Istomin and Palm proposed a model, ΔfH0(RX)=h[R]+h[X]+φ[R]φ[X], (the h[R] and h[X] are the contributions of alkyl R and substituent X to the ΔfH0(RX), respectively. φ[R]φ[X] represents the interaction of alkyl R and substituent X), to express the enthalpies of formation of monoderivatives of hydrocarbons ΔfH0(RX). However, in two-direction extending compounds R1-Y-R2, the Y substituent is attached to two alkyl groups (R1 and R2), and the intramolecular interactions are more complicated than that in monosubstituted alkanes. Thus, the Istomin-Palm model must be modified. In this work, the interactions among Y, R1, and R2 contributing to the enthalpy of formation, ΔfH0(R1-Y-R2), are divided into three parts: the interaction between R1Y and R2(φ[R2]φ[R1Y]), the interaction between YR2 and R1 (φ[R1]φ[YR2]), and the interaction between R1 and R2 (ψ[R1]ψ[R2]). These three interactions replace the φ[R]φ[X] term, and a new extended Istomin-Palm model, ΔfH0(R1-Y-R2)=h[R1]+h[R2]+h[Y] +φ[R1]φ[YR2]+φ[R2]φ[R1Y]+ψ[R1]ψ[R2], is proposed. In this model, h[Y] is the contribution of substituent Y to ΔfH0(R1-Y-R2). The h[R1] and h[R2] terms are the contributions of alkyls R1 and R2 to ΔfH0(R1-Y-R2). The last three terms are the total contribution of interactions among Y, R1, and R2. Furthermore, the interaction potential index IPI(X) reported in our recent work (Wu, Y. X.; Cao, C. Z.; Yuan, H. Chin. J. Chem. Phys. 2012, 25 (2), 153.) was employed to express the intrinsic interaction of Y with alkyl groups (φ[Y]), and two general expressions were established to estimate ΔfH0, in which one is for thioethers, secondary amines, ethers, and ketones, and the other is for esters. These two estimating equations give results, which are as accurate as G3 and G3MP2 models in calculating ΔfH0 for R1-Y-R2 compounds. Moreover, our method avoids time consuming calculations.