Preliminary characterisation of the above products by 1H and 13C NMR spectroscopy was consistent with the data reported in the literature, and indicative of the expected compounds. More in-depth NMR characterisation was then carried out for all ligands, as this aided in analysing the results of further complexation reactions. For example, diffusion coefficients and nitrogen-15 chemical shifts were measured by Diffusion Ordered Spectroscopy (DOSY) and 1H−15N NMR HMBC experiments, respectively. One consequence of this was the necessity to acquire spectra of the relevant ligands in the same solvent used for solution state characterisation of the complexes. While the NMR spectra were typically in agreement with the symmetric species reported in the literature, HL2 and HL3 exhibited additional signals when measured under strictly anhydrous conditions (Figure 2.1), indicating that the two halves of the molecule were no longer equivalent.
Figure 2.1: 1H NMR spectra of HL3 in CD3CN when measured at RT under wet (undried ligand and solvent) or dry (anhydrous, sealed sample) conditions. The inset shows a comparison of the downfield region. Residual
solvent signals are labelled (○).
2.3.1 Prototropy
Prototropy in pyrazole-NH systems has been extensively studied by NMR spectroscopy, and is one of the most thoroughly investigated examples of tautometrism.101 The activation barrier for this process is often low enough that only average 1H, 13C and 15N resonances are detected at RT, giving the appearance of a symmetric system.101 Ring substituents, solvent, concentration and temperature have all been found to influence the exchange rate.102 This rate can thus be slowed sufficiently under certain circumstances such that the signals from each half of the pyrazole unit are resolved on the NMR timescale.102
Scheme 2.7: Chemical shifts (above: 13C, below: 15N) of the pyrazole ring nuclei, illustrating the asymmetry of the HL2 and HL3 ligand systems when measured under anhydrous conditions in CD3CN.
The 1H NMR spectra of HL2 and HL3 in dry CD3CN at RT both show relatively sharp resonances at approximately δ = 13 ppm. Furthermore, in 1H−13C and 1H−15N HMBC
experiments the pyrazole methine (H4, Scheme 2.7) proton in both systems showed correlations with two different quaternary carbon atoms, and with two nitrogen atoms, respectively. The chemical shift values of the detected nitrogen nuclei are in good agreement with literature data reported for unsubstituted pyrazole measured in (CD3)2SO (−79.8 and −173.1 ppm for N2 and N1, respectively), where the pyrazole NH proton is localised.103–105 The chemical shifts of the quaternary carbon atoms were likewise assigned on the basis of literature comparison with unsubsituted pyrazole in (CD3)2SO101 and 3,5-bis(ethyl)-1H-pyrazole in the solid state,106 where the pyrazole NH is once again localised.
Figure 2.2: 1H NMR spectra of HL3 at various temperatures under anhydrous conditions in CD3CN. Partial coalescence is observed for several signals (see Figure 2.1 for assignments). Residual solvent signals are
labelled (○).
Additional experiments in the cases of HL2 and HL3 showed that introduction of a proton shuttle, such as water, or heating (Figure 2.2) of the sample both induced partial coalescence of all relevant signals, thus restoring the equivalence of the two halves of the ligand being studied. The averaging of these signals is consistent with exchange of the acidic NH proton between the two nitrogen atoms of the pyrazole ring in each system. Taken together, the above findings unambiguously demonstrate that the HL2 and HL3 ligands are asymmetric in dry CD3CN solutions at RT as a result of pyrazole-NH prototropy. The slow exchange in these systems may be supported by formation of intra-molecular hydrogen bonds, such as those observed in the solid state structure of AmdHL3, discussed below.
Figure 2.3: Molecular structure of AmHL3. Atoms are represented with fixed radii. The position of the pyrazole-NH was calculated geometrically. Symmetry operation used to generate equivalent atoms: 1/2−x, 1/2−y, −z.
The molecular structure of AmdHL3 is shown in Figure 2.3. This product crystallises from MeCN in the monoclinic C2/c space group, with four molecules per unit cell. The pyrazole ring is disordered about four positions, two of which are associated with a crystallographically imposed inversion centre. Nevertheless, the distance and orientation between the pyrazole- and isopropyl-nitrogen atoms (N1A···N4 = 2.732 Å for the conformation depicted in Figure 2.3) strongly supports the presence of an intra-molecular hydrogen bond.107,108 Furthermore, NMR spectroscopy indicates that this hydrogen bond persists in solution at RT in undried non-protic solvents such as CD3CN and CDCl3. This is evident from the asymmetry of the pyrazole ring, the significant shift in resonance of one of the four isopropyl groups, and the relatively sharp pyrazole-NH signal. Dissolution in CD3OD once again renders the pyrazole ring symmetric by restoring the proton tautomerism, although the two halves of each macrocyclic side arm remain inequivalent due to the high rotational barrier of the amide bond.109,110 While introducing an additional degree of complexity into the NMR spectra, the lower flexibility of the amide bonds together with the intra-molecular hydrogen bond may enhance crystallisation by limiting the conformations available to the molecule in solution. Furthermore, the hydrogen bonding in AmdHL3 may be thought of as a pronounced example of the more general case observed in HL2 and HL3. In contrast, no analogous behaviour was observed in the case of HL1.