Higher-Order Self-Assembly of Benzoic Acid in Solution

Benzoic acid forms hydrogen-bonded dimers in solution that further stack into tetramers by aromatic interactions. Both dimers and higher-order packing motifs are preserved in the resultant crystal structure. The finding hints at the significance in the hierarchy of intermolecular interactions in driving the self-association process in solution

Tautomeric Polymorphism of 4‑Hydroxynicotinic Acid

4-Hydroxynicotinic acid (4-HNA) was discovered to exist in the solid state as either 4-HNA or its tautomer 4-oxo-1,4-dihydropyridine-3-carboxylic acid (4-ODHPCA) in three polymorphs and two hydrates. Packing motifs differ as each of the three oxygen atoms acts as the hydrogen-bond acceptor, respectively, in the anhydrate forms, while in the hydrate forms, water molecules participate in hydrogen bonding with 4-HNA. Phase behaviors of the forms were characterized by differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and thermogravimetric analysis (TGA). It was found that anhydrates I and II converted into III during heating; the two hydrate forms dehydrated at different temperatures and eventually transformed into anhydrate III, and sublimation of all five forms led to form III when the crystals were heated. Quantum mechanical calculations were performed providing further insight into the polymorphism

High Chemoselectivity of an Advanced Iron Catalyst for the Hydrogenation of Aldehydes with Isolated CC Bond: A Computational Study

Knölker’s iron complex is a “green” catalyst that exhibits low toxicity and is abundant in nature. Density functional theory (DFT) was used to explore the highly chemoselective nature of the catalytic hydrogenation of CH₂CHCH₂CHO. An outer-sphere concerted hydrogen transfer was found to be the most reasonable kinetic route for the hydrogenation of the olefin. However, the CC hydrogenation reaction has a high free energy barrier of 28.1 kcal/mol, requiring a high temperature to overcome. By comparison, the CHO bond concerted hydrogen-transfer reaction catalyzed using Knölker’s iron catalyst has an energy barrier of only 14.0 kcal/mol. Therefore, only the CHO of CH₂CHCH₂CHO can be hydrogenated in the presence of Knölker’s catalyst at room temperature, due to kinetic domination. All computational results were in good agreement with experimental results

Glycine’s pH-Dependent Polymorphism: A Perspective from Self-Association in Solution

As a simple amino acid, glycine (Gly)’s polymorphism is pH-dependent. The α form is typically obtained from aqueous solution between pH of 4 and 9, while the γ is produced at either lower or higher pH. Formation of cyclic, hydrogen-bonded dimer in water is debated as a possible cause for the formation of the α form. To further understand the pH-dependent polymorphism, our current study examined the self-association of Gly in aqueous solutions under a wide range of pH, utilizing NMR, FTIR, and electronic calculation. The results indicate that glycine molecules form open, not cyclic, hydrogen-bonded dimers in water. It is revealed that the dimerization becomes significant between pH of 4 and 8 but remains trivial at the two pH extremes. The apparent connection between the pH-dependent polymorphism and self-association in solution implies that formation of the α form is driven by the dimerization, and moreover, charged molecular species at the extreme pH facilitate stabilization of γ nuclei

A Direct C–H Coupling Method for Preparing π‑Conjugated Functional Polymers with High Regioregularity

Highly regioregular conducting polymers such as poly­(3-substituted thiophene)­s (rrP3STs) are an important class of π-conjugated polymers that can be used in plastic electronic devices such as solar cells and field-effect transistors. But the current state of the art syntheses of rrP3STs all involve transition-metal-catalyzed cross-coupling of a heteroaryl halide or pseudohalide with a heteroaryl organometallic reagent. In this work, an efficient and mild method was developed using direct cross-coupling of sp² C–H bonds. More importantly, the method not only gave generally high regioregularity (up to 99%) but also can be applied for a series of substrate compounds with various structures and substituted groups. This should provide a general and direct way for the easy access to many functional/conducting polymers

Persistent Self-Association of Solute Molecules in Solution

The structural evolvement of a solute determines the crystallization outcome. The self-association mechanism leading to nucleation, however, remains poorly understood. Our current study explored the solution chemistry of a model compound, tolfenamic acid (TFA), in three different solvents mainly by solution NMR. It was found that hydrogen-bonded pairs of solute–solute or solute–solvent stack with each through forming a much weaker π–π interaction as the concentration increases. Depending on the solvent, configurations of the solution species may be retained in the resultant crystal structure or undergo rearrangement. Yet, the π–π stacking is always retained in the crystal regardless of the solvent used for the crystallization. The finding suggests that nucleation not only involves the primary intermolecular interaction (hydrogen bonding) but also engages the secondary forces in the self-assembly process

Structural Isomerization of 2‑Anilinonicotinic Acid Leads to a New Synthon in 6‑Anilinonicotinic Acids

Through structural modification of 2-anilinonicotinic acid by isomerization, a new synthon, acid-aminopyridine, is created, and the two original synthons, i.e., the acid–acid homosynthon and acid–pyridine heterosynthon are no longer observed in the newly designed 6-anilinonicotinic acids. The new synthon has a hydrogen-bond strength rivaling that of the acid–acid homosynthon and the acid–pyridine heterosynthon, as suggested by theoretical calculations, which explains its formation

Investigating the Interaction Pattern and Structural Elements of a Drug–Polymer Complex at the Molecular Level

Strong associations between drug and polymeric carriers are expected to contribute to higher drug loading capacities and better physical stability of amorphous solid dispersions. However, molecular details of the interaction patterns and underlying mechanisms are still unclear. In the present study, a series of amorphous solid dispersions of clofazimine (CLF), an antileprosy drug, were prepared with different polymers by applying the solvent evaporation method. When using hypromellose phthalate (HPMCP) as the carrier, the amorphous solid dispersion system exhibits not only superior drug loading capacity (63% w/w) but also color change due to strong drug–polymer association. In order to further explain these experimental observations, the interaction between CLF and HPMCP was investigated in a nonpolar volatile solvent system (chloroform) prior to forming the solid dispersion. We observed significant UV/vis and ¹H NMR spectral changes suggesting the protonation of CLF and formation of ion pairs between CLF and HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate the strength of associations between drug and polymers, as well as the molecular mobility of CLF. Finally, by correlating the experimental values with quantum chemistry calculations, we demonstrate that the protonated CLF is binding to the carboxylate group of HPMCP as an ion pair and propose a possible structural model of the drug–polymer complex. Understanding the drug and carrier interaction patterns from a molecular perspective is critical for the rational design of new amorphous solid dispersions

Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions

It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug–polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF–HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet–visible (UV–vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D ¹H–¹H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF–HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient–polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs

Small Molecules Based on Alkyl/Alkylthio-thieno[3,2‑<i>b</i>]thiophene-Substituted Benzo[1,2‑<i>b</i>:4,5-b′]dithiophene for Solution-Processed Solar Cells with High Performance

Two acceptor–donor–acceptor small molecules based on thieno­[3,2-<i>b</i>]­thiophene-substituted benzo­[1,2-b:4,5-<i>b</i>′]­dithiophene, DRBDT-TT with alkyl side chain and DRBDT-STT with alkylthio side chain, were designed and synthesized. Both molecules exhibit good thermal stability, suitable energy levels, and ordered molecular packing. Replacing the alkyl chain with alkylthio increases the dihedral angle between the thieno­[3,2-<i>b</i>]­thiophene (TT) and benzo­[1,2-b:4,5-<i>b</i>′]­dithiophene (BDT) unit, and thus slightly decreases its intermolecular interactions leading to its blue-shift absorption in the solid state. The best devices based on DRBDT-TT and DRBDT-STT both exhibited power conversion efficiencies (PCEs) over 8% with high fill factors (FFs) over 0.70 under AM 1.5G irradiation (100 mW cm^–2), which are attributed to their optimized morphologies with feature size of 20–30 nm and well-balanced charge transport properties. The devices based on DRBDT-STT exhibited relatively lower short-circuit current density (<i>J</i>_sc) and thus slightly lower PCE as compared to the devices of DRBDT-TT, mainly due to its relatively poorer absorption. These results demonstrate that thieno­[3,2-<i>b</i>]­thiophene-substituted benzo­[1,2-b:4,5-<i>b</i>′]­dithiophene derivatives could be promising donor materials for obtaining high efficiencies and fill factors