Design rationale for the compounds that will be discussed in this chapter

Pyridine-3,5-dicarboxamide was chosen as the central motif for this chapter due to a number of reasons, namely, it has a structurally similar core to BTA but with a greater potential for metal coordination and would be relatively easily derivatised with a number of side arms. Given that various pyridine-2,6-dicarboxamides were the subject of previous research within the Gunnlaugsson group and that there are much fewer examples of pyridine-3,5-dicarboxamides Figure 5.9 (a) Structure of the pyridine ligand used by Bai and co-workers; (b) a pair of zinc centres, each coordinated to three pyridine-based ligands. Images reproduced from reference 201.

Chapter 5. Structural studies of a series of pyridine-3,5-dicarboxamides

in the literature, it was decided that this motif would be a suitable core molecule for this study. It was also chosen as pyridine-2,6-dicarboxamides tend to chelate, while the 3,5 isomer should have three independent binding sites, which is comparable to BTA derivatives discussed in previous chapters. A number of side chains were used in for this study, ranging from some simple amino acids to the derivatives used in the BTA studies, with these derivatives discussed in this section are shown in Scheme 5.1.

5.3.1 Synthesis and characterisation of the pyridine derivatives

The synthetic scheme for the pyridine derivatives is shown in Scheme 5.1 and involved just one step, a coupling reaction between pyridine-3,5-dicarboxylic acid and the respective amino ester side arm. This reaction was achieved by dissolving the carboxylic acid in dry DCM, cooled in ice followed by the addition of the peptide coupling reagents, EDC.HCl and DMAP, and then the addition of the amine, with the reaction mixture left to stir at room temperature in an inert atmosphere for 72 h. The reaction solvent was removed under reduced pressure to reveal white/yellow oils in all cases, with the resultant oils dried in vacuo before the addition of water causing the precipitation of white/yellow solids which were isolated by filtration and dried in vacuo. The yields for these reactions varied from approximately 37 % to 65 %. The compounds

Scheme 5.1 Synthetic scheme for the pyridine derivatives discussed in this chapter where (i) EDC.HCl, DMAP,

Chapter 5. Structural studies of a series of pyridine-3,5-dicarboxamides

were all fully characterised, with these data available in the experimental and appendix sections. An example of a 1_{H NMR spectrum for one of these derivatives, 104, is shown in Figure 5.10,}

with the characteristic pyridine aromatic protons between approximately 8 and 9 ppm and amide proton shifts, the most downfield for all the derivatives, between 9 and 10 ppm shown in the inset. Once isolated, the derivatives were subject to a number of crystallisation attempts which will be discussed in the next section.

5.3.2 Attempts to hydrolyse the ester derivatives

A number of attempts to hydrolyse the pyridine ester derivatives were carried out in order to obtain the carboxylic acid compounds. The objective of this was to make a thorough comparison between the families of BTA-based ligands and pyridine-based ligands and to study the influence of side group functionality on the properties of both. The same method used in previous chapters, base hydrolysis using aqueous NaOH and MeOH, was first attempted, however isolation of the carboxylic acid derivative was not achieved. This is likely due to the protonation of the pyridine nitrogen during the acidic work-up of the reaction. Attempts were made to adjust the pH of the reaction mixture, and then extract the desired product, however, these too were unsuccessful. Moving on from this approach, it was decided to couple the benzyl ester protected alanine onto the pyridine-3,5-dicarboxylic acid core with the hope that this could

Figure 5.10 1_{H NMR (600 MHz, DMSO-d}

6) spectrum of 104 showing the characteristic aromatic and amide

Chapter 5. Structural studies of a series of pyridine-3,5-dicarboxamides

then be de-protected to reveal the alanine derivative of 104, Scheme 5.2. Despite a number of attempts to de-protect 109, isolation of the carboxylic acid derivative in a good yield and purity using the procedure previously reported by Kotova et al.188 was not successful. 1H NMR spectra from these attempts revealed the presence of a number of impurities and are shown below, in comparison with the methyl ester alanine derivative. An almost identical spectrum, minus the CH3 resonance, would be expected, however this was not the case. The spectrum of 110 shown

in Figure 5.11 displayed a number of impurities, particularly in the aliphatic region, most likely containing triethylsilane. Despite several purification attempts, it was not possible to isolate the pure product. Future work should focus on optimising this synthesis to result in a pure compound. After these unsuccessful attempts, the syntheses of the carboxylic acid derivatives Scheme 5.2 Proposed synthetic scheme for the synthesis of carboxylic acid terminated pyridine derivative 110, where (i) Et3N, HOBt, EDC.HCl, dry DCM, argon atmosphere, 72 h, (ii) TES, MeOH, Pd/C, 24 h.

Figure 5.111_{H NMR (400 MHz, DMSO-d}

Chapter 5. Structural studies of a series of pyridine-3,5-dicarboxamides

were abandoned and instead the focus of the remainder of this chapter was on the ester derivatives and their structural properties, which will be discussed in the next section.