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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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Hydrogen Bonding vs Dihydrogen Bonding in the Air Stable Primary Phosphine ortho‐Phosphinophenol
ortho‐Phosphinophenol (oPP) is an unusual example of an air‐stable primary phosphine and a valuable precursor to a variety of useful organophosphorus compounds. The presence of PH2 and OH functionalities offers the possibility of intermolecular and intramolecular P•••HO hydrogen bonding (HB). The close proximity of these two groups also offers the opportunity for intramolecular PH2•••HO dihydrogen bonding (DHB). This work provides experimental and computational evidence for these various types of interactions. In the solid state, oPP is associated by significant intermolecular P•••HO hydrogen bonds as revealed by a single crystal X‐ray structural determination. Multinuclear NMR and IR spectroscopic studies, coupled with DFT computational studies, suggest that oPP adopts multiple conformations in solution whose nature varies with the identity of the solvent. In the gas phase or non‐polar solvents (such as cyclohexane) an equilibrium between four conformations of oPP is proposed. Interestingly, in silico, an isomer having bifurcated intramolecular PH2•••HO DHB (PP4) is found to be more stable than an isomer having intramolecular P•••HO HB (PP1). In polar solvents (S), NMR studies indicate intermolecular OH•••HB play a dominant role on the 31P NMR chemical shifts.
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- Award ID(s):
- 2246810
- PAR ID:
- 10598656
- Publisher / Repository:
- Wiley-VCH GmbH, Weinheim
- Date Published:
- Journal Name:
- European Journal of Inorganic Chemistry
- ISSN:
- 1434-1948
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1002/ejic.202400260
