Experimental and DFT study of the partial oxidation of benzene by N2O over H-ZSM-5: acid catalyzed mechanism

The reaction mechanism for hydroxylation of benzene by N(2)O has been studied on chemically modified ZSM-5 catalysts. A maximum in catalytic activity and selectivity was reached for steamed samples under mild conditions (about 30% conversion with 94% selectivity). Chemical modifications, through ion exchange (H(+) versus Na(+)), have demonstrated the importance of the presence of Br?nsted acid sites. The results obtained suggest a Langmuir-Hinshelwood mechanism between benzene and N(2)O adsorbed on two distinct active sites. A density functional theory study considering the possible reaction intermediates also confirmed the possible formation of protonated nitrous oxide, leading to a Wheland-type intermediate, thus supporting an electrophilic aromatic substitution assisted by the confined environment provided by the active zeolite framework.     

Experimental evidence for multiple oxidation pathways in the (salen) Mn-catalyzed epoxidation of alkenes

The substrate electronic effects on the selectivity in the catalytic epoxidation of para-substituted cis stilbenes 2a-i were investigated by using (R,R)-[N,N'-bis(3,5-di-tBu-salicylidene)-1,2-cyclohexanediamine]manganese(III) chloride 1 in benzene as the catalyst with iodosobenzene as the terminal oxidant. A Hammett study of the selectivity results reveals a stronger electrophilic character than previously assumed in the (salen)Mn-catalyzed reaction. In general, the best correlations with the experimental values were obtained by using the Hammett sigma + values, which gave rho = -1.37 for the rate of cis-epoxide formation and rho = -0.43 for the rate of the stepwise process leading to the corresponding trans product. The reaction involves two separate pathways as indicated also by the competitive breakdown of the intermediate on the path to trans epoxide for methoxy-substituted substrates. The asynchronicity in the concerted pathway leading to cis epoxide is apparent for 4-methoxy-4'-nitrostilbene, which yields cis epoxide with 75% ee entirely as a result of electronic effects.     

Titanocene(III)‐Catalyzed Three‐Component Reaction of Secondary Amides,Aldehydes, and Electrophilic Alkenes

An umpolung Mannich‐type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one‐pot formation of C? N and C? C bonds by a titanocene‐catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N‐substituted γ‐amido‐acid derivatives and γ‐amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α‐amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.     

Synthesis of 5-Iodo-1,4-disubstituted-1,2,3-triazoles Mediated by in Situ Generated Copper(I) Catalyst and Electrophilic Triiodide Ion

Mixing copper(II) perchlorate and sodium iodide solutions results in copper(I) species and the electrophilic triiodide ions, which collectively mediate the cycloaddition reaction of organic azide and terminal alkyne to afford 5-iodo-1,4-disubstituted-1,2,3-triazoles. One molar equivalent of an amine additive is required for achieving a full conversion. Excessive addition of the amine compromises the selectivity for 5-iodo-1,2,3-triazole by promoting the formation of 5-proto-1,2,3-triazole. Based on preliminary kinetic and structural evidence, a mechanistic model is formulated in which a 5-iodo-1,2,3-triazole is formed via iodination of a copper(I) triazolide intermediate by the electrophilic triiodide ions (and possibly triethyliodoammonium ions). The experimental evidence explains the higher reactivity of the in situ generated copper(I) species and triiodide ion in the formation of 5-iodo-1,2,3-triazoles than that of the pure forms of copper(I) iodide and iodine.     

Occurrence of 2-methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, in human blood as a consequence of ethanol consumption

Acetaldehyde is a strongly electrophilic compound that is endogenously produced as a first intermediate in oxidative ethanol metabolism. Its high reactivity towards biogenic nucleophiles has toxicity as a consequence. Acetaldehyde readily undergoes a non-enzymatic condensation reaction and consecutive ring formation with cysteine to form 2-methylthiazolidine-4-carboxylic acid (MTCA). For analytical purposes, N-acetylation of MTCA was required for stabilization and to enable its quantification by reversed-phase chromatography combined with electrospray ionization–tandem mass spectrometry. Qualitative screening of post mortem blood samples with negative blood alcohol concentration (BAC) mostly showed low basal levels of MTCA. In BAC-positive post mortem samples, but not in corresponding urine specimens, strongly increased levels were present. To estimate the association between ethanol consumption and the occurrence of MTCA in human blood, the time curves of BAC and MTCA concentration were determined after a single oral dose of 0.5?g ethanol per kilogram of body weight. The blood elimination kinetics of MTCA was slower than that of ethanol. The peak concentration of MTCA (12.6?mg?L^-1) was observed 4?h after ethanol intake (BAC 0.07‰) and MTCA was still detectable after 13?h. Although intermediary acetaldehyde scavenging by formation of MTCA is interesting from a toxicological point of view, lack of hydrolytic stability under physiological conditions may hamper the use of MTCA as a quantitative marker of acetaldehyde exposure, such as resulting from alcohol consumption.     

Oxidation of α-amino acids promoted by the phthalimide N-oxyl radical: A kinetic and product study

A kinetic study of the hydrogen atom transfer (HAT) reaction from a series of N-Boc- or N-Acetyl-protected amino acids to the phthalimide N-oxyl radical (PINO) was carried out to obtain information about reactivity and selectivity patterns. With amino acids containing aliphatic side chains, the 2nd order rate constants are of the same order of magnitude, in agreement with a HAT process involving the Cα?H bond. Proline is the most reactive substrate suggesting that HAT process involves the C_δ?H bond instead of C_α?H bond. These results are confirmed by the product analysis of the aerobic oxidations of the corresponding N-Boc and N-Ac protected amino acids methyl esters promoted by N-hydroxyphthalimide. Comparison of our results with those reported for HAT reactions to other radical species indicates that PINO displays electrophilic characteristics that are intermediate between those observed for the more stable Br radical and the more reactive cumyloxyl radical.     

Copper‐Catalyzed α‐Amination of Phosphonates and Phosphine Oxides: A Direct Approach to α‐Amino Phosphonic Acids and Derivatives

A direct approach to important α‐amino phosphonic acids and its derivatives has been developed by using copper‐catalyzed electrophilic amination of α‐phosphonate zincates with O‐acyl hydroxylamines. This amination provides the first example of C? N bond formation which directly introduces acyclic and cyclic amines to the α‐position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope.     

Mechanism of the condensation of homocysteine thiolactone with aldehydes

Chemical reactivity of homocysteine thiolactone (HTL) has been implicated in cardiovascular disease. Owing to its aminoacyl-thioester character, HTL undergoes facile electrophilic and nucleophilic reactions at its amino and activated-carboxyl group, respectively. To gain insight into the mechanism of the reactions involving its amino group, the kinetics of the condensation of homocysteine thiolactone with formaldehyde, acetaldehyde, and pyridoxal phosphate, were analyzed in the pH range from 5 to 10. The reactions were first order with respect to HTL, aldehyde, and hydroxide ion concentrations. Of the two ionic species of HTL (pKa=6.67+/-0.05), the acid form HTL+ was approximately 100-fold more reactive than the base form HTL(0). The reactions of HTL with aldehydes involve intermediate adducts. The conversion of the intermediate carbinolamine to a product, 1,3-tetrahydrothiazine-4-carboxylic acid or its 2-substituted analogue, occurs in a two-step reaction. The first step involves hydrolysis of the thioester bond in the intermediate, facilitated by anchimeric assistance by the oxygen of the carbinolamine group of the intermediate. The second step involves an attack of the liberated thiolate on the aldehyde-derived carbon of the intermediate, affording 1,3-tetrahydrothiazine-4-carboxylic acid or its 2-substituted analogue. An unusual feature of these reactions is that the formation of the carbinolamine group increases the reactivity of the thioester bond of HTL approximately 10(4)-fold. The facile formation of tetrahydrothiazines may contribute to HTL elimination from the human body.     

Axial-selective prins cyclizations by solvolysis of alpha-bromo ethers

Prins cyclizations are intramolecular electrophilic additions of oxocarbenium ions. They lead to tetrahydropyrans with a heteroatom at the 4-position, and usually show moderate-to-high selectivity for equatorial substitution. We have found that Prins cyclizations carried out under specific conditions produce tetrahydropyrans with almost exclusive formation of the axial 4-substituent. TMSBr, AcBr, and TMSI all lead to axial-selective Prins cyclizations with alpha-acetoxy ether substrates in the presence lutidine. The mechanism appears to involve solvolysis of the intermediate alpha-bromo ether rather than specific or Lewis acid-catalyzed rearrangement. The scope of the reaction, the high yields, and the stereoselectivity make this a valuable new method for tetrahydropyran formation.     

New synthesis of isoxazolidines

A new synthesis of 5-substituted isoxazolidines was developed by direct isoxazolidine ring formation of allylic hydroxylamines under acidic conditions. The cyclization process is an electrophilic S_N1 type reaction. The formed carbocation intermediate is stabilized by electron rich groups (i.e., phenyl). A moiety that mediates oxonium ion formation (i.e., para-methoxy) accelerates the rate of product formation.     

Theoretical studies on the methylsulfenyl chloride addition to propene

Thiiranium heterocycles play an important role in biocatalytic processes of cells. Usually formation of thiiranium ions is known to proceed by the electrophilic additions of sulfenylhalides to substituted olefins, subsequently undergoing the regioselective and stereoselective nucleophilic attack of the halide atom on either C‐1 or C‐2 carbon atom of the thiiranium intermediate to gave two isomeric adducts. The detailed sequence of the reaction mechanism, the nature of intermediates, and transition states that occur in this electrophilic addition reaction are not well understood. In our work, this reaction has been modeled using Ab initio methods at the MP2/6‐31+G(d,f) level of theory to look into the mechanism of the reaction and to explain how the regioselectivity of the reaction is controlled. We focused on the electrophilic addition reaction of the methylsulfenyl chloride to propene. Our calculations show that the reaction is predicted to proceed via two distinct directions. The first direction proceeds when the starting reacting molecules formed the cis‐methyl‐oriented thiiranium intermediate, and the second direction is when the starting reactants resulted in the trans‐methyl‐oriented thiiranium intermediate. The calculated reaction potential energy surface profile suggests that the minimum energy pathway via the first direction is energetically more preferred than that via trans one. Moreover, calculation of the intrinsic reaction coordinate on the minimum energy pathway revealed the stepwise mechanism for the addition reaction. Thus the energetically preferred first reaction direction consists of the addition of methylsulfenyl chloride to the double bond of propene undergoing synchronous concerted transition state leading to the thiiranium intermediate formation (the rate‐limiting step in the electrophilic addition reaction); regioselective thiiranium intermediate ring‐opening process by the chloride anion attack on the C‐2 carbon of the thiiranium intermediate forming 2‐chloro adduct of kinetically controlled addition reaction; the isomerization reaction of 2‐chloro adduct to more energetically favorable thermodynamically stable 1‐chloro product. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:1–13, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20571     

Rapid access to halohydrofurans via Brønsted acid-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with water and electrophilic halides

A one-pot, two-step method to prepare 3-halohydrofurans efficiently by TfOH-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with H(2)O and N-halosuccinimide (NXS, X=1, Br, Cl) or Selectfluor is described. The reactions proceed rapidly under mild and operationally straightforward conditions with a catalyst loading as low as 1 mol % and afford the 3-halohydrofuran products in moderate to excellent yields and, in most cases, with preferential cis diastereoselectivity. The method was shown to be applicable to cyclopropyl methanols containing electron-withdrawing, electron-donating, and sterically demanding functional groups and electrophilic halide sources. The mechanism is suggested to involve protonation of the alcohol substrate by the Br?nsted acid catalyst and ionization of the starting material. This results in ring-opening of the cyclopropane moiety and in situ formation of a homoallylic alcohol intermediate, which undergoes subsequent intramolecular halocyclization on treating with the electrophilic halide source to give the halohydrofuran. The observed cis product selectivity is thought to be determined by the reaction proceeding through an in situ generated unsaturated alcohol intermediate that contains a (Z)-alkene moiety under the kinetically controlled conditions.     

Stereocontrolled formation of ketomethylene isosteres through tandem chain extension reactions

A zinc-mediated chain extension reaction is the key step in the preparation of gamma-keto amides derived from amino acids. The use of tandem reaction sequences, in which the intermediate zinc enolate is trapped with electrophilic reagents, results in the incorporation of alpha-substituents, which mimic the side chains found in natural amino acid systems. Use of the chiral amino acid L-proline as a stereo-directing element provides a diastereoselective route to various ketomethylene isosteres.     

Palladium-catalyzed tandem bis-allylation of isocyanates

A tandem bis-allylation of p-toluenesulfonyl isocyanate can be achieved by palladium-catalyzed three-component coupling reaction with allylstannanes and allyl chlorides. A high level of regioselectivity can be obtained by the appropriate choice of the allylic substituents. The reaction mechanism and the regiochemistry of the reaction can be explained by formation of an amphoteric bis-allylpalladium intermediate. This bis-allylpalladium intermediate undergoes an initial electrophilic attack on one of the allyl moieties followed by a nucleophilic attack on the other.     

Positioning a Carbon–Fluorine Bond over the π Cloud of an Aromatic Ring: A Different Type of Arene Activation

It is known that the fluoro group has only a small effect on the rates of electrophilic aromatic substitutions. Imagine instead a carbon–fluorine (C?F) bond positioned tightly over the π cloud of an aryl ring—such an orthogonal, noncovalent arrangement could instead stabilize a positively charged arene intermediate or transition state, giving rise to novel electrophilic aromatic substitution chemistry. Herein, we report the synthesis and study of molecule 1 , containing a rigid C?F???Ar interaction that plays a prominent role in both its reaction chemistry and spectroscopy. For example, we established that the C?F???Ar interaction can bring about a >1500 fold increase in the relative rate of an aromatic nitration reaction, affording functionalization on the activated ring exclusively. Overall, these results establish fluoro as a through‐space directing/activating group that complements the traditional role of fluorine as a slightly deactivating aryl substituent in nitrations.     

Intermolecular 1,4‐Carboamination of Conjugated Dienes Enabled by Cp*RhIII‐Catalyzed C−H Activation

A protocol for the three‐component 1,4‐carboamination of dienes is described. Synthetically versatile Weinreb amides were coupled with 1,3‐dienes and readily available dioxazolones as the nitrogen source using [Cp*RhCl₂]₂‐catalyzed C?H activation to deliver the 1,4‐carboaminated products. This transformation proceeds under mild reaction conditions and affords the products with high levels of regio‐ and E‐selectivity. Mechanistic investigations suggest an intermediate Rh^III–allyl species is trapped by an electrophilic amidation reagent in a redox‐neutral fashion.     

Acyl‐Directed ortho‐Borylation of Anilines and C7 Borylation of Indoles using just BBr3

Indoles are privileged heterocycles found in many biologically active pharmaceuticals and natural products. However, the selective functionalization of the benzenoid moiety in indoles in preference to the more reactive pyrrolic unit is a significant challenge. Herein we report that N‐acyl directing groups enable the C7‐selective C?H borylation of indoles using just BBr₃. This transformation shows some functional‐group tolerance and notably proceeds with C6 substituted indoles. The directing group can be readily removed in situ and the products isolated as the pinacol boronate esters. Acyl‐directed electrophilic borylation can be extended to carbazoles and anilines with excellent ortho selectivity. 4‐amino‐indoles are amenable to this process, with acyl group installation and directed electrophilic C?H borylation enabling selective formation of C5‐BPin‐indoles.     

Catalytic intermolecular allylic C-H alkylation

The first electrophilic Pd(II)-catalyzed allylic C H alkylation is reported, providing a novel method for formation of sp3-sp3 C C bonds directly from C H bonds. A wide range of aromatic and heteroaromatic linear (E)-alpha-nitro-arylpentenoates are obtained as single olefin isomers in excellent yields directly from terminal olefin substrates and methyl nitroacetate. The use of DMSO as a pi-acidic ligand was found to be crucial for promoting functionalization of the pi-allylPd intermediate. Products from this reaction are valuable synthetic intermediates and are readily transformed to amino esters via selective reduction and optically enriched alpha,alpha-disubstituted amino acid precursors via asymmetric conjugate addition.     

Unified mechanistic concept of electrophilic aromatic nitration: convergence of computational results and experimental data

The mechanism of electrophilic aromatic nitration was revisited. Based on the available experimental data and new high-level quantum chemical calculations, a modification of the previous reaction mechanism is proposed involving three separate intermediates on the potential energy diagram of the reaction. The first, originally considered an unoriented pi-complex or electron donor acceptor complex (EDA), involves high electrostatic and charge-transfer interactions between the nitronium ion and the pi-aromatics. It explains the observed low substrate selectivity in nitration with nitronium salts while maintaining high positional selectivity, as well as observed oxygen transfer reactions in the gas phase. The subsequent second intermediate originally considered an oriented "pi-complex" is now best represented by an intimate radical cation-molecule pair, C(6)H(6)(+)(*)()/NO(2), that is, a SET complex, indicative of single-electron transfer from the aromatic pi-system to NO(2)(+). Subsequently, it collapses to afford the final sigma-complex intermediate, that is, an arenium ion. The proposed three discrete intermediates in electrophilic aromatic nitration unify previous mechanistic proposals and also contribute to a better understanding of this fundamentally important reaction. The previously obtained ICR data of oxygen transfer from NO(2)(+) to the aromatic ring are also accommodated by the proposed mechanism. The most stable intermediate of this reaction on its potential energy surface is a complex between phenol and NO(+). The phenol.NO(+) complex decomposes affording C(6)H(6)O(+)(*)/PhOH(+) and NO, in agreement with the ICR results.     

Friedel-Crafts-type mechanism for the enzymatic elimination of ammonia from histidine and phenylalanine

The surprisingly high catalytic activity and selectivity of enzymes stem from their ability to both accelerate the target reaction and suppress competitive reaction pathways that may even be dominant in the absence of enzymes. For example, histidine and phenylalanine ammonia-lyases (HAL and PAL) trigger the abstraction of the nonacidic beta protons of these amino acids while leaving the much more acidic ammonium hydrogen atoms untouched. Both ammonia-lyases have a catalytically important electrophilic group, which was believed to be dehydroalanine for 30 years but has now been revealed by X-ray crystallography and UV spectroscopy to be a highly electrophilic 5-methylene-3,5-dihydroimidazol-4-one (MIO) group. Experiments suggest that the reaction is initiated by the electrophilic attack of MIO on the aromatic ring of the substrate. This incomplete Friedel-Crafts-type reaction leads to the activation of a beta proton and its stereospecific abstraction, followed by the elimination of ammonia and regeneration of the MIO group. The plausibility of such a mechanism is supported by a synthetic model. The application of the PAL reaction in the biocatalytic synthesis of enantiomerically pure alpha-amino beta-aryl propionates from aryl acrylates is also discussed.