Strength and directionality are the hallmark characteristics of binding for molecules with multiple hydrogen bonds. This is important in the area of molecular recognition and supramolecular construction. When coupled to a redox center, oxidation or reduction can affect hydrogen bonds by either strengthening or weakening bonding, and thus allow for greater control over this type of binding. One class of model compounds which can be used to investigate the effects of manipulating the characteristics of hydrogen bonding are bi-substituted ureas. An example previously studied in our group is 1-phenyl-3-(4-dimethylamino)phenylurea (UHH), which has a H-donor-donor (DD) motif. This compound was coupled with two guests that have a H-acceptor-acceptor (AA) motif, 1,4-dimethylpiperizine-2,3-dione (PZD) and 1,8-naphthyridine (naph), to investigate the effects of oxidation on hydrogen binding.

Cyclic voltammetry (CV) of UHH in the presence of PZD in methylene chloride shows a reversible, one electron oxidation wave whose E_1/2 shifts negative with an increase in concentration of PZD. This indicates an increase in hydrogen binding strength upon oxidation. It was originally thought to be due to stronger binding to the UHH radical cation, but additional CV investigations of isolated UHH revealed that it actually undergoes a two electron per two urea process as shown in equation 1 to give the doubly oxidized UH⁺ plus the protonated, still reduced, HUHH⁺. Since only HUHH⁺ retains the DD motif, it is more likely that it is strong H-bonding between HUHH⁺ and PZD that cause the observed potential shift. Analyzing the potential shift data based on this assumption gives binding constants K_red = 30 M⁻¹ and K_ox =700 M⁻¹. In contrast to PZD, CV studies of UHH in the presence of naph show the current for the oxidation increases with little change in E_1/2. This is rationalized by proton transfer from the UHH radical cation to the naph rather than the dimethylamino group on a reduced UHH, equation 2. This allows full oxidation of all the UHH, but results in conversion of the more favorable DD-AA H-bond motif to the less favorable AD-DA plus creates electrostatic repulsion. These effects counteract the increased acidity caused by oxidation, apparently resulting in no significant change in H-bonding strength.

In new studies, the phenylenediamine redox center in UHH has been replaced with a ferrocene redox center, producing the compound 1-ferrocenyl-3-phenylurea (FcUHH). This change limits the oxidation to a one electron process, equation 3, and removes the basic site that facilitates proton transfer. Initial CV experiments of FcUHH and PZD in methylene chloride show a reversible, one electron oxidation with a corresponding negative shift in E_1/2 with increasing concentration of PZD. The magnitude of the shift is comparable to UHH with PZD, and analysis of this data gives binding constants K_red = 80 M⁻¹ and K_ox = 500 M⁻¹. Since oxidation of the ferrocene to ferrocenium produces a +1 charge, as does protonation of the dimethyamino group of UHH, the similarity of this result to that observed with UHH and PZD supports the hypothesis that the potential shifts observed with UHH and PZD are due to H-bonding with the protonated, reduced urea. Similar studies will be performed with FcUHH and naph for comparison to the UHH and naph result.

One complication in the studies with FcUHH is that, to date, we have been unable to fully remove a small amount of 1,3-diphenylurea side-product. Since the N-H’s in FcUHH and 1,3-diphenylurea likely have similar polarity and thus affinity for PZD and naph, our existing binding constant measurements are flawed due to competition between FcUHH and diphenylurea for binding to the guest. This issue is currently being addressed with NMR titrations of 1,3-Diphenylurea with PZD and naph to measure these binding constants. This will allow a more accurate mathematical model to be constructed to fit the potential shift data for FcUHH and the guests. Moving forward, we hope to optimize the reaction conditions for the synthesis of FcUHH to prevent formation of the diphenylurea. However, whether we are successful with this or not, it is clear that the studies with FcUHH will provide an interesting and informative comparison to the earlier work with UHH and add to our understanding of redox-dependent H-bonding in general.