To understand the driving forces of aromatic stacking interactions in water, we have performed conformational searches, molecular dynamics simulations, potential of mean force (PMF) and free energy perturbation (FEP) calculations, syntheses, and NMR studies on sodium (2,2)-bis(indol-1-yl- methyl)acetate (1), sodium 3-indol-1-yl-2-methyl-propionate (2), and sodium 3-indol-1-yl-propionate (3). The conformational searches on 1 revealed that the isobutyric acid linker of 1 allows the molecule to adopt the tilted T- shaped stacked, off-center stacked, face-to-face stacked, and nonstacked conformations in a vacuum. The PMF and FEP calculations suggested that the most thermodynamically stable conformers in water are the tilted T-shaped stacked and nonstacked conformers. Independent NMR spectroscopic studies of 1-3 revealed that both the tilted T-shaped stacked and nonstacked conformers are populated in D2O and in d6-DMSO, and they are in a rapid equilibrium. Furthermore, the NMR studies found (i) a larger population of the tilted T, shaped stacked conformation of 1 at 22 °C in D2O than in d6-DMSO and (ii) more different populated stacked conformations of 1 at 60 °C in D2O than in d6-DMSO. One would expect larger populations of the stacked conformations in d6-DMSO, whose dielectric constant is smaller than that of water, if the electrostatic interaction were the only driving force of the aromatic stacking interactions. The results, therefore, suggest that the hydrophobic effect plays an important role in the stacking interaction of 1 in water.
ASJC Scopus subject areas
- Colloid and Surface Chemistry