1.13 kcal mol −1, respectively, and the -CF 3 rotation barrier was found to be 2.64, 2.03, 1.88, and 1.03 kcal mol −1, respectively. Similar trends were noted for the gauche-trans, trans-gauche, and gauche-gauche barriers for the -CH 2F and -CHF 2 groups. Inclusion of electron correlation at the MP2/6–31G ∗∗//6–31G ∗∗ level had negligible effect on the energy of the minimum and maximum energy conformers of the analogs. The calculations show that increasing fluorine substitution has a pronounced effect in opening the COC bond angle, presumably due to lone pair-lone pair repulsions. The central COC bond angle varied between 114 ° and 131 ° for the series, a range of values much larger than the COC angle of 107 ° given in MM3. The gas phase ab initio energy increases as the C OC bond angle increases. Fluorine substitution on one methyl group decreases the OC bond length of the carbon to which the fluorine is attached and increases the length of the other OC bond. Increasing the number of fluorine substituents on the same carbon leads to a more pronounced effect. Inclusion of solvation free energy, calculated by the Induced Polarization Charge Boundary Element Method, was found to have a negligible effect on the potential energy surface. Further, the difference between the calculated electrostatic contribution to the hydration free energy and enthalpy was on the order of 3%–4%.