Computer-aided molecular design is a strategy in which a set of structural groups are systematically combined to form molecules with desired properties. In this paper, a mathematical programming-based approach to computer-aided molecular design is presented. Using a set of structural groups, the problem is formulated as a mixed integer nonlinear program in which discrete variables represent the number of each type of structural groups present in the candidate compound. The augmented-penalty/outer-approximation algorithm is used to solve the MINLP to obtain compound(s) with an optimum value of an appropriate performance index such that molecular structural constraints, physical property constraints and process design limitations are met. With the current renewed interest in the environment, the suggested approach is applied to refrigerant design with an environmental constraint. The results indicate the viability of this approach.