A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives

Quiquempoix, Lucas; Bogdan, Elena; Wells, Neil J.; Questel, Jean‐Yves Le; Graton, Jérôme; Linclau, Bruno

doi:10.3390/molecules22040518

Cited by 14 publications

(12 citation statements)

References 34 publications

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“…The two exceptions to this trend occur when M = Et and A = S or P. Overall, both the sign and magnitude of these changes are consistent with the formation of intramolecular hydrogen bonds in similar systems. [71,72] The same trends are observed in the M06-2X/aTZ and MP2/TZ NMR data reported in the Supplementary Material. However, it should be noted that changes NMR chemical shifts (often denoted Δδ) have the opposite sign as those associated with isotropic shielding constants (Δσ).…”

Section: Resultssupporting

confidence: 78%

“…The cis/trans energy difference for 2-fluoro and 2-chlorophenol were found to be slightly larger and on the order of 3 or 4 kcal mol −1 from DFT and MP2 computations [50], which is perhaps not surprising given that phenols are significantly more acidic than cyclopentanols. Subsequent analyses of these constrained intramolecular contacts based on the electron density, orbitals and/or electrostatic potential [64,65,66,67,68,69,70,71,72,73] are avoided in the present study because they have been shown to yield rather inconsistent results [34,48].…”

Section: Resultsmentioning

confidence: 99%

“…In the gas phase, for example, when one water molecule donates a hydrogen bond to another to form the water dimer, the donor OH stretching frequency shifts to 3602 cm −1 which is 55 cm −1 lower than the symmetric OH stretch of the water monomer and 154 cm −1 lower than the asymmetric stretch [74,75]. Similar changes in spectroscopic and geometrical parameters are known to accompany intramolecular hydrogen bond formation [70,71,72,73,76,77].…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Cis/Trans Energetics in Epoxide, Thiirane, Aziridine and Phosphirane Containing Cyclopentanols: Effects of Intramolecular OH⋯O, S, N and P Contacts

2019

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A recent computational analysis of the stabilizing intramolecular OH⋯O contact in 1,2-dialkyl-2,3-epoxycyclopentanol diastereomers has been extended to thiiriane, aziridine and phosphirane analogues. Density functional theory (DFT), second-order Møller-Plesset perturbation theory (MP2) and CCSD(T) coupled-cluster computations with simple methyl and ethyl substituents indicate that electronic energies of the c i s isomers are lowered by roughly 3 to 4 kcal mol−1 when the OH group of these cyclopentanol systems forms an intramolecular contact with the O, S, N or P atom on the adjacent carbon. The results also suggest that S and P can participate in these stabilizing intramolecular interactions as effectively as O and N in constrained molecular environments. The stabilizing intramolecular OH⋯O, OH⋯S, OH⋯N and OH⋯P contacts also increase the covalent OH bond length and significantly decrease the OH stretching vibrational frequency in every system with shifts typically on the order of −41 cm−1.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Cis/Trans Energetics in Epoxide, Thiirane, Aziridine and Phosphirane Containing Cyclopentanols: Effects of Intramolecular OH⋯O, S, N and P Contacts

2019

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“…Therefore, a model of hydrogen bonding between the POSA fluorine atom and a polymer hydroxyl group is proposed in Figure D based on their proximity. Previous studies have shown O–H···F–C hydrogen bonds in various cases of small organic molecules − and wide utilization of fluorine substituents for lead optimization in drug discovery …”

Section: Resultsmentioning

confidence: 99%

Molecular Interactions in Posaconazole Amorphous Solid Dispersions from Two-Dimensional Solid-State NMR Spectroscopy

et al. 2019

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Molecular interactions between the active pharmaceutical ingredient and polymer have potentially substantial impacts on the physical stability of amorphous solid dispersions (ASDs), presumably by manipulating molecular mobility and miscibility. However, structural details for understanding the nature of the molecular contacts and mechanistic roles in various physicochemical and thermodynamic events often remain unclear. This study provides a spectroscopic characterization of posaconazole (POSA) formulations, a second-generation triazole antifungal drug (Noxafil, Merck & Co., Inc., Kenilworth, NJ, USA), at molecular resolution. One- and two-dimensional (2D) solid-state NMR (ssNMR) techniques including spectral editing, heteronuclear 1H–13C, 19F–13C, 15N–13C, and 19F–1H polarization transfer, and spin correlation and ultrafast magic angle spinning, together with the isotopic labeling strategy, were utilized to uncover molecular details in POSA ASDs in a site-specific manner. Active groups in triazole and difluorophenyl rings exhibited rich but distinct categories of interactions with two polymers, hypromellose acetate succinate and hypromellose phthalate, including intermolecular O–H···OC and O–H···F–C hydrogen bonding, π–π aromatic packing, and electrostatic interaction. Interestingly, the chlorine-to-fluorine substituent in POSA, one of the major structural differences from itraconazole that could facilitate binding to the biological target, offers an additional contact with the polymer. These findings exhibit 2D ssNMR as a sensitive technique for probing sub-nanometer structures of pharmaceutical materials and provide a structural basis for optimizing the type and strength of drug–polymer interactions in the design of amorphous formulations.

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“…Quantum calculations are an important means to analyze interactions such as these and the influence of such calculations represents a common theme in much of the work described here. Quiquempoix et al look at levoglucosan and its derivatives [ 29 ], while variously substituted aminobenzamides come under the scrutiny of Mphahlele et al [ 30 ]. Mammino considers the relevance of these interactions to an antioxidant [ 31 ]; the possibility of multiple intramolecular H-bonds, and their relevance to regioisomers, is discussed by Martínez-Cifuentes et al [ 32 ].…”

mentioning

confidence: 99%