Elucidating Conformation and Hydrogen-Bonding Motifs of Reactive Thiourea Intermediates.

Substituted diphenylthioureas (DPTUs) are efficient hydrogen-bonding organo-catalysts, and substitution of DPTUs has been shown to greatly affect catalytic activity. Yet, both the conformation of DPTUs in solution and the conformation and hydrogen-bonded motifs within catalytically active intermediates, pertinent to their mode of activation, have remained elusive. By combining linear and ultrafast vibrational spectroscopy with spectroscopic simulations and calculations, we show that different conformational states of thioureas give rise to distinctively different N-H stretching bands in the infrared spectra. In the absence of hydrogen-bond-accepting substrates, we show that vibrational structure and dynamics are highly sensitive to the substitution of DPTUs with CF groups and to the interaction with the solvent environment, allowing for disentangling the different conformational states. In contrast to bare diphenylthiourea (0CF-DPTU), we find the catalytically superior CF-substituted DPTU (4CF-DPTU) to favor the - conformation in solution, allowing for donating two hydrogen bonds to the reactive substrate. In the presence of a prototypical substrate, DPTUs in - conformation hydrogen bond to the substrate's C=O group, as evidenced by a red-shift of the N-H vibration. Yet, our time-resolved infrared experiments indicate that only one N-H group forms a strong hydrogen bond to the carbonyl moiety, while thiourea's second N-H group only weakly interacts with the substrate. Our data indicate that hydrogen-bond exchange between these N-H groups occurs on the timescale of a few picoseconds for 0CF-DPTU and is significantly accelerated upon CF substitution. Our results highlight the subtle interplay between conformational equilibria, bonding states, and bonding lifetimes in reactive intermediates in thiourea catalysis, which help rationalize their catalytic activity.