Beata Warżajtis

Factors Affecting Conformation of (R,R)-Tartaric Acid Ester, Amide and Nitrile Derivatives. X-Ray Diffraction, Circular Dichroism, Nuclear Magnetic Resonance and Ab Initio Studies

Abstract Derivatives 2a–15a of (R,R)-tartaric acid (1a) with all combinations of methyl ester, amide, N-methylamide and N,N-dimethylamide groups, as well as the corresponding O,O′-dibenzoyl derivatives 1b–15b and nitriles 16–18 have been synthesized. Their conformations have been studied by the NMR and CD methods in solution as well as by X-ray diffraction in the crystalline state. The preference for planar. T conformation of the four carbon chain is observed under conditions restricting the α-hydroxyacid, ester or amide group to be nearly planar, this conformation being stabilized by intramolecular hydrogen bonds of the S(5) motif and the electrostatic CO/C(β)H and CN/C(β)H coplanar bond interactions. The C=O/C(α)-O bond system tends to be either synplanar (ester, acid), or antiplanar (ester, primary and secondary amide). Ab initio calculations allowed to demonstrate that for the isolated molecules of diamides 10a and 15a there is strong preference for gauche G+(a,a) conformers, the driving force being the formation of the hydrogen bonded six-membered cycles of the S(6) motif joining the OH and C=O groups from two different halves of the molecule. The results compare favourably with the experimental values derived from NMR spectra of 15a in nonpolar solvent. In the absence of intramolecular hydrogen bonding the N,N-dimethylamide group is better accomodated in a gauche G− conformer. This releases the nonbonded interaction due to the amide methyl group anti to the carbonyl group.

Supramolecular organisation via hydrogen bonding in trimethoprim sulfonate salts

The present study deals with the crystal structures of four organic salts, namely, trimethoprim benzene sulfonate monohydrate 1, trimethoprim sulfanilate monohydrate 2, trimethoprim p-toluene sulfonate 3 and trimethoprim 3-carboxy-4-hydroxybenzene sulfonate dihydrate 4. Trimethoprim (TMP) is protonated at one of the ring nitrogens of the pyrimidine ring. Generally, in the TMP carboxylate complexes, the protonated pyrimidine ring is hydrogen-bonded to the carboxylate group forming a cyclic fork-like hydrogen-bonded bimolecular motif. In structures 1–3, the sulfonate group plays the role of the carboxylate anion. In compounds 1 and 2, there is no pairing of the pyrimidine rings because the pairing sites are blocked by water molecules donating hydrogen to the unprotonated ring nitrogen. Two of the cyclic motifs are bridged by the water molecule donating two hydrogen atoms, leading to a hydrogen-bonded supramolecular chain. This chain pairs with another chain running in the opposite direction. These two chains are cross-linked by O–H⋯O hydrogen bonds. In compound 2, two of the hydrogen atoms of the amino group of the sulfanilate bridge two methoxy oxygen of the two TMP cations via N–H⋯O hydrogen bonds resulting in a supramolecular zig-zag chain. In compound 3, two inversion related cyclic motifs are paired through a pair of N–H⋯N hydrogen bonds involving the 4-amino group and the N3 atom of the pyrimidine ring. In addition to the pairing, one of the sulfonate oxygen atoms bridges the 2-amino and 4-amino groups on either side of the paired bases, resulting in a self-complementary DADA (D represents the hydrogen bond donor and A represents hydrogen bond acceptor) array of quadruple hydrogen bonding patterns. In compound 4, one of the water molecules forms a hydrogen-bonded dimer with the inversion-related water molecule. The 3-carboxy-4-hydroxybenzene sulfonate moiety self-assembles into a supramolecular chain along the c axis through O–H⋯O hydrogen bonds. Two such oppositely running supramolecular chains are connected by dimeric and monomeric water molecules. The variation of supramolecular organization via hydrogen bonding in the four different trimethoprim sulfonate salts has been discussed.

Packing modes of (R,R)-tartaric acid esters and amides

The molecular packing modes of a series of mono- and diamides of (R, R)-tartaric acid are discussed on the basis of their crystal structures. Derivatives include combinations of methylester, amide, N-methylamide and N,N-dimethylamide groups, both symmetrically and asymmetrically substituted. The symmetrically substituted derivatives do not utilize their C(2) symmetry in the crystal. The packing of primary tartramides seems to be driven by NH.O=C hydrogen bonds and supplemented by strong OH.O=C and weak NH.OH bonds. On the other hand, in derivatives containing methylester and/or methylamide groups OH.OH.O=C hydrogen-bond patterns seem to dominate. Types of aggregates, characteristic for the investigated derivatives, include cyclic dimers and ring systems analogous to the dimers, but formed by two different although complementary functional groups, as well as sets of chains aligned in a manner resembling the helical arrangement of peptides. The helices are formed along the screw axis with an identity period of approximately 5 A. In tartramic acids, containing in one molecule both carboxyl and amide functions, in competition between the two groups to control the molecular arrangement, the latter dominates, unless it is N-substituted tartramide, in which case the carboxyl group predominates. Problems with packing, which occur in some of the structures owing to the steric bulk of the methyl groups, are overcome by changes in conformation (esters) or by co-crystallization with solvent water molecules (methylamides and dimethylamides). These derivatives are also more likely to crystallize with multiple asymmetric units.

(R,R)-Tartaric Acid Dimethyl Diester from X-Ray and Ab Initio Studies: Factors Influencing Its Conformation and Packing

The conformation of dimethyl (R,R)-tartrate has been analyzed on the basis of the single crystal X-ray diffraction method as well as by ab-initio quantum chemical studies. The results showed that the extended T conformation containing two planar hydroxyester moieties predominates in both ab-initio and X-ray studies. The lowest energy conformer in ab-initio calculations has C2 symmetry and hydrogen bonds between a hydroxyl group and the nearest carbonyl oxygen. The second in energetical sequence, with an energy difference of only 1.2 kcal/mol, is the asymmetrical conformer, which differs from the lowest energy form by the rotation of one of the ester groups by 180°. Intramolecular OH...O hydrogen bonds observed in this rotamer again involve only proximal functional groups. This conformer is present in the crystal structure of the studied compound, although its conformation in the solid state is no longer stabilized by intramolecular hydrogen bonds of the type mentioned above. In the crystal, hydroxyl groups are mostly involved in intermolecular hydrogen bonds and form only a weak intramolecular hydrogen bond with each other. The planar arrangement of the α-hydroxyester moieties combined with the extended conformation of the carbon chain seems to be stabilized by the intramolecular hydrogen bonds between neighboring functional groups and by the long range dipole-dipole interactions between two pairs of CO and (β)C-H bonds.

Pseudo-polymorphism and crystal engineering: hydrogen-bonded supramolecular networks in trimethoprim m-chlorobenzoate and trimethoprim m-chlorobenzoate dihydrate

This manuscript deals with the crystal structures of two pseudo-polymorphic forms, namely, trimethoprim m-chlorobenzoate (1) and trimethoprim m-chlorobenzoate dihydrate (2). In both the structures, the pyrimidine moieties of trimethoprim are protonated at one of the ring nitrogens. In both the forms, the carboxylate group interacts with the protonated pyrimidine ring to form the cyclic hydrogen-bonded bimolecular motif. These motifs are further self-organized into two different hydrogen-bonded networks. In compound 1, two of the centrosymmetrically-related motifs are hydrogen-bonded to give a complementary DDAA (D refers to the hydrogen bond donor and A refers to the hydrogen bond acceptor) array of quadruple hydrogen bonding pattern. In compound 2, two of the inversion-related motifs are paired through a pair of N–H⋯N hydrogen bonds involving the 2-amino group and the N3 atom. In addition to the pairing, one water molecule bridges the 4-amino group of one motif and the carboxylate oxygen of another motif on both sides of the pairing, leading to a complementary linear array of hydrogen bonds.

Solution and Solid-State Effects on NMR Chemical Shifts in Sesquiterpene Lactones: NMR, X-ray, and Theoretical Methods

Selected guaianolide type sesquiterpene lactones were studied combining solution and solid-state NMR spectroscopy with theoretical calculations of the chemical shifts in both environments and with the X-ray data. The experimental (1)H and (13)C chemical shifts in solution were successfully reproduced by theoretical calculations (with the GIAO method and DFT B3LYP 6-31++G**) after geometry optimization (DFT B3LYP 6-31 G**) in vacuum. The GIPAW method was used for calculations of solid-state (13)C chemical shifts. The studied cases involved two polymorphs of helenalin, two pseudopolymorphs of 6α-hydroxydihydro-aromaticin and two cases of multiple asymmetric units in crystals: one in which the symmetry-independent molecules were connected by a series of hydrogen bonds (geigerinin) and the other in which the symmetry-independent molecules, deprived of any specific intermolecular interactions, differed in the conformation of the side chain (badkhysin). Geometrically different molecules present in the crystal lattices could be easily distinguished in the solid-state NMR spectra. Moreover, the experimental differences in the (13)C chemical shifts corresponding to nuclei in different polymorphs or in geometrically different molecules were nicely reproduced with the GIPAW calculations.

The role of multiple parallel and antiparallel local dipoles for molecular structure and intermolecular interactions of oxalamides

The paper illustrates the role of dipole–dipole interactions in stabilizing the molecular structure and intermolecular interactions in oxalic acid diamides. A CSD search and quantum chemical calculations reveal that within the oxalamide molecule N–H and β(CO) bonds are oriented mutually parallel, so that the local dipoles formed along these bonds are antiparallel. Moreover, the all-trans conformation of secondary oxalamides gives rise to the cooperative intramolecular NH/CO and CH/CO dipolar interactions. Contrary to the situation in hydrogen bonded amide R22(8) dimers, in oxalamide R22(10) dimers the CO and N–H bonds from two different molecules are parallel, moreover, the angular distribution of proton donors around carbonyl acceptor is much more linear. These findings indicate the dominant role of dipole–dipole interactions in this bimolecular cyclic system. As parallel (and antiparallel) dipole–dipole interactions impose restraints on the position of four atoms such an approach provides an additional predictive value over the identification of hydrogen bonding that imposes restraints on the position of three atoms.

Synthesis, conformation and chiroptical properties of diaryl esters of tartaric acid.

Previously unknown diaryl esters of l-tartaric acid have been synthesized. Their conformations have been studied by DFT calculations, NMR and circular dichroism spectroscopy in solution, as well as by X-ray diffraction in the crystalline state. The four-carbon tartrate chain of diaryl esters was found to be extended in all cases, with a higher degree of nonplanarity in the crystals. Dinaphthyl tartrates show unusually strong exciton Cotton effects (A = -228 for di-1-naphthyl l-tartrate) due to the coupling of allowed 1B(b) transitions in naphthyl chromophores, despite the acyclic structure and significant distance (over 10 A) between the two chromophores.

Antioxidant properties of thio-caffeine derivatives: Identification of the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine as antioxidant and highly potent cytoprotective agent

A series of nine thio-caffeine analogues were synthesized and characterised by NMR, FT-IR and MS spectroscopic methods. Molecular structures of four of them were determined using single crystal X-ray diffraction methods. The antioxidant properties of all compounds, at concentration ranges from 0.025 to 0.1mg/mL, were evaluated by various chemical- and cell-based antioxidant assays. Human erythrocytes were used to examine in vitro haemolytic activity of all compounds and their protective effect against oxidative haemolysis induced by AAPH, one of the commonly used free radical generator. All compounds studied showed no effect on the human erythrocytes membrane structure and permeability with the exception of 8-(phenylsulfanyl)caffeine. Among the nine caffeine thio-analogues tested, the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine possessed exceptionally high antioxidant properties. Moreover, it protects human erythrocytes against AAPH-induced oxidative damage as efficiently as the standard antioxidant Trolox. Therefore, 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine may have a significant cytoprotective potential caused by its antioxidant activity.

Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen-κN7)] (1) and [AuCl3(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89μM, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128μM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.