NMR Studies Of Drugs. Chiral Solvating Agents for Direct Determination of Enantiomeric Excess of the Cardiac Antiarrhythmic,Mexiletine

The 400 MHz ¹H NMR spectra of the cardiac antiarrhythmic, mexiletine, 1, have been studied with different chiral solvating agents (CSA) to obtain a very promising method for direct determination of enantiomeric excess (e.e.) with limited amounts of 1. The methods included the use of β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA), and 2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE). Use of TFAE in CDCl₃ with the free base of 1 appeared to give the best results, with enantiomeric shift differences observed for the signals of the sidechain methyl, CH ₃CH, and the aryl methyls.     

1H NMR Spectral Simplification with Chiral Solvating Agents and with Achiral and Chiral Lanthanide Shift Reagents. Cis-4,5-Dihydro-4-Methyl-5-Phenyl-2-Oxazolamine, “Cis-4-Methylaminorex,” a Potent Stimulant and Anorectic

Abstract

The 60 MHz ¹H NMR spectra of racemic (+)-cis-4,5-dihydro-4-methyl-5-phenyl-2-oxazolamine, 1, have been studied at 28° in CDC1₃, solution with the achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), 2, and the chiral reagent tris[3?(heptafluoropropylhydroxymethy1ene)-d-camphor-ato]europium(III), 3. Additional NMR studies were performed at 400 MHz in CDC1, solution at 24° using the chiral solvating agents (CSA), (E)-(-)-2,2,2-trifluoro-1- (9-anthryl) ethanol, 4, and (R) - (+) -α-methoxy- α-(trifluoromethy1)phenylacetic acid, 5. Substantial enantiomeric shift differences, for the CH₃, signal of 1 using 3 or 5, and for the ortho aryl protons using4, which should make possible direct optical purity determinations of 1. Accurate 400 MHz data f o r chemical shifts and vicinal coupling constants of, of racemic cis-1 are presented, and compared with values for (optically active) (-)-trans-1; some dfferences are seen compared to previously reported data. solution. The LSR and CSA results are compared and Some additional data were obtained in C₆D₆ discussed.     

NMR Studies of Drugs. Phensuximide. 1H and 13C NMR Methods with Chiral Solvating Agents and Lanthanide Shift Reagents

NMR spectra of the racemic anticonvulsant, phensuximide, 1, in CDCl₃ solution, have been studied with additives to explore methods for potential direct determination of enantiomeric excess (% ee). Proton studies at 200 MHz with the chiral solvating agent (CSA) (-)-2,2,2-trifluoro-1- (9-recommended for ee analysis due to uncertainties of contributions to the NCH₃ from the CH₂ proton absorptions.     

Spectral Characteristics of the Reaction Products of 5-Phenyl-2,3,4-furantrione with o-Diamines

The ¹H and ¹³C NMR and mass spectra of 2-(2-amino-4,5-dimethylphenylcarbamoyl)-3-(hydroxyphenylmethyl)-6,7-dimethylqinoxaline (2), 3-(hydroxyphenylmethyl)-6,7-dimethylquinoxalin-2-carboxylic-γ-lactone (5), 3-(hydroxyphenylmethyl)-6,7-dimethylquinoxalin-2-carboxylic acid phenylhydrazide (6), 3-[2-hydroxy-2-phenyl-1-(phenylhydrazono)ethyl]-6,7-dimethyl-2(1H)-quinoxalinone (7), 2,3-dihydro-6,7-dimethyl-3-phenylhydrazono-2-phenylfuro[2,3-b]auinoxaline (8), 3-(hydroxyphenylmethyl)-6,7-dimethyl-1-phenylflavazole (9), and 3-(acetoxyphenylmethyl)-6,7-dimethyl-1-phenylflavazole (10) have been studied.     

Reaction between alkyl isocyanides and isopropylidene Meldrum’s acid in the presence of bidentate nucleophiles

Summary The reaction between alkyl isocyanides and isopropylidene Meldrum’s acid in the presence of 1,2-ethanediol leads to N ¹-(alkyl)-2-(5,7-dioxo-1,4-dioxepane-6-yl)-2-methylpropanamides. 1,3-Propanediol or 1,4-butanediol produce hydroxyalkyl 1-(tert-butyl)-4,4-dimethyl-2,5-dioxo-3-pyrrolidinecarboxylates. When the reaction was performed in the presence of catechol, bis(2-hydroxyphenyl) 2-[2-(tert-butylamino)-1,1-dimethyl-2-oxoethyl]malonate was obtained. 2-Aminophenols react with alkyl isocyanides in the presence of isopropylidene Meldrum’s acid to produce 1-alkyl-N ³-(2-hydroxyaryl)-4,4-dimethyl-2,5-dioxo-3-pyrrolidinecarboxamides in good yields.     

Synthesis,spectroscopic and structural characterisation of two p-nitrobenzamide compounds: experimental and DFT study

The title molecules, N-(1,5-dimethyl-3-oxo-2-phenyl-1H-3-(2H)-pyrazolyl)4-nitrobenzamide (C₁₈H₁₆N₄O₄·H₂O) (I) and 2,2-dimethyl-3-(4-nitrobenzoyl)-5-(phenylamino)-2,3-dihydro-1,3,4-thiyadiazole (C₁₇H₁₆N₄O₃S) (II), were prepared and characterised by ¹H NMR, ¹³C NMR, infrared spectroscopy (IR) and structural X-ray diffraction (XRD) techniques. The molecular geometries, vibrational frequencies of the title compounds in the ground state have been calculated by using the density functional theory (DFT) method with 6-31G(d) basis set, and compared with the experimental data. The calculated results showed that the optimised geometries from the DFT method agree with the X-ray structures well for both compounds. Theoretical calculations of harmonic vibration frequencies are in good agreement with experimental results. To determine conformational flexibility, the molecular energy profiles of the title compounds were obtained. Besides, molecular electrostatic potential (MEP), frontier molecular orbitals (FMO) analysis and thermodynamic properties of the title compounds were investigated by theoretical calculations.     

EPR Investigations on Molecular Orientation of Paramagnetic Liquid Crystals in a Surface-Stabilized Liquid Crystal Cell: Studies on a Smectic C or Chiral Smectic C Phase

By electron paramagnetic resonance spectroscopy we investigated the molecular orientation in a surface-stabilized liquid crystal (LC) cell, which includes a racemic (±) or an enantiomerically enriched (S,S) paramagnetic LC, (2S,5S)-2,5-dimethyl-2-tridecyloxyphenyl-5-[4-(4-tridecyloxy-benzenecarbonyloxy)phenyl]pyrrolidine-1-oxy (2), whose spin source is fixed inside the rigid core. For both the smectic C (SmC) phase of (±)-2 and the chiral smectic C (SmC^*) phase of (S,S)-2 in a surface-stabilized LC cell (antiparallel configuration, thickness of 4 μm), the profile of the observed g-value as a function of the angle between the applied magnetic field and the cell plane could be explained by the orientation model, where, with some disordering, the molecules align uniformly with the direction which tilts from the normal line of the smectic layer being orthogonal to the rubbing direction on the cell surface. We divided the effect from the disordering into two parts, one of which is concerning the direction of the molecular long axis and the other is concerning the rotation around the molecular long axis. As a result of the analysis, the SmC^* phase gave quite lower ordering concerning the direction of the molecular long axis and a little lower ordering concerning the rotation around the molecular long axis than the SmC phase at the same temperature (80 °C). The obtained lower ordering in the SmC^* phase is probably due to the chirality that would result in the formation of a helical superstructure in a bulky state. Authors' address: Yohei Noda, Laboratory of Electron Spin Chemistry, Department of Chemistry, Graduate School of Science, Kyoto University, 606-8502 Kyoto, Japan     

The SN3–SN2 spectrum. Rate constants and product selectivities for solvolyses of benzenesulfonyl chlorides in aqueous alcohols

Rate constants for a wide range of binary aqueous mixtures and product selectivities (S) in ethanol–water (EW) and methanol–water (MW) mixtures, are reported at 25 °C for solvolyses of benzenesulfonyl chloride and the 4‐chloro‐derivative. S is defined as follows using molar concentrations: S = ([ester product]/[acid product]) × ([water solvent]/[alcohol solvent]). Additional selectivity data are reported for solvolyses of 4‐Z‐substituted sulfonyl chlorides (Z = OMe, Me, H, Cl and NO₂) in 2,2,2‐trifluoroethanol–water. To explain these results and previously published data on kinetic solvent isotope effects (KSIEs) and on other solvolyses of 4‐nitro and 4‐methoxybenzenesulfonyl chloride, a mechanistic spectrum involving a change from third order to second order is proposed. The molecularity of these reactions is discussed, along with new term ‘S_N3–S_N2 spectrum’ and its connection with the better established term ‘S_N2–S_N1 spectrum’. Copyright © 2009 John Wiley & Sons, Ltd.     

NMR Spectroscopic Study of Camphanic Acid,Rh2[Camphanate]4, and its Adducts with 1,4-Benzodiazepines

The H and ¹³C NMR spectra of chiral camphanic acid, lactonc of (1S,3R)-1-hydroxy-2,2,3-trimethyl-cyclopentan-1,3-dicarboxylic acid (1), and dirhodium tetracamphanate complex (2) were completely assigned on the basis of one- and two-dimensional NMR experiments. The NMR spectra of the adducts of dirhodium tetracamphanate 2 with 5-pyrido-1, 4-benzodiazepin-2-ones 3 and 4, complexes with catalytic activity, support the assignation and also revealed two different types of axial complexation of these nitrogen ligands.     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Methastyridone, 2,2-Dimethyl-5-(2-Phenylethenyl)-4-Oxazolidinone

Abstract

The 60 MHz ¹H NMR spectra of methastyridone, 2,2-dimethyl-5-(2-phenylethenyl)-4-oxazolidinone, 1, have been studied at 28° in CDCl₃ solution with the achiral reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, Eu(FOD)₃, and the chiral reagent tris[3-(heptafluoropropylhydroxy-methylene)-d?camphorato]europium(III), 3, Eu(HFC)₃.     

Enantiomeric Composition of Chiral β-Hydroxylamides by 1H NMR Spectroscopy Using Chiral Solvating Agent

Studies of the perturbing effect of the trifluoromethylanthryl carbinol used as chiral solvating agent (CSA) upon the ¹H NMR spectra of chiral α-O-substituted β-hydroxylamides demonstrated the ability of this fluoroalcohol to afford diastereomeric solvates with these solutes. Thus, for all the tested amides, there is at least one possibility to proceed to their enantiomeric discrimination by ¹H NMR using CSA. The method was developed to determine (later and indirectly) a possible chiral recognition during in vitro enzymatic hydrolysis in locust biological tissues of N-acylaziridines conceived as proinsecticides of carboxylic acids, in view to eventually optimize their efficiency.     

Polymer-supported and polymeric chiral guanidines: Preparation and application to the asymmetric Michael reaction of iminoacetate with methyl vinyl ketone

Summary Polymer-supported and polymeric chiral guanidines carrying an imidazolidine skeleton are designed as polymer-based base catalysts. Thus, (R)-2-[(S)-1-hydroxymethyl-2-phenylethylimino]-4-phenylimidazolidine was newly prepared from (R)-phenylglycine as the key functional unit of these guanidines. Application of the polymer-based chiral guanidines to the asymmetric Michael reaction of t-butyl diphenyliminoacetate with MVK led to expected asymmetric induction in the Michael adduct with moderate enantioselectivity in the use of the latter polymeric chiral guanidines.     

Atomistic Engineering of Chemiluminogens: Synthesis,Properties and Polymerization of 2,3-Dihydro-Pyrrolo[3,4-d]Pyridazine-1,4-Dione Scaffolds

Two chemiluminescent compounds containing 2,5-di(thien-2-yl)pyrrole and pyridazine units, namely 5,7-di(thiophen-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-d]pyridazine-1,4(6H)-dione (5) and 6-phenyl-5,7-di(thiophen-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-d]pyridazine-1,4(6H)-dione (6), were successfully synthesized and electrochemically polymerized. The compounds have chemiluminescent properties and glow in the presence of hydrogen peroxide in basic medium. The intensity of the glow can be increased dramatically by using Fe³⁺ ions, hemin (1.0 ppm) or blood samples (1.0 ppm) as catalyst. The compounds 5 and 6 have one well-defined irreversible oxidation peak at 1.08 V and 1.33 V vs Ag/AgCl, respectively. Electrochemical polymerization of both 5 and 6 were carried out successfully by repeating potential scanning in the presence of BF₃. Et2O in an electrolyte solution of 0.1 M LiClO₄ dissolved in acetonitrile. The electronic band gaps (E_g) of the polymers P5 and P6 were found to be 2.02 eV and 2.16 eV, respectively. On the other hand, the corresponding polymers are electroactive and exhibited electrochromic features.

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Ultrasound-assisted three-component synthesis of 3-(5-amino-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-ones in water

Indium(III) chloride was found to be an efficient catalyst for the synthesis of 3-(5-amino-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-ones by one-pot, three-component reaction of dimedone, 1H-pyrazol-5-amines and isatins in water under ultrasonic irradiation. The advantages of this method are the use of a readily available catalyst, easy workup, excellent yields, and the use of water as a solvent that is considered to be relatively environmentally benign.     

EPR Equilibration Study of the O–H Bond Dissociation Enthalpy in a Benzyl Phenolic Antioxidant

The equilibrium of the reaction galvinoxyl radical + 4,4′-methylene-bis(2,6-di-tert-butyl-phenol) (IOH) ⇆ hydrogalvinoxyl + 4,4′-methylene-bis(2,6-di-tert-butyl-phenoxyl radical) was monitored by electron paramagnetic resonance spectroscopy between 213 and 293 K. The equilibrium constant was calculated for each temperature point and correlated to T ⁻¹ applying the Van't Hoff relationship lnK _R = (−ΔH _R ⁰/RT) + (ΔS _R ⁰/R). The reaction enthalpy was found to be 12.0 ± 0.9 kJ/mol and the bond strength in IOH (BDE_(O–H)) = 340.7 ± 3.0 kJ/mol. The thermochemical stabilization of the involved phenoxyls is discussed. Authors' address: Sara N. Mendiara, Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3350, Mar del Plata 7600, Argentina     

Quantum chemical study of the (Z)-2-penten-1-ol (HOCH2–CH = CHCH2CH3) + OH + O2 reactions

ABSTRACT

The mechanism and products of the reaction of (Z)-2-penten-1-ol [(Z)-PO21] with OH radical in the presence of O₂ have been elucidated by using high-level quantum chemical methods CCSD(T)/6-311+G(d,p)//BH&;HLYP/6-311++G(d,p). The calculations clearly indicate that addition channels contribute maximum to the total reaction and H-abstraction channels can be neglected at temperatures of 220–500 K. The rate constant for the reaction of OH radical with (Z)-PO21 at 298 K is computed to be 1.22 × 10^?10 cm³ molecule^?1 s^?1, which is in stronger agreement with the previously reported experimental values. The kinetic data obtained over the temperature range 220?500 K are used to derive an non-Arrhenius expression: k = 3.69 × 10^?13 × exp(1763.7/T) cm³ molecule^?1 s^?1. For the reaction of (Z)-PO21with OH radical in the presence of O₂, the major primary reaction products found in this study are propanal [CH₃CH₂C(O)H] and glycolaldehyde [HOCH₂C(O)H], whereas formaldehyde [HC(O)H], 2-hydroxybutanal [CH₃CH₂CH(OH)C(O)H] and the epoxide P18 are anticipated to be minor products. The calculated results are consistent with the recent experimental observations.     

Critical behaviour of Sn2P2S6 and Sn2P2(Se0.28S0.72)6 crystals under high hydrostatic pressures

Basing on the temperature dependences of optical birefringence for Sn₂P₂S₆ and Sn₂P₂(Se_0.28S_0.72)₆ crystals subjected to hydrostatic pressures, we prove unambiguously that Sn₂P₂S₆ reveals a tricritical point on its (p, T)-phase diagram with the coordinates (p, T) = (4.3 kbar, 259 K), so that the second-order phase transition transforms into the first-order one whenever the pressure increases above 4.3 kbar. We also find that increasing hydrostatic pressure applied to Sn₂P₂(Se_0.28S_0.72)₆ leads to the change in the phase transition character from tricritical to first order. Further increase in the pressure up to ~2.5 kbar imposes splitting of the first-order paraelectric-to-ferroelectric phase transition into two phase transitions, a second-order paraelectric-to-incommensurate one and a first-order incommensurate-to-ferroelectric transition.     

Fluorescence of 5-hydroxy-6-methyl-(1-thietanyl-3)-pyrimidine-2,4(1 H,3 H)-dione at the transition with the second singlet-excited S 2 level to the ground level in acetonitrile solutions

The influence of the excitation wavelength on the fluorescence spectra of 5-hydroxy-6-methyl-(1-thietanyl-3)pyrimidine-2,4(1H,3H)-dione (TOMU) in acetonitrile solutions has been studied. It is found that, upon excitation of the singlet S ₂ state of TOMU luminescence, occurs from not only the first excited S ₁ level (??_max. = 350 nm, quantum yield ??(S ₁ ?? S ₀) = (4.5 ± 0.5) × 10^?3), but also at the transition from the second S ₂ level to the ground level (??_max = 305 nm, ??(S ₂ ?? S ₀) = (1.0 ± 0.1) × 10^?3).     

Synthesis,Spectral Characterization,DNA Binding Studies and Antimicrobial Activity of Co(II), Ni(II), Zn(II), Fe(III) and VO(IV) Complexes with 4-Aminoantipyrine Schiff Base of Ortho-Vanillin

A series of transition metal complexes of Co(II), Ni(II), Zn(II), Fe(III) and VO(IV) have been synthesized involving the Schiff base, 2,3-dimethyl-1-phenyl-4-(2-hydroxy-3-methoxy benzylideneamino)-pyrazol-5-one(L), obtained by condensation of 4-aminoantipyrine with 3-methoxy salicylaldehyde. Structural features were obtained from their FT-IR, UV–vis, NMR, ESI Mass, elemental analysis, magnetic moments, molar conductivity and thermal analysis studies. The Schiff base acts as a monovalent bidentate ligand, coordinating through the azomethine nitrogen and phenolic oxygen atom. Based on elemental and spectral studies six coordinated geometry is assigned to Co(II), Ni(II), Fe(III) and VO(IV) complexes and four coordinated geometry is assigned to Zn(II) complex. The interaction of metal complexes with Calf thymus DNA were carried out by UV–VIS titrations, fluorescence spectroscopy and viscosity measurements. The binding constants (K_b) of the complexes were determined as 5?×?10⁵ M^?1 for Co(II) complex, 1.33?×?10⁴ M^?1 for Ni(II) complex, 3.33?×?10⁵ M^?1 for Zn(II) complex, 1.25?×?10⁵ M^?1 for Fe(III) complex and 8?×?10⁵ M^?1 for VO(IV) complex. Quenching studies of the complexes indicate that these complexes strongly bind to DNA. Viscosity measurements indicate the binding mode of complexes with CT DNA by intercalation through groove. The ligand and it’s metal complexes were screened for their antimicrobial activity against bacteria. The results showed the metal complexes to be biologically active, while the ligand to be inactive.     

Diversity oriented heterocyclizations of pyruvic acids,aldehydes and 5-amino-<Emphasis Type="Italic">N</Emphasis>-aryl-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-4-carboxamides: catalytic and temperature control of chemoselectivity

Heterocyclization reactions of pyruvic acids, aromatic aldehydes and 5-amino-N-aryl-1H-pyrazole-4-carboxamides yielding four different types of final compounds are described. The reactions involving arylidenpyruvic acids lead with high degree of selectivity to either 4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acids or 5-[(2-oxo-2,5-dihydrofuran-3-yl)amino]-1H-pyrazoles, depending on the catalyst type or temperature regime. The interactions based on arylpyruvic acids can take place under kinetic or thermodynamic control producing 7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic acids or 3-hydroxy-1-(1H-pyrazol-5-yl)-1,5-dihydro-2H-pyrrol-2-ones, respectively.