Stacking and Branching in Self-Aggregation of Caffeine in Aqueous Solution: From the Supramolecular to Atomic Scale Clustering

The dynamical and structural properties of caffeine solutions at the solubility limit have been investigated as a function of temperature by means of MD simulations, static and dynamic light scattering, and small angle neutron scattering experiments. A clear picture unambiguously supported by both experiment and simulation emerges: caffeine self-aggregation promotes the formation of two distinct types of clusters: linear aggregates of stacked molecules, formed by 2–14 caffeine molecules depending on the thermodynamic conditions and disordered branched aggregates with a size in the range 1000–3000 Å. While the first type of association is well-known to occur under room temperature conditions for both caffeine and other purine systems, such as nucleotides, the presence of the supramolecular aggregates has not been reported previously. MD simulations indicate that branched structures are formed by caffeine molecules in a T-shaped arrangement. An increase of the solubility limit (higher temperature but also higher concentration) broadens the distribution of cluster sizes, promoting the formation of stacked aggregates composed by a larger number of caffeine molecules. Surprisingly, the effect on the branched aggregates is rather limited. Their internal structure and size do not change considerably in the range of solubility limits investigated

Molecular Dynamics and Neutron Scattering Studies of Mixed Solutions of Caffeine and Pyridine in Water

Insight into the molecular interactions of homotactic and heterotactic association of caffeine and pyridine in aqueous solution is given on the basis of both experimental and simulation studies. Caffeine is about 5 times more soluble in a 3 <i>m</i> aqueous pyridine solution than it is in pure water (an increase from ∼0.1 <i>m</i> to 0.5 <i>m</i>). At this elevated concentration the system becomes suitable for neutron scattering study. Caffeine–pyridine interactions were studied by neutron scattering and molecular dynamics simulations, allowing a detailed characterization of the spatial and orientational structure of the solution. It was found that while pyridine–caffeine interactions are not as strong as caffeine–caffeine interactions, the pyridine–caffeine interactions still significantly disrupted caffeine–caffeine stacking. The alteration of the caffeine–caffeine stacking, occasioned by the presence of pyridine molecules in solution and the consequent formation of heterotactic interactions, leads to the experimentally detected increase in caffeine solubility