Insight into the Mechanism of Formation of Channel Hydrates via Templating

Cocrystallization
of modafinil, 1, and 1,4-diiodotetrafluorobenzene, 2, in toluene leads to the formation of a metastable modafinil
channel hydrate containing an unusual hydrogen bonded dimer motif
involving the modafinil molecules that is not seen in anhydrous forms
of modafinil. Computational methodologies utilizing bias drift-free
differential evolution optimization have been developed and applied
to a series of molecular clusters and multicomponent crystals in the
modafinil/water and modafinil/water/additive systems for the additive
molecules 2 or toluene. These calculations show the channel
hydrate is less energetically stable than the anhydrous modafinil
but more stable than a cocrystal involving 1 and 2. This provides theoretical evidence for the observed instability
of the channel hydrate. The mechanism for formation of the channel
hydrate is found to proceed via templating of the modafinil molecules
with the planar additive molecules, allowing the formation of the
unusual hydrogen-bonded modafinil dimer. It is envisaged that the
additive is then replaced by water molecules to form the channel hydrate.
The formation of the channel hydrate is more likely in the presence
of 2 compared to toluene due to the destabilizing effect
of the larger iodine molecules protruding into neighboring modafinil
clusters.