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Reports: DNI751850-DNI7: N-Alkyl Urea Peptoid Oligomers as a New Type of Self-Assembling, Highly Versatile Soft Materials for Applications Involving Organogelators

Neil Ayres, PhD, University of Cincinnati

The synthesis of N-alkyl urea oligomers is simple to perform, however when preparing longer oligomers, this synthetic route results in many steps. The purification and isolation of the synthetic intermediates is often the most challenging component.  For simple systems it would be beneficial to only need one oligomer that can be prepared in larger quantities.  We designed an N-alkyl-N,N-linked urea oligomer that contained hydroxyl functionalized N-alkyl groups to accomplish this (Compound 7, Scheme 1).    We chose to use a hydroxyl group as (in addition to being inherently useful) it is highly versatile and can easily be converted into many other functional groups.  However, hydroxyl groups are not compatible with the oligomer synthesis route.  As a result we used protecting group chemistry for the hydroxyl group during the oligomer synthesis.  The methoxy methyl ether (MOM ether) group is advantageous as it is a common protecting group and stable to the oligomer synthesis conditions.  The MOM groups were deprotected using a 2 M HCl solution at 40 °C  We demonstrated the synthetic versatility of the hydroxyl-functionalized oligomer by converting the –OH group to three other functional groups, namely alkyl chloride, alkyl azide and carboxylic acid (Scheme 1). Scheme 1. Functional group conversion of hydroxyl groups into alkyl chlorides, alkyl azides, and carboxylic acids.   Having completed the “universal” N-alkyl urea peptoid synthesis we focused our attention on using these oligomers as organogelators.  Our first molecules used ureidopyrimidone (UPy) terminal moieties to promote gelation in polar aprotic solvents through a balance of the insolubility of the UPy groups and the high solubility of the N-alkyl urea functional group (Scheme 2).   Scheme 2. Synthesis of Gelator 1 and 2.   The gelation abilities of both gelators in organic solvents were investigated using the “stable to inversion” method. As summarized in Table 1, both gelators formed gels in selected polar aprotic solvents.   Table 1. Gelation ability of 1 and 2 in organic solvents. Critical concentration value (wt % and concentration in mol/L (M)) is shown next to the gel symbol.
Solvent 1 2
n-Hexane P P
Toluene P P
Anisole P P
Pyridine G (7.5, 0.097 M) G (5.8, 0.056 M)
Tetrahydrofuran P P
Ethyl acetate P P
Chloroform P S
DMSO G (4.3, 0.061 M) G (6.0, 0.065 M)
DMF G (6.5, 0.082 M) G (6.6, 0.065 M)
Heavy mineral oil P P
G: gel; P: precipitate; S: soluble.
  The gel transition temperature (Tgel) is the temperature at which a gel undergoes a gel-sol transition and the value of Tgel reflects the thermodynamic stability of a gel. The Tgel increased as the weight percentage of gelators was increased until a plateau was reached. The organogels from gelator 1 show higher Tgel values than those from gelator 2. The differences in Tgel values between the two gelators presumably reflect differences in network organization in the gelled state.   Rheological measurements provide determinative evidence for gel formation. A weight ratio of 5 wt% of gelator 1 in DMSO was used to make a gel. The storage modulus, G', and the loss modulus, G”, of the 5 wt% gelator solution were plotted against time upon quenching from 80 oC to 25 oC (Figure 3a). The moduli increased continuously over the time span of the experiment, and eventually reached equilibrium values meaning formation of a stable gel.
Figure 3. (a) Time sweep of the storage (G') and loss (G”) modulus at 25°C after a quench from 80°C at frequency of 1 rad/s and strain of 1%. (b) Frequency sweep at 25°C at a strain of 1% (c) Strain sweep at 25°C at a frequency of 1 rad/s. Symbols: G' – black squares, G” – red circles.   The gel was then subjected to a frequency sweep over a frequency range of 100 to 0.01 rad/s. As shown in Figure 3b, G' was invariant with frequency confirming the dominant elastic (i.e., gel) character.   Having shown that UPy-functionalized N-alkyl urea peptoid oligomers act as gelators we modified our “universal” oligomer with UPy units and investigated their aggregation.  When 60 mg of the UPy-end functionalized oligomer B was dissolved in 1.0 mL of CHCl3, the solution was observed to undergo a marked increase in viscosity.  Indeed, after two days the vial could be inverted and the solution would not flow unless agitated.  This result strongly suggested that the UPy-modified N-alkyl urea peptoid oligomers were aggregating into higher molecular weight species Diffusion-ordered 1H NMR spectroscopy (DOSY) and concentration-dependent solution viscosity experiments were performed. The viscosity corrected self-diffusion constant (Dc) of solutions of oligomers becomes smaller with increasing concentration of oligomer in solution, implying that polymeric species are forming at higher concentrations. A double logarithmic plot of the specific viscosity against solution concentration showed a marked change in the slope from 1.006 to 2.785 at approximately 30 mM (Figure 4).

Figure 4. Solution viscosities of Compound B (top) and Compound 6 (bottom) at varying concentrations. The change in slope for Compound B occurs at ~ 30 mM.The slopes are shown in the Figure as m = x.xx.   The result shown in Figure 4 can be explained due to the presence of equilibrium in solution between polymers and low molecular weight species.  We investigated the viscosity of the oligomer containing MOM pendent groups without UPy groups (Compound 6) at different concentrations as a control experiment. The results are also plotted in Figure 4.    We have modified the oligomer with carbazole to investigate the afforded gels photochemistry (Scheme 3). These experiments are currently ongoing.   Scheme 3. Carbazole functionalized oligomers   This work has had a positive impact on my career and the training of students (Xiaoping Chen; Xinjun Yu) who have participated in the project.  Xiaoping and Xinjun have presented their findings at national meetings, garnering them exposure to other scientists and professional networking opportunities.  This work has lead to scientific discussions and potential collaborations both internally at the University of Cincinnati and with researchers at other institutions.  We anticipate that the remainder on this project will result in new findings that will be leveraged into several new research directions.