C2-symmetric Conformation Research Articles

Titanium (IV) μ-Oxo Complex Supported by Phenoxyimine Ligand: Synthesis, Crystal Structure Characterisation, DFT and Molecular Docking Studies

Background: Most of the transition elements in the 3d series (first row transition metals) have been discovered to be extremely significant and practical in biological systems. Naturally, many of the enzymes that are present in the human body system act as catalysts for biological processes and are made of coordination compounds or complexes. Objective: The complex has been characterised by various spectroscopic and analytic techniques. A suitable crystal analysed by X-ray diffraction establishes the formation of a stable binuclear µ-oxo-complex with a hexacoordinate titanium centre. Methods: A new crystalline complex [Ti{La}] has been synthesised in the reaction of titanium butoxide with a phenoxyimine ligand in a 1:1 stoichiometry in toluene at room temperature under a nitrogen atmosphere. The newly synthesised Ti complex has undergone density functional theory and docking study. Results: The crystal shows a monoclinic system with space group C 1 2/c 1. X-ray crystal structure analysis reveals that this complex has a rhomboidal Ti-O-Ti core and exhibits a C2 symmetric conformation with distorted octahedral geometry. Density Functional Theory (DFT) calculations giving insights into the frontier orbitals and mulliken charge analysis, which showed good correlation with the experimental findings. Additionally, in silico molecular docking of ligand and complex was carried out against the HER2 inhibitor kinase. Conclusion: This complex exhibits a higher binding energy of ΔGb = -19.7 kcal/mol with the active pocket of HER2 (PDB:7JXH) than the ligand ΔGb = -8.5 kcal/mol.

Per-Arylation of Pillar[n]arenes: An Effective Tool to Modify the Properties of Macrocycles

Installation of various substituents is a reliable and versatile way to alter the properties of macrocyclic molecules, but high-yield and controlled methods are not always available especially for multifold reactions. Herein, we report 10- and 12-fold introduction of aryl substituents onto both rims of cylinder-shaped pillar[n]arenes, which usually have alkoxy substituents slanting to the cylinder axes. Although alkoxy pillar[5]arenes exist as D5-symmetric enantiomeric pairs, arylated pillar[5]arenes provide crushed single-crystal structures and stereoisomerism including C2-symmetric conformations depending on the aryl groups. Pillar[n]arenes with 2-benzofuranyl groups display bright fluorescence with quantum yields of 88-90% and no host-guest complexation with electron-deficient molecules in solution due to large deviation from alkoxy compounds. A benzofuran-appended pillar[6]arene instead captures small gaseous molecules in the solid state, probably owing to outside spaces surrounded by aromatic rings.

The structure and racemization of 1,2-bis(pentaphenylphenyl)benzene

1,2-Bis(pentaphenylphenyl)benzene (2) was synthesized by the cycloaddition of 1,2-bis(phenylethynyl)benzene and tetracyclone. Its X-ray structure was determined, and the molecule adopts a C2-symmetric conformation in the crystal. Monomethoxy and dimethoxy derivatives of compound 2 were also prepared, and dynamic NMR studies of these compounds yielded a free energy of activation for racemization (ΔG‡rac) of 20.3 kcal/mol at 423 K. The results are compared with estimates of ΔG‡rac for 2 by various DFT methods.

A cyclopenta[hi]acephenanthrylene bearing two benzoannelated [3.3.3]propellane units: extension of triptindane chemistry

The McMurry reaction of triptindan-9-one (2), a three-fold benzoannelated Cs-symmetrical [3.3.3]propellane ketone, gave trans-9,9′-bitriptindanylidene (5), a sterically crowded stilbene hydrocarbon bearing two E-oriented triptindane moieties, in good yield. Photoisomerization of 5 generated the corresponding cis-stilbene 8 in a photostationary E:Z mixture (55:45), which adopts a similarly crowded C2-symmetrical conformation that is apparently static on the NMR timescale. Photocyclodehydrogenation of 5 via 8 in benzene solution afforded the title hydrocarbon 6, a 1,2,9,10-tetrahydrocyclopenta[hi]acephenanthrylene merged with two triptindane units, in 85% yield. X-ray structure analysis of 6 revealed an essentially planar phenanthrene unit but significant steric repulsion between the pairs of opposite methylene groups of the [3.3.3]propellane cores, giving rise to a C2-symmetrical conformation. Reaction of 2 under modified McMurry conditions (DME instead of THF as a solvent) gave the saturated dimer, 9,9′-bitriptindanyl 7, as a mixture of diastereomers. Attempts to synthesize “columnene” (4), an elusive barrelene derivative fused with two triptindane caps, by three-fold McMurry reaction of triptindane-9,10,11-trione (3) failed.

Twisted Macrocycles with Folded ortho-Phenylene Subunits.

Many foldamers, oligomers that adopt well-defined secondary structures, are now known, including many exhibiting functional behavior. However, examples of foldamer subunits within larger architectures remain rare, despite the importance of higher-order structure in biomacromolecules. Here, we investigate the dynamic covalent assembly of short o-phenylenes, a simple class of aromatic foldamers, into twisted macrocycles. o-Phenylene tetramers have been combined with rod-shaped p-phenylene-, tolane-, and diphenylbutadiyene-based linkers using imine formation. Macrocyclization proceeds efficiently, inducing folding of the o-phenylenes. The resulting [3 + 3] macrocycles (three o-phenylenes and three linkers) are shape-persistent, triangular structures with twisted cores and internal diameters up to approximately 2 nm. The homochiral D3-symmetric and heterochiral C2-symmetric conformers can be distinguished by NMR spectroscopy. Analysis of the conformational distribution for the p-phenylene-linked macrocycle suggests that the o-phenylene units are largely decoupled, with the less-symmetrical configuration therefore entropically favored. Conformational dynamics were assessed by variable-temperature NMR spectroscopy. Confinement within the macrocyclic architecture slows the inversion of the o-phenylene moieties.

Acetic anhydride at 100 K: the first crystal structure determination.

Acetic anhydride (ethanoic anhydride), (CH3CO)2O, is a widely used acetylation reagent in organic synthesis. The crystal and molecular structure, as determined by single-crystal X-ray analysis at 100 K, is reported for the first time. A crystal of the title compound (m.p. 200 K) suitable for X-ray diffraction was grown from the melt at low temperature. The title compound crystallizes in the orthorhombic space group Pbcn, with Z = 4. In the crystal, the molecule adopts an exact C2-symmetric conformation about a crystallographic twofold axis. The molecules are densely packed. Two of the methyl H atoms form short intermolecular contacts to a neighbouring carbonyl O atom, which can be viewed as weak hydrogen bonds.

Cs[H2NB2(C6F5)6] Featuring an Unequivocal 16-Coordinate Cation.

Cesium bis(perfluoro-triphenylborane)amide, Cs[H2NB2(C6F5)6] (1), has been prepared by the reaction of sodium salt and CsF in dichloromethane and water. The compound is exceptional for a [H2NB2(C6F5)6](-) salt in that it contains a monatomic solute-free cation. Determination of the molecular structure revealed a novel C2 symmetrical conformation of the weakly coordinating [H2NB2(C6F5)6](-) anion, which gives rise to an unprecedented 16-coordinate (CN 16) Cs(+) cation in a likewise unprecedented tetracosahedral arrangement of F atoms. The poor solubility of 1 allows nearly quantitative separation of Cs(+) from water, which suggests potential applications as an effective (134/137)Cs remover from nuclear waste solutions, administration as an antidote for (134/137)Cs poisoning, and use for (131/137)Cs radiotherapy (brachytherapy). Rb[H2NB2(C6F5)6]·CH2Cl2 (2) has also been characterized, featuring two inequivalent Rb(+) cations having CN 10, one of which involves Rb(+)(η(2)-Cl2CH2)2 coordination.

Structures of tetrasilylmethane derivatives (XMe2Si)2C(SiMe3)2 (X = H, Cl, Br) in the gas phase, and their dynamic structures in solution.

The structures of the molecules (XMe2Si)2C(SiMe3)2, where X = H, Cl, Br, have been determined by gas electron diffraction (GED) using the SARACEN method of restraints, with all analogues existing in the gas phase as mixtures of C1- and C2-symmetric conformers. Variable temperature (1)H and (29)Si solution-phase NMR studies, as well as (13)C NMR and (1)H/(29)Si NMR shift correlation and (1)H NMR saturation transfer experiments for the chlorine and bromine analogues, are reported. At low temperatures in solution there appear to be two C1 conformers and two C2 conformers, agreeing with the isolated-molecule calculations used to guide the electron diffraction refinements. For (HMe2Si)2C(SiMe3)2 the calculations indicated six conformers close in energy, and these were modeled in the GED refinement.

Gas-phase structures of sterically crowded disilanes studied by electron diffraction and quantum chemical methods: 1,1,2,2-tetrakis(trimethylsilyl)disilane and 1,1,2,2-tetrakis(trimethylsilyl)dimethyldisilane.

The gas-phase structures of the disilanes 1,1,2,2-tetrakis(trimethylsilyl)disilane [(Me3Si)2HSiSiH(SiMe3)2] (1) and 1,1,2,2-tetrakis(trimethylsilyl)dimethyldisilane [(Me3Si)2MeSiSiMe(SiMe3)2] (2) have been determined by density functional theoretical calculations and by gas electron diffraction (GED) employing the SARACEN method. For each of 1 and 2 DFT calculations revealed four C2-symmetric conformers occupying minima on the respective potential-energy surfaces; three conformers were estimated to be present in sufficient quantities to be taken into account when fitting the GED data. For (Me3Si)2RSiSiR(SiMe3)2 [R = H (1), CH3 (2)] the lowest energy conformers were found by GED to have RSiSiR dihedral angles of 87.7(17)° for 1 and -47.0(6)° for 2. For each of 1 and 2 the presence of bulky and flexible trimethylsilyl groups dictates many aspects of the geometric structures in the gas phase, with the molecules often adopting structures that reduce steric strain.

A Curtin-Hammett pentamethylene chain symmetrization process in the Bergman cyclization of an 11-membered ring enediyne

Pentamethylene chain conformational effects for the Bergman cyclization of the 11-membered ring enediyne, (3Z)-3-cycloundecene-1,5-diyne, 2, are examined theoretically with unrestricted Becke, three-parameter, Lee–Yang–Parr/6-31 G(d,p) calculations. A C1 symmetric enediyne conformation was found to be the global minimum, where its nonsymmetric pentamethylene chain prevented π-orbital alignment of the acetylene groups for C–C σ bond product formation. The Bergman cyclization of 2 was found to be conformationally dependent. In a Curtin–Hammett type process, the C1 symmetric 2 inverts to one of the CS or C2 symmetric conformers required for the Bergman cyclization, which produced a CS or C2 symmetric 1,4-diradical intermediate. The activation energy for the cyclization is slightly higher to reach the C2 symmetry diradical compared with the CS symmetry diradical. Copyright © 2012 John Wiley & Sons, Ltd.

Decachlorohexa-1,5-diene

The title compound, C6Cl10, cystallizes in a nearly C2-symmetrical gauche conformation. Both trichloro­vinyl groups are nearly planar [Cl—C—C—Cl torsion angles = −178.47 (12) and −179.93 (11)°] and the lengths of their C—Cl bonds increase from the terminal trans and cis C—Cl bonds to the inter­nal bonds. The Cl—C—Cl bond angles of the terminal dichloro­methyl­ene units are compressed to 111.75 (11) and 111.40 (11)°.

10,16-Dichloro-6,20-dioxa-3,23-diazatetracyclo[23.3.1.07,12.014,19]nonacosa-1(29),7,9,11,14(19),15,17,25,27-nonaene-4,22-dione methanol monosolvate

In the title compound, C25H22Cl2N2O4·CH3OH, the macrocyclic mol­ecule adopts a slightly distorted C 2-symmetric conformation. The macrocyclic mol­ecules are linked via N—H⋯O hydrogen bonds between the amide groups into chains extending along the [010] direction. The methanol mol­ecules bridge these chains via N—H⋯O and O—H⋯O hydrogen bonds with the formation of a two-dimensional polymeric structure parallel to (001). The methanol mol­ecule is disordered over two positions with the occupancy ratio of 9:1. The disorder of the solvent molecule is caused by weak intermolecular C—H⋯Cl hydrogen bonding.

4-Diethylamino-3,5-diisopropylbenzaldehyde

The title benzaldehyde, C17H27NO, was prepared via lithia­tion of bromoaniline and reaction with DMF. In the crystal, the molecule adopts a C2-symmetrical conformation; nevertheless, two modes of disorder are present: the orientation of the aldehyde group (occupancy ratio 0.5:0.5) and of symmetry-equivalent ethyl groups [occupancy ratio 0.595 (7):0.405 (7)]. The phenyl­ene ring and the carbonyl group are essentially coplanar [C—C—C—O torsion angle = −179.0 (4)°] but the dihedral angle between the mean planes of the phenyl­ene ring and the amino group = 67.5 (2)°. This and the long [1.414 (3) Å] aniline C—N bond indicate electronic decoupling between the carbonyl and amino groups. The angle sum of 359.9 (2)° around the N atom results from steric compression-induced rehybridization.

Problems with a conformation assignment of aryl-substituted resorc[4]arenes

Acid-catalyzed condensation of resorcinol with 3,5-diisopropoxybenzaldehyde and 3,5-dihydroxybenzaldehyde afforded aryl substituted resorc[4]arenes 1a and 1b, respectively. All 16 hydroxyls in 1b were acetylated providing resorc[4]arene 1c. The conformational behaviour of 1a, 1b and 1c was studied by NMR spectroscopy and quantum chemical calculations. It was found that the stabilization of their conformations is an effect of competing π-π and OH-π interactions, hydrogen bonding and steric features, respectively. As a result, C2 symmetrical boat conformations 1a, 1b and 1c with aryls in axial positions were identified in all cases. In case of 1c also the formation of C2 symmetrical conformation with aryls in equatorial positions (boat-eq) was identified. Moreover, compounds 1a and 1b being able to create hydrogen bonds, adopt also symmetrical C4 crown conformations. For 1c(boat-ax), the boat-boat conversion with energy barrier of 80 kJ/mol was observed, while the 1c(boat-eq) was found to be rigid in the whole accessible temperature range. Both conformers of 1c exhibit also second dynamic process – rotation of bridge aryl rings (ΔG‡ = 66 kJ/mol).

Synthesis of an ortho-Triazacyclophane: N,N′,N′′-Trimethyltribenzo-1,4,7-triazacyclononatriene

N,N',N''-trimethyltribenzo-1,4,7-triazacyclononatriene has been synthesized via sequential palladium-catalyzed Buchwald-Hartwig N-arylation reactions affording the 9-membered triaza o-cyclophane in 35% overall yield. An X-ray crystal structure shows the new cyclophane to have a C2-symmetric saddle conformation, as compared to the crown conformation exhibited by the related carbocyclic cyclotriveratrylene (CTV).

Conformational properties and metal ion transport by synthetic cyclic octapeptide cyclo(D-Leu-L-Pro)4

Cyclo(D-LeU-L-PrO)4 was synthesized and investigated on conformation, complexation with cations, and cation transport through liquid membrane. Cyclo(D-Leu-L-Pro)4 was found to take a C2-symmetric conformation in CDCl3 solution. However, the intramolecular transformation of conformation was so rapid on n.m.r. time scale that it appeared to take a C4-symmetric conformation in n.m.r. spectrum. Cyclo(D-Leu-L-Pro)4 formed a complex selectively with Ba2+, and the binding constant was estimated to be similar to that of its diastereomer, cyclo(L-Leu-L-Pro)4. However, the rate of complex formation in solution of CyClO(D-Leu-L-Pro)4 with Ba2+ was much faster than that of cyclo (L-Leu-L-Pro)4. This is because cyclo(D-Leu-L-Pro)4 forms the complex without accompanying the isomerization of peptide bonds. The efficiency of cation transport through a CHCl3 liquid membrane by Cyclo(D-LeU-L-PrO)4 was similar to that by cyclo(L-Leu-L-Pro)4, indicating that the rate-determining step of transport should be the diffusion of the complex across the boundary layer between aqueous phase and organic phase.

Vicinal diphosphoniums: electrostatic repulsion under covalent constraint

A series of five vicinal bis(alkyl-triarylphosphoniums) derived from o-bis(diphenyl-phosphino)benzene (o-dppb) is described. Each of them have been prepared by specific methods, and their formal electrostatic and possible van der Waals strain is compared through the P+...P+ distances in the crystal state. According to X-ray diffraction analyses, while the conformations of the dimethyl dication is C2 symmetric, the conformation of alka-1,n-diyl-diphosphoniums (n = 1, 2, 3) is pseudo-Cs symmetric. The solution structure of the dimethyldiphosphonium 2 was studied by NMR techniques after metathesis of the triflate counterions with enantiomerically pure X-PHAT chiral anions (X = TRIS, BIN). [(Delta)-BINPHAT] was indirectly shown to discriminate between the enantiomers of the diphosphonium, but no effective enantio-differentiation could be measured down to -70 degrees C in CD2Cl2. When associated to [(Delta)-TRISPHAT] counterions, progressive cleavage of the diphosphonium afforded the corresponding methyl-triphenyl-monophosphonium salt. In the bridged series, the diphosphoniacyclopentene dication was found to be stable in spite of the very short transannular P+...P+ distance (2.83 A). The naturally more relaxed homologous diphosphoniacyclohexene dication (P+...P+ = 3.28 A) was found to be flexible in solution, as indicated by the equivalence of the four protons of the +P-CH2CH2-P+ bridge from 20 degrees C to -80 degrees C in acetone-d6. The two diphosphoniacycloheptene dications exhibit no P+...P+ steric compression (ca 3.64 A), just as the dimethyl dication (3.70 A). In solution, the seven-membered ring of the +P-CH2CR2CH2-P+ dications (R = H, Me) remains rigidly Cs symmetric: no interconversion of the pseudo-axial and pseudo-equatorial R groups is evidenced at the NMR time scale at -95 degrees C (coalescence at -20 degrees C for R = H, at -65 degrees C for R = Me). According to DFT calculations at the B3PW91/6-31G** level in 1,2-dichloroethane (DCE: PCM, epsilon = 10.36), the lowest energy conformation is indeed Cs-symmetric. However a quasi-isoenergetic C2-symmetric conformation which is the most stable in the gas phase is also found, and is thus a likely intermediate in the observed Cs <==> Cs interconversion. This +P-CH2CMe2CH2-P+ diphosphonium was obtained by dialkylation of o-dppb with 2,2-dimethylpropan-1,3-diyl bistriflate in DCE at 80 degrees C. The use of this solvent was the key for the synthesis of this dication, which was however competitively produced along with some +P-CH2CH2-P+ dication. The latter was also obtained by a totally different route, by heating a sulfinylethyl monophosphonium salt of o-dppb in the presence of the cationic complex [Rh(cod)2][PF6]. A mechanism for this peculiar process is proposed.

Cis,cis,cis-1,5,9-Cyclododecatriene−Metal Complexes

The ligand properties of cis,cis,cis-1,5,9-cyclododecatriene (c,c,c-cdt) have been explored. For the known (c,c,c-cdt)Ni (1b) and (c,c,c-cdt)(AgNO3)3 (5) complexes and the new [(c,c,c-cdt)Cu(MeOH)]BF4 (6b), [(c,c,c-cdt)Cu][Al{OC(CF3)3}4] (6d), and (tBu2PC2H4PtBu2)Ni(η2-c,c,c-cdt) (7b) complexes, the molecular structures have been determined. The c,c,c-cdt ligand in 5 and 7b retains the C2 symmetrical helical conformation of the free c,c,c-cdt, whereas in 1b and 6b,d, it assumes a C3 symmetrical ratchet conformation. The coordination geometry of the metal in 6b is tetrahedral, and it is trigonal pyramidal in 1b and 6d. Details of the synthesis and chemical and spectroscopic properties of the complexes are reported.

Ab initio molecular orbital study of conformational properties of cyclohexyne, cycloheptyne, and cyclooctyne

AbstractThe structures and relative energies for the basic conformations of cyclohexyne (1), cycloheptyne (2), and cyclooctyne (3) have been calculated by the HF/6‐31G*, MP2/6‐31G*, and B3LYP/6‐31G* methods. The C2 symmetric twist conformer of 1 is calculated to be more stable than the planar C2v geometry. Ring inversion of the envelope conformation of 2 takes place via C2 symmetric twist transition state, which is 34.0 kJ mol−1 higher than the envelope form. The C2 symmetric chair conformation of 3 is calculated to be 11.7 kJ mol−1 more stable than the unsymmetrical twist‐boat (3‐TB) geometry. Interconversion of the chair conformation and 3‐TB takes place via an unsymmetrical transition state, which is 37.6 kJ mol−1 less stable than the chair form. Conformational racemization of the chiral 3‐TB takes place via the boat transition state. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006

Comparison of the ATP Binding Sites of Protein Kinases Using Conformationally Diverse Bisindolylmaleimides

The conformation of a bisindolylmaleimide may be controlled by the size of a macrocyclic ring in which it is constrained. A range of techniques were used to demonstrate that the tether controls both the ratio of the two limiting conformers (syn and anti) in solution and the extent of conjugation between the maleimide and indole rings. Screening the conformationally diverse bisindolylmaleimides against a panel of protein kinases allowed their ATP binding sites to be compared using a chemical approach which, like sequence alignment, does not require detailed structural information. This approach lead to the conclusion that several AGC group protein kinases (including PKCalpha, PKCbeta, MSK1, p70 S6K, PDK-1, and MAPKAP-K1alpha) may be best inhibited by bisindolylmaleimides which adopt a compressed approximately C2-symmetric anti conformation; in constrast, GSK3beta may be best inhibited by bisindolylmaleimides whose ground state is a distorted syn conformation. It is concluded that PDK-1, whose structure has been determined by X-ray crystallography, and its mutants, may serve as particularly useful surrogates for the study of PKC inhibitors.