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Capítulo 5. Incidencia de las características de los integrantes de las organizaciones de
The simplicity of the molecular structure of compound 6 gave rise to uncomplicated
1H and 13C NMR spectra. A singlet at 3.06 ppm with an integral of three in the 1H NMR spectrum of compound 6 was observed for the three equivalent protons of the methyl group, this indicated formation of compound 6. In the 13C NMR spectrum, a characteristic quartet at 124.8 ppm with 1J = 270.8 Hz, was observed for the two – CF3 groups. Additionally, a quartet at 132.8 ppm (2J = 33.0 Hz) was observed for the aromatic carbon directly attached to the –CF3 groups (-C-CF3) with the C=S carbon signal at 183.7 ppm.
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The synthesis of compound 7 was carried out as shown in Scheme 2.7 using a 2:1 ratio of amine:isothiocyanate. The reaction resulted in a good yield of 84%, after purification by silica gel column chromatography. A quartet at 3.60 ppm and triplet at 1.23 ppm, each with 3J = 7.3 Hz, corresponding to the protons of the ethyl group were observed in the 1H NMR spectrum, this indicated formation of compound 7.
The quartets at 124.8 ppm and 132.7 ppm, in the 13C NMR spectrum, were found to have J values of 270.2 and 33.0 Hz, respectively. These coupling constants correspond to values associated with one-bond and two-bond C-F coupling constants and therefore correspond to the carbons of the –CF3 groups (1J = 270.2 Hz) and the carbons ipso to the –CF3 groups (2J = 33.0 Hz).
Compound 8 (Scheme 2.7) was synthesised using a 1:1 ratio of amine:isothiocyanate. A white solid, in 75% yield, was generated after purification by silica gel column chromatography. LC/TOF-MS returned a (M+H+) of 360.0961 indicating formation of the product. However, the 13C and 1H NMR spectra of compound 8, in CDCl3, were complex. Doubling and broadening of the 13C signals was observed in the 13C NMR spectrum whilst the proton signals of the 1H NMR spectrum were broad and poorly resolved (Figure 2.18). It was thought that perhaps the complex spectra were the result of some form of chemical exchange occurring in solution, for example, restricted bond rotation or tautomerism.
Figure 2.18: 1H NMR spectrum of compound 8 in CDCl3. The residual solvent 1H signal was observed at 7.25 ppm.
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In NMR, chemical exchange involves the movement of a nucleus from one environment to another. A commonly encountered example of chemical exchange is restricted bond rotation about the C-N bond of amides, for example, N,N-dimethylformamide (DMF). As shown in Figure 2.19, DMF can be represented as two resonance forms. At room temperature, the partial double bond character of the C-N bond allows each of the methyl groups to experience different environments giving rise to a resonance signal for each of the methyl groups at different chemical shifts in the NMR spectra. However, by increasing the temperature of the NMR sample, the barrier to rotation (activation energy required for rotation about the single bond) can be overcome thus resulting in an increase in rotation about the C-N bond. This increase in rotation about the C-N bond allows the methyl groups to experience the same environment resulting in an NMR spectrum wherein both of the methyl groups are represented by one single resonance signal.
Figure 2.19: Resonance forms of DMF.
The organocatalytic property of the thiourea derivatives mentioned in section 2.1.1 is based on their ability to form H-bonds.76 A review of the literature found that thiourea derivatives, like Takemotos catalyst, have the ability to self-associate through intra- and intermolecular H-bonding interactions.96 In fact, this ability to self-aggregate can interfere with the catalytic ability of thiourea-based organocatalysts with high catalyst load and the use of protic solvents having been shown to result in lower enantioselectivities.96c,97 Studies by Tárkányi et al.96a,b using low temperature NMR spectroscopy demonstrated that at low temperature both a momomeric and dimeric species resulting from H-bond interactions of the thiourea catalysts can be observed. In both the cinchona-based thiourea organocatalyst and Takemotos catalyst an intramolecular H-bond interaction occurs between the tertiary amine and one of the thiourea NH’s giving rise to a monomeric species.96a,b Additionally, intermolecular H-bonding occurs between the thiourea NH’s of one
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molecule of catalyst and the thiourea sulfur atom of a second catalyst molecule resulting in the formation of a dimer.96a Furthermore, it is believed that the monomeric and dimeric forms are in equilibrium (chemical exchange) and that these self-aggregrates are the cause of the broadening effect of 1H NMR signals at room temperature.96b
Taking these studies into consideration, it was believed that the thiourea derivative, compound 8, may be undergoing self-association in CDCl3 and therefore resulting in a broadening effect of the signals in the NMR spectra. In order to investigate this, the NMR experiments were carried out using CD3OD in place of CDCl3. Methanol is a polar protic solvent with the ability to accept and donate H-bonds and should therefore interfere with the H-bonding interactions and disrupt the self-association of the thiourea derivatives. The disruption of H-bonding interactions should, in turn, result in sharper resonance signals in the NMR spectra. As observed with the cinchona-based organocatalysts96b, the 1H and 13C NMR spectra of compound 8 in CD3OD exhibited one set of sharp resonance signals indicating a loss in self-association (Figure 2.20).
Figure 2.20: 1H NMR spectrum of compound 8 in CD3OD. The residual solvent 1H signal was observed at 3.32 ppm and the 1H signal for H2O at 3.91 ppm.
To further confirm the occurrence of self-association of compound 8 a number of 1H NMR experiments were ran at higher temperatures. If the monomeric and dimeric
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thiourea species of the thiourea bifunctional catalysts can be observed in NMR spectra at low temperatures then by increasing the temperature the speed at which they are equilibrating should increase and give rise to sharper resonance signals in the NMR spectra. A series of experiments were carried out in CDCl3 at a range of temperatures from 25 oC to 54 oC (Figure 2.21).
Proposed structure of the dimeric form of compound 8.
Figure 2.21: A selection of the variable temperature (VT) 1H NMR spectra of compound 8 in CDCl3 and a proposed structure for the dimeric form of compound 8.
Spectra recorded at (–) 25 oC, (–) 30 oC, (–) 40 oC and (–) 50 oC.
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As can be seen in Figure 2.21, an increase in temperature resulted in sharper resonance signals. The 1H NMR signals showed no further improvement in lineshape above 50 oC thus the 13C NMR experiment (CDCl3) was also carried out at this temperature. The resulting 13C NMR spectrum exhibited only one set of sharper resonance signals unlike that observed at 25 oC.The results indicate that at room temperature compound 8 may exist as both a dimer and monomer as a result of H-bonding interactions and that an increase in temperature can increase the rate at which these species are interconverting. Additionally, the use of a protic solvent (CD3OD) appears to interrupt the H-bonding interactions resulting in NMR spectra with a single set of sharp resonance signals.
As with compound 6 and 7, in the 13C NMR spectrum of compound 8 (CD3OD) a quartet at 124.8 ppm with 1J = 270.8 Hz was assigned as the 13C signal of the –CF3
groups. The 13C signal representing the carbon atoms adjacent to the –CF3 groups (-C-CF3) was found at 132.7 ppm having a characteristic two-bond C-F coupling constant of 33.0 Hz. Due to the deshielding effect of the tertiary amine moiety the
13C signals for the carbon atoms of the two-carbon chain (-CH2CH2) were found at 58.6 and 43.0 ppm, downfield from those of the ethyl chain of compound 7. This was also the case for the protons of the two-carbon chain in the 1H NMR spectra (CD3OD), indicating formation of compound 8. The equivalent protons of the tertiary amine methyl groups were observed as a singlet at 2.33 ppm in the 1H NMR spectrum.
The reaction of one equivalent of N,N-diethylethylenediamine and one equivalent of 3,5-bis(trifluoromethyl)phenyl isothiocyanate at room temperature generated compound 9 (Scheme 2.7). As for the thiourea derivatives described thus far, compound 9 was purified by silica gel column chromatography, which resulted in a yellow oil in a 92% yield. LC/TOF-MS returned a (M+H+) of 388.1270 indicating formation of compound 9 and as seen with compound 8, the NMR spectra obtained in CDCl3 were complex with doubling of peaks and broad resonance signals being observed. Therefore, the NMR experiments were carried out in CDCl3 at 50 oC and also in CD3OD at room temperature (Figure 2.22). The resulting spectra exhibited only one set of sharp resonance signals indicating that in the aprotic solvent, at room
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temperature, compound 9 may be equilibrating between a monomeric and dimeric form as a result of H-bonding interactions.
Figure 2.22: 1H NMR spectra of compound 9 in (a) CDCl3 at 50 oC, (b) CDCl3 at 25
oC and (c) CD3OD at 25 oC. Solvent residual 1H signals were also observed in each spectrum.
In the 13C NMR spectrum the quartets at 124.7 and 132.7 ppm were found to have coupling constants characteristic of one-bond and two-bond C-F coupling (1J = 270.8 and 2J = 33.0 Hz, respectively,) and were therefore assigned as the carbon signals of the –CF3 (124.7 ppm) and –C–CF3 (132.7 ppm) moieties. As observed for compound 8, the 13C signals representing the carbons of the two-carbon chain linking the tertiary amine to the thiourea, were found downfield from those of – CH2CH3 group of compound 7 due to the electron-withdrawing effect of the tertiary amine N atom. The triplet and quartet found at 1.07 and 2.67 ppm in the 1H NMR spectrum (CD3OD), were assigned as the protons of the –CH2 and –CH3 of the –NEt2
group each having 3J = 7.1 Hz.
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The nucleophilic addition of cyclohexylamine to 3,5-bis(trifluoromethyl)phenyl isothiocyanate generated compound 10 (Scheme 2.8). Purification by silica gel column chromatography produced compound 10 as a white solid in a 95% yield. The presence of the cyclohexyl group gives rise to a slightly more complex 1H NMR spectrum in comparison to compounds 6 and 7, with multiplets representing the cyclohexyl protons found between 1 and 2 ppm. Two broad singlets at 8.42 and 6.13 ppm, integrating for one proton each, were identified as the protons of the thiourea NH’s. In the 13C NMR spectrum, the quartets corresponding to the carbons of the – CF3 groups and those directly attached to the –CF3 groups (-C-CF3) were observed at 122.8 and 132.9 ppm, respectively.