Goran V. Janjić

What Are the Preferred Horizontal Displacements in Parallel Aromatic–Aromatic Interactions? Significant Interactions at Large Displacements

Aromatic–aromatic interactions are of great importance in numerous molecular systems, from biomolecules to molecular crystals, and play an important role in different fields ranging from molecular recognition and catalysis to transport. The majority of drug molecules contain aromatic rings and their interactions are crucial for their activity. It is important to understand the aromatic–aromatic interactions and to find out the preferred horizontal displacements (offsets) for parallel aromatic–aromatic interactions. Aromatic interactions have been extensively studied between two benzene molecules. Highlevel ab initio calculations showed two low-energy geometries of the benzene dimer. 4] In the first one, CH groups of one benzene molecule interact with the p system of the other, forming a CH–p interaction. The energy of the interaction is 2.84 kcal mol . In the other geometry, two benzene molecules are parallel with an offset (horizontal displacement) of 1.51 , forming a stacking interaction. The interaction energy is similar, namely, 2.73 kcal mol . In spite of extensive studies on benzene–benzene interactions, 3] no studies on stacking interactions with large horizontal displacement have been performed. Our recent results reveal that the parallel alignment on water–aromatic interactions can be significantly strong at large horizontal displacements. This prompted us to study benzene–benzene interactions at large horizontal displacements. Herein, we present our result on the interactions of two benzene molecules in the parallel orientation. Since analysis of the data in the crystal structures from the Cambridge Structural Database (CSD) enable the study of noncovalent interactions, 6] our analysis is based on crystal structures from the CSD. We also performed DFT and CCSD(T) calculations. To the best of our knowledge, this is the first study describing the significance of parallel aromatic–aromatic interactions at large offsets (horizontal displacements). The statistical study was based on the crystal structures archived in CSD (November 2010 release, version 5.32) A CSD search was performed using the ConQuest 1.13 program to extract all structures containing a benzene molecule and satisfying the following criteria: a) a crystallographic R factor below 10 %, b) error-free coordinates, c) normalized H-atom positions, and d) no polymer structures. The geometrical parameters used to search CSD, and to characterize the interactions between parallel benzene molecules, are displayed in Figure 1.

Parallel alignment of water and aryl rings—crystallographic and theoretical evidence for the interaction

Analysis of crystal structures from the Cambridge Structural Database (CSD) that involve close contact between water and aryl rings revealed the existance of conformations where the water molecule or one of its O-H bonds is parallel to the aromatic ring plane at distances typical for stacking interactions; attractive interaction energies obtained from ab initio calculations performed on model systems are significant (e.g.DeltaE(CCSD(T)) = -1.60 kcal mol(-1)) and consistent with the observed structures.

Are C–H⋯O interactions linear? The case of aromatic CH donors

The angular distribution of the C–H⋯O interactions of aromatic C–H donors was studied by analyzing data in the Cambridge Structural Database (CSD) and by ab initio calculations. The analysis of the C–H⋯O interactions in the crystal structures from the CSD indicate that aromatic C–H donors do not show strong preference for linear contacts and that the preference depends on the type of the atom or group in the o-position to the interacting C–H group. Namely, the acceptor oxygen atom has possibility for simultaneous C–H⋯O interactions with the hydrogen atom in the o-position to the interacting C–H group. The C–H⋯O interactions of aromatic molecules with two hydrogen atoms in the o-positions do not show preference for linear contacts. Bifurcated interactions are observed in a substantial number of structures. Moreover, in the structures with a substituent in the o-position there is possibility for simultaneous interactions, depending on the nature of the substituent. The results of the ab initio calculations are in accord with the CSD data and show that the stabilization energy is larger for bifurcated than for linear interactions. The calculated energies at the MP2/cc-pVTZ level for linear C–H⋯O interactions of benzene with water, methanol, and acetone are 1.28, 1.47, 1.45 kcal mol−1; while for bifurcated interactions are 1.38, 1.63, and 1.70 kcal mol−1, respectively. Analysis of the data in the CSD and the ab initio calculations indicate that the vicinity of the other possible hydrogen donors in the aromatic molecules causes a small tendency for linear contact in the C–H⋯O interactions. The result that nonlinear interactions are not energetically disfavoured, because of the possibility for simultaneous interactions, can be very important for recognizing C–H⋯O interactions in biomolecules containing aromatic groups, like proteins.

Classification of stacking interaction geometries of terpyridyl square-planar complexes in crystal structures

Stacking interactions of terpyridyl square-planar complexes in crystal structures were studied analyzing data from the Cambridge Structural Database. In most of the crystal structures, two terpyridyl complexes were oriented “head-to-tail” or “head-to-head”, with “head-to-tail orientation” being most prevalent. The number of structures with other orientations was very small. Based on the analysis of interacting geometries, we classified overlaps of terpyridyl complexes into six types. The types were defined by values of several geometrical parameters and all interactions of the same type had very similar overlap patterns.

Crystallographic and ab initio study of pyridine CH–O interactions: linearity of the interactions and influence of pyridine classical hydrogen bonds

The CH–O interactions of pyridine with water molecules were studied by analysing the data in the Cambridge Structural Database (CSD) and by ab initio calculations. The analysis of the CH–O interactions in the crystal structures from the CSD indicates that pyridine C–H donors do not show preference for linear contacts. The results of the ab initio calculations are in accord with the CSD data and show that stabilization energy is larger for bifurcated interactions than for linear interactions. The calculated interaction energies at the MP2/cc-pVQZ level for linear CH–O interactions between water and pyridine ortho, meta, and para C–H groups are −1.24, −1.94 and −1.97 kcal mol−1, respectively. The calculated energies for bifurcated ortho–meta and meta–para interactions are −1.96 and −2.16 kcal mol−1. The data in the crystal structures from the CSD and ab initio calculations show a strong influence of simultaneous classical hydrogen bonds of pyridine on the CH–O interactions. The results show that simultaneous hydrogen bonds strengthen the CH–O interaction by about 20%. The calculated interaction energies for linear CH–O interactions between water and pyridine, with simultaneous hydrogen bonds, for ortho, meta, and para C–H groups are −1.64, −2.34, and −2.33 kcal mol−1, respectively, while those for ortho–meta and meta–para bifurcated interactions are −2.44 and −2.58 kcal mol−1. The energies of the meta–para bifurcated interactions calculated at the CCSD(T)(limit) level for pyridine without and with hydrogen bonds are −2.30 and −2.69 kcal mol−1, respectively. The result that nonlinear interactions are energetically favoured can be very important for recognizing the CH–O interaction of heteroaromatic rings in the crystal structures and biomolecules.

CH/π interactions in metal–porphyrin complexes with pyrrole and chelate rings as hydrogen acceptors

CH/π interactions in metal porphyrinato complexes were studied by analyzing data in crystal structures from the Cambridge Structural Database (CSD) and by quantum chemical calculations. The analysis of the data in the CSD shows that both five-membered pyrrole and six-membered chelate rings form CH/π interactions. The interactions occur more frequently with five-membered rings. The analysis of distances in crystal structures and calculated energies show stronger interactions with six-membered chelate rings, indicating that a larger number of interactions with five-membered rings are not the consequence of stronger interactions, but better accessibility of five-membered pyrrole rings. The calculated energies of the interactions with positions in six-membered rings are -2.09 to -2.83 kcal/mol, while the energies with five-membered rings are -2.05 to -2.26 kcal/mol. The results reveal that stronger interactions of six-membered rings are the consequence of stronger electrostatic interactions. Substituents on the porphyrin ring significantly strengthen the interactions. Substituents on the six-membered ring strengthen the interaction energy by about 20%. The results show that CH/π interactions play an important role in molecular recognition of metalloporphyrins. The significant influence of the substituents on interaction energies can be very important for the design of model systems in bioinorganic chemistry.

Geometries of stacking interactions between phenanthroline ligands in crystal structures of square-planar metal complexes

Stacking interactions of phenanthroline square-planar complexes in crystal structures were studied by analyzing data from the Cambridge Structural Database. In most of the crystal structures, two phenanthroline complexes were oriented “head to tail.” Phenanthroline complexes show a wide range of overlap geometries in stacking interactions, while short metal–metal distances were not observed. Stacking chains with alternating overlaps were the predominant type of packing in the crystal structures.

The influence of water molecule coordination onto the water–aromatic interaction. Strong interactions of water coordinating to a metal ion

The interactions between water molecules (non-coordinating and coordinating) and aromatic rings were studied by analyzing data in the Cambridge Structural Database and by quantum chemical calculations. The results show the influence of water coordination to a metal ion; interactions of coordinating water are stronger. The MP2/def2-QZVP interaction energies of non-coordinating water and neutral aqua complexes [ScCl3(H2O)3], [ZnCl2(H2O)4], [CdCl2(H2O)4], and [ZnCl2(H2O)2] with benzene molecule are −3.36, −5.10, −5.43, −6.86, and −5.14 kcal mol−1, respectively. Interactions of charged aqua complexes [ZnCl(H2O)5]+ and [Zn(H2O)6]2+ are stronger, −9.69 and −13.96 kcal mol−1, respectively. The calculations also reveal strong long-range interactions: at the distance of 3.0 A the interaction energies of neutral complexes are in the range of −4.11 to −4.91 kcal mol−1, while interaction energies of charged complexes are −6.37 and −10.76 kcal mol−1.

Influence of supramolecular structures in crystals on parallel stacking interactions between pyridine molecules

Parallel stacking interactions between pyridines in crystal structures and the influence of hydrogen bonding and supramolecular structures in crystals on the geometries of interactions were studied by analyzing data from the Cambridge Structural Database (CSD). In the CSD 66 contacts of pyridines have a parallel orientation of molecules and most of these pyridines simultaneously form hydrogen bonds (44 contacts). The geometries of stacked pyridines observed in crystal structures were compared with the geometries obtained by calculations and explained by supramolecular structures in crystals. The results show that the mean perpendicular distance (R) between pyridine rings with (3.48 Å) and without hydrogen bonds (3.62 Å) is larger than that calculated, because of the influence of supramolecular structures in crystals. The pyridines with hydrogen bonds show a pronounced preference for offsets of 1.25-1.75 Å, close to the position of the calculated minimum (1.80 Å). However, stacking interactions of pyridines without hydrogen bonds do not adopt values at or close to that of the calculated offset. This is because stacking interactions of pyridines without hydrogen bonds are less strong, and they are more susceptible to the influence of supramolecular structures in crystals. These results show that hydrogen bonding and supramolecular structures have an important influence on the geometries of stacked pyridines in crystals.

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.