In this paper, a novel mixed integer non‐linear programming model for single component refrigerant design is presented. At the heart of the approach is a new formulation for structural feasibility that allows multiple bonds, connectivity and isomers. The strategy defines a set of structural groups (consisting of atoms), subsets of which are combined to form refrigerant molecules. Molecules formed this way must obey structural and stability constraints. The design objective is to build a refrigerant molecule that has desired physical properties and performance characteristics. These attributes are formulated as mathematical programming constraints and performance objectives which involve both continuous and integer variables. 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 and the flexibility of the approach.