The interaction potential index IPI(X) of 16 kinds of substituents X (X=OH, SH, NH2, Br, Cl, I, NO2, CN, CHO, COOH, CH3, CH=CH2, C≡CH, Ph, COCH3, COOCH3) were proposed, which are derived from the experimental enthalpies of formation ΔfH?(g) values of monosubstituted straight-chain alkanes. Based on the IPI(X) and polarizability effect index, a simple and effective model was constructed to estimate the ΔfH?(g) values of monosubstituted alkanes RX (including the branched derivatives). The present model takes into account not only the contributions of the alkyl R and the substituent X, but also the contribution of the interaction between R and X. Its stability and prediction ability was confirmed by the results of leave-one-out method. Compared with previous reported studies, the obtained equation can be used to estimate enthalpies of formation for much more kinds of monosubstituted alkanes with less parameters. Thus, it is recommended for the calculation of the ΔfH?(g) for the RX.