Pyramidalization of the Carboxamide sp2-Center in Peptide Structures.

A CSD search in the Cambridge Crystallographic Database for the substructure N-CαH-C'(═O)-N gave 24,180 peptide structures for analysis of the pyramidalization of the sp2-hybridized carboxamide group C'(═O)NCα, which had not been investigated before. The dependence of the pyramidalization θ = O-N-C'-Cα on the rotation angle ψ = O═C'-Cα-N about bond C'-Cα resulted in a curve with three maxima, three minima, and six zero-crossings. Surprisingly, the ψ/θ analysis of the individual amino acid building blocks showed that all of them exhibited similar curves, irrespective of their different R substituents. This unusual behavior is explained by a 3-fold short-range potential set up by the three covalent bonds, emanating from Cα. The tie-up of the rotation angle ψ and the pyramidalization θ in a rigid coupling is remarkable. In the 24,180 peptide structures, subjected to X-ray crystallography, there is no dynamics. For peptides in solution, the rotation/pyramidalization curve ψ/θav determines the degree of pyramidalization θ, when the rotation angle ψ runs through a full 360° circle. Density functional theory (DFT) calculations of alaninamide supported the analysis.

Twofold and Threefold Sinusoidal Patterns in Coupled Molecular Motions of 184,025 Structures of Phenylethane, Nitroethane, and Carboxylate Derivatives.

Scatter plot analyses for 14,169 phenylethanes of the substructure Cß-CαH2-Ph with three open coordination positions at Cß and 150,568 phenylethanes of Cß-CαHX-Ph with an additional open coordination position X at Cα have been performed, based on searches in the Cambridge Structural Database. The correlation of rotation angle ψ = Cß-Cα-Ci-Co with a pyramidalization angle θ = Co-Co'-Ci-Cα in a 360° rotation about the bond Cα-Ci reveals a sinusoidal pattern with three maxima and minima, whereas the correlation of rotation angle ψ with bond angle ω = Cß-Cα-Ci and bond length d = Cß-Cα results in sinusoidal patterns with two maxima and minima. A total of 3993 nitro derivatives of the substructure Cß-CαHX-NO2 confirm the results and show that atoms Ci/Co/Co' in the phenyl compounds can be replaced by atoms N/O/O' without any change in the two- and threefold patterns. In 15,295 methyl acetates of the substructure Cß-CαHX-C'(═O)OMe, pyramidalization of the group CαC'(═O)OMe results in a chiral flat tetrahedron with four different corners. (Rθ)/(Sθ) selectivity in the configuration of the tetrahedron is induced by the bonds Cα-Cß, Cα-H, and Cα-X, emanating from the tetrahedral center Cα. It is surprising that bonds as different as Cα-Cß, Cα-H, and Cα-X (X = H, C, N, O, S, etc.) give almost the same induction intensities.

Rotation about a Covalent Bond and Pyramidalization of an Adjacent sp2 Center are a Synchronized Molecular Motion.

The correlation of the rotation about the Cα-C' bond and the pyramidalization of the sp2-hybridized carbon atom C' and its three bonding partners to a flattened tetrahedron in the substructure Cß-CαH-C'(═O)-OMe of substituted methyl acetates revealed that the two processes are not independent of each other but parts of a common molecular motion, as outlined in the preceding back-to-back paper. In the present study, we generalized the substructure to Xß-CαH-C'(═Y)-Z with X, Y, and Z = O, N, C, and S, extending the analysis to several hundred thousand structures of the type carboxylates, carboxamides, ketones, imines, olefins, peptides, lactates, carbothioates, and phenyl derivatives, retrieved from the Cambridge Structural Database. ψ/θ Scatter plots of the individual structure points and their averaging in ψ/θav curves result in wavelike patterns with three maxima and minima and inversion symmetry at ψ = 0° and ±180 for a 360° rotation of Cß about the Cα-C' bond. The pyramidalization of the sp2-hybridized group CαCiCoCo', which is part of the aromatic system, even disturbs the planarity of phenyl rings. Density functional theory calculations confirm the results of the CSD search.

Chirality of the Conformation Attacks the Planarity of the sp2 Carbon Atom in a Covalent Bond.

The correlation of the rotation about the bond C'-Cα and the pyramidalization of the sp2 hybridized carbon atom C' and its three bonding partners to a flattened tetrahedron was investigated for the substructure Cß-CαH-C'(═O)-OMe. A search in the Cambridge Structural Database (CSD) gave 15,295 structures with a substituted methyl acetate group at the end of the molecules. The scatter plot of the rotation angle ψ = O═C'-Cα-Cß versus the pyramidalization angle θ = O(MeO)C'Cα and the ψ/θav curve show an unusual undulating pattern with three maxima and minima for a 360° rotation about the bond C'-Cα. There is no net chiral induction from the (Mψ)/(Pψ) conformations of the bond C'-Cα to the (Rθ)/(Sθ) configurations of the flattened tetrahedron because the contributions of the three maxima and minima cancel each other. The wavelike ψ/θav curve demonstrates that the rotation about the bond C'-Cα and the pyramidalization of the group C'(═O)(OMe)Cα are not independent processes. They are coupled with each other in one common molecular motion. The ψ/θav curve appears as the third harmonic of a sinusoidal fundamental frequency. DFT calculations of the propanoate anion, methyl propanoate, and methyl 2-methylpropanoate confirm the results of the CSD search.

Chiral Selectivity in the Achiral Amino Acid Glycine.

A Cambridge Structural Database (CSD) search for the zwitterion of glycine, the only natural amino acid which does not have a chiral center at Cα, and its derivatives H3N-CαH2-C'(Ocis)Otrans(H/R/M) gave 425 hits, 420 of which are chiral because of the ψ conformation with regard to the central C'-Cα bond (ψ = OcisC'CαN ≠ 0 or 180°). Chiral ψ conformations distort the planar carboxylic group CαC'(Ocis)Otrans group stereoselectively to an asymmetric flat tetrahedron with four different corners, specified by (Rθ)/(Sθ). Negative rotation angles ψ predominantly induce pyramidalization angles θ = OtransC'CαOcis below -180°, resulting in a high diastereoselectivity for (Mψ,Sθ)-glycine. Positive rotation angles ψ preferentially give (Pψ,Rθ)-glycine. Density functional theory calculations confirm the results of the data analysis, indicating an increase of pyramidalization θ for increasing rotation angles ψ. This is corroborated by the analysis of section averages of the structural data, showing an increase of the ψ/θ selectivity in the series 1.5, 2.8, 3.5, and 6.0 for increasing rotation angles ψ. Without any chiral bias, 419 glycine derivatives crystallize in the ratio racemate/conglomerate 359:65.

Selective distortion of the planar group Cα C'(O)O to a chiral flat tetrahedron in the amino acid alanine.

Based on a Cambridge Structural Database (CSD) search, a meta-analysis of 116 structures of alanine H3 NCα H(CH3 )C'(O)O and its derivatives H3 NCα H(CH3 )C'(O)O(H/R/M), protonated, esterified, or coordinated at the carboxylic group, shows that in the first step of a chirality chain, the L configuration at Cα induces (M) and (P) conformations with respect to rotation around the central C'─Cα bond. In the second step, the (M) and (P) conformations selectively distort the planar carboxylic group Cα C'(Ocis )Otrans to asymmetric flat (R) and (S) tetrahedra. High diastereoselectivities are caused by the two players attraction N…Ocis and repulsion Otrans …CMe , which work together in (L,M,R) configurations but against each other in (L,P,S) configurations.

Chirality in amino acids beyond the Cα configuration.

Based on a CSD search, a meta-analysis of 1179 structures of 19 natural amino acids H3 NCα H(R)C'(O)O and their derivatives H3 NCα H(R)C'(O)O(H/R/M), protonated, esterified, or coordinated at the carboxylic group, shows that the chirality chain with its two steps, established in the preceding paper for alanine, can be extended to natural amino acids. High diastereoselectivities are observed in the induction from the L configuration at Cα to the -ψ and +ψ conformations, which in turn distort the planar carboxylic group Cα C'(Ocis )Otrans to asymmetric flat tetrahedra, showing that the chirality chain is an integral part of natural amino acids.

The Chirality Chain in Valine: How the Configuration at the Cα Position through the O cis C'CαN Torsional System Leads to Distortion of the Planar Group CαC'(O cis )O trans to a Flat Tetrahedron.

Solid-state structures, based on a Cambridge Structural Database (CSD) search, show that there is a CαN/C'O cis attraction in the torsional system O cis C'CαN of valine, causing a chirality chain. The Cα configuration controls the chirality of the rotation around the C'-Cα bond, which in turn induces a distortion of the planar unit CαC'(O)O to a flat asymmetric tetrahedron. Conformational "reactions" take place in an energy profile with respect to clockwise and counterclockwise rotation around the C'-Cα bond as well as stretching and flattening of the tetrahedron. The molecular property CαN/C'O cis attraction of valine is maintained in its di- and tripeptides.

Trend-Analysis of Solid-State Structures: Low-Energy Conformational 'Reactions' Involving Directed and Coupled Movements in Half-Sandwich Compounds [CpFe(CO){C(=O)R}PPh3].

Invited for this month's cover picture are Prof. Dr. Henri Brunner from the University of Regensburg (Germany) and Prof. Dr. Takashi Tsuno from Nihon University (Japan). The cover picture shows the conformational reaction of JIDLUD→FIHTUL. The order of sample points of solid-state structures reveals information concerning low-energy, directed, and coupled movements in molecules. Read the full text of their Communication at https://doi.org/10.1002/open.201800007.

Trend-Analysis of Solid-State Structures: Low-Energy Conformational 'Reactions' Involving Directed and Coupled Movements in Half-Sandwich Compounds [CpFe(CO){C(=O)R}PPh3].

Trends in solid-state structures were used to identify preferred intramolecular movements in half-sandwich compounds [CpFe(CO){C(=O)R}PPh3]. Three weak interactions were analyzed: 1) the CH/π donor-acceptor interaction of phenyl rings in the PPh3 ligand, 2) the PhPPh3 face-on Cp stabilization, and 3) the hydrogen bond between the oxygen atom of the acyl group and an ortho-C-H bond of one of the PPh3 phenyl rings. Clockwise and counter-clockwise rotations established directed and coupled movements of the PPh3 ligand, the acyl group, and the phenyl rings within the PPh3 ligand.

PPh3 Propeller Diastereomers: Bonding Motif PhPPh3 Face-On π-Ar in Half-Sandwich Compounds [(π-Ar)LL'MPPh3].

Chiral-at-metal compounds (R Ru,S C)/(S Ru,S C)-[CyRu(1O-2N)PPh3]PF6 and (R Ru,S C)/(S Ru,S C)-[CyRu(2O-1N)PPh3]PF6 were prepared using anions 1O-2N- and 2O-1N- of the Schiff bases, derived from the hydroxynaphthaldehydes and (S)-1-phenylethylamine. The pure (R Ru,S C)-diastereomers were obtained by crystallization. In the unit cell of (R Ru,S C)-[CyRu(1O-2N)PPh3]PF6, there are three independent molecules, which differ in the propeller sense of the PPh3 ligand. Molecules [1] and [2] have (M PPh3 )-configuration and molecule [3] has (P PPh3 )-PPh3 configuration. PPh3 diastereoisomerism is discussed including other pairs of compounds, differing only in the PPh3 configuration. A conformational analysis reveals an internal stabilization inside the PPh3 ligand by a system of attractive CH/π interactions and a new bonding motif PhPPh3 face-on π-Ar, both characteristic features of [(π-Ar)LL'MPPh3] compounds. The propeller diastereomers interconvert via a low-energy pathway and a high-energy pathway, corroborated by density functional theory calculations.

Comment on "Conformational analysis of triphenylphosphine ligands in stereogenic monometallic complexes: tools for predicting the preferred configuration of the triphenylphosphine rotor" by J. F. Costello, S. G. Davies, E. T. F. Gould and J. E. Thomson, Dalton Trans., 2015, 44, 5451.

In half-sandwich compounds of the type [Cp*ML1L2PPh3] the PPh3 propeller is stabilized by attractive CH/π interactions in which Co-H bonds specifically interact with the Ci and Co atoms of neighbouring phenyl rings, as in the T-shaped benzene dimer (i/o = ipso/ortho). This stabilization was not taken into account in a recent conformational analysis based on van der Waals energy calculations and minimization of steric compression (Dalton Trans., 2015, 44, 5451-5466). It is shown that in all 116 structures discussed in this analysis the CoH-Ci/o distances fall below the sum of the van der Waals radii, establishing attractive CH/π interactions, although the short contacts could easily be avoided by phenyl rotation to relieve steric strain. In 53 of the described structures there are acyl substituents which form conformation-determining Co-HO(acyl) hydrogen bonds that are not taken into account in the recent analysis. The steric-only model is not an adequate description of M-PPh3 complexes.

Methyl/phenyl attraction by CH/π interaction in 1,2-substitution patterns.

In 1,2-Me,Ph substitution patterns of organic compounds the methyl group attracts one of the phenyl sides to establish a CH/π bond with one of the ortho carbon atoms (the C(o) side), leading to a characteristic tilting of the phenyl ring around its C(i)-C(p) axis. This phenyl rotation shortens the C(Me)-C(o) distances to bonding contacts between the methyl hydrogen atoms and the ortho carbon atom C(o) well below the van der Waals distance of 3.70 Å. On the other hand, it elongates the C(Me)-C(o') distances outside of the reach of any CH/π interaction (>3.70 Å). Our study is based on a search in the Cambridge Structural Database for substructures Me-C═C-Ph, Me-C-C-Ph, and Me-C-N-Ph with 1,2-Me,Ph substitution patterns. In the 1,2-Me,Ph substitution motif the torsion angle C(Me)-C-C-C(i) determines the length of the C(Me)-C(i) and C(Me)-C(o) distances. For aromatic compounds these torsion angles are close to 0°, but in five- and six-membered ring compounds and in open-chain compounds the torsion angles vary considerably. Universally, for torsion angles up to 80° CH/π bonds were found, whereas the long C(Me)-C(i) and C(Me)-C(o) distances for torsion angles >80° do not allow a CH/π interaction. The results of the present CSD analysis are supported by calculations.

Chirality in distorted square planar Pd(O,N)2 compounds.

Salicylidenimine palladium(II) complexes trans-Pd(O,N)2 adopt step and bowl arrangements. A stereochemical analysis subdivides 52 compounds into 41 step and 11 bowl types. Step complexes with chiral N-substituents and all the bowl complexes induce chiral distortions in the square planar system, resulting in Δ/Λ configuration of the Pd(O,N)2 unit. In complexes with enantiomerically pure N-substituents ligand chirality entails a specific square chirality and only one diastereomer assembles in the lattice. Dimeric Pd(O,N)2 complexes with bridging N-substituents in trans-arrangement are inherently chiral. For dimers different chirality patterns for the Pd(O,N)2 square are observed. The crystals contain racemates of enantiomers. In complex two independent molecules form a tight pair. The (RC) configuration of the ligand induces the same Δ chirality in the Pd(O,N)2 units of both molecules with varying square chirality due to the different crystallographic location of the independent molecules. In complexes and atrop isomerism induces specific configurations in the Pd(O,N)2 bowl systems. The square chirality is largest for complex [(Diop)Rh(PPh3 )Cl)], a catalyst for enantioselective hydrogenation. In the lattice of two diastereomers with the same (RC ,RC) configuration in the ligand Diop but opposite Δ and Λ square configurations co-crystallize, a rare phenomenon in stereochemistry.

Ligand dissociation: planar or pyramidal intermediates?

In organometallic chemistry, ligand dissociation is a key intermediate step in many useful processes. The dissociation of halide from an 18-electron half-sandwich complex (that is, with a single cyclopentadienyl ligand) of the type [CpRu(P-P')Hal] leaves an unsaturated 16-electron intermediate [CpRu(P-P')](+), which is then ready for subsequent addition reactions. Does the intermediate maintain its structure with a vacant site in place of the dissociated ligand, or does it rearrange, either concurrent with its formation or subsequently? In other words, are the 16-electron species planar or pyramidal? The outcome is relevant for chiral-at-metal compounds [CpML(1)L(2)L(3)] because an intermediate [CpML(1)L(2)] retains its chirality with respect to the metal atom as long as it is pyramidal, whereas it loses its chiral information if it becomes planar. In this Account, we address experimental results and theoretical calculations that help illuminate the energetics of structural rearrangements after halide dissociation. The rate-determining step in the halide exchange and racemization reactions of (R(Ru))- and (S(Ru))-[CpRu(P-P')Cl] is the cleavage of the Ru-Cl bond to give pyramidal intermediates (R(Ru))- and (S(Ru))-[CpRu(P-P')](+), which have kept the original metal configurations. These unsaturated intermediates can react with added ligands, such as Br(-) or I(-) (k(2) paths). The substitution products form with retention of the metal configuration. However, the pyramidal intermediates (R(Ru))- and (S(Ru))-[CpRu(P-P')](+) can also invert to their mirror images (k(3) paths). For (R(Ru))- and (S(Ru))-[CpRu(P-P')](+), the barrier of the pyramidal inversion (k(3)) is much higher than that of the halide addition (k(2)). The competition ratio k(3)/k(2) determines how much racemization occurs in a ligand exchange reaction. The competition ratio k(3)/k(2) can be determined from the ratio of the (R(Ru))- and (S(Ru))-products, which is constant throughout the course of the reaction. For compounds like [CpRu(P-P')Hal], k(3)/k(2) is much smaller than 1, resulting in an energy profile that resembles a basilica. These results, established with chiral-at-metal compounds, are supported by calculations that show that 16-electron half-sandwich intermediates with sigma-donating ligands, such as [CpM(NH(3))(2)], adopt planar structures, whereas strongly pi-bonding ligands, as in [CpM(CO)(2)], lead to pyramidal intermediates. The computed activation energies for the pyramidal inversion are on the order of 10 kcal/mol, with the planar species being transition states. The ligand dissociation behavior of 18-electron transition metal complexes is compared with nucleophile dissociation in main group compounds with octet configurations; here we include new computational results. Without exception, unsaturated main group intermediates, such as the carbenium ions formed in S(N)1 reactions, are planar. Our results and analysis help put transition metal chemistry on a firmer mechanistic foundation, and chiral-at-metal compounds are invaluable to this end.

Distribution and subcellular localization of a water-soluble hematoporphyrin-platinum(II) complex in human bladder cancer cells.

The water-soluble porphyrin-platinum complex diammine[7,12-bis[1-(polyethyleneglycol-750-monomethylether-1-yl)ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionato]platinum(II) (PEG-HPPt) was studied with respect to cellular accumulation, subcellular localization, behavior in 3D-cell aggregates and degree of DNA platination on the low-differentiated J82 cells, a model of invasive bladder cancer, and UROtsa, a normal urothelial cell line. Accumulation studies with 2D and spheroid cell cultures revealed that the concentration of PEG-HPPt was 1.7-times higher in J82 cancer cells than in UROtsa cells. Despite its high molecular weight, penetration of PEG-HPPt was not restricted to the peripheral cells of the spheroids. Fluorescence microscopic analysis showed that PEG-HPPt was localized in essential cellular targets of photodynamic therapy. DNA platination in J82 and UROtsa cells was higher by PEG-HPPt than by cisplatin, whereas there was no significant difference between the two cell lines.

Combined chemotherapeutic and photodynamic treatment on human bladder cells by hematoporphyrin-platinum(II) conjugates.

Four porphyrin-platinum complexes, conceived as a new approach in cancer therapy by combining the cytostatic activity of cisplatin or oxaliplatin and the photodynamic effect of hematoporphyrin in the same molecule, were studied in detail with respect to solubility and stability in cell culture medium as well as in terms of cytotoxicity and phototoxicity against J82 bladder cancer cells and UROtsa, normal urothelial cells. This study demonstrated that the most active and promising compound among the porphyrin-platinum conjugates investigated was the water-soluble porphyrin-platinum complex 4 (diammine[7,12-bis[1-(polyethyleneglycol-750-monomethylether-1-yl)ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionato]platinum(II)) which exhibited a synergistic antiproliferative effect compared to cisplatin and hematoporphyrin alone or a combination of the drugs.