(1E,4Z,6E)-5-Hy­droxy-1,7-bis­(2-meth­oxy­phen­yl)-1,4,6-hepta­trien-3-one

In the title compound, C21H20O4, the central hepta­trienone unit is approximately planar, with a maximum atomic deviation of 0.1121 (11) Å; the two benzene rings are twisted with respect to the hepta­trienone mean plane by 2.73 (5) and 29.31 (4)°. The mol­ecule exists in the enol form and the hy­droxy group forms an intra­molecular hydrogen bond with the neighboring carbonyl group. Weak inter­molecular C—H⋯O hydrogen bonding is present in the crystal structure

Synthesis and evaluation of halogenated nitrophenoxazinones as nitroreductase substrates for the detection of pathogenic bacteria

The synthesis and microbiological evaluation of 7-, 8- and 9-nitro-1,2,4-trihalogenophenoxazin-3-one substrates with potential in the detection of nitroreductase-expressing pathogenic microorganisms are described. The 7- and 9-nitrotrihalogenophenoxazinone substrates were reduced by most Gram negative microorganisms and were inhibitory to the growth of certain Gram positive bacteria; however, the majority of Gram positive strains that were not inhibited by these agents, along with the two yeast strains evaluated, did not reduce the substrates. These observations suggest there are differences in the active site structures and substrate requirements of the nitroreductase enzymes from different strains; such differences may be exploited in the future for differentiation between pathogenic microorganisms. The absence of reduction of the 8-nitrotrihalogenophenoxazinone substrates is rationalized according to their electronic properties and correlates well with previous findings

A sensitive and specific β-alanyl aminopeptidase-activated fluorogenic probe for the detection of Pseudomonas aeruginosa

We report the synthesis of the sensitive and specific fluorogenic self-immolative substrate 8b, which is hydrolzyed by β-alanyl aminopeptidase (BAP), resulting in a 1,6-elimination and the release of the highly fluorescent hydroxycoumarin 6b. This fluorophore 6b is retained within bacterial colonies, so has potential for the detection of P. aeruginosa (a BAP producer); it also has potential in liquid media due to the rapid and strong signal release from the substrate 8b, and lack of self-quenching or photobleaching.NHMR

Experimental and Theoretical Charge Density Distribution in Pigment Yellow 101

The charge density distribution in 2,2'-Dihydroxy-1,1'-naphthalazine (Pigment Yellow 101; P.Y.101) has been determined using high-resolution X-ray diffraction and multipole refinement, along with density functional theory calculations. Topological analysis of the resulting densities highlights the localisation of single/double bonds in the central C=N-N=C moiety of the molecule in its ground state. The density in the N—N is examined in detail, where we show that very small differences between experiment and theory are amplified by use of the Laplacian of the density. Quantification of hydrogen bonds highlights the importance of the intramolecular N—H…O interaction, known to be vital for retention of fluorescence in the solid state, relative to the many but weak intermolecular contacts located. However, a popular method for deriving H-bond strengths from density data appears to struggle with the intramolecular N—H…O interaction. We also show that theoretical estimation of anisotropic displacements for hydrogen atoms brings little benefit overall, and degrades agreement with experiment for one intra-molecular contact.NH&MR

An analysis of the experimental and theoretical charge density distributions of the piroxicam-saccharin co-crystal and its constituents

Experimental and theoretical charge density analyses of piroxicam (1), saccharin (2) and their 1:1 co-crystal complex (3) have been carried out. Electron density distribution (EDD) was determined through the use of high-resolution single crystal X-ray diffraction and the data were modelled using the conventional multipole model of electron density according to the Hansen-Coppens formalism. A method for optimising the core density refinement of sulfur atoms is discussed, with emphasis on the reduction of residual electron density that is typically associated with this atom. The asymmetric unit of complex (3) contains single molecules of saccharin and the zwitterionic form of piroxicam. These are held together by weak interactions (hydrogen bonds, π-π and van der Waals interactions), ranging in strength from 4 to 160 kJmol-1, working together to stabilise the complex;. analysis of the molecular electrostatic potential (MEP) of the complexes showed electron redistribution within the cocrystal, facilitating the formation of these generally weak interactions. Interestingly, in the zwitterionic form of piroxicam, the charge distribution reveals that the positive and negative charges are not associated with the formal charges normally associated with this description, but are distributed over adjacent molecular fragments. The use of anisotropic displacement parameters (ADPs) for hydrogen atoms in the multipole model was also investigated but no improvement in the quality of the topological analysis was found.The University of Sydney Bridging Support Scheme. The Danish National Research Foundation (Center for Materials Crystallography, DNRF-93

A comparison of the experimental and theoretical charge density distributions in two polymorphic modifications of Piroxicam.

Experimental charge density distribution studies of two polymorphic forms of piroxicam, β- piroxicam (1) and piroxicam monohydrate (2), were carried out via high-resolution single crystal X-ray diffraction experiments and multipole refinement. The asymmetric unit of (2) consists of two discrete piroxicam molecules, (2a) and (2b), and two water molecules. Geometry differs between (1) and (2) due to the zwitterionic nature of (2) which results in the rotation of pyridine ring around the C(10)–N(2) bond by approximately 180°. Consequently, the pyridine and amide are no longer co-planar and (2) forms two exclusive, strong hydrogen bonds, H(3) …O(4) and H(2) …O(3), with bond energy of 66.14 kJ mol-1 and 112.82 kJ mol- 1 for (2a), 58.35 kJ mol-1 and 159.51 kJ mol-1 for (2b) respectively. Proton transfer between O(3) and N(3) in (2) results in significant differences in surface electrostatic potentials. This is clarified on calculation of atomic charges in the zwitterion shows the formally positive charge of the pyridyl nitrogen is redistributed over the whole of the pyridine ring instead of concentrated at N-H. Similarly, the negative charge of the oxygen is distributed across the benzothiazinecarboxamide moiety. Multipole derived lattice energy for (1) is -304 kJ mol-1 and that for (2) is -571 kJ mol-1, which is in agreement with the experimentally determined observations of higher solubility and dissolution rates of (1) compared to (2)

Exploring the binding of barbital to a synthetic macrocyclic receptor. A charge density study

Experimental charge density distribution studies, complemented by quantum mechanical theoretical calculations, of a host–guest system composed of a macrocycle (1) and barbital (2) in a 1:1 ratio (3) have been carried out via high-resolution single-crystal X-ray diffraction. The data were modeled using the conventional multipole model of electron density according to the Hansen–Coppens formalism. The asymmetric unit of macrocycle 1 contained an intraannular ethanol molecule and an extraannular acetonitrile molecule, and the asymmetric unit of 3 also contained an intraannular ethanol molecule. Visual comparison of the conformations of the macrocyclic ring shows the rotation by 180° of an amide bond attributed to competitive hydrogen bonding. It was found that the intraannular and extraannular molecules inside were orientated to maximize the number of hydrogen bonds present, with the presence of barbital in 3 resulting in the greatest stabilization. Hydrogen bonds ranging in strength from 4 to 70 kJ mol–1 were the main stabilizing force. Further analysis of the electrostatic potential among 1, 2, and 3 showed significant charge redistribution when cocrystallization occurred, which was further confirmed by a comparison of atomic charges. The findings presented herein introduce the possibility of high-resolution X-ray crystallography playing a more prominent role in the drug design process

Using electron density to predict synthon formation in a 4-hydroxybenzoic acid : 4,4'-bipyridine co-crystal

Experimental charge density distribution studies complemented by quantum mechanical theoretical calculations of 4-hydroxybenzoic acid (4HBA) (1), 4,4'-bipyridine (44BP) (2) and one polymorphic form of the co-crystal containing 4HBA and 44BP molecules in a 2:1 ratio (3), have been carried out via high resolution single-crystal X-ray diffraction. Synthon formation was found to be the main driving force for crystallisation in both (1) and (3) with a carboxylic acid homosynthon present in (1) and a heterosynthon in (3) comprised of a carboxylic acid from 4HBA and a pyridine nitrogen and aromatic hydrogen from 44BP. Topological analysis revealed the bonding in the homosynthon to be stronger than the heterosynthon (305.88 versus. 193.95 kJ mol-1) with a greater number of weak interactions in (3) helping to stabilise the structure. The distance from the hydrogen and hydrogen bond acceptor to the bond critical point (bcp) was also found to be a significant factor in determining bond strength, potentially having a greater effect than lone pair directionality. Two different methods of lattice energy calculations were carried out and both methods found (1) to be more stable than (3) by ~40 and 10 kJmol-1 for the LATEN and PIXEL methods respectively. Energy framework diagrams reveal (1) to be dominated by coulombic forces while both coulombic and dispersion forces are prominent in (3) contributing equally to the lattice energy. This study examined the utility of homosynthons and heterosynthons in future crystal engineering endeavours and concluded that although in this case the single molecule crystal was more thermodynamically stable, the asymmetry of the co-crystal system allowed it to form a wider range of interactions resulting in only a small reduction in stability. This highlights the potential of using heterosynthons to develop co-crystals to improve pharmaceuticals. These findings highlight the utility of high resolution single crystal X-ray crystallography in rationalising observed physical properties

An experimental and theoretical charge density study of theophylline and malonic acid cocrystallization

The pharmaceutical agent theophylline (THEO) is primarily used as a bronchodilator and is commercially available in both tablet and liquid dosage forms. THEO is highly hygroscopic, reducing its stability, overall shelf-life, and therefore usage as a drug. THEO and dicarboxylic acid cocrystals were designed by Trask et al. in an attempt to decrease the hygroscopic behaviour of THEO; cocrystallisation of THEO with malonic acid (MA) did not improve the hygroscopic stability of THEO in simulated atmospheric humidity testing. The current study employed high-resolution X-ray crystallography, and Density Functional Theory (DFT) calculations to examine the electron density distribution (EDD) changes between the cocrystal and its individual components. The EED changes identified the reasons why the THEO:MA cocrystal did not alter the hygroscopic profile of THEO. The cocrystal was equally porous, with atomic packing factors (APF) similar to those of THEO 0.73 vs. 0.71, respectively. The THEO:MA (1) cocrystal structure is held together by an array of interactions; a heterogeneous synthon between the imidazole and a carboxylic fragment stabilising the asymmetric unit, a pyrimidine-imidazole homosynthon, and an aromatic cycle stack between two THEO moieties have been identified, providing 9.7–12.9 kJ mol−1 of stability. These factors did not change the overall relative stability of the cocrystal relative to its individual THEO and MA components, as shown by cocrystal (1) and THEO being equally stable, with calculated lattice energies within 2.5 kJ mol−1 of one other. The hydrogen bond analysis and fragmented atomic charge analysis highlighted that the formation of (1) combined both the EDD of THEO and MA with no net chemical change, suggesting that the reverse reaction — (1) back to THEO and MA — is of equal potential, ultimately producing THEO hydrate formation, in agreement with the work of Trask et al. These results highlight that a review of the EDD change associated with a chemical reaction can aid in understanding cocrystal design. In addition, they indicate that cocrystal design requires further investigation before becoming a reliable process, with particular emphasis on identifying the appropriate balance of synthon engineering, weak interactions, and packing dynamics

Analyzing hydration differences in cocrystal polymorphs: high-resolution X-ray investigation of caffeine-glutaric acid cocrystals

Two polymorphic forms of caffeine (CAF)–glutaric acid (GLU) cocrystals have been studied via high-resolution X-ray crystallography and Bader’s quantum theory of atoms in molecules (QTAIM). For both the monoclinic, 1, and triclinic, 2, systems the experimental charge density distributions of the 1:1 ratio of CAF and GLU polymorphs have been determined and compared. Previous studies have determined that 1 is less stable than 2, in relative humidity (RH) testing. A topological analysis of the electron density distribution (EDD) revealed little difference between the two polymorph internal systems. The packing densities (0.76 vs 0.74) and lattice energies (−101.1 vs −107.1 kJ mol–1) of 1 and 2, respectively, are nearly equivalent, implying that the differences in hygroscopicity between the two polymorphs are not due to crystal lattice porosity or stability. A topological analysis of the number and strength of hydrogen bonds for 1 and 2 revealed nine hydrogen bonds in both polymorphs. “Classical” (O–H···X) hydrogen bonds were similarly present in both polymorphs, stabilizing the cocrystals. However, the sum of the stability produced from the “nonclassical” (C–H···X) bonds is higher in 2: −27.6 vs −38.2 kJ mol–1 for 1 and 2, respectively. One of the nine hydrogen bonds in 1 and 2 varies from the others, caused by the torsional rotation of the aliphatic carbon chain in GLU. This bond is critical for packing stabilization, creating a parallelogram-like packing arrangement in 2 in comparison to ribboning in 1. A Hirshfeld surface analysis found that the percentages of O–H···X hydrogen bonds were nearly identical in 1 and 2 (23.9% vs 22.1%); however, the H···H contacts were higher in 2 (61.4% vs 65.8% for 1 and 2, respectively), suggesting that more hydrogen-based contacts require competitive displacement by water in the hydration of 2 in comparison to 1. Additionally, a stabilizing aromatic cycle stack between CAF molecules is present in 2 due to the varied parallelogram packing arrangement, which was absent in 1; this provided ∼11.3 kJ mol–1 of stability to the system of 2. The solid-state entropies and molecular dipole moments (MDMs) of 1 and 2 supported the relative stability of the individual polymorphs, with 1 having a higher entropy and dipole moment in comparison to 2 (123.2 vs 112.8 J K–1 mol–1 and 7.45 and 4.93 D for 1 and 2, respectively), implying that it has the potential to hydrate more rapidly. These findings are in good agreement with previous experimental RH stability studies, giving further insight into the information gained from thermally averaged ground-state crystal electron density data