Density functional theory (DFT) was used to study the heat of formation (HOFs), electronic structure, energetic properties and thermal stability for a series of purine derivatives with difluoroamino groups. The isodesmic reaction method was employed to calculate the HOFs of the energies obtained from electronic structure calculations. Results indicated that the position of difluoroamino groups could influence the values of HOFs. The bond dissociation energies and bond orders of the weakest bonds were analyzed to investigate the thermal stability of the purine derivatives. Furthermore, the detonation velocities and pressure were evaluated by using the Kamlet–Jacobs equations based on the theoretical densities and detonation heat (Q). The cylinder wall velocities ( ) were also calculated using the simplified calculational method. Compared with the conventional explosives, two purine derivatives may be regarded as the potential candidates for practical HEDCs.