Intermediate Alkyl Research Articles

Origins of the Selectivity for Borylation of Primary over Secondary C−H Bonds Catalyzed by Cp*-Rhodium Complexes

Detailed experimental and computational studies of the high selectivity for functionalization of primary over secondary sp(3) C-H bonds in alkanes by borane reagents catalyzed by Cp*Rh complexes are reported. Prior studies have shown that Cp*Rh(X)(Bpin) (X = H or Bpin), generated from Cp*Rh(H)(2)(Bpin)(2) and Cp*Rh(H)(2)(Bpin)(3), are likely intermediates in these catalytic reactions. To allow analysis of the system by H/D exchange, the current studies focused on reactions of Cp*Rh(D)(2)(Bpin)(2) through the 16-electron species Cp*Rh(D)(Bpin). Density functional theory (DFT) calculations of the reaction between Cp*Rh(H)(BO(2)C(2)H(4)) and the primary and secondary C-H bonds of propane indicate that the lowest energy pathway for C-H bond cleavage occurs to form an isomer in which the alkyl and boryl groups are trans to each other, while the lowest energy pathway for functionalization of the primary C-H bond occurs by formation of the isomer in which these two groups are cis to each other. The barrier for formation of the rhodium complex by cleavage of secondary C-H bonds is higher than that by cleavage of primary C-H bond. The alkyl intermediates are formed reversibly, and steric effects cause the barrier for B-C bond formation from the secondary alkyl intermediate to be higher than that from the primary alkyl intermediate. Experimental studies are consistent with this computational analysis. H/D exchange occurs between (Cp*d(15))Rh(D)(2)(Bpin)(2) and n-octane, indicating that C-H bond cleavage occurs reversibly and occurs faster at primary over secondary C-H bonds. The observation of small amounts of H/D exchange into the secondary C-H bonds of linear alkanes and the clear observation of H/D exchange into the secondary positions of cyclic alkanes without formation of products from functionalization are consistent with the high barrier calculated for B-C bond formation from the secondary alkyl intermediate. A series of kinetic experiments are consistent with a mechanism for H/D exchange between (Cp*d(15))Rh(D)(2)(Bpin)(2) and n-octane occurring by dissociation of borane-d(1) to form (Cp*d(15))Rh(D)(Bpin). Thus, the origin of the selectivity for borylation of primary over secondary C-H bonds is due to the cumulative effects of selective C-H bond cleavage and selective C-B bond formation.

Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors

This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Aβ40 was observed.

ChemInform Abstract: Nickel Complexes of a Pincer Amidobis(amine) Ligand: Synthesis, Structure, and Activity in Stoichiometric and Catalytic C—C Bond‐Forming Reactions of Alkyl Halides.

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Nickel Complexes of a Pincer Amidobis(amine) Ligand: Synthesis, Structure, and Activity in Stoichiometric and Catalytic CC Bond‐Forming Reactions of Alkyl Halides

The synthesis, properties, and reactivity of nickel(II) complexes of a newly developed pincer amidobis(amine) ligand ((Me)NN(2)) are described. Neutral or cationic complexes [((Me)NN(2))NiX] (X = OTf (6), OC(O)CH(3) (7), CH(3)CN (8), OMe (9)) were prepared by salt metathesis or chloride abstraction from the previously reported [((Me)NN(2))NiCl] (1). The Lewis acidity of the {((Me)NN(2))Ni} fragment was measured by the (1)H NMR chemical shift of the coordinated CH(3)CN molecule in 8. Electrochemical measurements on 1 and 8 indicate that the electron-donating properties of NN(2) are similar to those of the analogous amidobis(phosphine) (pnp) ligands. The solid-state structures of 6-8 were determined and compared to those of 1 and [((Me)NN(2))NiEt] (3). In all complexes, the (Me)NN(2) ligand coordinates to the Ni(II) ion in a mer fashion, and the square-planar coordination sphere of the metal is completed by an additional donor. The coordination chemistry of (Me)NN(2) thus resembles that of other three-dentate pincer ligands, for example, pnp and arylbis(amine) (ncn). Reactions of 2 with alkyl monohalides, dichlorides, and trichlorides were investigated. Selective C-C bond formation was observed in many cases. Based on these reactions, efficient Kumada-Corriu-Tamao coupling of unactivated alkyl halides and alkyl Grignard reagents with 1 as the precatalyst was developed. Good yields were obtained for the coupling of primary and secondary iodides and bromides. Double C-C coupling of CH(2)Cl(2) with alkyl Grignard reagents by 1 was also realized. The scope and limitations of these transformations were studied. Evidence was found for a radical pathway in Ni-catalyzed C-C cross-coupling reactions, which involves Ni(II) alkyl intermediates.

Chemical, physical and electrical properties of aged dodecylbenzene 2: thermal ageing of single isomers in air

The linear isomer of dodecylbenzene (DDB), 1-phenyldodecane, was aged at temperatures of 105 and 135 degC in air and the resultant products were analyzed using a range of analytical techniques. On ageing, the 1-phenyldodecane darkened, the acid number, dielectric loss and water content increased and significant oxidation peaks were detected in the infrared spectrum. When aged in the presence of copper, a characteristic peak at 680 nm was also detected by UV/visible spectroscopy but, compared with previous studies of a cable-grade DDB, the strength of this peak was much increased and no appreciable precipitate formation occurred. At the same time, very high values of dielectric loss were recorded. On ageing in the absence of copper, an unusually strong infrared carbonyl band was seen, which correlates well with the detection of dodecanophenone by gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. It was therefore concluded that the ageing process proceeds via the initial production of aromatic ketones, which may then be further oxidized to carboxylic acids. In the presence of copper, these oxidation products are present in lower quantities, most of these oxidation products being combined with the copper present in the oil to give copper carboxylates. The behavior is described in terms of a complex autoxidation mechanism, in which copper acts as both an oxidizing and a reducing agent, depending on its oxidation state and, in particular, promotes elimination via the oxidation of intermediate alkyl radical species to carbocations.

Rhodium-catalyzed deuterioformylation of the ketal-masked β-isophorone: Evidence for a tertiary alkyl rhodium intermediate as a precursor of the main reaction product acetaldehyde derivative

The rhodium-catalyzed deuterioformylation of the ketal-masked β-isophorone 7,9,9-trimethyl-1,4-dioxa-spiro[4.5]dec-7-ene ( 1) under 100 atm of syngas, at 100 °C, gives the trideuterated acetaldehyde derivative 2 as the main product, originating from a primary alkyl rhodium intermediate c via isomerization of the tertiary one a. Theoretical calculations indicate that secondary and tertiary rhodium alkyl intermediates are formed in a similar amount and hence their evolution to aldehydes occurs with different rates.

Mechanistic approaches to palladium-catalyzed alkene difunctionalization reactions

Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.

Infrared Spectroscopy Characterization of the Chemistry of C4Hydrocarbons on Pt(111) Single-Crystal Surfaces

The uptake and thermal chemistry of a number of C4 hydrocarbons on Pt(111) single-crystal surfaces were characterized by reflection−absorption infrared spectroscopy (RAIRS). The compounds studied include butane, 1-butene, cis-2-butene, trans-2-butene, and 1,3-butadiene as well as 1-iodobutane, 2-iodobutane, 1-bromo-2-butene, and 1-bromo-3-butene, precursors for the formation of corresponding alkyl and alkenyl intermediates. Much of the chemistry reported here agrees with previous work on similar systems, and conforms with the general idea of hydrogenation, dehydrogenation, and H−D exchange reactions occurring by single hydrogen incorporation and elimination steps according to the so-called Horiuti Polanyi mechanism. In addition, though, a couple of surprising observations are presented of particular relevance to the mechanism of carbon−carbon double bond isomerizations. In particular, it was seen that although the isomerization of trans- to cis-2-butene is more favorable and occurs at lower temperatures than the reverse cis-to-trans conversion, β-hydride elimination from the common 2-alkyl intermediate produces trans-2-butene preferentially. This indicates that it is the relative adsorption energy of the alkene what determines selectivity in these reactions.

The Synthesis of C‐3β Functionalized Indoles via a Hydroboration/Suzuki—Miyaura Coupling Sequence.

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The synthesis of C-3β functionalized indoles via a hydroboration/Suzuki–Miyaura coupling sequence

A method for the functionalization of C-3β of vinyl indoles is described. The procedure involves a hydroboration, followed by a Suzuki–Miyaura cross-coupling with the intermediate alkyl borane. Triflates, bromides, and iodides are suitable coupling partners, allowing access to a variety of elaborated indole compounds.

Specifics of the mechanism of formation and molecular-mass distribution of hydrocarbons in fischer-tropsch synthesis on Co/SiO2 Mn+ catalysts

It was shown that molecular-mass distributions of hydrocarbons produced over Co/SiO2 · Fe(III), Co/SiO2 · Cr(III), and Co/SiO2 · Zn(II) catalysts are described well by a mathematical model proposed earlier for rationalizing the distribution of products formed in the presence of a Co/SiO2 · Zr(IV) catalyst with a probability α. This model is based on the concept that α1-hydrocarbons are produced from alkyl intermediates and α2-hydrocarbons (α1 < α2) are formed from alternative surface compounds. The primary α1-products are olefins, and ethylene is involved in chain growth with a lower value of α. Reasons for the speculation that the difference in the pattern of molecular-mass distribution of hydrocarbons produced on cobalt and iron catalysts is due to the difference in the mechanism of formation of α1-hydrocarbons are given.

Facile Functionalization of a Metal Carbon Bond by O-Atom Transfer

The facile conversion of M-R to M-OR that could be useful for the functionalization of electron-rich metal alkyl intermediates is shown to proceed via a Baeyer-Villiger-type pathway involving a nonredox, electrophilic, O-atom insertion in reactions with non-peroxo O-donors.

A density functional theory study of the hydrogenolysis reaction of CH 3SH to CH 4 on the catalytically active (100) edge of 2H-MoS 2

The breaking of the C S bond is a crucial step in hydrodesulfurization, the removal of the sulfur atom from sulfur-containing molecules in crude oil. Thus the hydrogenolysis reaction of CH 3SH to CH 4 was studied by means of density functional theory on the catalytically active (100) edge of 2H-MoS 2, with and without Co and Ni promoter atoms. Thiol adsorption, C S bond breaking, and the formation and desorption of CH 4 were investigated with different sulfur and hydrogen surface coverages. CH 3SH first adsorbs molecularly with its S atom in a bridging mode between two surface Mo atoms, followed by S H bond cleavage with moderate activation energy. The subsequent concerted C S bond breaking and CH 4 formation occurs through a reaction of the adsorbed CH 3S group with the H atom of a neighbouring SH group at the molybdenum sulfide surface. Sulfur atoms, hydrogen atoms adsorbed on sulfur atoms, and promoter atoms (Co and Ni) at the catalyst surface weaken the bonding of adsorbed CH 3S and lower the energy barrier for CH 4 formation. Although the reactions of thiols on the metal sulfide surface are similar to reactions on metal surfaces, the chemistry is different. The reactions occur between intermediate alkyl and hydrogen fragments bonded to sulfur atoms, not to metal atoms.

Evidence for formation and different evolution of tertiary rhodium alkyl intermediates under rhodium-catalyzed deuterio-(hydro)formylation of 1-( n-pyridyl)-1-phenylethenes

Deuterioformylation of the vinylidenic substrates 1-( n-pyridyl)-1-phenylethenes, in the presence of phosphine modified Rh 4(CO) 12 as catalyst precursor, was carried out at 100 atm of CO and D 2 (1:1), 80 °C and at partial and complete substrate conversion. The direct 2H NMR analysis of the crude reaction mixture led to the conclusion that, under these conditions, the branched alkyl rhodium intermediate is formed almost exclusively. It can: (i) β-eliminate, (ii) undergo migratory insertion on CO or (iii) oxidative addition of deuterium to various extents depending on the position of the nitrogen atom with respect to the olefinic double bond, thus accounting for the observed different chemo- and regioselectivities.

α,β-Unsaturated and cyclopropyl acyl radicals, and their ketene alkyl radical equivalents. Ring synthesis and tandem cyclisation reactions

Treatment of the alpha,beta-unsaturated selenyl esters 12 and 14 with Bu(3)SnH-AIBN produces the corresponding 2-cyclohexenones 13 and 15 respectively via presumed alpha-ketene alkyl radical intermediates, viz. 10. By contrast, the 2,7-diene esters 34 and 39 undergo tandem radical cyclisations producing diquinanes, e.g.(76%), and the corresponding allene-substituted alpha,beta-unsaturated selenyl ester 48 gives the cyclooctadienone 56 on treatment with Bu(3)SnH-AIBN in refluxing benzene. The selenyl ester 19 derived from chrysanthemic acid produces a mixture of the gamma,delta-unsaturated aldehyde 22 and the corresponding dimer 25a on treatment with Bu(3)SnH-AIBN. Furthermore, in the presence of methanol the only product from this reaction was the bis(methyl ester) dimer 25b, thereby lending further credence to the involvement of ketene alkyl radical intermediates in these reactions, and in the aforementioned reactions involving 2,6- and 2,7-diene selenyl esters. Treatment of the cyclopropane selenyl esters and , containing keto- and oxy-group functionality in their side-chains, with Bu(3)SnH-AIBN led to excellent syntheses of the enol lactone 66 (76%) and the trans-fused bicyclo[6.1.0]nonane 67 (80-95%) respectively.

Zr-Catalyzed Coupling Reaction of Alkyl Halides, Tosylates, and Sulfates with β-Phenethyl Grignard Reagents via Styrene-Zirconate Intermediates

β-Phenethylmagnesium chlorides react with alkyl halides, tosylates, and sulfates in the presence of a catalytic amount of Cp 2 ZrCl 2 to afford 2-arylalkanes via alkylation of styrene-zirconate intermediates at the benzylic position. Competitive reaction using mixtures of alkyl halides (alkyl-X; X = F, Cl, Br) showed that the reactivities of the halides increase in the order of alkyl-Cl < alkyl-F < alkyl-Br with the relative rates of 1: ] 9:428.

Tandem cyclisations involving α-ketenyl alkyl radicals. New syntheses of the natural triquinanes pentalenene and modhephene

New synthetic approaches to the angular and propellane sesquiterpene triquinanes (+/-)-pentalenene 2 and (+/-)-modhephene 3, respectively, are described. The syntheses are based on tandem cyclisations involving alpha-ketene alkyl radical intermediates produced from alpha,beta-unsaturated acyl radical species, as highlighted in Schemes 2 and 4.

Competing Reactions of Secondary Alcohols with Sodium Hypochlorite Promoted by Phase-Transfer Catalysis

With aqueous hypochlorite and a phase transfer catalyst, secondary alcohols undergo hitherto unreported free radical reactions that compete with and effectively limit traditional ketone syntheses. Product mixture profiles are determined by reactant ratios, organic cosolvent, and availability of oxygen to the system. Under argon, over half of substrate alcohols, PhCH(OH)R, are converted to benzaldehyde and free radical products through beta-scission of intermediate alkyl hypochlorites. Secondary alcohols with R containing three or more carbons also may undergo delta chlorination.

Vinylcyclopropylacyl and polyeneacyl radicals. Intramolecular ketene alkyl radical additions in ring synthesis

Treatment of a variety of substituted vinylcyclopropyl selenyl esters, e.g. 11, with Bu(3)SnH-AIBN in refluxing benzene leads to the corresponding acyl radical intermediates, which undergo rearrangement and intramolecular cyclisations via their ketene alkyl radical equivalents producing cyclohexenones in 50-60% yield. By contrast, treatment of conjugated triene selenyl esters, e.g. 32, with Bu(3)SnH-AIBN produces substituted 2-cyclopentenones via intramolecular cyclisations of their ketene alkyl radical intermediates. Under the same radical-initiating conditions the selenyl esters derived from o-vinylbenzoic acid and o-vinylcinnamic acid undergo intramolecular cyclisations producing 1-indanone and 5,6-dihydrobenzocyclohepten-7-one respectively in 60-70% yields. A tandem radical cyclisation from the alpha,beta,gamma,delta-diene selenyl ester 31 provides an expeditious synthesis of the diquinane 35 in 69% yield.

The one-electron reduction of primary alkyl iodides at palladium and palladiated surfaces: a facile source of alkyl radicals?

A large palette of primary alkyl halides RI were reduced at smooth palladium electrodes (as well as palladiated copper, platinum and glassy carbon) in organic solvents such as dimethylformamide, propylene carbonate and acetonitrile in the presence of tetraalkylammonium salts. All exhibited under such experimental conditions a very large cathodic activation when compared to bare platinum and glassy carbon. Thus, shifts towards less cathodic potentials were so large that the first reduction step turned to a diffusion one-electron process. Under the described conditions, the reduction of RIs occurred in two one-electron steps, suggesting then the intermediate alkyl radical formation. Microcoulometries at the level of the first step confirmed that the reaction is monoelectronic with quantitative loss of iodide.The transient formation of free radicals is also supported by GC/MS results (presence of R–R and R(–H) type compounds after electrolysis).