AB-INITIO ROTATIONAL BARRIERS AND SOLVATION FREE-ENERGIES OF FLUORINATED DIMETHYL ETHERS

Halogenated ethers are a significant class of inhalation anesthetics, but current molecular mechanics packages have not been parameterized t o deal with this class of compounds. Here a first step is made towards the determination of these parameters for halogenated ether anestheti cs by calculation of the -CH3, -CF3, -CH2F, and -CHF2 rotational barri ers in a series of ten fluorinated dimethyl ethers. With the 6-31G* b asis set, the shape and magnitude of the rotational barrier was found to be dependent on the number and location of fluorine substituents. I nceasing the number of fluorine substituents on the opposite methyl gr oup leads to a decrease in the rotational barrier. With zero, one, two , and three fluorines on the opposite methyl group, the -CH3 rotation barrier was found to be 2.53, 1.76, 1.02, and 1.13 kcal mol(-1), respe ctively, and the -CF3 rotation barrier was found to be 2.64, 2.03, 1.8 8, 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 -CHF2 groups. Inclusion of electron correlation at the MP2/6-31 G*//6-31G** level had negligible effect on the energy of the minimum and maximum energy conformers of the analogs. The calculations show th at increasing fluorine substitution has a pronounced effect in opening the C-O-C bond angle, presumably due to lone pair-lone pair repulsion s. The central C-O-C bond angle varied between 114 degrees and 131 deg rees for the series, a range of values much larger than the C-O-C angl e of 107 degrees given in MM3. The gas phase ab initio energy increase s as the C-O-C bond angle increases. Fluorine substitution on one meth yl group decreases the O-C bond length of the carbon to which the fluo rine is attached and increases the length of the other OC bond. Increa sing the number of fluorine substituents on the same carbon leads to a more pronounced effect. Inclusion of solvation free energy, calculate d by the Induced Polarization Charge Boundary Element Method, was foun d to have a negligible effect an 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%.