Hard Electrophiles Research Articles

Indirect Electroreductive Cyclization and Electrohydrocyclization Using Catalytic Reduced Nickel(II) Salen

[Chemical reaction: See text] We describe efforts to achieve the electroreductive cyclization (ERC) and the electrohydrocyclization (EHC) reactions using catalytic nickel(II) salen as a mediator. While nickel(II) salen proved effective, the analogous cobalt complex as well as nickel(II) cyclam were not. The transformations were achieved in yields ranging from 60 to 94% using either a mercury pool or an environmentally preferable reticulated vitreous carbon (RVC) cathode. These examples represent the first instances wherein a nickel salen complex has been used in this manner. Clear differences between the voltammetric behavior of the ERC and EHC substrates were observed. The bisenoate 14, for example, displays a substantially larger catalytic current. When the structurally modified mediator 31 was used, the electron-transfer pathway shuts down. Instead, the reduced form of 31 behaves as an electrogenerated base, leading to the formation of the intramolecular Michael adduct 23. Presumably, the methyl groups of the modified ligand diminish the ability of the reduced form of the complex to serve as a nucleophile but not as a base. Aldehyde 23 was also characterized as a side product of the nickel(II) salen mediated electroreductive cyclization of 11. Given that it is absent from nonmediated processes, its formation is linked to the presence of the mediator. To account for the results, we favor the existence of a mechanistic continuum involving an equilibrium between nickel(II) salen (15) and two reduced forms, one being the metal-centered species 16, the other being a ligand-centered species 17. We postulate that one form may be more prominently involved with the chemistry than another, depending upon the electronic properties/requirements of the substrate, and suggest that the equilibrium will shift to accommodate the need. Thus, for a hard electrophile like an alkyl halide, the properties of 16 ought to dominate, whereas 17 ought to predominate as the reactive species accounting for the chemistry described herein since it properly matches a soft ligand-centered nucleophile with a soft electron deficient alkene.

A New Entry in Catalytic Alkynylation of Aldehydes and Ketones: Dual Activation of Soft Nucleophiles and Hard Electrophiles by an Indium(III) Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A New Entry in Catalytic Alkynylation of Aldehydes and Ketones: Dual Activation of Soft Nucleophiles and Hard Electrophiles by an Indium(III) Catalyst

[reaction: see text] A new entry in catalytic alkynylation of carbonyl compounds was developed in which dual activation of both soft nucleophiles (terminal alkynes) and hard electrophiles (aldehydes and ketones) is achieved using an indium(III) catalyst. Preliminary mechanistic studies using in situ IR and NMR spectroscopic analysis are also discussed.

Mechanism based structure-activity relationships for skin sensitisation--the carbonyl group domain

The biological activity of skin-sensitising chemicals is related to their ability to react either directly or after metabolic activity with appropriate skin proteins. For direct-acting electrophilic compounds, this ability can be modelled by the Relative Alkylation Index (RAI) by a combination of electrophilicity and hydrophobicity parameters. Several SARs based on this approach are reported. In this present work, electrophilicity parameters based on Taft substituent constants are used together with Leo and Hansch log P fragment values to calculate RAI values for hard electrophiles having a reactive carbonyl group. These are then applied to analysis of sensitisation data obtained in the murine Local Lymph Node Assay (LLNA) for two series of diketones as well as a homologous series of alpha, beta-unsaturated aldehydes. The sensitisation potentials of these reactive electrophiles show good correlations with the RAI. These findings re-affirm the view that physicochemical parameters are the key to eliciting the relationship between chemical structure and a toxic endpoint. They provide further evidence of the value of SAR studies in identifying mechanisms of sensitisation and aiding risk assessments without the need for extensive animal testing.

ChemInform Abstract: Preparation and Reactivity Studies of 1,2‐Bis‐triisopropylsilanylsulfanyl‐alkenes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Preparation and reactivity studies of 1,2-bis-triisopropylsilanylsulfanyl-alkenes

The cross-coupling reaction of bis-triisopropylsilyl disulfide 1 on alkynes yielded 1,2-bis-triisopropylsilanylsulfanyl-alkenes 2, a new chemical class. A series of tri and tetrasubstituted olefins 2 were prepared and their behavior toward electrophiles was studied. The triisopropylsilyl groups could be readily removed by treatment with TBAF at 0°C for 1 h or cesium acetate at 70°C for 2 h. Soft and hard electrophiles were submitted to 2 under these conditions. The electrophiles can either react to yield double-addition products with alkyl and activated halides, epoxides and acyl chlorides or cyclic adducts with chloroformate derivatives. In the latter case, 1,3-dithiol-2-ones or 1,3-dithiol-2-thiones are prepared.

Twenty Years of Chemistry of Selenium Stabilized Carbenium Ions

This overview summerizes the most important aspects of our present day knowledge about the title species. The material is presented in two sections; the first one reminds salient physico-chemical results related to the stabilization of carbenium ions by selenium moieties and the second one gives examples of the synthetic usefullness of these electrophiles. Gas phase proton affinity measurements complemented by ab initio MO calculations revealed that the intrinsic carbocation stabilizing ability of the Group 16 elements decreases from oxygen to tellurium. However, this ability is not connected in a straightforward manner to the dispersion of the cation's positive charge. The latter is the largest for the most stable species, i.e. oxocarbenium ions, and it decreases downwards in Group 16. Therefore, coulombic (i.e. electrostatic) factors must play a significant role in the overall stabilization. It follows that oxocarbenium should be considered as hard electrophiles undergoing rapid charge contolled reactions with hard nucleophiles, whereas seleno- and tellurocarbenium ions are soft electrophiles giving rise to slow reactions with the same hard nucleophiles. The ability of a series of selenocarbenium ion precursors to undergo useful inter- and intramolecular C, C bond forming reactions is illustrated.

Structure-activity relationships in the murine local lymph node assay for skin sensitization: alpha,beta-diketones.

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after metabolic activation, with appropriate skin proteins. For direct acting electrophilic compounds, this ability can be modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity parameters. Several structure-activity relationships based on this approach have been reported, but most of them cover guinea pig sensitization test data on what chemists would classify as relatively soft electrophilic chemicals. In the present work, an electrophilicity parameter based on Taft substituent constants is derived for hard electrophiles having a reactive carbonyl group, and is used to calculate RAI values for the analysis of sensitization test data obtained in the murine local lymph node assay (LLNA) for a series of alpha, beta-diketones. The sensitization potential of these reactive hard electrophilic carbonyl compounds in the LLNA shows a good correlation with the RAI. Overall, the findings reaffirm our view that physical organic chemistry is the key to understanding why some chemicals sensitize more strongly than others, while some do not sensitize at all, and provide further evidence of the value of the LLNA for SAR studies.

Density Functional Study of Protonated, Acetylated, and Mercurated Derivatives of Ferrocene: Mechanism of the Electrophilic Substitution Reaction

The mechanism of the electrophilic substitution reaction of ferrocene has been investigated using density functional theory. In particular, reactions with two hard electrophiles (protonation and acetylation) and one soft electrophile (mercuration) have been studied at the LDA and B-PW91 levels of theory using a triple-ζ STO basis set. A general description of the reactions has been obtained, leading to results in agreement with experiment. Acetylation is found to occur via exo attack, whereas mercuration follows an endo mechanism. In the case of protonation, evidence for a rapid equilibrium between metal-protonated and agostic ring-protonated ferrocene is obtained, and no clear conclusion concerning the exo or endo mechanism can be deduced. The calculated proton affinities corresponding to both metal-protonated and agostic ring-protonated structures are in excellent agreement with experiment.

The electronic factor in QSAR: MO-parameters, competing interactions, reactivity and toxicity.

Reactive chemicals pose unique problems in the development of SAR and QSAR in environmental chemistry and toxicology. Models of the stereoelectronic interactions of reactive toxicants with biological systems require formulation of parameters that quantify the electronic structure of the chemicals. A review of early approaches to modeling reactivity is presented in this work, with emphasis on the generalized polyelectronic perturbation theory. Applications of GPPT are demonstrated with QSARs for predicting toxicity of soft electrophiles and proelectrophiles using superdelocalizability and the charges on frontier orbitals. Prediction of toxicity for hard electrophiles such as organophosphates require atomic charges and bond orders in the QSAR. Special considerations for the orthogonality of factors and for the classification of reactive chemicals are reviewed.

Unprecedented route to enolates from silyl enol ethers and enol acetates: reaction with hard and soft electrophiles

Reaction of silyl enol ethers with lithium, sodium or, better, potassium alkoxides resulted in a rapid formation of enolates which were trapped with hard electrophiles and benzaldehyde. Moreover, in the aldolisation reaction, only a catalytic amount of alkali alkoxide is needed. This methodology is also applied to enol acetate. During these reactions a non-basic species, ether or ester, is produced with the enolate.

Allenyl Enolates — A New Class of Chiral Ambident Nucleophiles, 1. Reaction with C and Si Electrophiles

AbstractThe regio‐ and stereoselectivity of the reaction of allenyl enolates obtained by 1,6‐addition of lithium dimethylcuprate to acceptor‐substituted enynes 1 with C and Si electrophiles is examined. It is found that allyl bromide reacts at C‐4 to give 4‐substituted 2,4‐dienoates 2; in contrast, methyl triflate and carbonyl compounds react at C‐2 to yield 2‐substituted β‐allenic esters 3–12. The hard electrophile chlorotrimethylsilane reacts at the enolate oxygen atom to provide allenyl enol ether 14. The regioselectivity of these trapping reactions depends only on the nature of the electrophile; the stereoselectivities, on the other hand, are a function of both the steric properties of the allenyl enolate and the type of electrophile. The regio‐and stereoselectivities are rationalized in terms of charge control and frontier‐orbital control, of kinetic and thermodynamic control, and of steric interactions in intermediates and transition states.

Further evidence to understand the stereochemistry of the reactions of α‐sulfinyl carbanions

AbstractThe stereochemistry of the α‐sulfinyl carbanion has been studied. It has been elucidated that a 2‐pyridylmethyl substituent on the sulfinyl sulfur chelates onto the counter cation in an ion pair to fix the conformation of the anion at a particular orientation. Then, the steric bulk of the other substituent plays a role to control the reacting face. A soft electrophile such as methyl iodide attacks the anion from the more open side. On the other hand, a hard electrophile such as a proton is initially trapped by the polar part of the ion pair and no steric effect operates.

Influence of electrophilic character and glutathione depletion on chemical dysmorphogenesis in cultured rat embryos

To examine the importance of reduced intracellular glutathione (GSH) in the modulation of dysmorphogenesis and to gain insight into the electrophilic character of the embryotoxic intermediates generated in the rat embryo from N-acetoxy-2-acetylaminofluorene (AAAF) and acetaminophen (APAP) in cultured embryos, the effects of GSH depletion on the embryotoxicity, dysmorphogenesis and covalent binding of these agents were examined. Both AAAF (90μM) and APAP (500 μM) produced concentration-dependent, statistically significant (P ⩽ 0.05) decreases in embryonic length as well as embryonic and visceral yolk sac protein content when rat embryos were exposed in vitro between days 10 and 11 of gestation. The predominant malformations observed upon exposure to AAAF and APAP were prosencephalic hypoplasia and abnormal neurulation respectively. Exposure of conceptuses to [ 3H]APAP followed by separation and fractionation of the cellular RNA, DNA and protein via density gradient centrifugation resulted in detectable binding in fractions that contained protein, but not DNA or RNA. This suggested that the rat conceptus is capable of bioactivating APAP to a soft electrophile that selectively arylates protein. In contrast, conceptuses exposed to [ 3H]AAAF exhibited detectable binding to RNA, DNA and protein, indicative of conversion to both hard and soft electrophiles. Depletion of GSH was accomplished by pretreating conceptuses with 500 μM l-buthionine- S, R-sulfoximine (BSO) from the start of the culture period (day 9.5) until the morning of day 10. When conceptuses were depleted previously of GSH by BSO, exposure to APAP resulted in significant potentiation (relative to APAP alone) of the observed embryotoxicity. These conceptuses displayed further decreases in both embryonic size and protein content of the embryo and yolk sac, as well as increased incidence of abnormally open anterior neuropores and increased binding (3-fold) of [ 3H]APAP to protein. In contrast, pretreatment with BSO did not potentiate the AAAF-elicited decreases in embryonic size or protein content, nor the severity of prosencephalic hypoplasia, although a slight increase in binding of [ 3H]AAAF to DNA was observed. Taken together, these data are consistent with the concept that abnormal neurulation elicited by APAP results from the generation of one or more soft electrophilic species, whereas elicitation of prosencephalic hypoplasia by AAAF appears to be a consequence of conversion to a relatively hard electrophile(s).

β-silylation of N-alkylpyrroles, experimental support of theoretical calculations

The β-substitution of N-alkylpyrroles which is “unusual” but predicted by theoretical calculations, was supported by the 1H-NMR and GC/MS analysis of the reaction products of 1-methylpyrrole-2,5-d 2 ( 1a ) with trimethylsilyl trifluoromethane-sulfonate ( 2 ) in triethylamine ( 3 ). Thus, 1a gives with 2 in 3 predominantly the β-isomer 5b (two deuteriums) and small amounts of the α-isomer 4a (one deuterium). The formation of these products of such a deuterium distribution evidently supports the results of theoretical calculations which indicate that the electron density is the major factor controlling the electrophilic substitution of N-alkylpyrroles with hard electrophiles. The thermodynamic stability of the α-substituted form I (Scheme 1) is assumed to be the second factor governing this reaction, since the α α β isomerization was conclusively ruled out.

Reaction potential map analysis of chemical reactivity?III

Reaction potential maps (RPM) have been introduced as a new tool for the study of molecular reactivity. The equipotential energy maps, which are created on given planes around a molecule, define reaction contours towards specific counter-reagent models and are evaluated by perturbation theory. Since the calculated interaction energy involves electrostatic, polarization, exchange, and charge transfer energies, the RPM's can be used to predict site selectivity in a variety of chemical reactions. We found that the calculated RPM's of the SCN− anion explained well the experimental observations that it reacts at the S atom with soft electrophiles and at the N atom with hard electrophiles. The difference in reactivity between SCN− and OCN− was clearly shown by the RPM's of these anions. The ambident nucleophilic nature of the NO 2 − and the CH2CHO− anions was also well represented by their RPM's.