Abstract: Based on the electrostatic effects of the alkyl R and the substituent X, combining the polarizability effect index PEI(R) of alkyl R and the electronegativity χX of substituent X, the interaction of R and X in monosubstituted alkane RX was quantified. It was taken as the parameters that the eigenvalues (X1CC and X1CH) of the orbital-connecting matrices of Ci—Cj and Ci—H bonds together with the interaction of R and X in RX. A general expression to estimate the enthalpies of formation ΔfH0(RX, l) for monosubstituted alkanes RX (where, X=Cl, Br, I, OH, SH, NO2, CN, NH2, CHO and COOH) in liquid-phase was established： ΔfH0(RX, l)＝－39.5001ΣX1CC＋33.5508NCC－0.0789ΣX1CH－25.7087NCH＋0.1557ΣSij＋0.9976H(X)－ 27.6642 PEI(R)×χX＋31.5043χX Where the NCC and NCH are the numbers of C—C and C—H bonds in the RX molecule respectively, the H(X) is the contribution of the substituent X to theΔfH0(RX, l). The equation can be used to predict the enthalpy of formation well for RX in liquid-phase with a correlation coefficient R=0.9999 and a standard derivation SD=2.87 kJ•mol^-1. What is more, each of the items in the equation has its explicit physical meaning. The obtained equation can help us further understand the correlation between molecular structures and their properties. The stability of the above equation was tested by the leave-one-out cross-validation method. The research result shows that the famous Luo's equation is a specific expression of the above equation, which can be regarded as a od progress in this field of Luo's research. This work maybe explores a novel way to investigate the interaction of the substituents in more complex compounds.