RESUMO
Building blocks have been identified that can be functionalised by sequential nucleophilic aromatic substitution. Some examples are reported that involve the formation of cyclic benzodioxin and phenoxathiine derivatives from 4,5-difluoro-1,2-dinitrobenzene, racemic quinoxaline thioethers, and sulfones from 2,3-dichloroquinoxaline and (2-aminophenylethane)-2,5-dithiophenyl-4-nitrobenzene from 1-(2-aminophenylethane)-2-fluoro-4,5-dinitrobenzene. Four X-ray single-crystal structure determinations are reported, two of which show short intermolecular N-O N "π hole" contacts.
Assuntos
Halogênios , Cristalografia por Raios X , Halogênios/química , Estrutura Molecular , Modelos Moleculares , Quinoxalinas/químicaRESUMO
The absolute configuration and stability of two thianthrene chiral sulfoxides has been determined by means of X-ray single-crystal structure determinations. The analyses and configurations allow verification that the diastereomeric sulfoxides are stable in solution and are not interconverting, which has been suggested in some studies of sulfoxides. The two thianthrene sulfoxides have slightly different Rf values, which allowed their separation using flash chromatography on silica. The spots run back-to-back, which posed a challenge for their separation. The pure, separated compounds in solution remain as separate, single spots on a Thin Layer Chromatography (TLC) plate.
Assuntos
Sulfóxidos , Estereoisomerismo , Sulfóxidos/química , Cristalografia por Raios X/métodos , Modelos Moleculares , Cromatografia em Camada Fina/métodos , Fenantrenos/química , Estrutura MolecularRESUMO
A porous structure formed from sheets with cavities and two close packed structures were crystallised from building blocks prepared from 2,4-difluoronitrobenzene, a diamine linker and n-butylamine. The porous structure crystallised from a flexible building block prepared using 1,4-diaminobutane as linker. The close packed structures were prepared using either piperazine or 1,4-bis(aminomethyl)benzene as a linker and have less conformational freedom.
Assuntos
Porosidade , Conformação MolecularRESUMO
A number of liquid crystal dimers have been synthesised and characterised containing secondary or tertiary (N-methyl) benzanilide-based mesogenic groups. The secondary amides all form nematic phases, and we present the first example of an amide to show the twist-bend nematic (NTB) phase. Only two of the corresponding N-methylated dimers formed a nematic phase and with greatly reduced nematic-isotropic transition temperatures. Characterisation using 2D ROESY NMR experiments, DFT geometry optimisation and X-ray diffraction reveal that there is a change in the preferred conformation of the benzanilide core on methylation, from Z to E. The rotational barrier around the N-C(O) bond has been measured using variable temperature 1H NMR spectroscopy. This dramatic change in shape accounts for the remarkable difference in liquid crystalline behaviour between these secondary and tertiary amide-based materials.
RESUMO
In this study, treatment of anhydrous trazodone powder with ammonium carbamate in warm water crystallised two new polymorphs or dihydrates of trazodone after 5 h, whose structures were determined by X-ray single crystal diffraction. Each dihydrate contains infinite zigzag hydrogen-bonded chains of water molecules, which are stabilised by the N4 acceptor atom of the piperazine ring and the pendant carbonyl O1 atom of the triazole ring, as well as other water molecules. The strong dipole moment expected for the O1 atom makes it a good hydrogen bond acceptor for stabilising the chains of water molecules. Each molecule of trazodone has a similar conformation in both hydrates, except for the propyl chains, which adopt different conformations: anti-gauche in the ß hydrate (triazole N-C-C-C and C-C-C-piperazine N) and anti-anti in the γ hydrate. Both piperazine rings adopt chair conformations, and the exocyclic N-C bonds are in equatorial orientations. The Hirshfeld surfaces and two-dimensional fingerprint plots for the polymorphs were calculated using CrystalExplorer17, which indicated contacts significantly shorter than the sum of the van der Waals radii in the vicinity of the piperazine N4 and triazole O1 atoms corresponding to the strong hydrogen bonds accepted by these atoms.
RESUMO
Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e., fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-l-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy, and quantum mechanical calculations are consistent with fluorination at C3 having negligible effects on the hydrogen bond donor capacity of the C4 hydroxyl, but inverting the natural preference of Hyp from C4-exo to C4-endo pucker. In spite of this, F-Hyps still bind to the von Hippel-Lindau (VHL) E3 ligase, which naturally recognizes C4-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3 R,4 S)-F-Hyp over the corresponding (3 S,4 S) epimer by VHL. We show that (3 R,4 S)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia-inducible factor 1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands that form part of PROTAC (proteolysis targeting chimera) conjugates for targeted protein degradation. Despite a weakened affinity, Hyp substitution with (3 S,4 S)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary Kd for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists, and drug discoverers alike.
Assuntos
Prolina/análogos & derivados , Prolina/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Teoria da Densidade Funcional , Ligação de Hidrogênio , Modelos Químicos , Conformação Molecular , Prolina/síntese química , Ligação Proteica , Estereoisomerismo , Proteína Supressora de Tumor Von Hippel-Lindau/químicaRESUMO
(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues 1a-c were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate 5a followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative 1c retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of 1c by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound 14 which retained robust agonism at 1 µM and appears to be suitable for future use in pull-down assays and far western blotting for PLD-mGluR isolation.
Assuntos
Ácido Caínico/análogos & derivados , Ácido Caínico/farmacologia , Fusos Musculares/efeitos dos fármacos , Fosfolipase D/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Ligantes , Camundongos , Modelos Moleculares , Fusos Musculares/fisiologia , Receptores de Glutamato Metabotrópico/agonistasRESUMO
The complete polyoxidometallate anion in the title compound, (CH6N3)4[H6V4As6O30]·4H2O, is generated by crystallographic inversion symmetry. The polyhedral building units are distorted VO6 octa-hedra and AsO3OH tetra-hedra. The VO6 units feature a short formal V=O double bond and are linked by a common edge. Two such V2O6 double octahedral units are linked by four isolated AsO3OH tetra-hedra to complete the anion, which features two inter-nal O-Hâ¯O hydrogen bonds. In the crystal, O-Hâ¯O hydrogen bonds between the polyoxidometallate anions generate (01-1) sheets. The sheets are connected by cation-to-cluster N-Hâ¯O hydrogen bonds, and cation-to-water N-Hâ¯O links also occur. The O atom of one of the water mol-ecules is disordered over two sites in a 0.703â (17):0.297â (17) ratio.
RESUMO
The polyhedral building blocks of the layered inorganic network in the mixed-valence title compound, (NH4)(V(IV)O2)(V(V)O2)(TeO3), are vertex-sharing V(V)O4 tetra-hedra, distorted V(IV)O6 octa-hedra and TeO3 pyramids, which are linked by V-O-V and V-O-Te bonds, forming double layers lying parallel to (100). The presumed Te(IV) lone-pairs of electrons appear to be directed inwards into cavities in the double layers. The charge-balancing ammonium cations lie between the layers and probably inter-act with them via N-Hâ¯O hydrogen bonds.
RESUMO
In the title compound, C40H50O6, a symmetrical steroid oxalate diester, the dihedral angle between the CO2 planes of the oxalate linker is 61.5â (5)° and the C-C bond length is 1.513â (6)â Å. The steroid B, C and D rings adopt half-chair, chair and envelope conformations, respectively, in both halves of the mol-ecule, which adopts an overall shallow V-shaped conformation. In the crystal, mol-ecules are linked by weak C-Hâ¯O inter-actions, forming a three-dimensional network.
RESUMO
The title compounds, K(+)·C7H7BF3O(-), (I), and K(+)·C6H4BF4 (-), (II), are mol-ecular salts containing para-substituted phenyl-tri-fluorido-borate anions. In each compound, the B atom adopts a distorted tetra-hedral BCF3 geometry. Despite their different compositions and space groups, the irregular KF8 coordination polyhedra of the potassium cations in the structures are almost identical. These polyhedra share faces and edges, generating infinite (010) layers in (I) and infinite (001) layers in (II). In (I), adjacent layers are stacked in an AAA fashion, whereas in (II), they are stacked in an ABAB sequence.
RESUMO
In the title benzohydrazide hydrate, C14H12N2O3·H2O, the dihedral angle between the aromatic rings is 58.11â (6)° and the C=O and N-H groups adopt an anti orientation. The main twist in the mol-ecule occurs about the C(=O)-Car (ar = aromatic) bond, with an N-C(=O)-Car-Car torsion angle of -43.5â (2)°. In the crystal, the components are linked by N-Hâ¯O, O-Hâ¯N and O-Hâ¯O hydrogen bonds. These inter-actions generate [10-1] chains, with adjacent organic mol-ecules linked by inversion symmetry generating either pairs of N-Hâ¯O links [R 2 (2)(16) loops] or pairs of O-Hâ¯O links [R 2 (2)(20) loops]. Pairs of water mol-ecules are located in the R 2 (2)(20) loops and form their own O-Hâ¯O and O-Hâ¯N hydrogen bonds to adjacent organic mol-ecules in the chain. Finally, an inter-chain O-Hâ¯O hydrogen-bond link from the 4-hy-droxy group generates (010) sheets.
RESUMO
The title compound, poly[[di-aqua-bis-[1,5-bis-(pyridin-4-yl)pentane-κ(2) N:N']cadmium] bis-(perchlorate) 1,5-bis-(pyridin-4-yl)pentane ethanol mono-solvate], [Cd(C15H18N2)2(H2O)2](ClO4)2·C15H18N2·C2H6O, is a layered coordination polymer built up from highly squashed 4(4) nets in which the octa-hedral trans-CdO2N4 nodes (Cd site symmetry -1) are linked by the bifunctional ligands, forming infinite (110) sheets. The cationic sheets are charge-balanced by inter-layer perchlorate ions. A free 1,5-bis-(pyridin-4-yl)pentane mol-ecule and an ethanol mol-ecule of crystallization are also found in the inter-sheet region. A number of O-Hâ¯O, O-Hâ¯N and C-Hâ¯O hydrogen bonds help to consolidate the layered structure.
RESUMO
In the title compound, C9H13N3O, the cyclo-hexyl-idene ring adopts a chair conformation and the bond-angle sum at the C atom linked to the N atom is 359.6°. The cyano-acetohydrazide grouping is close to planar (r.m.s. deviation for the non-H atoms = 0.031â Å) and subtends a dihedral angle of 64.08â (4)° with the four C atoms forming the seat of the chair. The C=O and N-H groups are in a syn conformation (O-C-N-H = -5°). In the crystal, inversion dimers linked by pairs of N-Hâ¯O hydrogen bonds generate R 2 (2)(8) loops; this dimer linkage is reinforced by a pair of C-Hâ¯O inter-actions, which generate R 2 (2)(14) loops. The dimers are linked by C-Hâ¯Nc (c = cyanide) inter-actions into [100] ladders, which feature C(4) chains and R 4 (4)(20) loops.
RESUMO
In the title compound, {(C6H8N)[Zn2(HPO3)2(H2PO3)]}n, the constituent ZnO4, HPO3 and H2PO3 polyhedra of the inorganic component are linked into (010) sheets by Zn-O-P bonds (mean angle = 134.4°) and the layers are reinforced by O-Hâ¯O hydrogen bonds. The protonated templates are anchored to the inorganic sheets via bifurcated N-Hâ¯(O,O) hydrogen bonds.
RESUMO
In the title compound, C12H7N3OS, the essentially planar thia-zole ring (r.m.s. deviation = 0.022â Å) forms dihedral angles of 84.88â (9) and 1.8â (3)° with the phenyl ring and the -C(CN)2 group (r.m.s. deviation = 0.003â Å), respectively. The mol-ecule has approximate local Cs symmetry. In the crystal, molecules are linked via C-Hâ¯N hydrogen bonds, forming chains propagating along [101]. The crystal studied was found to be an inversion twin with a refined 0.63â (1):0.37â (1) domain ratio.
RESUMO
In the title compound, C16H13Cl2N3O2S, the dihedral angle between the aromatic rings is 6.62â (2)° and the C=N-N=C torsion angle is 176.2â (4)°. The thia-zine ring shows an envelope conformation, with the S atom displaced by 0.633â (6)â Å from the mean plane of the other five atoms (r.m.s. deviation = 0.037â Å). The Cl atom is an an axial conformation and is displaced by 2.015â (6)â Å from the thia-zine ring plane. In the crystal, mol-ecules are linked by C-Hâ¯O inter-actions, generating a three-dimensional network. Very weak aromatic π-π stacking inter-actions [centroid-centroid separations = 3.928â (2)â Å] are also observed.
RESUMO
In the title compound, C(17)H(16)BrN(3)O(2)S, the dihedral angle between the aromatic rings is 1.24â (15)° and the C=N-N=C torsion angle is 167.7â (3)°. The conformation of the thia-zine ring is an envelope, with the S atom displaced by 0.805â (3)â Å from the mean plane of the other five atoms (r.m.s. deviation = 0.027â Å). In the crystal, C-Hâ¯O inter-actions link the mol-ecules into C(10) [010] chains. A weak C-Hâ¯π inter-action is also observed.
RESUMO
In the title compound, C(18)H(16)ClN(3)O(2)S, the dihedral angle between the aromatic rings is 4.81â (2)° and the alkyl chain takes on an extended conformation [N-C-C-C = 179.2â (4)°]. The conformation of the thia-zine ring is an envelope, with the S atom displaced by -0.805â (3)â Å from the mean plane of the other five atoms (r.m.s. deviation = 0.046â Å). The Cl atom is an axial conformation and is displaced by 1.761â (4)â Å from the thia-zine ring plane. In the crystal, inversion dimers linked by pairs of C-Hâ¯O inter-actions generate R(2) (2)(20) loops and further C-Hâ¯O hydrogen bonds link the dimers into (001) sheets. Weak aromatic π-π stacking inter-actions [centroid-centroid separations = 3.870â (3) and 3.883â (3)â Å] are also observed.