Conformational preferences of furan- and thiophene-based arylamides: a combined computational and experimental study

Abstract

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 corresponding 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, in contrast to 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.

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

“…The second of these challenges-force field accuracy-is arguably more difficult. There have been many attempts to parameterize all-atom force fields for peptoids 15,47,48 and other foldamers, 49,50 but the chemical diversity of peptidomimetics makes the development of a general-purpose force field for foldamers difficult. Here, we have opted to pursue a slightly different philosophy for foldamer simulation which utilizes our Bayesian Inference of Con-formational Populations (BICePs) algorithm.…”

Hybrids of Salicylalkylamides and Mannich Bases: Control of the Amide Conformation by Hydrogen Bonding in Solution and in the Solid State

“…Compound C has been shown to contain an intramolecular H-bond by fluorescence spectroscopy [49], which can only be ascribed to the presence of the β-form in solution. Derivatives of C have received much attention for design of arylamide oligomers [67,68] and supramolecular recognition units [69]. Ab initio methods revealed a persistent intramolecular hydrogen bond between the 2-methoxy group and N H of the amide in a nonpolar environment, such as chloroform.…”

Helical arylamide foldamers: structure prediction by molecular dynamics simulations

“…[14][15][16][17][18] The essence of this strategy is to take into consideration specific foldamer building block effects and non-covalent interactions between adjacent monomers that are crucial for arylamide foldamer structure control.…”