Cooperativity and Feedback Mechanisms in the Single-Crystal-to-Single-Crystal Solid-State Diels–Alder Reaction of 9‑Methylanthracene with Bis(<i>N</i>‑cyclobutylimino)-1,4-dithiin

Electron donor-to-acceptor interactions between 9-methylanthracene and bis­(<i>N</i>-cyclobutylimino)-1,4-dithiin lead to the formation of chiral charge-transfer (CT) crystals. The structure consists of charge-transfer stacks where these two molecules arrange in a 1:1 alternating arrangement. These undergo a topochemical thermal single-crystal-to-single-crystal (SCSC) [2 + 4] Diels–Alder reaction in the solid state. CT crystals were reacted at 40 °C, their structures were determined by X-ray diffraction at various degrees of conversion, and they were examined using Hirshfeld surfaces and lattice energy calculations to find evidence of reaction cooperativity and feedback mechanisms. The results show that steric effects between product molecules and reactant molecules during the SCSC reaction influence the formation of products along the <i>b</i> axis, resulting in a more ordered structure than initially suggested by the crystal structure analysis. A maximum reaction conversion of around 96% was obtained, which indicates that the reaction is also nonrandom within the charge-transfer stacks. Lattice and intramolecular energy calculations show that the energy of an inherently metastable crystal obtained via the SCSC reaction is slightly higher compared to that of the recrystallized product crystal. Finally, structural analysis using CrystalExplorer shows that the shape, size, and surface curvature of the Hirshfeld surface are not much changed by the reaction, indicating that the reaction cavity remains relatively constant and that the reaction is under topochemical control

Do 12-Membered Cycloalkane Rings Only Exist As One Conformation in the Solid-State? A Detailed Solid-State Analysis Involving Polymorphs of <i>N,N</i>′‑Biscyclododecyl Pyromellitic Diimide

Conformational flexibility in molecules plays a key role in many chemical and biological processes. It is a common belief that the larger the cycloalkane the more flexible it will be, and the more conformations it will adopt. While theoretical studies have shown that cyclododecane has many possible conformations, they have also consistently shown that one conformation is slightly more stable. In this work, we examine the effect of substitution and crystal packing on the conformation of singly substituted cyclododecane rings. This has been done by exploiting polymorphism in an attempt to induce new conformations in a specific molecule, as well as by examining structures reported in the Cambridge Structural Database (CSD). To this end, three polymorphs of <i>N,N</i>′-biscyclododecyl pyromellitic diimide (PMDI-12) have been identified and their structures elucidated. To rationalize the differences between the various polymorphs, molecule···molecule interaction energies have been calculated using atom–atom potential methods. Though the conformation of the PMDI-12 molecules as a whole may differ, examination of the conformation of the 12-membered ring indicates that it is conformationally identical in all three polymorphs. Examination of 20 other organic and organometallic structures containing this group in the CSD, indicates that they have the same conformation (only one possible exception in the 34 rings examined in this work), which suggests that the 12-membered ring adopts a single conformation ([3333] with <i>D</i>₂ symmetry) in the solid-state that is relatively unaffected by crystal packing

Do 12-Membered Cycloalkane Rings Only Exist As One Conformation in the Solid-State? A Detailed Solid-State Analysis Involving Polymorphs of <i>N,N</i>′‑Biscyclododecyl Pyromellitic Diimide

Conformational flexibility in molecules plays a key role in many chemical and biological processes. It is a common belief that the larger the cycloalkane the more flexible it will be, and the more conformations it will adopt. While theoretical studies have shown that cyclododecane has many possible conformations, they have also consistently shown that one conformation is slightly more stable. In this work, we examine the effect of substitution and crystal packing on the conformation of singly substituted cyclododecane rings. This has been done by exploiting polymorphism in an attempt to induce new conformations in a specific molecule, as well as by examining structures reported in the Cambridge Structural Database (CSD). To this end, three polymorphs of <i>N,N</i>′-biscyclododecyl pyromellitic diimide (PMDI-12) have been identified and their structures elucidated. To rationalize the differences between the various polymorphs, molecule···molecule interaction energies have been calculated using atom–atom potential methods. Though the conformation of the PMDI-12 molecules as a whole may differ, examination of the conformation of the 12-membered ring indicates that it is conformationally identical in all three polymorphs. Examination of 20 other organic and organometallic structures containing this group in the CSD, indicates that they have the same conformation (only one possible exception in the 34 rings examined in this work), which suggests that the 12-membered ring adopts a single conformation ([3333] with <i>D</i>₂ symmetry) in the solid-state that is relatively unaffected by crystal packing

Do 12-Membered Cycloalkane Rings Only Exist As One Conformation in the Solid-State? A Detailed Solid-State Analysis Involving Polymorphs of <i>N,N</i>′‑Biscyclododecyl Pyromellitic Diimide

Conformational flexibility in molecules plays a key role in many chemical and biological processes. It is a common belief that the larger the cycloalkane the more flexible it will be, and the more conformations it will adopt. While theoretical studies have shown that cyclododecane has many possible conformations, they have also consistently shown that one conformation is slightly more stable. In this work, we examine the effect of substitution and crystal packing on the conformation of singly substituted cyclododecane rings. This has been done by exploiting polymorphism in an attempt to induce new conformations in a specific molecule, as well as by examining structures reported in the Cambridge Structural Database (CSD). To this end, three polymorphs of <i>N,N</i>′-biscyclododecyl pyromellitic diimide (PMDI-12) have been identified and their structures elucidated. To rationalize the differences between the various polymorphs, molecule···molecule interaction energies have been calculated using atom–atom potential methods. Though the conformation of the PMDI-12 molecules as a whole may differ, examination of the conformation of the 12-membered ring indicates that it is conformationally identical in all three polymorphs. Examination of 20 other organic and organometallic structures containing this group in the CSD, indicates that they have the same conformation (only one possible exception in the 34 rings examined in this work), which suggests that the 12-membered ring adopts a single conformation ([3333] with <i>D</i>₂ symmetry) in the solid-state that is relatively unaffected by crystal packing

Tuning the pharmacokinetic performance of quercetin by cocrystallization

Quercetin (QUE) is a widely studied nutraceutical with a number of potential therapeutic properties. Although QUE is abundant in the plant kingdom, its poor solubility (≤20 μg/mL) and poor oral bioavailability have impeded its potential utility and clinical development. In this context, cocrystallization has emerged as a useful method for improving the physicochemical properties of biologically active molecules. We herein report a novel cocrystal of the nutraceutical quercetin (QUE) with the coformer pentoxifylline (PTF) and a solvate of a previously reported structure between QUE and betaine (BET). We also report the outcomes of in vitro and in vivo studies of QUE release and absorption from a panel of QUE cocrystals: betaine (BET), theophylline (THP), l-proline (PRO), and novel QUEPTF. All cocrystals were found to exhibit an improvement in the dissolution rate of QUE. Further, the QUE plasma levels in Sprague–Dawley rats showed a 64-, 27-, 10- and 7-fold increase in oral bioavailability for QUEBET·MeOH, QUEPTF, QUEPRO, and QUETHP, respectively, compared to QUE anhydrate. We rationalize our in vivo and in vitro findings as the result of dissolution–supersaturation–precipitation behavior.</p

A piezoelectric ionic cocrystal of glycine and sulfamic acid

Cocrystallization of two or more molecular compounds can dramatically change the physicochemical properties of a functional molecule without the need for chemical modification. For example, coformers can enhance the mechanical stability, processability, and solubility of pharmaceutical compounds to enable better medicines. Here, we demonstrate that amino acid cocrystals can enhance functional electromechanical properties in simple, sustainable materials as exemplified by glycine and sulfamic acid. These coformers crystallize independently in centrosymmetric space groups when they are grown as single-component crystals but form a noncentrosymmetric, electromechanically active ionic cocrystal when they are crystallized together. The piezoelectricity of the cocrystal is characterized using techniques tailored to overcome the challenges associated with measuring the electromechanical properties of soft (organic) crystals. The piezoelectric tensor of the cocrystal is mapped using density functional theory (DFT) computer models, and the predicted single-crystal longitudinal response of 2 pC/N is verified using second-harmonic generation (SHG) and piezoresponse force microscopy (PFM). The experimental measurements are facilitated by polycrystalline film growth that allows for macroscopic and nanoscale quantification of the longitudinal out-of-plane response, which is in the range exploited in piezoelectric technologies made from quartz, aluminum nitride, and zinc oxide. The large-area polycrystalline film retains a damped response of ≥0.2 pC/N, indicating the potential for application of such inexpensive and eco-friendly amino acid–based cocrystal coatings in, for example, autonomous ambient-powered devices in edge computing