On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility

Abstract

Although they are both highly polar liquids, there are a number of compounds, such as many pharmaceuticals, which show vastly different solubilities in methanol compared with water. From theories of the hydrophobic effect, it might be predicted that this enhanced solubility is due to association between drugs and the less polar -CH 3 groups on methanol. In this work, detailed analysis on the atomic structural interactions between water, methanol and the small molecule indole -which is a precursor to many drugs and is sparingly soluble in water yet highly soluble in methanol -reveal that indole preferentially interacts with both water and methanol via electrostatic interactions rather than with direction interactions to the -CH 3 groups. The presence of methanol hydrogen bonds with π electrons of the benzene ring of indole can explain the increase in solubility of indole in methanol relative to water. In addition, the excess entropy calculations performed here suggest that this solvation is enthalpically rather than entropically driven.

On the structure of prilocaine in aqueous and amphiphilic solutions

“…In both cases, the most probable nearest neighbour water density around this group is located either above or below the plane of the methylphenyl ring, similar to what occurs for cocaine and indole in solution. 10,22,43 That there is more water present in the absence of methanol is also consistent with investigations on indole, where methanol was found to displace some of the hydration density from around the phenyl ring. 43 The correlation at shorter distances for g CBHw (r) compared to g CBOw (r) is indicative of an electrostatic p-H interaction.…”

“…10,22,43 That there is more water present in the absence of methanol is also consistent with investigations on indole, where methanol was found to displace some of the hydration density from around the phenyl ring. 43 The correlation at shorter distances for g CBHw (r) compared to g CBOw (r) is indicative of an electrostatic p-H interaction. However, the absence of a clearly defined peak in the g CBHw (r), suggests that there is no highly-directed hydrogen bonding (Fig.…”

The structures of liquid pyridine and naphthalene: the effects of heteroatoms and core size on aromatic interactions

“…This may help to explain the similarity between in the g(r,y) for pyridine and benzene, which have a similar molecular topology. Looking forward, the outcome of molecular simulations can be used to guide further calculations of entropic contributions from knowledge of the full orientational correlation function, 65,66 which further emphasises the importance of experimental data to provide reliable structural ensembles. Finally our analysis highlights intriguing discrepancies between our experimental findings and the results from ab initio and classical molecular simulation, with wide-ranging consequences for computational studies of condensed sp 2 carbon.…”

On the hydration and conformation of cocaine in solution

“…This is similar to what has been observed for many benzene containing systems, where the presence of at least some π-water interactions occur above and below the plane of the benzene ring. [32,33,34,35,36] Interestingly, for CFB in the CHCl 3 /H 2 O solution the hydration around the benzene ring has changed from the case of pure water, where the water density has been shifted away from the face of the benzene rings towards the carbomethoxy oxygen atoms. This dehydration is likely due to the fact there is very little water present in the system and water is preferentially bound to the groups with higher partial charges.…”

“…This suggests that for CFB in an amphiphilic environment that the tropane ring and ester groups are preferentially hydrated over the benzene ring, which is similar to what occurs for the hydration of the benzene ring in indole when transfered from pure water to methanol/water solutions. [35]…”