Abstract
The crystallization of 28 binary and ternary cocrystals of quercetin with dibasic coformers is analyzed in terms of a combinatorial selection from a solution of preferred molecular conformations and supramolecular synthons. The crystal structures are characterized by distinctive O-H⋯N and O-H⋯O based synthons and are classified as nonporous, porous and helical. Variability in molecular conformation and synthon structure led to an increase in the energetic and structural space around the crystallization event. This space is the crystal structure landscape of the compound and is explored by fine-tuning the experimental conditions of crystallization. In the landscape context, we develop a strategy for the isolation of ternary cocrystals with the use of auxiliary template molecules to reduce the molecular and supramolecular 'confusion' that is inherent in a molecule like quercetin. The absence of concomitant polymorphism in this study highlights the selectivity in conformation and synthon choice from the virtual combinatorial library in solution.
Highlights
Polymorphism (Groth, 1906–1919; Deffet, 1942) is intrinsic to organic compounds and multiple crystalline phases exist because of contrasting kinetic and thermodynamic preferences during crystallization (Desiraju, 2002, 2007, 2013)
The isolation of different crystal forms in a quercetin cocrystal system is an illustration of combinatorial crystal synthesis in that there is an inherent selection of a particular molecular conformation and a particular supramolecular synthon in any given case
We have recently described the formation of cocrystal polymorphs as combinatorial synthesis based solely on selection from a synthon library
Summary
Polymorphism (Groth, 1906–1919; Deffet, 1942) is intrinsic to organic compounds and multiple crystalline phases exist because of contrasting kinetic and thermodynamic preferences during crystallization (Desiraju, 2002, 2007, 2013). Using the cocrystal landscapes of quercetin (Kavuru et al, 2010) with dibasic coformers, i.e. tetramethylpyrazine (TMP), 4,40-bipyridine (44BP), 1,2-bis(4-pyridyl)ethylene (DPE-1), 1,2-bis(4pyridyl)ethane (DPE-2), 4,40-azopyridine (44AP), phenazine (PHE), we extend here the idea of a combinatorial library towards prenucleation events where a conformationally flexible compound has a large number of virtual conformations. This approach allows one to consider the aggregation of these flexible molecules towards heteroclusters as synthon selection from a virtual library leading eventually to nucleation events and the final crystal structure (Desiraju, 1997a; Davey et al, 2013). Precise experimental details of each crystal structure are provided in the supporting information
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