X-substituted Phenyl Research Articles

Mono- and di-anionic coordination modes of arylazosalicylates in their bis(η5-cyclopentadienyl)titanium(IV) complexes: Syntheses and crystal structures

The bis(η5-cyclopentadienyl)titanium(IV) complexes of 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acids (H2LXASA) where the aryl group is an X-substituted phenyl ring such that X = CH, COEt, CMe, CF, CCl, CBr and N have been synthesised. Two types of titanium(IV) compounds viz. (i) [Ti(η5-C5H5)2(O2CC6H3(OH-2)(NNC6H4(H-4)-5))2] (3) and [Ti(η5-C5H5)2(O2CC6H3(OH-2)(NNC6H4(OC2H5-4)-5))2] (4), and (ii) [Ti(η5-C5H5)2(O2CC6H3(O-2)(NNC6H4(CH3-4)-5))] (5), [Ti(η5-C5H5)2(O2CC6H3(O-2)(NNC6H4(F-4)-5))] (6), [Ti(η5-C5H5)2(O2CC6H3(O-2)(NNC6H4(Cl-4)-5))] (7), [Ti(η5-C5H5)2(O2CC6H3(O-2)(NNC6H4(Br-4)-5))] (8) and [Ti(η5-C5H5)2(O2CC6H3(O-2)(NNC5H4(N-4)-5))] (9) were isolated and characterised by IR, 1H and 13C NMR spectroscopic techniques. The crystal and molecular structures of 3–9 have been determined by single crystal X-ray crystallography. Compounds 3 and 4 conform to the formula Cp2Ti(HLXASA-κO)2 with a monodentate carboxylate ligand while those of 5–9 conform to Cp2Ti(LXASA-κ2O1,O2) with the dianions chelating the titanium atoms via carboxylate-O and hydroxy-O atoms. The common feature of the molecular structures is the adoption of distorted tetrahedral geometries based (Cp)2O2 donor sets. HydroxylOH…O(carbonyl) bonding leads to supramolecular chains in the crystal of 4 but, these are absent in 3. Persistent CpCH…O(carbonyl) interactions, with the carbonyl atoms accepting two or three such interactions, lead to supramolecular chains with helical (5, 7 and 8) or linear (6 and 9) topologies; C–X…π interactions also play an important role in the packing of 6–8.

Synthesis, Reactions, and Physicochemical Characterization of Mixed Ligand Complexes of Zinc(II) Containing Schiff Bases and Pyrazoline Ligands

A series of mixed ligand complexes of Zn(II) of molecular formula Zn(C15H12N2OX)(C6H4OCHNY) where X= ‒H, ‒CH3, ‒OCH3, Cl, and Y=C7H7, C5H4N, C6H4NO2, (C15H12N2OX) = [3(2′hydroxyphenyl)-5-(4′-X-substituted phenyl) pyrazolines], and (C6H4OCHNY) = Schiff base have been synthesized. These complexes were prepared by reacting the solution of ZnCl2 in THF with sodium salts of Schiff base ligands. The resulting product was treated with sodium salts of various pyrazolines ligands in 1:1 molar ratio. The synthesized complexes have been characterized by elemental analysis (C, H, N), Volhard's method, melting point, spectroscopic (IR, UV-Visible, ESR, FAB-MS), and magnetic studies. Antibacterial and antifungal potential of complexes of these newly synthesized derivatives are also discussed.

Quantitative characterization of the global philicity patterns of common diene/dienophile pairs in cycloaddition reactions II: the interacting pair model

We present a unified model of electrophilicity and nucleophilicity that considers the electrophile/nucleophile pair in an interacting regime, thereby avoiding the arbitrariness of defining them as the opposite ends of a unique reactivity scale. The model is validated against rate coefficients for the cycloaddition of azomethine ylides towards substituted acetylenes and Michael addition of a series of 1-(X-substituted phenyl)-2-propyn-1-ones towards hydrazine.

Synthesis and Biological Evaluation of Direct Thrombin Inhibitors Bearing 4-(Piperidin-1-yl)pyridine at the P1 Position with Potent Anticoagulant Activity

The design and synthesis of a new class of nonpeptide direct thrombin inhibitors, built on the structure of 1-(pyridin-4-yl)piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (6) showing poor thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure-activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound 13b, which showed excellent fIIa inhibition (Ki = 6 nM), weak anti-Xa activity (Ki = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound 13b showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), 13b demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg(-1)), with a significant 43% prolongation of the activated partial thromboplastin time (aPTT), over controls (P < 0.05).

Michael-type Reactions of 1-(X-substituted phenyl)-2-propyn-1-ones with Alicyclic Secondary Amines in MeCN and H2O: Effect of Medium on Reactivity and Transition-State Structure

Second-order rate constants (<TEX>$k_N$</TEX>) have been measured spectrophotometrically for Michael-type reactions of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with a series of alicyclic secondary amines in MeCN at <TEX>$25.0{\pm}0.1^{\circ}C$</TEX>. The <TEX>$k_N$</TEX> value increases as the incoming amine becomes more basic and the substituent X changes form an electron-donating group (EDG) to an electron-withdrawing group (EWG). The Br<TEX>${\o}$</TEX>nsted-type plots are linear with <TEX>${\beta}_{nuc}$</TEX> = 0.48 - 0.51. The Hammett plots for the reactions of 2a-f exhibit poor correlations but the corresponding Yukawa-Tsuno plots result in much better linear correlations with <TEX>${\rho}$</TEX> = 1.57 and r = 0.46 for the reactions with piperidine while <TEX>${\rho}$</TEX> = 1.72 and r = 0.39 for those with morpholine. The amines employed in this study are less reactive in MeCN than in water for reactions with substrates possessing an EDG, although they are ca. 8 pKa units more basic in the aprotic solvent. This indicates that the transition state (TS) is significantly more destabilized than the ground state (GS) in the aprotic solvent. It has been concluded that the reactions proceed through a stepwise mechanism with a partially charged TS, since such TS would be destabilized in the aprotic solvent due to the electronic repulsion between the negative-dipole end of MeCN and the negative charge of the TS. The fact that primary deuterium kinetic effect is absent supports a stepwise mechanism in which proton transfer occurs after the rate-determining step.

Aminolysis of X-Substituted Phenyl Diphenylphosphinates: Effect of Amine Nature on Reactivity and Transition-State Structure

A kinetic study is reported for aminolysis of X-substituted phenyl diphenylphosphinates (1a-i) in 80 mol % H(2)O/20 mol % dimethyl sulfoxide at 25.0 +/- 0.1 degrees C. The Brønsted-type plot for the reactions of 2,4-dinitrophenyl diphenylphosphinate (1a) with primary amines is linear with beta(nuc) = 0.53. The reactions of 1a-i with ethylamine also result in a linear Brønsted-type plot with beta(lg) = -0.81. These beta(nuc) and beta(lg) values are slightly larger than those reported previously for the reactions of 1a with secondary amines (beta(nuc) = 0.38) and for those of 1a-i with piperidine (beta(lg) = -0.66) but typical for reactions that proceed through a concerted mechanism. It has been concluded that aminolysis of 1a-i proceed through a concerted mechanism and the nature of amines does not affect the reaction mechanism. However, the reactions with primary amines have been suggested to proceed through a later transition state (i.e., more bond formation and bond rupture in the transition state) on the basis of the larger beta(nuc) and beta(lg) values. The concerted mechanism has been further supported from the fact that the Yukawa-Tsuno plot for the reactions of 1a-i with ethylamine exhibits an excellent linear correlation with rho = 2.24 and r = 0.22. Weakly basic primary amines are less reactive than secondary amines of similar basicity. However, strongly basic ethylamine is ca. 2-fold more reactive than piperidine toward 1a, although the former is 0.35 pK(a) units less basic than the latter.

Analysis of Linear Free-Energy Relationships Combined with Activation Parameters Assigns a Concerted Mechanism to Alkaline Hydrolysis of X-Substituted Phenyl Diphenylphosphinates

A kinetic study is reported for alkaline hydrolysis of X-substituted phenyl diphenylphosphinates (1 a-i). The Brønsted-type plot for the reactions of 1 a-i is linear over 4.5 pK(a) units with beta(lg)=-0.49, a typical beta(lg) value for reactions which proceed through a concerted mechanism. The Hammett plots correlated with sigma(o) and sigma(-) constants are linear but exhibit many scattered points, while the corresponding Yukawa-Tsuno plot results in excellent linear correlation with rho=1.42 and r=0.35. The r value of 0.35 implies that leaving-group departure is partially advanced at the rate-determining step (RDS). A stepwise mechanism, in which departure of the leaving group from an addition intermediate occurs in the RDS, is excluded since the incoming HO(-) ion is much more basic and a poorer nucleofuge than the leaving aryloxide. A dissociative (D(N) + A(N)) mechanism is also ruled out on the basis of the small beta(lg) value. As the substituent X in the leaving group changes from H to 4-NO(2) and 3,4-(NO(2))(2), DeltaH++ decreases from 11.3 kcal mol(-1) to 9.7 and 8.7 kcal mol(-1), respectively, while DeltaS++ varies from -22.6 cal mol(-1) K(-1) to -21.4 and -20.2 cal mol(-1) K(-1), respectively. Analysis of LFERs combined with the activation parameters assigns a concerted mechanism to the current alkaline hydrolysis of 1 a-i.

A Kinetic Study on Michael-type Reactions of 1-(X-Substituted Phenyl)-2-propyn-1-ones with Amines: Effect of Amine Nature on Reactivity and Mechanism

Second-order rate constants have been measured spectrophotometrically for the Michael-type reaction of 1-(Xsubstituted phenyl)-2-propyn-1-ones (2a-f) with amines in <TEX>$H_2O$</TEX> at 25.0 <TEX>${\pm}$</TEX> 0.1 <TEX>${^{\circ}C}$</TEX>. A linear Brønsted-type plot is obtained with <TEX>${\beta}_{nuc}$</TEX> = 0.25 <TEX>${\pm}$</TEX> 0.02, a typical <TEX>$\beta_{nuc}$</TEX> value for reactions which proceed through a stepwise mechanism with attack of amine on the electrophilic center being the rate-determining step. Secondary alicyclic amines are found to be more reactive than isobasic primary amines. The Hammett plot for the reactions of 2a-f with morpholine is not linear, i.e., the substrate with a strong electron-donating group (e.g., 4-MeO) exhibits a negative deviation from the Hammett plot. However, the Yukawa-Tsuno plot for the same reactions exhibits an excellent linear correlation with ρ = 0.62 and r = 0.82. Thus, it has been proposed that the nonlinear Hammett plot is not due to a change in the ra te-determining step but due to ground-state stabilization through resonance interactions.

The α-Effect in Reactions of sp-Hybridized Carbon Atom: Michael-Type Reactions of 1-Aryl-2-propyn-1-ones with Primary Amines

[reaction: see text] Second-order rate constants (kN) have been measured for the Michael-type reaction of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with a series of primary amines in H2O at 25.0 +/- 0.1 degree C. A linear Brønsted-type plot with a small beta(nuc) value (beta(nuc) = 0.30) has been obtained for the reactions of 1-phenyl-2-propyn-1-one (2c) with non-alpha-nucleophile amines. Hydrazine is more reactive than other primary amines of similar basicity (e.g., glycylglycine and glycine ethyl ester) and results in a positive deviation from the linear Brønsted-type plot. The reactions of 2a-f with hydrazine exhibit a linear Hammett plot, while those with non-alpha-nucleophile amines give linear Yukawa-Tsuno plots, indicating that the electronic nature of the substituent X does not affect the reaction mechanism. The alpha-effect increases as the substituent X in the phenyl ring of 2a-f becomes a stronger electron-donating group. However, the magnitude of the alpha-effect for the reactions of 2a-f is small (e.g., kN(hydrazine)/kN(glycylglycine) = 4.6-13) regardless of the electronic nature of the substituent X. The small beta(nuc) has been suggested to be responsible for the small alpha-effect. A solvent kinetic isotope effect (e.g., kN(H2O)/kN(D2O) = 1.86) was observed for the reaction with hydrazine but absent for the reactions with non-alpha-nucleophile amines. The reactions with hydrazine and other primary amines have been suggested to proceed through a five-membered intramolecular H-bonding structure VI and a six-membered intermolecular H-bonding structure VII, respectively. The transition state modeled on VI can account for the substituent dependent alpha-effect and the difference in the solvent kinetic isotope effect exhibited by the reactions with hydrazine and other primary amines. It has been proposed that the beta(nuc) value is more important than the hybridization type of the reaction site to determine the magnitude of the alpha-effect.

X-ray crystallographic and theoretical studies of substituted phenyl 3,5-di[N-methyl] carbamoyl-1,4-dihydropyridines: Targets for Ca2+ antagonist

A series of 4(x-substituted phenyl)-1,4-dihydropyridines (x=2—CF3 (1), 2-CH3 (2), 2-OCH3 (3) and 2,4-Cl (4)) with a new substituent, the N-methylcarbamoyl (CONHCH3) group at C3 and C5 are crystallographically characterized and a comparison has been made with important conformational parameters obtained theoretically. The dihydropyridine rings are in shallow boat conformation. The phenyl substituent orientation is synperiplanar. Both the carbonyl groups are oriented anticlinal in 1, 2 and 3; but in 4, one is synclinal and the other synperiplanar with the adjacent double bond. The presence of solvent molecules in 1 (CH3OH), 2 (CH3OH), and 3 (H2O) has significantly changed the hydrogen bonding pattern. Theoretical studies at the semiempirical AM1 MO level reproduces the general features of the structures. The near planarity of the DHP ring and the orientation of the phenyl substituent make 1 and 2 encouraging targets for pharmacological, study. Crystallographic Data:1: a = 8.793(2), b = 29.962(5), c = 8.215(2) A, β = 115.28(2)°, Monoclinic, P21/c;2: a = 8.799(2), b = 15.789(3), c = 14.074(2) A, β = 100.25(2)°, Monoclinic, P21/n; 3: a = 8.347(1), b = 8.986(1), c = 13.749(2) A, α = 97.50(1), β = 94.78(1), γ = 101.38(1)° Triclinic, P1¯4: a = 12.928(3), b = 14.506(3), c = 9.740(2) A, Orthorhombic, Pca21.

The photochemical decomposition of azo compounds (a spin trap study)

Abstract The radical products formed in the photochemical decomposition of azo compounds (R 1 N 2 R 2 ) dissolved in various solvents were investigated. Nitrosodurene, 2-methyl-2-nitroso-propane and 5,5-dimethyl-1-pyrroline- N -oxide (DMPO) were used as spin traps. In the first group of azo compounds, in which R 1 was X-substituted phenyl and R 2 was SO 3 Na or SO 2 Ph, the spin adducts of R 1 and R 2 were observed. In the second group of azo compounds (R 1 = R 2 = R, where R was a tertiary-substituted carbon), the carbon-centred radicals R . were formed and trapped if irradiated in an argon atmosphere. When irradiated in air, the initially formed radicals R . were converted to oxygen-centred radicals (presumably peroxy or alkoxy) and trapped by DMPO; . OH radicals were also observed as further intermediates.

Crystal structures and pharmacologic activities of 1,4-dihydropyridine calcium channel antagonists of the isobutyl methyl 2,6-dimethyl-4-(substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nisoldipine) series.

A series of isobutyl methyl 2,6-dimethyl-4-(X-substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylates (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, 4-F, 2-CF3, 3-CF3, and 4-Cl) related to and including nisoldipine (X = 2-NO2) has been synthesized, their solid-state structures determined by X-ray analysis (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, and 4-F), and their pharmacologic activities determined, as the racemic compounds, against [3H]nitrendipine binding and K+-depolarization-induced tension responses in intestinal smooth muscle as measures of Ca2+ channel antagonist activity. Comparisons of structure are presented to previously analyzed 1,4-dihydropyridines. The degree of 1,4-dihydropyridine ring puckering is dependent on the nature and position of the phenyl ring substituent and the adopted interring conformation. Different ester substituents affect 1,4-dihydropyridine ring puckering to a small extent in most cases. Pharmacologic and radioligand binding activities for the nine compounds studied show a parallel dependence on phenyl ring substituent, but the compounds are approximately 10-fold more active in the radioligand binding assay than in the pharmacologic assay. Consistent with a previous report for the nifedipine series (Fossheim et al. J. Med. Chem. 1982, 25, 126), pharmacologic activity increases with increasing 1,4-dihydropyridine ring planarity.