Intermediate Alkyl Research Articles

Palladium‐Catalyzed Oxygenation of Unactivated sp3 C—H Bonds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Identification of neutral 4- O-alkyl quinolone nonpeptide GnRH receptor antagonists

A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.

Palladium-Catalyzed Oxygenation of Unactivated sp3 C−H Bonds

This communication describes a new palladium-catalyzed method for the oxygenation of unactivated sp3 C-H bonds. A wide variety of alkane substrates containing readily available oxime and/or pyridine directing groups are oxidized with extremely high levels of chemo-, regio-, and in some cases diastereoselectivity. The substrate scope of these reactions is discussed, and the high selectivities are rationalized on the basis of the requirements of putative palladium alkyl intermediates.

4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as sigma receptor ligands with agonist sigma2 activity.

Several 1-cyclohexylpiperazine derivatives related to sigma(2) receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (33, K(i) = 0.34 nM) were synthesized and tested in radioligand binding assays, to attempt a structure-affinity relationship study. Intermediate alkyl chain length and methoxyl group position on the tetralin nucleus were varied. A few naphthalene analogues were also prepared. High affinities were found in sigma(2) receptor binding for almost all compounds, some of which displayed K(i) values in subnanomolar range, but low sigma(2)/sigma(1) selectivities were found. The highest sigma(2) affinities were displayed by compounds with an intermediate alkyl chain of three (32 and 43) or five methylenes (39 and 46). Quite high sigma(1) receptor affinity was found for compounds with a four-methylene chain; 36 (K(i) = 0.036 nM) and 45 (K(i) = 0.22 nM) displaying good sigma(1)/sigma(2) selectivity (406- and 139-fold, respectively). Moreover, homologues of compound 33 displayed also satisfactory selectivities over dopamine D(2)-like, serotonin 5-HT(3), and adrenergic alpha(1) receptors. These compounds and a few others were tested in the inhibition of the electrically evoked contractions in guinea pig bladder and were demonstrated to be full sigma(2) agonists. The activity values correlated well to the affinity scale (EC(50) in microM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.

Design of a Novel Molecular-Imprinted Rh−Amine Complex on SiO2and Its Shape-Selective Catalysis for α-Methylstyrene Hydrogenation

A new molecular-imprinted Rh−amine complex with a template-shaped cavity acting as a shape-selective reaction space was prepared by metal-complex attaching and molecular imprinting techniques on a SiO2 surface. Rh(η3-C3H5)3 reacted with SiO2, and the precursor was attached on the surface to form a bidentate structure Rh(C3H5)(OSi)2. α-Methylbenzylamine with a shape similar to that of a half-hydrogenated alkyl intermediate of α-methylstyrene coordinated to the attached Rh as a template ligand. Then SiO2−matrix overlayers were stacked on the surface by the hydrolysis−polymerization of Si(OCH3)4 surrounding the attached Rh complexes with the amine template. Final evacuation at 373 K promoted the removal of the template ligand from the Rh complex embedded in the surface pore of the SiO2−matrix overlayers. All the structures of the attached Rh complexes were characterized by the means of ICP, XPS, ESR, FT-IR, solid-state MAS NMR, EXAFS, DFT, GC, and H2 adsorption. The imprinted Rh complex has an unsaturated structure Rh(amine)(OSi)(HOSi) and exhibits high catalytic activity for α-methylstyrene hydrogenation. On the contrary, the other supported Rh complexes before imprinting are inactive for the hydrogenation. Furthermore, the active Rh complex is durable under the reaction condition despite the unsaturated conformation which usually tends to gather each other. The imprinted cavity locating on the active Rh center acts as a shape-selective reaction space for α-methylstyrene. The inhibition of the hydrogenation by the use of seven amines with different shapes demonstrates the shape-selective behavior of the imprinted Rh complex discriminating one methyl group and the position of the phenyl ring.

In Situ Examination of the Structure of Model Reversed-Phase Chromatographic Interfaces by Sum-Frequency Generation Spectroscopy

Model reversed-phase chromatographic interfacial systems were examined using sum-frequency generation (SFG) spectroscopy to study the effect of solvent on the structure and conformation of the stationary phase. Monolayers formed from mixed C18 and C1 alkysilanes (both polymeric octadecyltrichlorosilane-methyl trichlorosilane mixed monolayers and monomeric octadecyldimethylchlorosilane-trimethylchlorosilane mixed monolayers) on fused silica were examined in contact with air, deuterated acetonitrile (CD3CN), D2O, and mixtures of CD3CN and D2O. When mixed composition (C18 and C1) monolayers were examined, significant disorder was observed in the alkyl chains for all solvents examined at intermediate alkyl chain densities for the polymeric materials, and at all chain densities for the monomeric materials. Maximum order for intermediate polymeric chain densities was found to occur in contact with 40−50 vol % D2O solutions. These results indicate that solvent microheterogeneity has a large effect on alkyl chain...

Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D(3) receptor ligands.

The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D(4) receptor ligand, has been modified searching for structural features that could lead to D(3) receptor affinity. Changes in the aromatic ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D(3) affinity (K(i) = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D(3) receptor and decreased the D(4) affinity (compounds 18-26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way, we identified several high-affinity D(3) ligands (0.13 nM < K(i)'s < 4.97 nM) endowed with high selectivity over D(2), D(4), 5-HT(1A), and alpha(1) receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of (11)C labeling in the O-methyl position.

Syntheses of 3-substituted 2,3-dihydrobenzofuranes, 1,2-dihydronaphtho(2,1-b)furanes, and 2,3-dihydro-1H-indoles by tandem ring closure-S(RN)1 reactions.

3-Substituted 2,3-dihydrobenzofuranes (7a-c), 1,2-dihydronaphtho(2,1-b)furanes (10a-c), and N-substituted 2,3-dihydro-1H-indoles (8a-c, 9a,b) are obtained in very good yields by S(RN)1 photostimulated reactions in liquid ammonia from adequate haloaromatic compounds ortho-substituted with a suitable double bond (3a,b; 4a,b; 5a; 6a,b) and Me3Sn-, Ph2P-, and -CH2NO2 anions. The novelty of the work involves the versatile application of a 5-exo ring closure process during the propagation cycle of the S(RN)1 reaction; the alkyl radical intermediates formed react with the nucleophiles to afford the ring closure-substituted heterocycles. The factors governing the observed product distribution are discussed.

The surface chemistry of alkyl and arylphosphate vapor phase lubricants on Fe foil

The surface chemistry of tributylphosphate (TBP) and tricresylphosphate (TCP) on a polycrystalline Fe surface was studied using temperature programmed reaction spectroscopy and Auger electron spectroscopy to illustrate some of the initial steps in the reaction mechanisms of alkyl and arylphosphate vapor phase lubricants. During heating, TBP [(C 4H 9O) 3P=O] adsorbed on the Fe surface decomposes via C–O bond scission to give butyl surface intermediates [C 4H 9–] that react via β-hydride elimination to desorb as 1-butene [CH 3CH 2CH=CH 2] and H 2 without appreciable carbon deposition onto the surface. The thermal decomposition of 1-iodobutane [I-C 4H 9] on Fe was observed to proceed via the same β-hydride elimination mechanism. In contrast to tributylphosphate, meta-tricresylphosphate ( m-TCP) [(CH 3–C 6H 4O) 3P=O] decomposes on Fe via P–O bond scission to produce methylphenoxy intermediates [CH 3–C 6H 4O–]. During heating to 800 K, methylphenoxy intermediates either desorb as m-cresol [CH 3–C 6H 4–OH] via hydrogenation or decompose further to generate tolyl intermediates [CH 3–C 6H 4–]. Some of the tolyl intermediates desorb as toluene [CH 3–C 6H 5] via hydrogenation but the majority decompose resulting in H 2 and CO desorption and carbon deposition onto the Fe surface. The P–O bond scission mechanism of m-TCP was verified by showing that the temperature programmed reaction spectra of m-cresol yield products that are almost identical to those of m-TCP. These results provide insight into the origin of the differences in the performance of alkyl and arylphosphates as vapor phase lubricants. The alkylphosphates decompose via alkyl intermediates that readily undergo β-hydride elimination and desorb into the gas phase as olefins, thus removing carbon from the surface. In contrast, the arylphosphates generate aryloxy intermediates by P–O bond scission and aryl intermediates by further C–O bond scission. Neither of these intermediates can undergo β-hydride elimination and thus they decompose to deposit carbon onto the Fe surface. The higher efficiency for carbon deposition may be the primary reason for the superior performance of the arylphosphates over alkylphosphates as vapor phase lubricants.

Synthesis of new 3-methylthio-5-aryl-4-isothiazolecarbonitriles with broad antiviral spectrum

The isothiazole derivative 3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile, coded IS- 50, which in previous studies had exhibited a broad antipicornavirus spectrum of action, was selected as the model for the synthesis of a new series of 3-methylthio-5-aryl-4-isothiazolecarbonitriles. These compounds were prepared in good yield (from 66 to 82%) by alkylation of 3-methylthio-5-(4-hydroxyphenyl)-4-isothiazolecarbonitrile with suitable bromides in the presence of acetone; only the 4-cyanophenoxy derivatives were obtained in a yield of less than 30%. All the compounds were screened against a panel of 17 representative human rhinovirus (HRV) serotypes belonging to both A and B groups, enteroviruses polio 1, ECHO 9 and Coxsackie B1, cardiovirus EMC, measles virus, and herpes simplex virus type 1 (HSV-1). Our results demonstrate that HRV 86 (group A) and HRVs 39 and 89 (group B) are the rhinovirus serotypes more susceptible to the action of these compounds. Isothiazole derivatives with a longer intermediate alkyl chain exhibited good activity against polio 1 and ECHO 9. The compound bearing a butyl group between the two phenoxy rings showed the lowest IC 50 against Coxsackie B1 and measles viruses. No activity against HSV-1 was detected with any of the compounds screened.

Outstanding Mechanistic Questions in Heterogeneous Catalysis

This Feature Article summarizes key results from our studies on the kinetics of chemical reactions on solid surfaces as they relate to heterogeneous catalysis. Emphasis is placed on the identification of specific issues of relevance to the design of catalytic processes, particularly the need for highly selective catalytic reactions. From the kinetic point of view, issues of selectivity translate into controlling relative activation energies within a small fraction of their absolute value. In the case of catalytic reforming of hydrocarbons, the nature of the final products is determined by the regioselectivity of an early dehydrogenation from surface alkyl intermediates (from the α, β, or γ position), a step greatly affected by the electronic structure of the metal used as catalyst. In the case of partial oxidation reactions, both the geometry of the local ensemble of surface atoms in the catalytic site and the presence of surface species such as hydroxide groups play determining roles in defining selectivity. A third factor is adsorption geometry, which often varies with changing reaction conditions: variations in concentration of the modifier in chiral catalysis, for example, may lead to dramatic changes in the enantioselectivity of hydrogenation processes. High pressures can induce new types of bonding between adsorbates and surfaces as well, opening new mechanistic routes for catalytic reactions: the hydrogenation of olefins, where π bonding occurs on top of strongly bonded carbonaceous deposits, falls into this category. Finally, the inhomogeneous distribution of adsorbates within the surface can be manifested in the formation of local islands, and those can promote specific catalytic reactions; witness, for instance, the effect of islanding on reactivity in the catalytic oxidation of carbon monoxide and during the catalytic reduction of nitrogen oxide.

Teaching a palladium polymerization catalyst to mono-oxygenate olefins

Catalyst systems consisting of a palladium(II) diphosphine complex with weakly or non-coordinating counterions are efficient catalysts for the hydrocarbonylation of olefins. With these catalyst systems, the oxo-synthesis can be fully exploited to produce, at will, aldehydes/alcohols by hydroformylation or monoketones by hydro-acylation of olefins. The reactions described here constitute the first examples of selective formation of ketones by hydrocarbonylation of higher olefins and the first examples of Pd catalyzed hydroformylation of olefins. Variation of ligand, anion and/or solvent can be used to steer the reaction selectively towards aldehydes/alcohols, ketones or oligoketones. Non-coordinating anions and arylphosphine ligands produce primarily (oligo)ketones; increasing ligand basicity shifts selectivity towards monoketones, while increasing ligand basicity and/or increasing anion coordination strength leads to high selectivity for hydroformylation products, aldehydes and alcohols. For the mechanisms of the aldehyde-producing step, we propose protonation of Pd(II)-acyl intermediates, assisted by the coordination of the anion, followed by reductive elimination of the aldehyde and heterolytic dihydrogen cleavage. For selective saturated monoketone formation we propose protonation at the Pd(II)-alkyl stage, now assisted by chelating carbonyl coordination followed by reductive elimination of the ketone and heterolytic dihydrogen cleavage. Unsaturated ketone formation involves g -hydride elimination from the same Pd(II)-alkyl intermediates.

On the Mechanism of the Hydroxycarbonylation of Styrene with Palladium Systems

We present a review concerning the mechanism involved in the hydroxycarbonylation of styrene. We discuss the intermediates proposed in the literature, the effect of the acidic medium, the reactivity and kinetics, as well as the results of theoretical calculations on hydroxycarbonylation and related reactions. We have performed an in situ high-pressure NMR study to obtain more insight into the mechanisms that control the regioselectivity and have assessed how this is affected by the phosphorus ligand and the catalyst precursor. We observed palladium hydride and palladium acyl species and we suggest a catalytic cycle involving palladium hydride, palladium alkyl, and palladium acyl intermediates.

Phosphinofenchol or metastable phosphorane? Phosphorus derivatives of fenchol.

Not the expected phosphinofenchol 1 but phosphorane 2 is obtained after reaction of 2-lithio(diphenylphosphino)benzene with (-)-fenchone. Surprisingly, ONIOM(B3LYP/6-31G*:UFF) computations of 1 and 2 as well as B3LYP analyses of smaller model systems point to a lower thermodynamic stability of phosphoranes relative to their isomeric alkoxyphosphines. An analogue inherent instability is computed for the methylphosphorane 10, which is also synthesized and characterized by X-ray analysis. Decreasing ring size in cyclic phosphoranes, that is, from five- to four-membered ring systems, destabilizes cyclic phosphoranes even more. This computational prediction is verified experimentally by reaction of lithiomethyl(diphenylphosphine) with (-)-fenchone and subsequent isolation of the corresponding phosphinofenchol. Protonation or alkylation of phosphoranide intermediates can account for the formation of metastable phosphoranes.

Hydrocarbon selectivity model for the slurry phase Fischer–Tropsch synthesis on precipitated iron catalysts

A new hydrocarbon product distribution model for Fischer–Tropsch-synthesis (FTS) reaction has been developed. The model is based on the assumption that there are two types of active sites on the catalyst surface: type-1, where growth of hydrocarbon intermediates occurs, and type-2, where reversible readsorption of 1-olefins occurs. The readsorbed 1-olefins form alkyl intermediates, C n H 2 n+1 , on the surface, which in turn can participate in several reactions: chain growth propagation, hydrogenation to n-paraffins, and dehydrogenation to 2-olefins. Chain growth is considered on the basis of methylene monomer (CH 2) insertion mechanism. Steady-state mass balances for adsorbed intermediates C 1–C 50 and equations for the product formation rates were derived. The model has been tested using results from experiments conducted over long periods of time under industrially relevant conditions in a slurry reactor. The model predictions provide information on hydrocarbon product distribution, 2-olefin content and total olefin content as a function of carbon number. The curved line for the distribution of paraffins and olefins can be fitted well with the proposed hydrocarbon selectivity model, over the entire range (C 1–C 50) of carbon numbers. The kinetic model proposed in this paper can be used for interpretation of experimental data, comparison of performance of different catalysts, and reactor modelling and simulation studies.

A structure-affinity relationship study on derivatives of N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a high-affinity and selective D(4) receptor ligand.

N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (1), a high-affinity and selective dopamine D(4) receptor ligand, was chosen as a lead, and structural modifications were done on its amide bond and on its alkyl chain linking the benzamide moiety to the piperazine ring and by preparing some semirigid analogues. The binding profile at dopamine D(4) and dopamine D(2), serotonin 5-HT(1A), and adrenergic alpha(1) receptors of 16 new compounds was determined. From the results emerged that the modification of the amide bond and the elongation of the intermediate alkyl chain caused a decrease in dopamine D(4) receptor affinity. All prepared semirigid analogues displayed D(4) receptor affinity values in the same range of the opened counterparts.

Towards a chemical understanding of the Fischer–Tropsch reaction: alkene formation

A new understanding of the Fischer–Tropsch reaction to alkenes on a chemical basis is developed. This uses the ideas of organometallic chemistry and homogeneous catalysis derived from model systems, combined with the results of experiments using 13CH 13CH–X (X = H, Br, etc.) compounds as probes to investigate the heterogeneously catalysed hydrogenation of CO over metal catalysts. The labelled probe experiments on the hydrogenation of carbon monoxide, to alkenes and alkanes over heterogeneous catalysts under Fischer–Tropsch (FT) conditions, have confirmed that the key species in the reactions are surface methylenes (formed from adsorbed CO) which are polymerised. However, new evidence favours coupling of surface methylenes with alkenyl intermediates rather than with the alkyl intermediates which were previously proposed. Mass-spectroscopic investigations of the hydrocarbon products show the incorporation of two 13C atoms when 13C 2-vinyl probes are added over rhodium, ruthenium or cobalt catalysts; for Ru and Co the hydrocarbons also contain significant amounts of 13C 1 arising from cleavage of the vinylic probe. Iron is a poorer catalyst under these conditions but resembles rhodium. The involvement of vinyl/alkenyl intermediates has led to the elaboration of a new alkenyl cycle for the FT reaction, based on the principles of organo-transition metal reactions developed during studies of the coupling of organic ligands on model complexes. The quantitative data from the probe reactions can conveniently be mathematically modeled using a simple steady state approach; good agreement between experiment and theory is found. Oxygenates such as ethanol are also formed in the Fischer–Tropsch reactions, especially over Rh, but their origin is not yet clear.

Free radical mechanism for photoinduced isonitrile–nitrile isomerization in solution

The photoinduced isomerization reaction in benzene solution from RNC to RCN was found to follow a free radical chain mechanism, where R represented –C(CH 3) 3, –CH(CH 3) 2, –CH 3, –CH 2CH 3, and –CH 2CH 2CH 3, respectively. The alkyl radical intermediates R. in the isomerization reaction were detected by electron spin resonance (ESR) spectroscopy in combination with spin traps PBN and ND. Initiation of the isomerization in condensed-phase can be explained by a homolytic bond breaking between R group and nitrogen atom in the photo-irradiated isonitrile derivatives at room temperature. The products analysis by GC was also supported the conclusion of free radical chain mechanism.

Synthesis and mesophase behaviour of mesogens bearing omega, alpha, alpha-trihydroperfluoroalkoxy end tails

One series of two-ring and two series of three-ring liquid crystal compounds, all containing omega, alpha, alpha-trihydroperfluoroalkoxy terminal tails, were prepared and characterized by IR, NMR, MS and elemental analysis. Their phase transition behaviour was investigated by DSC and polarizing optical microscopy. Biphenylene derivatives with the omega, alpha, alpha-trihydroperfluoroalkoxy end group form a stable smectic A phase. In the three-ring system, biphenylene ester compounds exhibit a smectic phase without a nematic phase. The compounds exhibit smectic A and smectic C phases when the terminal groups are intermediate length alkyl and fluorinated alkyl chains. Mesogens with fluorinated tails have a broader smectic C phase than the non-fluorinated mesogens.

Comparative investigation of the regioselectivity in styrene and α-methylstyrene hydroalkoxycarbonylation as a function of palladium catalyst structure

Catalytic pathways of the styrene and α-methyl-styrene hydroalkoxycarbonylation in the presence of Pd(PPh3)2Cl2 and Pd(PPh3)2Cl2/SnCl2 catalyst precursors have been suggested. As a method, deuterium labelling with EtOD has been applied and it resulted in mixtures of mono- and polydeuterated reaction products, detected and determined by NMR methods. Comparative elucidation of the mechanisms governing these systems does support the assumption that the hydrido route is operative. The different behaviour of the metal–alkyl intermediates accounts for the observed strong influence of catalyst and substrate structure on regioselectivity.