Chirality is one of the fundamental properties found in nature. It is thus desirable to introduce chirality into a molecular structure so that ‘optical activity’ can be accessed. This arises from the ability of a pair of enantiomers to interact with polarised light resulting in an equal and opposite rotation of the polarisation direction.357 Also, there are several advantageous biological properties chiral molecules possess, such as, a molecule’s enantiomer’s ability to discriminate between enantiomers of an analyte and also bind preferentially to particular chiral biological systems allowing them to be used as probes for substrates such as DNA.358 Molecular chirality presents a decisive challenge in host-guest recognition and other asymmetric catalysis such that attention has been turned towards 3D scaffolds like chiral interlocked systems in designing efficient enantioselective receptors.359 Furthermore,
molecular chirality can be transferred to supramolecular systems through endowing the coordination environments of metal centres, for example, with the chiral information inherent to the chelating motif.357 Propagation of the chiral information through supramolecular interactions in the formation of materials, such as gels,309,326 is also a highly topical area of research. More relevantly, there have been several reports of mechanically interlocked catenanes possessing an inherent chirality arising from the chirality of the precursors359-360 but also from achiral precursors273,361-363 wherein the chirality arises as a result of the mechanical bond, such was the case with self-templated homocircuit [2]catenanes discussed in Section 1.11.266,272,274-275 To the best of my knowledge, there are no reports of chiral self-templated homocircuit [2]catenanes from starting materials possessing a classical chiral element such as a chiral centre.359
With this in mind, chiral btp ligands 103R/S derivatised at the N1 triazolyl position with chiral 4'-substituted “arm” moieties were synthesised according to Scheme 5.2. The methyl ester chiral btp ligand 109R/S was synthesised in a two step one-pot diazo-transfer– deprotection–‘click’ reaction from alkyne 43 and the chiral amine.156 In the first step, the relevant azide was formed in situ from (R/S)-methyl 4-(1-aminoethyl)benzoate through the
Scheme 5.2 Synthesis of chiral btp ligands 103R/S. (i)CuSO4⋅5H2O, ImSO2N3⋅H2SO4 and K2CO3
in CH3OH, rt, 15 h; (ii)Sodium ascorbate, K2CO3, DMF/ tBuOH/ H2O (5:5:3), rt, 18 h; (iii) NaOH(aq),
MeOH, rt, 17 hrs (iv) 1) Et3N, DMAP, CH2Cl2/ DMF (4:1), 0°C, 30 mins 2) EDCI⋅HCl, 0°C, 30
Cu(II) catalysed diazo transfer reaction in the presence of transfer reagent, ImSO2N3⋅H2SO4 and K2CO3. The progress of the reaction could easily be monitored through colour change. Initially, the reaction mixture was cyan in colour and upon successful formation of the azide after 15 hours the suspension turned lilac (Figure 1.33, Section 1.9.1).156 The second step consisted of the addition of sodium ascorbate and K2CO3 after which the mixture was degassed to give a suspension which was a dull yellow colour in appearance. A solution of 43 in DMF was then added and allowed to stir at room temperature for 18 hours giving rise to an orange suspension upon completion of CuAAC. The reaction mixture was washed with aqueous EDTA/NH4OH solution, in order to scavenge Cu(II) ions, and then extracted into EtOAc. After the solvent was removed under reduced pressure, the methyl ester btp ligands 109R/S were purified by automatic flash chromatography (gradient DCM: CH3OH (98:2) and obtained in high purity as confirmed by elemental analysis and in excellent yield of 76- 81%. The carboxylic acid ligands 110R/S were successfully prepared by ester hydrolysis of 109R/S by stirring with aqueous NaOH in CH3OH solution in 73-82% yield. Btp olefin precursors 103R/S were synthesised from 110R/S by amide coupling reaction with allylamines. The amide coupling was carried out by EDCI⋅HCl activation in the presence of Et3N and DMAP. Btp olefins 103R/S were obtained as white powders in 38-48% yield after automatic flash chromatography (gradient DCM:CH3OH (95:5). All ligands were fully characterised by 1H and 13C NMR, HRMS, IR and CHN.
1H NMR spectroscopy confirmed successful synthesis of the desired btp olefins; the spectra of each enantiomer were identical as expected, therefore, the proton resonances will be discussed in terms of 103R only (Figure 5.2). The singlet at 8.22 ppm in CDCl3, with an integration of 2, was assigned to the triazolyl CH resonance by HSQC and HMBC. The doublet at 8.14 ppm corresponded to the 3- and 5-pyridyl protons while the triplet at 7.96 ppm corresponded to the 4-pyridyl proton integrating to 1. The aryl proton resonances on the benzene rings can be found further upfield at 7.49 ppm and 6.92 ppm. The broadened singlet at 6.80 ppm was assigned as the amide proton by selective TOCSY. The doublet of doublets of doublets from 6.03 ppm, with an integration of 2, and the pair of doublets between 5.39 ppm and 5.24 ppm, integrating to 4, were assigned to the internal and terminal olefin protons, respectively. Between these resonances appeared a quartet at 5.59 ppm, corresponding to the methine proton of the chiral centre. The methylene protons of the aliphatic chain adjacent to the amide and olefin appeared further upfield at 4.15 ppm. Finally, the doublet at 1.63 ppm integrating to 6 protons was characteristic of the methyl substituent at the chiral centre. The 13C NMR spectrum, HSQC and HMBC allowed assignment of the
Figure 5.21H NMR spectrum of chiral btp olefin 103R (400 MHz, CDCl
3) with resonances labelled. carbonyl and quaternary carbons. ESI+ mass spectrometry analysis displayed a characteristic peak at m/z = 588.2853, which agreed with the m/z calculated for [M+H]+. Elemental analysis confirms bulk purity from expected atomic abundances of C = 65.52, H = 5.53, N= 20.62, for the monohydrate of 103R.
5.3.1 Investigation into self-templating of 103R/S in solution by 1H NMR
spectroscopy and mass spectrometry
It was observed that the chemical shift of certain proton resonances of the chiral btp olefins 103R/S was rather sensitive to the choice of solvent. High polarity solvents such as DMSO-d6 gave sharp resonance signals, see Figure 5.4(A), whereas in less polar solvents, such as CDCl3, signs of self-templating dimerisation (shown for 103R only below) were manifested as broadening of certain signals and significant changes in chemical shifts; these changes were concentration-dependent. At low concentration the 1H NMR spectrum of 103R in CDCl3 containing low quantities of H2Odisplayed certain peaks which were broadened, in particular the triazolyl peak t. (Figure 5.3). This indicated several hydrogen bonding interactions at play in the self-assembly. Upon increasing the concentration of the solution of 103R to 30 mM, while keeping the H2O content in the CDCl3 constant, a significant change in chemical shift of certain proton resonances was observed. The triazolyl proton resonance t became sharper and underwent an upfield shift from 8.44 ppm to 8.30 ppm. It remained somewhat broadened compared to the less effected resonances upon increasing concentration, which was suggestive of it partaking in hydrogen bonding interactions. The
Figure 5.3 The dramatic changes in chemical shift of btp triazolyl (t), aryl (w and x) and amide (p) proton resonance signals upon increasing concentration of 103R from (A) 1mM to (B) 30 mM in anhydrous CDCl3 and (C) subsequently upon increasing the H2O concentration to 75 mM in
the same solution (400MHz, CDCl3).
aryl protons w and x, underwent a significant shift upfield from 7.62 ppm and 7.14 ppm to 7.34 ppm and 6.71 ppm, respectively. This indicated a significant change in the chemical environment upon increasing concentration. Finally, the amide proton resonance p, became deshielded from 6.55 ppm to 6.94 ppm, an observation which coincided with a greater abundance of molecules being involved in hydrogen bonding at 30 mM than at 1 mM. The methine proton y and methyl proton z adjacent to it were also shifted upfield from 5.83 ppm and 1.82 ppm to 5.64 ppm and 1.46 ppm, respectively. Upon increasing the H2O content of this solution of 103R inCDCl3 the broadened triazolyl resonance decreased in chemical shift with a concomitant sharpening of the resonance indicating the break-up of these intermolecular hydrogen bonding interactions by the more polar solvent content. The proton resonance signals associated with the aryl ‘arms’ w and x, became deshielded from 7.33 ppm and 6.72 ppm to 7.57 ppm and 7.04 ppm, respectively. The amide proton became more shielded as it changed chemical shift from 6.94 ppm to 6.66 ppm. And finally, the methine proton y and methyl proton z adjacent to it were shifted downfield to 5.78 ppm and 1.63 ppm,
respectively. The above experiment corroborated the rationale that dimerisation was occurring through non-classical hydrogen bonding of anti-anti oriented btp motifs,102,156,160 the effect of which on the triazolyl proton resonance’s chemical shift was clear at high concentration. The variability in the aryl and amide proton resonance shifts also supported the argument that the chiral 4'-substituted “arms” were pre-organising in a manner which was resulting in a significant change in the moiety’s chemical environment through amide hydrogen bonding interactions. We will discover in section 5.10.1 that this was in contrast to the invariance in the chemical environment of the protons of the 3'-substituted “arms” for 105. This change in chemical environment of the aryl ‘arms’ was also a feature in the RCM of chiral btp olefins 103R/S using similar anhydrous solvent conditions and concentration ranges as the above.