Pyridyl Substituents Research Articles

Thin molecular films of supramolecular porphyrins.

A relevant series of symmetric supramolecular porphyrins has been obtained by attaching four [RuII(bipy)2Cl] groups to the pyridyl substituents of meso-tetra(4-pyridyl)porphyrin and its metallated derivatives. These compounds display a rich electrochemistry and versatile catalytic, electrocatalytic and photochemical properties, associated with the ruthenium-bipyridine and the porphyrin complexes. These properties can be transferred to the electrodes by attaching thin molecular films of the compounds, by dip-coating, electrostatic assembly or electropolymerization. In this way, the interesting properties of those supermolecules and supramolecular assemblies can be used to prepare molecular devices and sensors.

Structural aspects of high affinity ligands for the α4β2 neuronal nicotinic receptor

Neuronal nicotinic acetylcholine receptors (nAChRs) are a heterogeneous family of related ion channels that are widely distributed throughout the central and peripheral nervous systems. They all share a common architecture of five subunit proteins that combine at the cell surface to create a ligand-gated cation permeable pore. Significant effort is currently being expended by medicinal chemistry teams to synthesize ligands that exhibit selectivity for central over peripheral nAChR subtypes. Within the CNS, multiple nAChR subtypes are recognized, and the discovery of ligands exhibiting selectivity among these subtypes offers an opportunity for the development of novel therapeutic agents. The α4β2 subtype is one of the most abundant nAChR subtypes within the CNS, and has been the primary focus of high affinity ligand design. Nicotine (1), and more recently, epibatidine (2) have served as structural templates for the design of the majority of active compounds. Although the diversity of nAChR ligands is growing, the structural requirements necessary for high affinity binding with the α4β2 receptor remain poorly understood. The putative pharmacophoric elements common to all potent α4β2 ligands include (1) a basic or quaternized nitrogen atom, and (2) a less basic nitrogen or a carbonyl oxygen that presumably interact with electron rich and electron deficient sites on the receptor, respectively. The family of currently known high affinity analogs consists of a diverse array of azacycles containing a basic amine. Several additional basic amine fragments have been identified, including the pyrrolizidine nucleus (exemplified by 8) and the 2-azabicyclo[2.2.1]heptane skeleton (exemplified by 9). In addition, we have found that the furo[2,3-b]pyridine heterocycle (compound 10) serves as useful bioisosteric replacement for the pyridyl substituent of nicotine. A preliminary pharmacophore model is proposed in which a reasonable superposition of the putative pharmacophoric elements of the diverse array of high affinity ligands for the α4β2 nAChR reported herein may be accommodated.

Cyclocondensation of 2-phenacyl-1H-benzimidazole with acylhydrazines: Synthesis and tautomerism of 2-(pyrazol-4-yl)-1H-benzimidazoles

The previously unknown 2-(pyrazol-4-yl)benzimidazoles containing aryl groups in the pyrazolyl ring have been obtained by the reaction of 2-phenacyl-1H-benzimidazole with aroylhydrazines. The compounds with nitrophenyl and pyridyl substituents in the pyrazole ring show pyrazolyl tautomerism with differences in the1H NMR spectra. A semi-empirical method is proposed to determine the tautomeric composition of the synthesized pyrazoles.

Vasodilating and antiarrhythmic activity of heteryl lactones

A new series of unsaturated γ- and δ-lactones with pyridyl, quinolyl and nitrophenyl substituents ( 9, 10) have been synthesized by the condensation of unsaturated methyl lactones with heteryl aldehyde or nitrobenzaldehyde in the base-catalysed aldol reaction. The antiarrhythmic, vasodilating and cardiotonic activities of the synthesized compounds have been studied in vivo and ex vivo . 3-Cyano-5,5-dimethyl-4-[4'-(4-pyridyl)-1',3'-butadienyl)]-2(5H)-furanone ( 9e) displayed a significant vasodilating activity. The antiarrhythmic activity of this compound was higher, but its toxicity lower than that of the procainamide reference drug. Five-membered lactones, particularly 3-cyano-4-(4-pyridylvinyl)-5,5-dimethyl-2(5H)-furanone ( 9c), exhibited a remarkable cardiotonic activity. The replacement of a pyridyl substituent by a nitrophenyl group in the pyranone derivative did not change the cardiovascular activity and toxicity.

ChemInform Abstract: Synthesis and Reactions of 4‐Hydroxy‐2(1H)‐pyridones with Thienyl and Pyridyl Substituents in Position 6 Starting with Azomethines and Malonates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and reactions of 4‐Hydroxy‐2(1H)‐pyridones with thienyl and pyridyl substituents in position 6 starting with azomethines and malonates

AbstractThe reaction of 4 with substituted diethyl malonates 5a, or “magic malonates” (bis‐2,4,6‐trichlorophenylmalonates 5b) leads to 4‐hydroxy‐2(1H)‐pyridones 6. The azomethines 4 are prepared via the Strecker compounds 3 starting with methyl ketones 1, anilines, and potassium cyanide. Chlorination of pyridones 6 with sulfuryl chloride leads to compounds 7 while nitration gives 9.

Structure and relaxivity of macrocyclic gadolinium complexes incorporating pyridyl and 4-morpholinopyridyl substituents

Octadentate N5O3 ligands containing a coordinating pyridyl group form kinetically stable complexes with Eu and Gd that resist protonation; the structure of a representative Gd complex reveals a short Gd–Npy bond [2.535(1) Å], and the water exchange rate (kex298=2.7×106 s-1) is sufficiently fast so as not to limit the pH independent relaxivity (R1p298=5.3 mM-1 s-1, 20 MHz).

Spectroelectrochemical studies and molecular orbital calculations on mononuclear complexes [Mo(TpMe,Me)(NO)Cl(py)] (where py is a substituted pyridine derivative): electrochromism in the near-infrared region of the electronic spectrum

Reaction of [Mo(TpMe,Me)(NO)Cl2] [where TpMe,Me is hydrotris(3,5-dimethylpyrazolyl)borate] with substituted pyridine derivatives (py-R) affords the complexes [Mo(TpMe,Me)(NO)Cl(py-R)] [1, R=4-(1-butylpentyl); 2, R=4-Ph; 3, R=3-Ph; 4, R=4-benzoyl; 5, R=3-benzoyl; 6, R=4-acetyl; 7, R=3-acetyl; 8, R=4-cyano; 9, R=3-cyano; 10, R=4-Cl; 11, R=3-Cl; 12, py-R=isoquinoline]. Two of the complexes, 5 and 8, have been crystallographically characterised. These neutral, 17-electron complexes [formally Mo(I)] were examined by UV/VIS/NIR spectroelectrochemistry. All of them undergo a chemically reversible one-electron reduction to the 18-electron monoanion at potentials which are sensitive to the nature of the pyridyl substituent R. Whereas the neutral (17-electron) forms of the complexes only show transitions in the UV and visible regions of the spectrum of the type we have described before, the reduced forms of the complexes show intense, low-energy transitions ascribable to MLCT transition from the electron-rich metal centre [formally Mo(0)] to the π* orbitals of the pyridyl ligands. The 4-substituted pyridines show only one such low-energy transition (e.g. for [1]-, λmax=830 nm; Iµ=12000 d mol-1 cm-1), but those complexes in which the pyridyl ligand has a strongly electron-withdrawing substituent at the C3 position of the pyridyl ligand develop two new MLCT transitions on reduction of which one is well into the near-IR region: e.g. for complex [5]-, λmax=717 nm; Iµ=5300 d mol-1 cm-1 and λmax=1514 nm; Iµ=2500 d mol-1 cm-1. These spectroscopic results have been rationalised by ZINDO calculations which were used both to calculate the frontier molecular orbitals of the complexes, and to calculate the electronic spectra of the reduced complexes. The strong near-IR transitions in the reduced complexes with 3-substituted pyridines, especially [5]- and [7]-, are of particular significance for the development of electrochromic dyes for use in electro-optic switching in this region of the spectrum.

A Novel Convenient Method to Synthesize Unsymmetrical 1,1′‐Disubstituted Ferrocenes Consisting of Various Phosphino, Thiolato and Pyridyl Substituents

AbstractA novel convenient method for preparing unsymmetrical 1,1′‐disubstituted ferrocenyl phosphine ligands by using the readily accessible 1,1′‐dibromoferrocene as a precursor is described. The method is of interest for modifying the chelating ferrocenyl phosphine ligands in view of the growing influence of homogeneous catalysis in organic synthesis, manipulation of materials and production of high optical yield.

Investigations of neurotrophic inhibitors of FK506 binding protein via Monte Carlo simulations.

The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 as well as for their potential as building blocks for chemical inducers of protein dimerization. Relative binding affinities were computed and analyzed for ligands differing by a phenyl ring, an external phenyl or pyridyl substituent, and a pipecolyl or prolyl ring. Such results are, in general, valuable for inhibitor optimization and, in the present case, bring into question some of the previously reported binding data.

A synthesis of 1-pyridylnaphthalene lignan analogs

A new series of 1-arylnaphthalene lignan analogs having a variety of pyridyl substituents at the C-1 position were synthesized in moderate to good yields by means of the Diels-Alder reaction by utilizing 1-pyridylisobenzofuran precursors with dimethyl fumarate, methyl acrylate, or dimethyl acetylene dicarboxylate, followed by BF 3·Et 2O-mediated aromatization.

Synthesis and Calcium Channel-Modulating Effects of Alkyl (or Cycloalkyl) 1,4-Dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate Racemates and Enantiomers

A group of racemic alkyl (or cycloalkyl) 1,4-dihydro-2,6- dimethyl-3-nitro-4-(2-, 3-, or 4-pyridyl)-5-pyridinecarboxylate isomers (6-14) were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with an alkyl (or cycloalkyl) 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridyl isomers acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle selective calcium channel antagonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers acted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2-pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity where the relative activity profile was cyclopentyl and cyclohexyl > t-Bu, i-Bu, and Et > MeOCH2CH2 > Me. The point of attachment of the C-4 pyridyl substituent was a determinant of GPLA agonist activity where the potency order was generally 4- and 3-pyridyl > 2-pyridyl. (+)-Cyclohexyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridyl)-5- pyridinecarboxylate [(+)-14a] was a less potent calcium antagonist (IC50 = 5.27 x 10(-6) M) than the (-)-enantiomer (IC50 = 7.48 x 10(-8) M) on GPILSM. In the GPLA assay, (+)-14a exhibited a much more potent agonist effect (EC50 = 8.45 x 10(-6) M) relative to the marginal agonist effect produced by (-)-14a. The C-4 2-pyridyl compounds (enantiomers) constitute a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a new drug design concept directed toward the treatment of congestive heart failure, and for use as probes to study the structure-function relationships of calcium channels.

Ivestigation of energy‐ and charge‐transfer processes using self‐organized porphyrin aggregates

AbstractSelf‐assembled triads and pentads are formed from Zn‐porphyrin or Zn‐chlorin dimers and pyridyl‐substituted free base of porphyrins, chlorins or tetrahydroporphyrins. A two‐point co‐ordination of the central Zn ions in the dimer with the nitrogen atoms of the pyridyl substituents of the free bases is essential for the complex formation. The complexation process has an equilibrium constant of the order of 107 M−1 at room temperature. An activation energy of the thermal dissociation of the complexes of 0.8 eV is found, which does not differ very much for different kinds of aggregates. Competing energy and charge transfer processes taking place in the aggregates have been identified by temperature dependent steady state fluorescence measurements.

Tetracarbonylmolybdenum complexes of 2-(phenylazo)pyridine ligands. Correlations of molybdenum-95 chemical shifts with electronic, infrared, and electrochemical properties

The complexes cis-Mo(CO) 4(X-2-(phenylazo)pyridine) (X = 4-CH 3O, 4-CH 3, 4-Cl, 5-Br, 5-CF 3, {6-CH 3} and cis-Mo(CO) 4(2-(2-CH 3-phenylazo)pyridine) have been synthesized and characterized by cyclic voltammetry, by visible and infrared spectroscopy, and by 1H, 13C, and 95Mo NMR spectroscopy. The 95Mo chemical shift correlates with the lowest energy electronic transition, with the sum of the carbonyl stretching frequencies, with the first oxidation potential, and with Hammett σ parameters for the pyridyl substituents. The failure of the complexes cis-Mo(CO) 4(6-CH 3-2-(phenylazo)pyridine) and cis-Mo(CO) 4(2-(2-CH 3-phenylazo)pyridine) to fit some of the correlations is attributed to steric or electronic effects. The effect of a substituent on the pyridyl ring of 2-(phenylazo)pyridine appears to be entirely an inductive one operating through the σ bonding. It is suggested that the 2-(phenylazo)pyridines might be appropriately viewed as ligands whose strong π-acceptor ability resides with the azo group, while the pyridyl group acts primarily as a pyridine whose basicity has been decreased by the strong electron-withdrawing 2-phenylazo substituent.

Supramolecular liquid-crystalline materials: molecular self-assembly and self-organization through intermolecular hydrogen bonding

Supramolecular liquid-crystals are molecular complexes formed from different and independent molecular species through specific molecular interactions such as hydrogen bonding. We have recently developed new types of H-bonded liquid-crystalline materials obtained by molecular self-assembly processes: (1) doubly H-bonded liquid-crystalline complexes through a molecular recognition process between 2,6- bis(acylamino)pyridines and benzoic acids, (2) liquid-crystalline polymer blends involving an H-bonding interaction between poly(4-vinylphenol) and a thermotropic main-chain polyester containing a lateral pyridyl substituent, (3) liquid-crystalline networks built through hydrogen bonds between multifunctional H-bonding components. These new materials may bridge a gap between liquid crystals and supramolecular systems.

Complexation and Interchromophoric Interactions in Self-Organized Porphyrin and Chlorin Triads

Spectral properties and equilibrium constants of multimolecular complexes (triads) formed by 2-fold coordination of dipyridyl-substituted free bases of porphyrin, chlorin, or tetrahydroporphyrin with Zn−porphyrin and Zn−chlorin dimers bridged by either of two different spacers between the monomeric entities have been studied in methylcyclohexane at room temperature. The ability of the dimers bridged by a −CH2−CH2− spacer to form complexes with the free bases is found to be much lower than that for the dimers with a phenyl spacer having complexation constants up to KC = 5 × 107 M-1. The complexation equilibrium is also affected strongly by the chemical nature of the free base and the position of the pyridyl substituents. Spectral effects occurring upon complexation in absorption spectra of the dimers are mainly due to ligation effects. Strong quenching of the dimer fluorescence in the complexes is attributed to effective singlet−singlet energy transfer (ET) to the ligands.

Synthesis of stable tail-to-tail-conjugated primary enamines containing hetarene substituents

A method is described that allows the preparation of stable conjugated primary enamines containing furyl or pyridyl substituents. In a template reaction (butadiene)zirconocene is 1,4-selectively coupled to two 2-cyanopyridine equivalents to give the nine-membered metallacycle 8b. Subsequent treatment with methanol removes the bent metallocene template and leads to the formation of 1,6-diamino-1,6-bis(2-pyridyl)-1,3,5-hexatriene ( 9b). The 1,6- diamino-1,6-bis(2-furyl)-1,3,5-hexatriene system ( 9a) was prepared analogously (69% isolated). Subsequent addition of benzonitrile to (butadiene)ZrCp 2 followed by 2-cyanopyridine or 2-cyanofurane gave the respective unsymmetrically substituted 1,6-diaminohexatrienes in good yield.

Crystalline complexes, coordination polymers and aggregation modes of tetra(4-pyridyl)porphyrin

Aggregation patterns of tetra(4-pyridyl)porphyrin and of its zinc(II) complex in seven new solid materials have been investigated by X-ray diffraction. The metalloporphyrin compound forms two types of coordination polymers through ligation of the porphyrin periphery on one molecule to the metal center of an adjacent porphyrin. These include one-dimensional chains with a zigzag conformation, as well as three-dimensional, extensively interlinked, polymeric structures. The non-metallated compound reveals a characteristic layered arrangement and interporphyrin stacking of the type which is commonly observed in the structures of tetraphenylporphyrin derivatives. In the absence of a metal center, the basic functionality of the pyridyl substituents is utilized for effective H-bond directed coordination and co-crystallization with solvent/guest components. The stoichiometry of the porphyrin solvation, and the consequent interporphyrin organization in the solid phase, are quite sensitive to the nature of the coordinating solvent.

Triosmium clusters with 2-pyridylphosphines as ligands

Room-temperature reactions of [Os3(CO)10(MeCN)2] with the tertiary phosphines (L), diphenyl(2-pyridyl)phosphine, phenyldi(2-pyridyl)phosphine, and tri(2-pyridyl)phosphine, led to clusters of the type[Os3(CO)11L]1, [Os3(CO)10L2]2, and [Os3(CO)10(µ-L)]3 which is the major product in each case. Clusters 1 and 2 have ligands L co-ordinated through the phosphorus atom alone, whereas 3 contain diaxially co-ordinated bridging ligands through one P and one pyridyl substituent. Two isomers of 3[L = PPh(2-C5H4N)2] are in rapid exchange in solution above room temperature and the clusters 3[L = PPh2(2-C5H4N) or P(2-C5H4N)3] gain a time-averaged plane of symmetry by a process which is the counterpart of this isomerisation; dynamic transfer of pyridine co-ordination between two metal atoms is proposed on 1H, 13C-{1H} and 31P-{1H}NMR evidence. Protonation of 3[L = PPh2(2-C5H4N)] arrests this process. Thermal treatment of 3[L = PPh2(2-C5H4N)] led to a major product [Os3(σ-Ph){µ3-PPh(2-C5H4N)}(CO)9](60%)(crystal structure reported) which contains the five-electron donating phenyl(2-pyridyl) phosphido bridge and a terminal phenyl ligand. Minor products are the cluster [Os3(µ-C5H4N)-(µ-PPh2)(CO)10](6%)(crystal structure reported), [Os2(µ-C5H4N)(µ-PPh2)(CO)6](trace), which is derived from the former, and [Os3(µ-PhCO){µ3-PPh(2-C5H4N)}(CO)9](trace). These clusters are generated by cleavage of either phosphorus–phenyl or phosphorus–2-pyridyl bonds; cleavage of a bond within the five-membered ring forming the bridge is less favoured than that of an exocyclic substituent.

Redox tuning of binuclear rhenium(V) complexes: The influence of pyridine substituents on the voltammetry of μ-oxobis[cis-dichloro-cis-dipyridyloxorhenium(V)

The recent interest in the voltammetry of the dioxorhenium(V) complexes of pyridine prompted us to investigate the voltammetry of μ-oxo-bis[cis-dichloro-cis-dipyridyloxorhenium(V)] complexes. Seven compounds containing pyridines with electron-withdrawing or electron-donating substituents were synthesized and their redox behavior characterized by variable potential sweep rate cyclic voltammetry and variable pulse height differential pulse voltammetry. Four one-electron redox couples are observed within the accessible potential range of CH2Cl2 containing 0.10 M n-Bu4NPF6 as the supporting electrolyte. The dimeric structure remains intact for the two oxidation and first reduction processes. The complex undergoes a reversible heterolytic cleavage of the μ-oxo linkage following the second reduction process. The redox potential for each process correlates with the inductive effect of the pyridyl substituent.