Hybridization of Long Pyridine‐Dicarboxamide Oligomers into Multi‐Turn Double Helices: Slow Strand Association and Dissociation, Solvent Dependence, and Solid State Structures

Abstract

Oligoamides of 2,6-diaminopyridine and 2,6-pyridinedicarboxylic acid comprised of 5, 7, 9, 11, or 13 units and bearing 4-isobutoxychains on all pyridine rings and tert-butyl-carbamate terminal groups have been synthesized stepwise, along with an 11 mer having benzyl-carbamate terminal groups. The crystal structure of all five Boc-terminated compounds has been obtained and shows a highly regular and conserved double helical hybridization motif of up to 3 complete turns for the 13 mer. Four pyridine units span one helical turn and define a helix pitch of ca 7 A. Solution studies in CDCl(3) demonstrated that the Boc-terminated oligomers strongly hybridize in this solvent, and that K(dim) values increase with oligomer length. The K(dim) values are 31000 and 7 x 10(5) L mol(-1) for the 7 mer and the 9 mer, respectively, and are too high to be measured by NMR for the 11 mer and the 13 mer. Hybridization and dissociation kinetics at 2 mM proceed at decreasing rates upon increasing oligomer length. The rate was faster than minutes for the 7 mer, of the order of hours for the 9 mer, and days for the 11 mer and 13 mer. The same trend was observed in [D(5)]pyridine but with considerably lower K(dim) values and faster kinetics. The benzylcarbamate 11 mer was also found to hybridize into a double helix but with reduced K(dim) values and faster kinetics compared to its Boc-terminated analogue. Combined with previous studies, the results presented here frame a global understanding of the hybridization of these pyridinecarboxamide oligomers and provide useful guidelines for the design of other artificial double helices.

Structural analysis of two foldamer-type oligoamides – the effect of hydrogen bonding on solvate formation, crystal structures and molecular conformation

“…The DMF solvent does not form any medium or strong hydrogen bonds with the other molecules. PXRD studies also indicate that the DMF 20 solvate of the pyridine variant 3 has five isomorphous solvates (acetone, 1,4-dioxane, DMA, pyridine and THF), but only DMF produced crystals suitable for single crystal XRD measurement. The ethyl acetate solvate was at first discovered during the recrystallization phase of the synthesis when the crude product 25 was dissolved in hot EtOAc and cooled in a refrigerator.…”

“…1 While hydrogen bonds are 20 not as stable and rigid as the covalent bonds, they still are a significant stabilizing force that results in a preferred molecular conformation in the solid state and even in solution. Hydrogen bonds are often used as key elements in crystal engineering because they are well understood and often predictable.…”

“…15,16 Aromatic oligoamides composed of pyridine-2,6-dicarboxamide and N,Npyridine-2,6-formamide monomers have been prepared and analyzed by Lehn et al 17,18 and Huc et al [19][20] . Huc et al [21][22][23][24] have also extensively studied aromatic oligoamide foldamers 20 composed mainly of substituted quinoline monomers and napthpyridine monomers. 25 In this paper we discuss the effects of weak intra-and intermolecular interactions on the molecular conformation, the folding properties, the crystal packing and the solvate formation, 25 through a comprehensive solid state structural analysis of two foldamer-type oligoamides.…”

“…1a). The molecular chains 20 are connected by weak hydrogen bonds, Van der Waals forces and parallel displaced π-stacking interactions between two of the 1,2-substituted phenyl rings.…”

“…Again, molecules connect to each other with two hydrogen bonds forming an 14 motif. The unexpected curved molecular conformation, where both of the inner C=O groups (2, 3) are facing inwards, may in fact be caused by the DMSO that stabilizes the curved structure by forming a hydrogen bond into 20 an amide hydrogen with a D motif. In both of the 2-DMSO I and 2-DMSO II solvates, the closest DMSO molecule to the benzene variant 2 is located near the central benzene ring.…”