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1. Hydrogen Bonding in Amorphous Indomethacin

   https://doi.org/10.3390/pharmaceutics16081002  

   Benmore, C J; Yarger, J L; Davidowski, S K; Shrader, C D; Smith, P A; Byrn, S R (July 2024, Pharmaceutics)

   Amorphous Indomethacin has enhanced bioavailability over its crystalline forms, yet amorphous forms can still possess a wide variety of structures. Here, Empirical Potential Structure Refinement (EPSR) has been used to provide accurate molecular models on the structure of five different amorphous Indomethacin samples, that are consistent with their high-energy X-ray diffraction patterns. It is found that the majority of molecules in amorphous Indomethacin are non-bonded or bonded to one neighboring molecule via a single hydrogen bond, in contrast to the doubly bonded dimers found in the crystalline state. The EPSR models further indicate a substantial variation in hydrogen bonding between different amorphous forms, leading to a diversity of chain structures not found in any known crystal structures. The majority of hydrogen bonds are associated with the carboxylic acid group, although a significant number of amide hydrogen bonding interactions are also found in the models. Evidence of some dipole–dipole interactions are also observed in the more structurally ordered models. The results are consistent with a distribution of Z-isomer intramolecular type conformations in the more disordered structures, that distort when stronger intermolecular hydrogen bonding occurs. The findings are supported by 1H and 2H NMR studies of the hydrogen bond dynamics in amorphous Indomethacin. 

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2. Counterintuitive torsional barriers controlled by hydrogen bonding

   https://doi.org/10.1039/d0cp03285a  

   Barbero, Héctor; Meunier, Antoine; Kotturi, Kondalarao; Smith, Ashton; Kyritsakas, Nathalie; Killmeyer, Adam; Rabbani, Ramin; Nazimuddin, Md; Masson, Eric (September 2020, Physical Chemistry Chemical Physics)

   null (Ed.)

   The torsional barriers along the C aryl –C aryl axis of a pair of isosteric disubstituted biphenyls were determined by variable temperature 1 H NMR spectroscopy in three solvents with contrasted hydrogen bond accepting abilities (1,1,2,2-tetrachloroethane-d 2 , nitrobenzene-d 5 and dimethyl sulfoxide-d 6 ). One of the biphenyl scaffolds was substituted at its ortho and ortho ′ positions with N ′-acylcarbohydrazide groups that could engage in a pair of intramolecular N–H⋯O=C hydrogen bonding interactions at the ground state, but not at the transition state of the torsional isomerization pathway. The torsional barrier of this biphenyl was exceedingly low despite the presence of the hydrogen bonds (16.1, 15.6 and 13.4 kcal mol −1 in the three aforementioned solvents), compared to the barrier of the reference biphenyl (15.3 ± 0.1 kcal mol −1 on average). Density functional theory and the solvation model developed by Hunter were used to decipher the various forces at play. They highlighted the strong stabilization of hydrogen bond donating solutes not only by hydrogen bond accepting solvents, but also by weakly polar, yet polarizable solvents. As fast exchanges on the NMR time scale were observed above the melting point of dimethyl sulfoxide-d 6 , a simple but accurate model was also proposed to extrapolate low free activation energies in a pure solvent (dimethyl sulfoxide-d 6 ) from higher ones determined in mixtures of solvents (dimethyl sulfoxide-d 6 in nitrobenzene-d 5 ). 

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3. Methyl 2-hydroxy-4-iodobenzoate

   https://doi.org/10.1107/S2414314624003948  

   Kimble, Marten J; Myers, Shea D; Benedict, Jason B (May 2024, IUCrData)

   The structure of the title compound, C₈H₇IO₃, at 90 K has monoclinic (P2₁/c) symmetry. The extended structure is layered and displays intermolecular and intramolecular hydrogen bonding arising from the same OH group. 

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4. Shape‐Shifting Tetralactam Macrocycles: Protonation‐Activated Convergent Hydrogen Bonding

   https://doi.org/10.1002/chem.202503496  

   Liu, Dexin; Victoria, Andrew; Mariscal, Alexander; Conces, Jay; Mampilly, Sandra; Cui, Yunpeng; Wojtas, Lukasz; Cai, Jianfeng; Liu, Wenqi (January 2026, Chemistry – A European Journal)

   ABSTRACT Integrating high binding affinity with dynamic, stimuli‐responsive control represents a pivotal objective in synthetic receptor design, with far‐reaching implications for sensing, separation, and molecular machinery. We report a class of shape‐shifting tetralactam macrocycles featuring embedded 2,4‐pyridinedicarboxamide units as switching elements. In their neutral state, these macrocycles adopt divergent hydrogen‐bonding conformations that exhibit low substrate affinity. Upon protonation, a reversible conformational reorganization occurs, reorienting four amide N–H groups toward the cavity to form a convergent, high‐affinity hydrogen‐bonding pocket. Conformational switching was confirmed by X‐ray crystallography and solution‐phase NMR. Upon protonation, these macrocycles exhibit >10⁵‐fold binding enhancement, achieving association constants up to 135,000 M⁻¹for the polyhalide anion BrIBr⁻. Computational analysis reveals that this dramatic increase arises from synergistic hydrogen bonding, electrostatic attraction, and van der Waals interactions. These findings establish a robust strategy for designing adaptive hydrogen‐bonding receptors that combine dynamic switching with high substrate affinity and selectivity. The ability to toggle between low‐ and high‐affinity states without sacrificing structural integrity sets the stage for expanding the scope of smart molecular systems with tunable recognition properties. 

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5. On the nature of hydrogen bonding in the H2S dimer

   https://doi.org/10.1038/s41467-024-53444-6  

   Jäger, Svenja; Khatri, Jai; Meyer, Philipp; Henkel, Stefan; Schwaab, Gerhard; Nandi, Apurba; Pandey, Priyanka; Barlow, Kayleigh R; Perkins, Morgan A; Tschumper, Gregory S; et al (December 2024, Nature Communications)

   Abstract Hydrogen bonding is a central concept in chemistry and biochemistry, and so it continues to attract intense study. Here, we examine hydrogen bonding in the H₂S dimer, in comparison with the well-studied water dimer, in unprecedented detail. We record a mass-selected IR spectrum of the H₂S dimer in superfluid helium nanodroplets. We are able to resolve a rotational substructure in each of the three distinct bands and, based on it, assign these to vibration-rotation-tunneling transitions of a single intramolecular vibration. With the use of high-level potential and dipole-moment surfaces we compute the vibration-rotation-tunneling dynamics and far-infrared spectrum with rigorous quantum methods. Intramolecular mode Vibrational Self-Consistent-Field and Configuration-Interaction calculations provide the frequencies and intensities of the four SH-stretch modes, with a focus on the most intense, the donor bound SH mode which yields the experimentally observed bands. We show that the intermolecular modes in the H₂S dimer are substantially more delocalized and more strongly mixed than in the water dimer. The less directional nature of the hydrogen bonding can be quantified in terms of weaker electrostatic and more important dispersion interactions. The present study reconciles all previous spectroscopic data, and serves as a sensitive test for the potential and dipole-moment surfaces. 

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