The structures and the Lennard-Jones (U) parameters of anesthetic 1-chloro-1,2,2-trifluorocyclobutane (F3) and nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6) were optimized by using ab initio calculations in conjunction with liquid and gas phase molecular dynamics simulations. Geometry optimization of various isomers of F3 and F6 was carried out with MP2/6-311 +G(2d,p) that reproduced the experimental pucker angles of the precursors perfluorocyclobutane and cyclobutane more accurately than with B3LYP/6-311+G(2d,p). Frequency calculations were performed to ensure that the optimized structures were at minimums of the potential energy surfaces. The partial atomic charges of F3 and F6 from the Merz-Singh-Kollman MP2/6-311 +G(2d,p) calculations and the LJ parameters optimized previously for other halogenated compounds were used to start molecular dynamics simulations. The LJ parameters were then optimized through iterative adjustments to regenerate the heat of vaporization and the densities of F3 and F6 until the differences between the calculated values and the experimental values or empirical predicted values were less than 2%. With the optimized structures, the partial atomic charges, and the LJ parameters, F3 and F6 are readily usable as an anesthetic -nonimmobilizer pair in molecular dynamics simulations aimed at understanding the molecular mechanisms of general anesthesia.