TY - JOUR
T1 - Conformational preferences of furan- and thiophene-based arylamides
T2 - A combined computational and experimental study
AU - Galan, Jhenny F.
AU - Tang, Chi Ngong
AU - Chakrabarty, Shubhashis
AU - Liu, Zhiwei
AU - Moyna, Guillermo
AU - Pophristic, Vojislava
PY - 2013/7/28
Y1 - 2013/7/28
N2 - 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.
AB - 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.
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U2 - 10.1039/c3cp50353d
DO - 10.1039/c3cp50353d
M3 - Article
C2 - 23765415
AN - SCOPUS:84879878247
SN - 1463-9076
VL - 15
SP - 11883
EP - 11892
JO - Physical Chemistry Chemical Physics
JF - Physical Chemistry Chemical Physics
IS - 28
ER -