Synthesis and structural characterisation of amides from picolinic acid and pyridine-2,6-dicarboxylic acid

Coupling picolinic acid (pyridine-2-carboxylic acid) and pyridine-2,6-dicarboxylic acid with N-alkylanilines affords a range of mono- and bis-amides in good to moderate yields. These amides are of interest for potential applications in catalysis, coordination chemistry and molecular devices. The reaction of picolinic acid with thionyl chloride to generate the acid chloride in situ leads not only to the N-alkyl-N-phenylpicolinamides as expected but also the corresponding 4-chloro-N-alkyl-N-phenylpicolinamides in the one pot. The two products are readily separated by column chromatography. Chlorinated products are not observed from the corresponding reactions of pyridine-2,6-dicarboxylic acid. X-Ray crystal structures for six of these compounds are described. These structures reveal a general preference for cis amide geometry in which the aromatic groups (N-phenyl and pyridyl) are cis to each other and the pyridine nitrogen anti to the carbonyl oxygen. Variable temperature 1H NMR experiments provide a window on amide bond isomerisation in solution.

Our efforts to characterise the acid chloride intermediate(s) were unsuccessful: we were able to isolate a low-melting orange solid (mp , 40-50uC) but this quickly decomposed before it could be further characterised.
The N-methyl mono-amide 5a has been prepared previously by Habib and Rees, who reported its synthesis, melting point and elemental analysis 26 , and more recently by Okamoto et al. as part of an investigation into acid-induced conformational changes in aromatic amides 14 . Habib and Rees prepared 5a via the acid chloride, reacting picolinic acid 3 and thionyl chloride in benzene, then adding Nmethylaniline dropwise and heating at reflux; Okamoto activated acid 3 as the mixed anhydride by reaction with ethyl chloroformate and triethylamine, before adding N-methylaniline. The 4-chloro derivative 6a was not isolated in either of these previous syntheses.
Bis-amides 7a-c were prepared in a similar manner, from pyridine-2,6-dicarboxylic acid 4 in one pot (Figure 3b). This gave compounds 7a-c as crystalline solids in excellent yield (86-90%); chlorinated byproducts were not observed from the reactions of dicarboxylic acid 4. Compounds 7a and 7b appear previously in the literature, but details of their synthesis and characterisation are incomplete. Ried and Neidhardt studied ''hydrogenolysis'' of the N-methyl compound 7a and related quinoline carboxylic acids upon reaction with lithium aluminium hydride 27 . The N-methyl (7a) and N-ethyl (7b) analogues have been used to generate metal complexes 17,18 and in metal extraction experiments [19][20][21] , while Dobler et al. conducted computational experiments to describe the interaction between ligands of this type and lanthanide cations 28 . Kapoor and coworkers recently reported synthesis and structural characterisation of related thioamide derivatives 29 .
Crystallographic investigations. The geometry of the amide bond in compounds such as these has received attention previously with a view to potential applications in molecular switches and devices [14][15][16] . N-Alkylationspecifically N-methylationhas been shown to induce a change from trans-preferential to cis-preferential amides ( Figure 4).
Thus while the amide bond in benzanilide 11 (R 5 H) is trans, the corresponding bond in N-methylbenzanilide 12 (R 5 Me) is preferentially cis, both in the crystalline state and in solution 16 . Likewise crystallographic and NMR characterisation of 5a reported by Okamoto et al. show that the two aromatic groups adopt a cis relationship in that compound too 14 . To investigate the geometry of the amides prepared in the current study, single crystal X-ray structures were determined for the mono-amides 5b and 5c, 4-chloro mono-amides 6b and 6c, and bisamides 7a and 7c ( Figures 5 and 6; Supplementary Information).
The structures of the N-methyl (7a) and N-ethyl (5b, 6b) compounds reveal cis amide geometry in all cases: the aromatic groups (N-phenyl and pyridyl) are cis to each other, and the methyl or ethyl substituent is cis to the carbonyl group. There is also a general preference for the pyridine nitrogen to sit anti to the carbonyl oxygen(s). Among the mono-amides, these groups are anticlinal in 5b (the O-C-C-N dihedral angle is 123.9u), 6b (126.5u) and 6c (137.6u), but synclinal in 5c (56.7u) ( Figure 5). Of the bis-amide structures, the pyridine nitrogen is anticlinal to both carbonyls in the tetraphenyl compound 7c: there are two inequivalent molecules of 7c in the crystal structure, which exhibit dihedral angles around the bond in question of 141.6u and 131.9u/139.1u and 149.8u respectively. However in the dimethyl compound 7a, the pyridine nitrogen is anti to one of the amide carbonyls (137.2u) but syn to the other (257.2u), whichin combination with the two cis amide bondspositions the two phenyl groups in close proximity and an edge-to-face arrangement ( Figure 6).
Variable temperature NMR experiments. In light of the recent work by Okamoto et al. using 1 H NMR to follow cis/trans isomerisation in related aromatic amides 14 , we were interested to note evidence for slow conformational change in the 1 H NMR spectra of compounds 7a-c. The room temperature 1 H NMR spectra of 7a-c are generally poorly resolved with considerable line broadening (in contrast to the spectra of corresponding monoamides 5a-c in which equivalent line broadening is not observedsee Supplementary Information). Variable temperature 1 H NMR data for the ethyl substituted ligand 7b (Figure 7) show that signals resolve as the temperature is increased, confirming that the observed line broadening arises due to slow conversion between amide conformational isomers at room temperature. For example the signal at , 3.7 ppm, due to the methylene protons of the ethyl group, is a broad apparent singlet at 300 K but a clearly resolved quartet at 350 K (see inset in Figure 7).
Conclusion. Amides derived from picolinic acid 3 and pyridine-2,6dicarboxylic acid 4 have potential applications in catalysis, coordination chemistry and molecular switches. These compounds are readily prepared via the acid chloride or applying peptide coupling reagents. X-Ray crystal structures reveal that the generally preferred geometry of these amides positions the aromatic groups cis to each other and the pyridine nitrogen anti to the carbonyl oxygen. Variable temperature NMR experiments indicate slow cis/trans isomerisation in solution for the bis-amide series.

Methods
Amide synthesis. General procedure 1. Thionyl chloride (8.0 mL, 109 2 mmol) was added to picolinic acid 3 (1.00 g, 8.20 mmol) and the resulting suspension was refluxed for 16 h. The orange coloured solution was reduced in vacuo to give the acid chloride as a bright orange oil. The oil was dissolved in dry DCM (40 mL) and cooled to 0uC. A solution of N-alkylaniline (16.20 mmol) and triethylamine (2.20 mL, 16.20 mmol) in dry DCM (20 mL) was added via cannula. The resulting purple coloured solution was stirred at 0uC for 20 min and at room temperature for 16 h after which time the solution had become dark brown. The solution was washed with half-saturated aqueous ammonium chloride solution (2 3 12 mL), water (2 3 6 mL) and dried (Na 2 SO 4 ), then concentrated in vacuo.
General procedure 2. Thionyl chloride (4.0 mL, 60 mmol) was added to 2,6-pyridinedicarboxylic acid 4 (0.50 g, 3.0 mmol) and the resulting suspension was refluxed under an argon atmosphere for 16 h to give a clear yellow solution. Excess thionyl chloride was removed in vacuo and the acid chloride was dissolved in dry CH 2 Cl 2 (10 mL) and cooled to 0uC. A solution of N-alkylaniline (12.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) in dry DCM (2.5 mL) was added via cannula. The resulting mixture was stirred at room temperature for 16 h during which time a white precipitate formed. The suspension was washed with half-saturated aqueous ammonium chloride solution (2 3 6 mL) and water (2 3 3 mL), then dried (Na 2 SO 4 ) and concentrated in vacuo.