N‐Benzylnicotinamide and N‐benzyl‐1,4‐dihydronicotinamide: useful models for NAD+ and NADH

3‐Aminocarbonyl‐1‐benzylpyridinium bromide (N‐benzylnicotinamide, BNA), C₁₃H₁₃N₂O⁺·Br⁻, (I), and 1‐benzyl‐1,4‐dihydropyridine‐3‐carboxamide (N‐benzyl‐1,4‐dihydronicotinamide, rBNA), C₁₃H₁₄N₂O, (II), are valuable model compounds used to study the enzymatic cofactors NAD(P)⁺ and NAD(P)H. BNA was crystallized successfully and its structure determined for the first time, while a low‐temperature high‐resolution structure of rBNA was obtained. Together, these structures provide the most detailed view of the reactive portions of NAD(P)⁺ and NAD(P)H. The amide group in BNA is rotated 8.4 (4)° out of the plane of the pyridine ring, while the two rings display a dihedral angle of 70.48 (17)°. In the rBNA structure, the dihydropyridine ring is essentially planar, indicating significant delocalization of the formal double bonds, and the amide group is coplanar with the ring [dihedral angle = 4.35 (9)°]. This rBNA conformation may lower the transition‐state energy of an ene reaction between a substrate double bond and the dihydropyridine ring. The transition state would involve one atom of the double bond binding to the carbon ortho to both the ring N atom and the amide substituent of the dihydropyridine ring, while the other end of the double bond accepts an H atom from the methylene group para to the N atom.     

1‐Chloro‐3,6‐di­methoxy‐2,5‐di­methyl­benzene and 1‐chloro‐3,6‐di­methoxy‐2,4‐di­methyl­benzene

The title compounds, 1‐chloro‐3,6‐di­methoxy‐2,5‐di­methyl­benzene, (IIIa), and 1‐­chloro‐3,6‐di­methoxy‐2,4‐di­methyl­benzene, (IIIb), both C₁₀H₁₃ClO₂, were obtained from 2,5‐ and 2,6‐di­methyl‐1,4‐benzo­quinone, respectively, and are intermediates in the synthesis of ammonium quinone derivatives. The isomers have different substituents around the methoxy groups and crystallize in different space groups. In both mol­ecules, the methoxy groups each have different orientations with respect to the benzene ring. In both cases, one methoxy group lies in the plane of the ring and can participate in conjugation with the aromatic system, while the second is almost perpendicular to the plane of the aromatic ring. The C—O—C bond angles around these substituents are also different: 117.5 (4) and 118.2 (3)° in (IIIa) and (IIIb), respectively, when the methoxy groups lie in the plane of the ring, and 114.7 (3) and 113.6 (3)° in (IIIa) and (IIIb), respectively, when they are out of the plane of the ring.     

Bond Length Alternation and Internal Dynamics in Model Aromatic Substituents of Lignin

Broadband microwave spectra were recorded over the 2-18 GHz frequency range for a series of four model aromatic components of lignin; namely, guaiacol (ortho-methoxy phenol, G ), syringol (2,6-dimethoxy phenol, S ), 4-methyl guaiacol ( MG ), and 4-vinyl guaiacol ( VG ), under jet-cooled conditions in the gas phase. Using a combination of ¹³C isotopic data and electronic structure calculations, distortions of the phenyl ring by the substituents on the ring are identified. In all four molecules, the r_C(1)-C(6) bond between the two substituted C-atoms lengthens, leading to clear bond alternation that reflects an increase in the phenyl ring resonance structure with double bonds at r_C(1)-C(2), r_C(3)-C(4) and r_C(5)-C(6). Syringol, with its symmetric methoxy substituents, possesses a microwave spectrum with tunneling doublets in the a-type transitions associated with H-atom tunneling. These splittings were fit to determine a barrier to hindered rotation of the OH group of 1975 cm⁻¹, a value nearly 50 % greater than that in phenol, due to the presence of the intramolecular OH⋅⋅⋅OCH₃ H-bonds at the two equivalent planar geometries. In 4-methyl guaiacol, methyl rotor splittings are observed and used to confirm and refine an earlier measurement of the three-fold barrier V₃=67 cm⁻¹. Finally, 4-vinyl guaiacol shows transitions due to two conformers differing in the relative orientations of the vinyl and OH groups.     

The Scent of Maibowle – π Electron Localization in Coumarin from Its Microwave-Determined Structure

The microwave spectra of the natural substance coumarin, a planar aromatic molecule with the specific scent of maibowle, a popular fruit punch served in spring and early summer, were recorded using a molecular jet Fourier transform microwave spectrometer working in the frequency range from 4.0 to 26.5 GHz. The rotational constants and centrifugal distortion constants were determined with high precision, reproducing the spectra to experimental accuracy. The spectra of all singly-substituted ¹³C and ¹⁸O isotopologues were observed in their natural abundances to determine the experimental heavy atom substitution r_s and semi-experimental equilibrium r_e^SE structures. The experimental bond lengths and bond angles were compared to those obtained from quantum chemical calculations and those of related molecules reported in the literature with benzene as the prototype. The alternation of the C−C bond lengths to the value of 1.39 Å found for benzene reflects the localization of π electrons in coumarin, where the benzene ring and the lactone-like chain −CH=CH−(C=O)−O− are fused. The large, negative inertial defect of coumarin is consistent with out-of-plane vibrations of the fused rings.     

Etude de composés d'addition d'acides de Lewis,XXXIV [1] Composés d'addition de benzoquinone-1, 4 avec TiCl4

The adduct 1,4-benzoquine · TiCl₄ has been prepared in CH₂Cl₂ solution at about ?60°. Its IR. spectrum has been recorded at the same temperature. The experimental study of the vibrational frequencies has been completed by the calculation of the fundamental vibrations in the molecular plane, using Wilson's FG method, with slightly simplified models of 1,4-benzoquinone · TiCl₄ (13 masses) and 1,4-benzoquinone · 2 TiCl₄ (14 masses); analysis by use of internal and symmetry coordinates. An assignment of most of the observed bands is proposed and the conclusion is reached that the complex, when solid, is (1,4-benzoquinone · TiCl₄)_n. The force constants F(C? O) are 9,85 · 10⁵ dyne/cm for the quinone and 8,8 · 10⁵ dyne/cm for the disturbed carbonyl bond of the polymerized complex in the model proposed. At ordinary temperature in benzene solution of the components the adduct 1,4-benzoquinone. TiCl₄ · benzene precipitated; with the help of the models, the fundamental vibrations of its IR. spectrum have been assigned.     

Structure of Mellitic Trianhydride

Mellitic trianhydride (MTA; benzene‐1,2 : 3,4 : 5,6‐hexacarboxylic trianhydride), a powerful π‐electron acceptor, crystallizes in the cubic space group Pa3 with four molecules in the unit cell and is orientationally twofold disordered. The molecules are packed exclusively via edge‐to‐face contacts also seen in the isomorphous crystal structures of benzene hexacarbonitrile, benzene hexamine, and all‐trans‐hexachlorocyclohexane. The orthorhombic crystal structure of benzene is also related to these cubic cases, albeit in distorted fashion. The MTA molecules are non‐planar in the crystal, taking the shape of a shallow propeller with approximate D₃ symmetry. The non‐planarity is ascribed to nucleophilic‐electrophilic intermolecular interactions between the five‐membered‐ring O‐atoms and the carbonyl C‐atoms. Due to the disorder, the two non‐equivalent inner C,C bond lengths of the benzene ring of MTA cannot be resolved. The MTA molecules in the polar crystals of the 1 : 1 molecular charge‐transfer complexes with triphenylene and 9,10‐dimethylanthracene are ordered and practically planar, and, within experimental error, show equal inner C,C lengths, despite severe adjacent bond‐angle distortions. Accordingly, the structure of MTA provides no evidence in support of a so‐called `Mills‐Nixon effect'.     

Reaction of bicyclo[2.2.1]hepta-2,5-diene with the arenesulfenamide—phosphorus(v) oxohalide system: chemo-, regio-, and steroselectivity

The chemo-, regio- and stereoselectivities of electrophilic sulfenylation of bicyclo[2.2.1]hepta-2,5-diene with arenesulfenamides activated by phosphorus(v) oxohalides were studied. The ratio of the products of endo- to exo-attack of the diene by the electrophilic species depends on the solvent nature. The proportions of the products formed upon addition to one double bond and upon homoallylic participation of the second double bond depend on solvent polarity, the nature of the halogen, the substituents in the sulfenamide benzene ring, and on the reaction time. In addition, the formation of mixed adducts was proven for the reaction carried out in acetonitrile and the formation of disulfenylation products was found in the reaction with excess sulfenylating reagent. Isomerization of exo-3-arylthio-endo-2-halobicyclo[2.2.1]hept-5-enes to the products formed with homoallylic participation of the second double bond, exo-5-arylthio-endo-3-halotricyclo[2.2.1.0^2,6]heptanes, was shown to be possible.     

Synthesis and 13C NMR Spectra of N-Substituted para-Quinone Imines: II. N-Arylthio- and N-Arylsulfonyl-1,4-benzoquinone Imines with Enhanced Electron-withdrawing Character of the Quinoid Ring

Introduction of chlorine substituents into quinone imine fragment results in virtually the same variations in the chemical shifts of the quinoid ring carbons both in N-arylthio and N-arylsulfonyl-1,4-benzoquinone imines as compared to the unsubstituted analogs. In both classes of chloro-substituted compounds the effect of substituents in the benzene ring on the character and the range of chemical shifts variations for the carbon signals from the quinoid ring also turned out to be identical. Any differences observed may be due to the change in the geometry of the molecules, in particular, to the increase in the bond angle C = N-S.     

Synthesis and investigation of cytotoxicity of new N- and S,S-substituted-1,4-naphthoquinone (1,4-NQ) derivatives on selected cancer lines

1,4-Naphthoquinones (1,4-NQ) have been reported to possess a variety of pharma-cological properties including antibacterial, antifungal, antiviral, anti-inflammatory, anti-artherosclerotic, and anticancer effects. In this study, new N- and S,S-substituted-1,4-NQ derivatives were synthesized in excellent yields and were completely characterized by spectroscopic analysis IR, NMR (¹H and ¹³C), MS and microanalysis. The cytotoxic activities of 1,4-NQ derivatives were examined against to A-549, DU145, HCT-116 and MDA-MB-231 cancer cells. Among these compounds, 2-[4-(2-furoyl)piperazine-1-yl]-3-chloro-1,4-NQ 5 and 2,3-bis(cyclobuthylsulfanyl)-1,4-NQ 17 were identified as the most potent anticancer agents with cytotoxic activity against three cell lines (breast (MDA-MB-231), prostate (DU145), colorectal (HCT-116).     

Molecular structure of ethynylbenzene from electron diffraction and ab initio molecular orbital calculations

The molecular structure and benzene ring distortions of ethynylbenzene have been investigated by gas-phase electron diffraction and ab initio MO calculations at the HF/6-31G^* and 6-3G^** levels. Least-squares refinement of a model withC _2v, symmetry, with constraints from the MO calculations, yielded the following important bond distances and angles:r _g(C _i -C _o )=1.407±0.003 Å,r _g(C _o -C _m )=1.397±0.003 Å,r _g(C _m -C _p )=1.400±0.003 Å,r _g(Cr _i -CCH)=1.436 ±0.004 Å,r _g(C=C)=1.205±0.005 Å, C _o -C _i -C _o =119.8±0.4°. The deformation of the benzene ring of ethynylbenzene given by the MO calculations, including o-C_i-C_o=119.4°, is insensitive to the basis set used and agrees with that obtained by low-temperature X-ray crystallography for the phenylethynyl fragment, C₆H₅-CC-, in two different crystal environments. The partial substitution structure of ethynylbenzene from microwave spectroscopy is shown to be inaccurate in the ipso region of the benzene ring.     

(Z)‐2‐(3‐Methoxy­benzyl­idene)‐1‐aza­bicyclo­[2.2.2]octan‐3‐one

The crystal structure of the title compound, C₁₅H₁₇NO₂, contains two nearly identical but crystallographically independent mol­ecules, each with a double bond connecting an aza­bicyclic ring system to a 3‐methoxy­benzyl­idene moiety. The space group is triclinic P. The benzene ring is twisted by 18.44 (5) and 22.35 (4)° with respect to the plane of the double bond connected to the azabicyclic ring system for the two mol­ecules. In addition to C—H⋯π inter­actions, mol­ecules are held together in the solid state by van der Waals inter­actions.     

Bond Length Alternation Observed Experimentally: The Case of 1H-Indazole

Bond length alternation is a chemical phenomenon in benzene rings fused to other rings, which has been mainly predicted theoretically. Its physical origin is still not clear and has generated discussion. Here, by using a strategy that combines microwave spectroscopy, custom-made synthesis and high-level ab initio calculations, we demonstrate that this phenomenon is clearly observed in the prototype indazole molecule isolated in the gas phase. The 1H-indazole conformer was detected by rotational spectroscopy, and its 17 isotopologues resulting from single and double heavy atom substitution (¹³C and ¹⁵N) were also unambiguously observed. Several experimental structures were determined and, in particular, the most useful semi-experimental equilibrium structure (r_e^SE), allowed determination of the heavy atom bond lengths to milli-Ångstrom precision. The experimentally determined bond length alternation is estimated to correspond to 60:40 contributions from the two resonant forms of 1H-indazole.     

Molecular structure of phenylsilane: a study by gas-phase electron diffraction and ab initio molecular orbital calculations

The molecular structure of phenylsilane has been determined accurately by gas-phase electron diffraction and ab initio MO calculations at the MP2(f.c.)/6-31G* level. The calculations indicate that the perpendicular conformation of the molecule, with a Si–H bond in a plane orthogonal to the plane of the benzene ring, is the potential energy minimum. The coplanar conformation, with a Si–H bond in the plane of the ring, corresponds to a rotational transition state. However, the difference in energy is very small, 0.13 kJ mol⁻¹, implying free rotation of the substituent at the temperature of the electron diffraction experiment (301 K). Important bond lengths from electron diffraction are: <r_g(C–C)>=1.403±0.003 Å, r_g(Si–C)=1.870±0.004 Å, and r_g(Si–H)=1.497±0.007 Å. The calculations indicate that the C_ipso–C_ortho bonds are 0.010 Å longer than the other C–C bonds. The internal ring angle at the ipso position is 118.1±0.2° from electron diffraction and 118.0° from calculations. This confirms the more than 40-year old suggestion of a possible angular deformation of the ring in phenylsilane, in an early electron diffraction study by F.A. Keidel, S.H. Bauer, J. Chem. Phys. 25 (1956) 1218.     

Two 1,4‐dihydropyridine derivatives with potential calcium‐channel antagonist activity

The title compounds, benzyl 4‐(3‐chloro‐2‐fluorophenyl)‐2‐methyl‐5‐oxo‐4,5,6,7‐tetrahydro‐1H‐cyclopenta[b]pyridine‐3‐carboxylate, C₂₃H₁₉ClFNO₃, (I), and 3‐pyridylmethyl 4‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]‐2,6,6‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate, C₂₆H₂₄F₄N₂O₃, (II), belong to a class of 1,4‐dihydropyridines whose members sometimes display calcium modulatory properties. The 1,4‐dihydropyridine ring in each structure has a shallower than usual shallow‐boat conformation and is nearly planar in (I). In each structure, the halogen‐substituted benzene ring is oriented such that the halogen substituents are in a synperiplanar orientation with respect to the 1,4‐dihydropyridine ring plane. The oxocyclopentene ring in (I) is planar, while the oxocyclohexene ring in (II) has a half‐chair conformation, which is less commonly observed than the envelope conformation usually found in related compounds. In (I), the frequently observed intermolecular N—H...O hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighbouring molecule links the molecules into extended chains; there are no other significant intermolecular interactions. By contrast, the amine group in (II) forms an N—H...N hydrogen bond with the pyridine ring N atom of a neighbouring molecule. Additional C—H...O interactions complete a two‐dimensional hydrogen‐bonded network. The halogen‐substituted benzene ring has a weak intramolecular π–π interaction with the pyridine ring. A stronger π–π interaction occurs between the 1,4‐dihydropyridine rings of centrosymmetrically related molecules.     

Resolution and chiroptical properties of [32](1,4)barrelenophanedicarbonitrile

(±)-[3₂](1,4)Barrelenophane was completely resolved into its enantiomers by HPLC separation using a chiral stationary phase (Chiralcel OD) with hexane/propan-2-ol (1:9). The specific rotations and circular dichroism spectra of (+)- and (−)-[3₂](1,4)barrelenophanes indicated the enantiomeric relationships. The longest absorption band at 360 nm (ε 541, CH₂Cl₂) is identified mainly as AN intramolecular charge transfer band between the benzene ring and the double bond conjugated with cyano groups. The X-ray structure of the (+)-isomer has been determined.     

Proton chemical shifts in NMR: Part 17. Chemical shifts in alkenes and anisotropic and steric effects of the double bond

The ¹H NMR spectra of a number of alkenes of known geometry were recorded in CDCl₃ solution and assigned, namely ethylene, propene, 4-methylcyclohexene, 1,4-dimethylcyclohexene, methylene cyclohexane (in CFCl₃–CD₂Cl₂ at 153 K), 5-methylene-2-norbornene, camphene, bicyclopentadiene, styrene and 9-vinylanthracene. These results together with literature data for other alkenes, i.e. 1,3- and 1,4-cyclohexadiene, norbornene, norbornadiene, bicyclo[2.2.2]oct-2-ene and α- and β-pinene, and other data allowed the determination of the olefinic shielding in these molecules. The shielding was analysed in terms of the magnetic anisotropy and steric effects of the double bond together with a model (CHARGE7) for the calculation of the two- and three-bond electronic effects. For the aromatic alkenes ring current and π-electron effects were included. This analysis showed that the double bond shielding arises from both anisotropic and steric effects. The anisotropy is due to the perpendicular term only with a value of Δχ(CC) of −12.1 × 10⁻⁶cm³mol⁻¹. There is also a steric deshielding term of 82.5/r⁶ (r in Å). The shielding along the π-axis changes sign from shielding at long range (>2.5 Å) to deshielding at short range (<2 Å). The model gives the first comprehensive calculation of the shielding of the alkene group. For the data set considered (172 proton chemical shifts) ranging from δ=0.48 to 8.39, the r.m.s. error of observed vs calculated shifts was 0.11 ppm. Copyright © 2001 John Wiley & Sons, Ltd.     

Polymerization of 1,3‐dienes with functional groups. II. Free‐radical polymerization of N‐(2‐methylene‐3‐butenoyl)piperidine

The free‐radical homopolymerization and copolymerization behavior of N‐(2‐methylene‐3‐butenoyl)piperidine was investigated. When the monomer was heated in bulk at 60 °C for 25 h without an initiator, about 30% of the monomer was consumed by the thermal polymerization and the Diels–Alder reaction. No such side reaction was observed when the polymerization was carried out in a benzene solution with 1 mol % 2,2′‐azobisisobutylonitrile (AIBN) as an initiator. The polymerization rate equation was found to be R_p ∝ [AIBN]^0.507[M]^1.04, and the overall activation energy of polymerization was calculated to be 89.5 kJ/mol. The microstructure of the resulting polymer was exclusively a 1,4‐structure that included both 1,4‐E and 1,4‐Z configurations. The copolymerizations of this monomer with styrene and/or chloroprene as comonomers were carried out in benzene solutions at 60 °C with AIBN as an initiator. In the copolymerization with styrene, the monomer reactivity ratios were r₁ = 6.10 and r₂ = 0.03, and the Q and e values were calculated to be 10.8 and 0.45, respectively. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1545–1552, 2003     

Application of electrochemically generated molybdenum‐based catalyst system to the ring‐opening metathesis polymerization of norbornene and a comparison with the tungsten analogue

This study describes the application of the electrochemically generated molybdenum‐based catalyst system MoCl₅? e^?? Al? CH₂Cl₂ to ring‐opening metathesis polymerization of bicyclo[2.2.1]hept‐2‐ene (norbornene). The results are compared with those previously obtained by the WCl₆? e^?? Al? CH₂Cl₂ system. The polymer product has been characterized by ¹H and ¹³C NMR, IR and gel‐permeation chromatography techniques. This molybdenum‐based catalyst system has led to a mainly trans stereoconfiguration (ca 60%) of the double bonds, in contrast to the polymer obtained with the tungsten‐based analogue, where the cis content is 60%. Analysis of the poly(1,3‐cyclopentylenevinylene) microstructure by ¹³C NMR spectroscopy revealed that the polymer having σ_c = 0.41 (fraction of double bonds with cis configuration) contains a slightly blocky distribution (r_tr_c > 1) of the double‐bond dyads (r_tr_c = 1.44). In addition, the influence of reaction parameters, e.g. reaction time, electrolysis time and catalyst aging time, on conversion has been analysed in detail. Copyright © 2005 John Wiley & Sons, Ltd.     

1‐(7‐Chloro‐1,4‐dihydroquinolin‐4‐ylidene)thiosemicarbazide and its hydrochloride: evidence for the existence of a stable imine tautomer in the solid state of 4‐aminoquinoline free bases,an anomalous case in nitrogen heterocycles

In the solid state, crystals of both 1‐(7‐chloro‐1,4‐dihydroquinolin‐4‐ylidene)thiosemicarbazide–methanol–water (2/1/1), 2C₁₀H₉ClN₄S·CH₃OH·H₂O, (I), and its hydrochloride salt {systematic name: [(7‐chloro‐1,4‐dihydroquinolin‐4‐ylidene)azaniumyl]thiourea chloride}, C₁₀H₁₀ClN₄S⁺·Cl⁻, (II), assume the imine tautomeric form, contrary to other 4‐amino‐7‐chloroquinolines. Of particular interest are the N—C bond lengths, which have appreciable double‐bond character, and the C—N—C aromatic ring bond angle. Both of these parameters have been studied extensively in 4‐amino‐substituted quinolines. The crystal structures of (I) and (II) in this study provide interesting examples of the amino–imino tautomerism which exists in this class of compound and is, to the best of our knowledge, hitherto unreported.     

Ring cleavage of dihydropyrimidine skeleton

The first observation of ring cleavage between positions 1 and 2 of a 1,4-dihydropyrimidine skeleton was reported upon the nucleophilic addition of 4,6-unsubstituted 1,4-dihydropyrimidine with 3 equiv of an aniline derivative or phenylhydrazine in the presence of 0.1 equiv of pyridinium p-toluenesulfonate (PPTS) in CH₂Cl₂; the nucleophilic reactions of 4-methyl-6-unsubstituted 1,6(3,4)-dihydropyrimidine with the same amines gave conventional substituted products at position 2. The effect of this ring opening was found to be due to the electron density of the benzene ring of a nucleophilic amine. On the other hand, aralkylamines, alkylamines, or heterocyclic amines did not cleave the skeleton. The ring-opening chemical structure was confirmed by X-ray crystallographic analysis. This characteristically different phenomenon may be due to the pattern of two CC double bonds of 1,4-DP and 1,6(3,4)-DP as well as to the effect of two substituted groups on the DP ring.