Ortho Alkylation Research Articles

Reductive activation of arenes

Reductive alkylation of benzonitrile, ortho-, meta-, para-tolunitriles, and 1-naphthonitrile by sequential action of alkali metal and alkyl bromide in liquid ammonia results in corresponding alkylarenes and 1-alkyl-1-cyanocyclohexa-2,5-dienes. The experimental conditions for target synthesis of the specified products are found. A method of synthesis of 1-(ω-bromoalkyl)-1-cyanocyclohexa-2,5-dienes based on the interaction of two-electronic reduction products of aromatic nitriles with α,ω-dibromoalkanes Br(CH2)nBr (n = 3−5) is developed.

The cytotoxicity of ortho alkyl substituted 4-X-phenols: A QSAR based on theoretical bond lengths and electron densities

A new method called quantum topological molecular similarity (QTMS) was recently proposed [O’Brien, S. E.; Popelier, P. L. A. J. Chem. Inf. Comp. Sci. 2001, 41, 764] and has been shown to be successful in a variety of medicinal, ecological and physical organic QSAR/QSPRs. QTMS method uses electronic descriptors drawn from ab initio wavefunctions of geometry-optimized molecules. We investigated a remarkable and unusual set of ortho alkyl-substituted phenols [Selassie, C. D.; Verma, R. P.; Kapur, S.; Shusterman, A. J.; Hansch, C. J. Chem. Soc., Perkin 2002, II, 1112], recently studied by the Hansch group. Our results do not support their proposal that a steric factor is important in the determination of the cytotoxicity of this set of substituted phenols. Thus, we conclude that the cytotoxicity of these sterically encumbered phenols is dependent primarily on electronic and radical effects, and that steric issues do not appear to be a critical distinguishing factor.

Preagostic Rh−H Interactions and C−H Bond Functionalization: A Combined Experimental and Theoretical Investigation of Rhodium(I) Phosphinite Complexes

Three Rh−phosphinite complexes with the general structural formula [RhCl(i-Pr2POXy)(L)]2 (Xy = 2,3-xylyl; L = PPh3, PMe3, t-BuNC) were synthesized. Characterization of these complexes using crystallographic and spectroscopic techniques revealed rare examples of preagostic C−H···M interactions. 1H NMR chemical shielding calculations on a geometry-optimized model complex were used to provide a connection between the solution and solid-state data, which additionally supported assignment of the preagostic interaction. One of these Rh−phosphinite complexes (L = PPh3) was used to catalyze the ortho alkylation of phosphinites and phenols with an unactivated alkene. Finally, DFT calculations were used to provide evidence for the involvement of the observed preagostic interaction in the cyclometalation step of the catalytic cycle.

Ortho Alkylation of Aromatic Ketimine with Functionalized Alkene by Rh(I) Catalyst

[reaction: see text] The reaction of the imine of aromatic ketones with functionalized alkenes was performed under a catalytic amount of (PPh3)3RhCl, and corresponding ortho-alkylated ketones were obtained after hydrolysis. A variety of functional groups in the alkene were tolerated in this ortho alkylation. This procedure expands the scope of ortho alkylation to the direct ortho functionalization of aromatic ketones.

Vapour phase alkylation of ortho-, meta- and para-cresols with isopropyl alcohol in the presence of sol–gel prepared alumina catalyst

Nanosized γ-Al 2O 3 catalyst was prepared by the alkoxide sol–gel method and characterized by XRD and TEM. The porous nature of the catalyst was studied by nitrogen adsorption–desorption isotherms. Acidity of the synthesised material was analyzed by pyridine-adsorbed FT-IR spectroscopy. The gas phase alkylation of isomeric methylphenols (cresols) with isopropyl alcohol over sol–gel prepared alumina catalyst was studied. The reactions were carried out in a continuous process at the atmospheric pressure with dependence on temperature, starting at 210 °C up to the point when the amount of alkylated cresols dropped due to decomposition. Both, O- and C-alkylated products were obtained at lower temperatures, while at higher temperatures ortho-isopropylated derivatives of isomeric cresols were the main products. According to the present method isopropylated cresols can be efficiently obtained with selectivity higher than 90%.

Synthesis of 1,2,3,4-tetrahydroisoquinolines and 2,3,4,5-tetrahydro-1 H-2-benzazepines combining sequential palladium-catalysed ortho alkylation/vinylation with aza-Michael addition reactions

1-Substituted 1,2,3,4-tetrahydroisoquinolines and 2,3,4,5-tetrahydro-1 H-2-benzazepines were synthesised from o-iodoalkylbenzene, N-Cbz-bromoalkylamine and an electron-poor olefin through a one-pot palladium-catalysed sequence involving ortho alkylation, alkenylation and intramolecular aza-Michael reaction.

New Chromium Complexes for Ethylene Oligomerization: Extended Use of Tridentate Ligands in Metal-Catalyzed Olefin Polymerization

A family of chromium complexes bearing tridentate pyridine-based ligands are disclosed as highly active precatalysts for the oligomerization of ethylene. The ligands are comprised of two distinct types: Type 1, in which both ketone groups of 2,6-diacetylpyridine are converted to imines to produce pyridine bisimine NNN ligands; and Type 2, in which only one ketone group of 2,6-diacetylpyridine is condensed with an aniline derivative to give monoimine NNO coordination sets. Ligands of either type are coordinated to chromium(II) or chromium(III) chlorides, and activation of the resultant complexes with methylaluminoxane (MAO) produces highly active ethylene oligomerization and polymerization catalysts. Catalysts of Type 1 (NNN set) generally produce 1-butene when only two ortho alkyl substituents are present but switch to making waxes or polyethylene when the size and/or number of ortho substituents are increased. Catalysts of Type 2 (NNO set) produce waxes and polyethylene under all of the substitution pat...

Intramolecular alkene Friedel–Crafts cyclization of 1-allyl-1- N-( ortho-alkylphenylamino)cyclohexanes. A useful route to alkyl substituted dihydrospiro[(1 H)quinoline-2,1 ′-cyclohexanes]. Unprecedented ipso-substitution of alkyl groups

An unprecedented intramolecular Friedel–Crafts ipso-alkylation at the ortho-alkyl group of the N-arylamino moiety of 1-allyl-1- N-arylaminocycloalkanes to give alkyl substituted dihydrospiro[(1 H) quinoline-2,1 ′-cycloalkanes] is reported. Unexpected results were explained in the context of intramolecular ipso-substitution of alkyl groups and their 1,2-rearrangement. A plausible mechanism for this type of Friedel–Crafts alkylation by an alkene moiety promoted by a Brönsted acid (H 2SO 4) is proposed.

Excited-state proton transfer to solvent of protonated aniline derivatives in aqueous solution: a remarkable effect of ortho alkyl group on the proton-dissociation rate

Proton dissociation from the lowest excited singlet state of protonated aniline (AN) derivatives in aqueous solution has been studied by picosecond time-resolved fluorescence measurements. The proton-dissociation rate is significantly influenced by introduction of ortho alkyl group(s) to AN as 1.4×10 10 s −1 for AN, 4.1×10 9 s −1 for 2-toluidine and 1.7×10 9 s −1 for 2,6-xylidine. The remarkable decrease of the proton-dissociation rate by alkylation is attributed partly to change in exothermicity of the reactions. The activation barrier for the proton-dissociation reaction is increased in the alkylated ANs, suggesting that the hydrophobic effects of the alkyl group on the water structure in the vicinity of the amino group influences the rate of proton transfer to solvent.

Atroposelectivity in the electrophilic substitution reactions of laterally lithiated and silylated tertiary amides

Lateral lithiation–electrophilic quench of 2-alkyl-1-naphthamides and 2,6-dialkylbenzamides yields products containing an atropisomeric Ar–CO axis and a new stereogenic centre with high (generally >95 ∶ 5) diastereoselectivity. With imines as electrophiles, single diastereoisomers containing an atropisomeric axis and two new stereogenic centres are formed. 2,6-Dialkylbenzamides may be functionalised stereoselectively at both the 2- and 6-positions, leading (with imines) to symmetrical compounds bearing 1,7-related stereogenic centres. 2-Alkylbenzamides with only one ortho alkyl group are not atropisomeric at ambient temperature but are functionalised diastereoselectively by lateral lithiation–electrophilic quench at −78 °C. Stabilisation of the atropisomeric products by further lithiation and alkylation proves their diastereoselective formation. The lack of stereospecificity in the fluoride-promoted reaction of a laterally silylated 1-naphthamide with an aldehyde suggests that reported reactions of laterally silylated benzamides may also be controlled by the rotationally restricted amide group.

Mechanism of Aromatic Hydrocarbon Acylation by Substituted Benzoic Acids: A Novel Reaction Pathway

Aromatic hydrocarbons are susceptible to direct acylation by benzoic acids with high yields bearing ortho or para alkyl groups as substituents under Friedel–Crafts reaction conditions. The α-H of the alkyl moiety seems to be responsible for the observed relatively high reaction rates of conversion. Carbanion-like species are proposed as reaction intermediates, which also operate as strong bases in the reaction rate-determining steps. Trapping experiments, deuterium isotopic effects, and kinetics data favor a concerted reaction pathway where proton transfer from the hydrocarbon molecule to a carbanionic intermediate takes place with a simultaneous electrophilic attack of the carbonylic carbon atom.

A new practical method for regioselective nucleophilic aromatic alkylation of ortho- or para-methoxy-substituted aromatic esters with Grignard reagents

A new practical method for the regioselective nucleophilic aromatic alkylation of o- or p-methoxy-substituted aromatic carboxylic acids via their triethylcarbinyl ester derivatives by conducting the reactions with alkyl/aryl Grignard reagents in toluene has been developed.

High pressure auto-ignition and oxidation mechanisms of o-xylene, o-ethyltoluene, and n-butylbenzene between 600 and 900 K

A complex phenomenology of auto-ignition, similar to n-alkanes and n-alkenes, has been revealed between 600–900 K and at pressures above 14 bar by studying in a rapid compression machine stoichiometric mixtures of o-xylene ( o-methyltoluene), o-ethyltoluene, or n-butylbenzene in oxygen with lower concentrations than in air. Extensive chemical analyses of the reacting mixtures before ignition were performed to elucidate the mechanisms of reaction. The classical low temperature scheme, modified for the reactivities of benzylic-type hydrogen atoms and radicals, is valid. It appears that the addition of molecular oxygen to benzylic-type radicals leads to a double peroxidation and low temperature branching only when the transfer of hydrogen in the isomerization step occurs either from an ortho-alkyl group, or from another carbon atom of the same alkyl chain. The products observed are shown to be consistent with the proposed mechanism. The same complex pattern of auto-ignition is found, not only for o-xylene, o-ethyltoluene, and n-butylbenzene, but also for 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, n-propylbenzene, and ethylbenzene. When easily transferable hydrogen atoms are not available for selective radicals such as peroxy radicals, branching occurs through completely different pathways, which require higher temperatures and pressures. Then, the pattern of auto-ignition is much simpler, as already observed for toluene, m-xylene, p-xylene, and 1,3,5-trimethylbenzene [1].

Indo study of the angular dependences of isotropic hyperfese interaction constants in the model conformations of the nitrobenzene radical anion

The UHF/INDO calculations of the model conformations of the nitrobenzene radical onion show that rotation of the nitro group relative to the plane of the benzene ring is accompanied by a pyramidal distortion of the group caused by the pseudo-Jahn-Teller effect (vibronic interaction between the ground n and totally symmetric lowest excited σ states). The angular dependences of the14N,13C,1H, and17O Isotropic hyperfine interaction constants are analyzed. Experimental ESR data are interpreted for the radical anions of nitrobenzene derivatives with ortho-alkyl groups.

Functionalisation of tetraalkylsilanes derived from CH activation; towards annulations of diterpenoids

Vinyl trialkylsilanes are efficient substrates for use in the ortho alkylation of aromatic ketones catalysed by zerovalent ruthenium complexes, giving, e.g. (2-trimethylsilylethyl)acetophenones. Methods for the selective desilylation–functionalisation of such tetraalkylsilanes are investigated. Some diterpenoid tetraalkylsilanes derived from the ruthenium-catalysed insertion of vinyltrimethylsilane have been functionalised by benzylic bromination of an ArCH 2CH 2SiMe 3 fragment with NaBrO 3–Na 2S 2O 5 (optimally), leading to a 1,2-dibromoethyl derivative. Further transformations culminated in the overall conversion of ArCH 2CH 2SiMe 3 into ArCOCH 3. Attempted aldol coupling of the resulting 1,4-diketone provoked skeletal reorganisation. A tetraalkylsilane was converted into a silanol (ArCH 2CH 2SiMe 2OH) by the action of aluminium chloride and water, but further oxidation of this silanol to the primary alcohol (ArCH 2CH 2OH) was unsuccessful.

Chemometrical Analysis of Substituent Effects. XIII. Comparison of Substituent Effects on Dissociation and Chemical Shift in 13C NMR Spectra of Mono- and Disubstituted Benzoic Acids

The 13C chemical shifts have been measured of the carboxyl carbon atoms for all the 2-, 3-, and 4-substituted benzoic acids with H, CH3, CH3O, F, Cl, Br, I, and NO2 substituents, as well as for all 3,4-, 3,5-, and 2,6-disubstituted benzoic acids with combinations of CH3, CH3O, Cl (or Br), NO2 substituents and for symmetrically 2,6-disubstituted derivatives with Et, EtO, PrO, i-PrO, and BuO substituents. The chemical shifts of carboxylic group carbon atoms of the 3- and 4-substituted derivatives show correlation only with the substituent constants σI. For the 2-substituted derivatives was found the dependence only on σI and on the υ constant describing steric effects (s = 0.122, R = 0.996, without the CH3 derivative which has a distinct anisotropic effect). The substituent effects on the carboxylic carbon chemical shift show additivity with 3,4-, 3,5-, and 2,6-substituents, and the 2,6-disubstituted derivatives show a linear synergic effect of substituents due obviously to the steric hindrance to resonance. Application of the principal component analysis to the data matrix involving all the combinations of mono- and disubstitution involving the above-mentioned substituents has proved an identical substituent effect from all the positions on the chemical shift described by one latent variable, steric effects and anisotropic behaviour of methyl at the 2 and 2,6 positions being predominantly described by the second latent variable (with the total explained variability of 99.5%). Comparison of substituent effects on the chemical shift of carboxylic carbon with that on the dissociation constant measured in the same solvent has confirmed the anisotropy due to ortho methyl group, the ortho halogen substituents in monosubstituted derivatives also having a different effect. The dependence of chemical shift on pKa was not very close for the derivatives studied (s = 1.005, R = 0.690). The inclusion of anisotropy of ortho alkyl group by means of an indicator variable improved the correlation (s = 0.533, R = 0.925), and omitting of 2-F, 2-Cl, 2-Br, and 2-I substituents gave a regression without deviating points (s = 0.352, R = 0.968).

Symmetrical and unsymmetrical 2,6-dialkyl-1,1′-biaryls by combined catalysis of aromatic alkylation via palladacycles and Suzuki-type coupling

The title compounds are made readily accessible by a catalytic procedure, occurring under mild conditions, based on palladium-mediated ortho alkylation of aromatic iodides with alkyl bromides followed by reaction with arylboronic acids.

Selective Ortho alkylation of phenol with alcohols over catalysts derived from hydrotalcite-like anionic clays

The vapour phase alkylation of phenol with a series of alcohols containing different number of carbons ranging from C1 to C8 were investigated over catalysts derived from magnesium-aluminium hydrotalcite with Mg/Al atomic ratio 3 (MgAl 3.0-HT). The results indicated that at 623 K the catalytic activity for phenol conversion increased with increasing chain length of linear long chain alcohols to give 2-alkylated linear alkyl phenols, without any isomerisation of the alkyl moiety. Isomorphous substitution of Mg2+ by Cu2+ or Ni2+ in the MgAl 3.0-HT resulted in an increase in selectivity of 2-alkyl and 2,6-dialkylphenols (≈60%) in the alkylation of phenol with 1-hexanol or 1-octanol.

Novel Intramolecular Cyclization Reaction Involving a Thionitroso Group: Formation of a 3,3a-Dihydro-2,1-benzisothiazole from an o-Alkylthionitrosoarene

Abstract A thionitrosoarene generated by the desulfurization reaction of a stable N-thiosulfinylaniline bearing a bowl-type substituent underwent the intramolecular cyclization reaction involving the ortho-alkyl group to afford the corresponding 3,3a-dihydro-2,1-benzisothiazole. The intermediacy of the thionitrosoarene was corroborated by a trapping experiment with aniline.

Anionic Polymerization of Monomers Containing Functional Groups. 10. Anionic Polymerizations of N-Aryl-N-(4-vinylbenzylidene)amines

Anionic polymerizations of seven styrenes para-substituted with N-arylimino groups were carried out in THF at −78 °C with oligo(α-methylstyryl)dipotassium and -dilithium as the initiators. The N-aryl functionalities contained phenyl (1), 2-(tert-butyl)phenyl (2), 2,6-dimethylphenyl (3), 2,6-diethylphenyl (4), 2,6-diisopropylphenyl (5), 4-cyanophenyl (6), and 2,3,4,5,6-pentafluorophenyl (7) groups. The monomers 3−5 underwent anionic polymerization quantitatively to produce the polymers having predicted molecular weights based on molar ratios of monomers to initiators and narrow molecular weight distributions, the Mw/Mn values being around 1.1. On the other hand, no polymeric products were obtained from the polymerization mixture of 1, 2, 6, and 7 under identical conditions. The bulkiness of the two ortho alkyl substituents on the N-aryl moiety was necessary to achieve the anionic living polymerization of styrenes bearing N-arylimino groups. Well-defined new block copolymers having poly(5) segments were synthesized by the sequential addition of 5 and styrene or tert-butyl methacrylate. The resulting poly(3−5) could be quantitatively transformed into the poly(4-formylstyrene) having tailored chain structures by the acid hydrolysis of N-arylimino moieties.