Calculating the free-energy barriers of liquid-phase chemical reactions with explicit solvent is a considerable challenge. Most studies use the energy and entropy of minimized single-point geometries of the reactants and transition state in implicit solvent using normal mode analysis (NMA). Explicit-solvent methods instead make use of the potential of mean force (PMF). Here, we propose a new energy-entropy (EE) method to calculate the Gibbs free energy of reactants and transition states in explicit solvent by combining quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations with multiscale cell correlation (MCC). We apply it to six nucleophilic substitution reactions of the hydroxide transfer to methyl and ethyl halides in water, where the halides are F, Cl, and Br. We compare EE-MCC Gibbs free energy barriers using two Hamiltonians, self-consistent charge density functional based tight-binding (SCC-DFTB) and B3LYP/6-31+G* density functional theory (DFT) with respective PMF values, EE-NMA values using B3LYP/6-31+G* and M06/6-31+G* DFT in implicit solvent and experimental values derived via transition state theory. The barriers using SCC-DFTB are found to agree well with the PMF and experiment and previous computational studies, being slightly higher but improving on the lower values obtained for the implicit solvent. Achieving convergence over many degrees of freedom remains a challenge for EE-MCC in explicit-solvent QM/MM systems, particularly for the more expensive B3LYP/6-31+G* and M06/6-31+G* DFT methods, but the insightful decomposition of entropy over all degrees of freedom should make EE-MCC a valuable tool for deepening the understanding of chemical reactions.