We have tested the accuracy of the DFTB/MM model for reproducing the free energy profiles for three different reactions in water: (i) the cis/trans isomerization of proline and a proline peptide, (ii) the intramolecular and waterassisted proton transfer in pterin, and (iii) the SN 2 reaction of chloromethane with sodium fluoride. For these reactions, we have assessed the quality of different methods and parameters used in DFTB to describe the free energy activation barriers and the difference between reactants and products by comparing them to experimental data or highlevel ab initio results. Overall, we find that DFTB2/MM can qualitatively describe the free energy activation barriers for all reactions compared to ab initio simulations, besides the pterin water-assisted proton transfer, in which a sequential instead of simultaneous proton transfer is found. The DFTB3 reproduces well the activation barriers, but it tends to favor weak endothermic reaction when ab initio and/or experimental data indicates the contrary. As for DFTB2, DFTB3/MM predicts a sequential water-assisted proton transfer for pterin. For the SN 2 reaction, the relative stability between chloromethane and fluoromethane is not only dependent on the DFTB method used but also on the QM/MM van der Waals parameters that are usually taken from the forcefields. We show that optimized QM/MM vdW parameters are fundamental to representing the exothermic reaction in favor of fluoromethane.