Electron and Nuclear Positions in the Short Hydrogen Bond in Urotropine-N-oxide·Formic Acid

Abstract

The crystal structure of urotropine-N-oxide.formic acid, as determined from multiple temperature single-crystal X-ray diffraction experiments in the range 123-295 K and from neutron diffraction at 123 K, is reported. There is a strong hydrogen bonding interaction between the OH of formic acid and the N-oxide of urotropine, with the oxygen-oxygen distance ranging from 2.4300(10) to 2.4469(10) A. The electron density of the hydrogen atom associated with this interaction was located in the Fourier difference maps of the spherical atom refinement after all heavy atom positions were determined. The maximum of the electron density associated with the hydrogen bond is located approximately 1.16 A from the formate segment, though the distribution of electron density is very broad. The electron density associated with the H atom is thus shown by these accurate X-ray diffraction experiments to be approximately centered at all temperatures studied. This was conclusively confirmed by single-crystal neutron diffraction data obtained at 123 K, from which statistically equivalent O-H distances of 1.221(7) and 1.211(7) A were obtained.

The Challenge for Engineering Pharmaceutical Crystalline Solids: Scientific and Regulatory Affairs Perspectives for Crystal Structure Design and Prediction

“…Crystal structure prediction (CSP) for PCCs and PSs, relaying on the quantum mechanical (QM) calculations for the crystal lattice energy for PCCs and PSs, indicates that the formation of these multicomponent crystals is determined by compromising either the negative enthalpy changes, always in enthalpy driven formation of PSs, as well in some PCCs and PCC solvates with entropy changes or positive enthalpy change for some entropically driven formation of PCCs, not always leading toward the free energy minimization, that is due to propensity and propagation of heterosynthons to replace homosynthons, because of difference in energies of intra-and intermolecular forces that contribute the lattice energy. (29) This confirms the difference in the thermodynamic stability between PCcs and PSs comparing to their parent components and propose modeling for their crystal structure prediction to offer designing the accurate experimental crystallization screening strategies. (30)(31)(32) Though the computed energies of the crystals structures, ranged by the frequencies of synthons appearing within the CSD, reveal that at least 50% of the lattice energy is contributed by heterosynthons and to a few strong H-bonds between heterodymers and adjunct molecules, the higher energy value of surpamolecular synthon carboxylic acid-pyridine(carboxylate/pyridinium, ionized coupled moieties) for PSs for ∼10 kJ/mol, comparing for carboxylic acid -pyridine (neutral pair) confirmed the proton transfer that distinguishes PSs from PCCs.…”

Methanesulfonic acid salt forms of carbamazepine and 10,11-dihydrocarbamazepine

“…Hydrogen-bond distances and angles for (5) and (6) are listed in Tables 4 and 5, respectively. A structural precedent for the intermediate protonation state can be found in the urotropine N-oxideformic acid structure, which was determined from multipletemperature (123-295 K) single-crystal X-ray diffraction data and from neutron diffraction data at 123 K (Nygren et al, 2005), and from the variable-temperature neutron diffraction study of the pentachlorophenol-4-methylpyridine complex (Steiner et al, 2001). The design of pharmaceutical cocrystal materials to engineer enhanced physicochemical properties or stability into an API can utilize the acid-base interaction as a driver for cocrystal formation and the ÁpK a value (pK a base À pK a acid) and is often used to predict the formation of either a salt or cocrystal from the reaction.…”

Structural characterization of p-benzosemiquinone radical in a solid state: the radical stabilization by a low-barrier hydrogen bond

“…To characterize this type of hydrogen bond variable-temperature X-ray (VT-XRD) diffraction was used. Recently Wilson and coworkers (Parkin et al, 2004;Nygren et al, 2005) showed that this method is very efficient for describing a proton disorder. The variabletemperature neutron diffraction gives the average position of the proton (Wilson, 2001;Wilson et al, 2001;Steiner et al, 2001;Cowan et al, 2003Cowan et al, , 2005Parkin et al, 2004;Vishweshwar et al, 2004), whereas VT-XRD gives the distribution of electron density along the hydrogen bond.…”