Evaluation of the donor character for urea-based foldamers throughout the empirical estimation of pK_a

H-bond donor capabilities are a key factor for (thio)urea-based helical foldamers to catalyze challenging enantioselective C–C bond-forming reactions. In this investigation, we have characterized that property by computing the pK_a of the (thio)ureas in the reactive site of several foldamers. pK_a estimations were carried out employing an empirical method, alternative to traditional thermodynamic cycles which avoids using the free energy of the proton. It was found that the acidity increases with the length of the foldamer’s helix and that certain substitutions made in the backbone structure could have similar electronic effects than direct substitutions on the ureas, while keeping intact structural parameters. These results show different alternatives to increase the H-bond donor capabilities of foldamers, and by characterizing each of them, it provides key insights for the design of improved catalysts in the area of enantioselective C–C bond-forming reactions.