In the unsubstituted TS2 structure, the dominant E interaction involves the delocalization of the isocyanate oxygen lone pair into the closest water O-H* orbital. As electron density is removed from the C-O* orbital via substituent effects, the C-O bond elongates and the isocyanate oxygen lone pair cannot delocalize as easily. To summarize, electron withdrawing substituents on the isocyanate species lower the barrier to reaction via the pathways through both TS1 and TS2. This principle can almost certainly be generalized to RNCO reactions with different R-OH species and even related reactants such as R 2 N-H, because the reaction motif will remain rather consistent. However, more complicated molecules reacting with RNCO might convolute these well-behaved trends, introducing new factors such as sterics, dispersion interactions, and exotic electronic structure features. Nevertheless, we expect our trends to hold given similar reaction motifs and the fact that the isocyanate substituents are not involved in the active site of the reaction. It is also key to note that the same correlations hold and maintain their fidelity when using the 298 K Gibbs energies, which usually shift all estimated values by approximately 11 kcal mol -1 regardless of the substituent. Thus, our substituent analysis seems robust to higher temperature conditions.