Intramolecular Hydrogen Bonding in ortho -Substituted Arylamide Oligomers: A Computational and Experimental Study of ortho -Fluoro- and ortho -Chloro- N -methylbenzamides (original) (raw)
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Structural Tuning and Conformational Stability of Aromatic Oligoamide Foldamers
Chemistry (Weinheim an der Bergstrasse, Germany), 2017
A series of aromatic oligoamide foldamers with two or three pyridine-2,6-dicarboxamide units as their main folding motifs and varying aromatic building blocks as linkers have been synthetized to study the effects of the structural variation on the folding properties and conformational stability. Crystallographic studies showed that in the solid state the central linker unit either elongates the helices and more open S-shaped conformations, compresses the helices to more compact conformations, or acts as a rigid spacer separating the pyridine-2,6-dicarboxamide units, which for their part add the predictability of the conformational properties. Multidimensional NMR studies showed that, even in solution, foldamers show conformational stability and folded conformations comparable to the solid-state structures.
We examine the conformational preferences of the furan-and thiophene-based arylamides N-methylfuran-2-carboxamide (3) and N-methylthiophene-2-carboxamide (4) using a combination of computational methods and NMR experiments. The compound choice stems from their use as foldamer building blocks. We quantify the differences in the conformational rigidity of the two compounds, which governs foldamer conformations. Specifically, we demonstrate the effects of intramolecular hydrogen bonding (H-bonding), geometrical patterns and solvent polarity on arylamide conformations by comparing 3, 4 and previously studied ortho-methoxy N-methylbenzamide (1) and ortho-methylthio N-methylbenzamide (2). The study reveals that compound 3, despite its non-optimal S(5)-type H-bond geometry, retains a large portion of the H-bonded (eclipsed) conformation even in polar protic solvents. This behaviour is consistent with the quantum mechanical (QM) torsional energy profile. The percentages of H-bonded conformers that 3 retains are just slightly smaller than those of 1, which has a stronger S(6)-type H-bond. As for 2 and 4, the replacement of the O atom in 1 by an S atom in 2 results in a 70-90% loss of the H-bonded conformer in solution. However, the equivalent O to S replacement in 3 (leading to 4) causes only 15-30% loss of the eclipsed conformers in 4. Therefore, conformational preferences of 4 are very different from 2, opposite from the similarity between 3 and 1. This study shows how the interplay of several forces modulates the conformational flexibility of arylamides. It also attests the strategy we are developing, which leads to accurate prediction of foldamer structure. The vital component of this strategy is the re-parameterization of critical force field parameters based on QM potential energy profiles, as well as validation of these parameters using experimental data in solution.
CrystEngComm, 2012
The crystal structures and molecular conformations of two foldamer-type oligoamides were analyzed. One polymorphic form and seven solvates were found for N 1 ,N 3-bis(2-benzamidophenyl)benzene-1,3dicarboxamide (the benzene variant), and two polymorphic forms and six solvates for N 2 ,N 6-bis(2benzamidophenyl)pyridine-2,6-dicarboxamide (the pyridine variant). Three crystal structures of the benzene variant and six structures of the pyridine variant were solved using single crystal X-ray diffraction. The crystal structures showed that the different modes of intramolecular hydrogen bonding strongly affect the conformation and folding of the molecules, which is most evidently seen with the strongly folded helical structure of the pyridine variant. NOESY experiments suggest that the intramolecular hydrogen bonding is stable enough to retain a folded or partially folded conformation even in solution. 65 CREATED USING THE RSC ARTICLE TEMPLATE (VER. 3.0)-SEE WWW.RSC.ORG/ELECTRONICFILES FOR DETAILS
2004
details, tables of calculated geometrical parameters, and xyz coordinates for 1-7 and for 14 conformations of 6. Abstract: The role of an ortho-alkylthioether group in controlling the conformation around the ring À N bonds of meta-connected arylamide oligomers is studied. Density functional theory (DFT) geometries of model compounds, including acetanilide, an ether acetanilide, and a thioether acetanilide, and their corresponding diamides, show that for either monoamide or diamide the alkyl side chain of the thioether should be perpendicular to the aryl plane, whereas for the ether monoamide, the alkyl side chain is in the aryl plane. DFT ring À N torsional potentials and constrained geometries of the model compounds demonstrate that carbonylÀS repulsion leads to a high torsional barrier and that intramo-lecular NÀH···S and CÀH···O hydrogen bonds and ring-amide conjugation lead to N À H having a preferred orientation in the benzene plane pointing towards S. The NÀH bond lengthens and the ortho-ring CÀH bond shortens in a regular pattern in the approach to the preferred orientation. Calculated IR frequencies for the NÀH stretch show a clear red shift between model compounds without and with the thioether side chain.
Conformational stability of oligoferrocene oligoamide foldamers
Journal of Organometallic Chemistry, 2016
Organometallic oligoamides built from three to four ferrocene amino acid units (H-Fca-OH, 1-amino-1 0ferrocene carboxylic acid) fold into hydrogen bonded secondary structures featuring eight-membered rings by cooperative hydrogen bonds. NMR studies and DFT calculations (CAM-B3LYP, LANL2DZ, IEFPCM (THF)) reveal that the organometallic zigzag foldamer structures are highly resistant toward denaturation by hydrogen bond acceptors such as dimethyl sulfoxide and 2,4-lutidine. Replacing one ferrocene amino acid unit by the organic a-amino acid glycine at the C-terminal end (Fca / Gly) significantly destabilizes the secondary zigzag structure facilitating denaturation by DMSO. Highly stabilized ordered poly(Fca) architectures are very attractive for future applications of switchable hydrogenbonded redox-active materials.
Chemistry - A European Journal, 2013
Dedicated to Prof. Andrew D. Hamilton on the occasion of his 60th birthday A major effort in modern bio-organic chemistry focuses on the design, synthesis and structural characterisation of foldamers: [1] non-natural oligomers that adopt well-defined secondary, tertiary and quaternary structures. [2-5] One ultimate objective of such studies is to recapitulate the functional behaviour of biomacromolecules. [6] Particular emphasis has been placed on inhibitors [7-12] of a-helix-mediated [13] protein-protein interactions [14]-an endeavour that in its own right represents a major challenge. [15, 16] The development of synthetic methodologies that allow access to smallto-medium sized libraries of foldamers incorporating diverse side chains, represents the cornerstone upon which such studies are pursued. In this regard, it is noteworthy that the most robust methodology exists for peptoids, [17] b-peptides [18] and more recently oligoureas; [19] templates that have seen the most significant use in a biological context. [7, 20] We [21-24] and others [25-29] have recently reported on the use of aromatic oligoamides [5] as potential a-helix mimetics. [30, 31] Rather than topographical mimicry of the a-helix (as is the case for b, [32] a/b [7, 9, 12] and other foldamers [8]), these compounds mimic an a-helix by presenting key side chains from a rodlike template in a spatial orientation that matches that of the a-helix (Figure 1). [33] Although solution methods for assembly of very large [34] and long aromatic oligoamides [35] have been described, a significant advance in this area would be the ready availability of solid-phase methods tolerant to a diverse array of side chains; this would facilitate li
Conformational properties of O-alkylated benzamides
Tetrahedron, 2012
In this article, we report the synthesis, solid-state and solution-state conformational studies of O-alkylated aromatic benzamides based on two scaffolds. Intramolecular hydrogen bonding provides conformational pre-organization and side chains can interact with each other within a molecule. In the solidstate three-dimensional arrangement, the molecules further interact with each other through noncovalent interactions. Given, the demonstrated potential of this class of scaffolds to act as helix mimetics for the inhibition of proteineprotein interactions (PPIs), these results provide key insight for future inhibitor design.