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An elaborate network of highly inducible phase 2 proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of malignancy and chronic degenerative diseases. Many chemical and phytochemical agents, all of which react with thiol groups, induce the phase 2 response through their reactivity with critical cysteine thiols of Keap1. We recently found that the anti-inflammatory potencies (suppression of iNOS and COX-2 expression) of a series of triterpenoids with Michael reaction centers were closely correlated with the potencies of these agents to induce the phase 2 response. We now report that representatives of seven recognized chemical classes of inducers, including isothiocyanates, bisbenzylidenes, arsenicals, heavy metals, and vicinal dithiols, showed highly correlated inducer and anti-inflammatory potencies spanning more than six orders of magnitude of concentrations in established cells and in primary mouse peritoneal macrophages. Potency measurements were expressed as the [D.sub.m] values (median effect concentration) by use of the Median Effect Equation. Whereas the phase 2 induction required the functional integrity of both the repressor Keap1 and the transcription factor Nrf2, the effectiveness of inducers in blocking the up-regulation of iNOS by inflammatory cytokines was related to the nature of the cytokine and the inducer concentration. These studies identify suppression of inflammation as a consistent property of inducers of the phase 2 response and strongly suggest that this property is a central aspect of their chemoprotective actions. Keap1 | NAD(P)H:quinone oxidoreductase | Nrf2 | sulforaphane | inducible NOS

The fabrication of nonaromatic divalent nickel corroles with benzoate moiety by ring contraction of nickel meso-tetraarylporphyrins is reported. The corroles are found to be reactive molecules that could be acylated, halogenated, nitrated, or deoxygenated under very mild conditions.

The activation energies for the oxidation of nine primary alcohols of general molecular formula RC[H.sub.2]OH are compared with theoretically evaluated global electrophilicity values. The theoretical values can be correlated with the reaction rates only for single-step reactions.

The simple, inexpensive electrophiles [I.sub.2], ICl, and PhSeBr in nitromethane were used to perform a general synthesis of 2H-benzopyrans in good yields through electrophilic cyclization. The methodology resulted in vinylic halides or selenides under mild reaction conditions, tolerating a variety of functional groups including methoxy, alcohol, aldehyde and nitro groups.

(4-Hydroxy)mandelate synthase (HmaS) and (4-hydroxyphenyl)pyruvate dioxygenase (HPPD) are two [alpha]-keto acid dependent mononuclear non-heme iron enzymes that use the same substrate, (4-hydroxyphenyl)pyruvate, but exhibit two different general reactivities. HmaS performs hydrogen-atom abstraction to yield benzylic hydroxylated product (S)-(4-hydroxy)mandelate, whereas HPPD utilizes an electrophilic attack mechanism that results in aromatic hydroxylated product homogentisate. These enzymes provide a unique opportunity to directly evaluate the similarities and differences in the reaction pathways used for these two reactivities. An [Fe.sup.II] methodology using CD, magnetic CD, and variable-temperature, variable-field magnetic CD spectroscopies was applied to HmaS and compared with that for HPPD to evaluate the factors that affect substrate interactions at the active site and to correlate these to the different reactivities exhibited by HmaS and HPPD to the same substrate. Combined with density functional theory calculations, we found that HmaS and HPPD have similar substrate-bound complexes and that the role of the protein pocket in determining the different reactivities exhibited by these enzymes (hydrogen-atom abstraction vs. aromatic electrophilic attack) is to properly orient the substrate, allowing for ligand field geometric changes along the reaction coordinate. Elongation of the [Fe.sup.IV]==O bond in the transition state leads to dominant [Fe.sup.III]--[O*.sup.-] character, which significantly contributes to the reactivity with either the aromatic [pi]-system or the C--H [sigma]-bond. magnetic circular dichroism | density functional calculations | reaction coordinates

4-Aryl-6-methyl-3,4-dihydro-2(1H)-pyrimidinone esters (DHPMs) readily undergo metalation at the C-6 methyl position on treatment with lithium diisopropylamide at -10 degree Celsius. The resulting anion intermediates could be treated with electrophilic reagents to afford functionalized DHPMs that are chemically elaborated mainly at the C-6 position.

A new reactivity descriptor delta f(r) provides useful information on both stabilizing and destabilizing interactions between a nucleophile and an electrophile and helps to identify the electrophilic/nucleophilic behavior of a specific site within a molecule. It is shown that the new descriptor correctly predicts the site reactivity induced by different donor and acceptor groups in substituted phenyl molecules.

The valuable chiral sources C(9),C(10)-disubstituted camphors can be enantiospecifically obtained from the corresponding C(9)-substituted camphors by a general and straightforward method. The method involves the electrophilic treatment of a key 2-methylenenorbornan-1-ol intermediate, followed by a controlled tandem carbon-carbon double-bond addition, Wagner-Meerwein rearrangement of the norbornane framework.

Aminoalkynes and related heterocyclic systems react with CF3SO3H for generating dicationic electrophiles that can react with benzene and other arenes. These novel species are composed of vinyl cations with adjacent positive charge centers that can be used to prepare products with good yields from inter and intramolecular reactions.

The scope and limitations of a method are examined for predicting the regioisomer distribution in electrophilic aromatic substitution reactions that are under kinetic control. The predictions from the method is used for halogenations and also for nitrations, the method has given useful predictions for heterocyclic substrates.

The potential of halogen-magnesium exchange reactions, followed by quenching with electrophiles was explored for the functionalization of the pyridazin-3(2H)-one core. A tandem reaction involving nucleophilic substitution via addition elimination and bromine-magnesium exchange was observed with 2-benzyl-5-bromo-4-methoxy while 2-b enzyl-4-bromo-5-methoxy and 2-benzyl-4,5-dibromopyridazin-3(2H)-one gave exclusively C-4 metalation.

The kinetics of reactions of acceptor-stabilized carbanions with benzylidenebarbituric and -thiobarbituric acids, are determined in a dimethyl sulfoxide solution and the electrophilicity parameters are determined by using second-order rate constants. The studies have shown that the electrophilicities of these acids are comparable to those of analogously substituted benzylidenemalononitriles.

Cyclopentadienylidenetriphenylphosphorane (the Ramirez ylide) is shown to be like pyrrole that is undergoing electrophilic substitution on the cyclopentadienide ring at either the 3- or the 2-position, depending on the electrophile. The analysis of all compounds is used for developing a reliable method for the unambiguous assignment of the regiochemistry of adducts formation.

The reactions between strongly electron-rich aromatic substrates (1,3,5-tris(N,N-dialkylamino)benzenes, neutral carbon super nucleophiles) and diazonium salts have produced moderately stable [sigma] complexes. The final products of the double diazo-coupling reactions have provided evidence that is a clear instance of complete reversibility of the diazo-coupling reaction.

The unique effect of internal vinylic halogen substitution in directing the iodocyclization of unsaturated amides is demonstrated. The reaction proceeds through lactamization rather than the usual lactonization resulting in efficient synthesis of 5-,6-, and 7-membered cyclic iminoketones.

The preparation of variety of phenethylamines containing a potentially free primary amine after appropriate deprotection is reported. The synthesis is achieved by using organotrifluoroborates as reagent in Suzuki-Miyaura cross-coupling reaction of aryl electrophiles.

The multifaceted studies to develop the electrophilic chemistry of thia-PAHs are reported. The process is applied to generate a series of carbocations from four-ring-fused thia-PAHs and their regioisomeric methoxy derivatives.

The rates of proton-transfer reactions from hydrogen-bond energies, reaction energies, electrophilicity indices, bond lengths and vibration frequencies of the reactive bonds are calculated using the reaction path of the intersecting-state model in transition-state theory with semiclassical correction for tunneling (ISM/scTST). These calculations explain the roles of the reaction energy, electrophilicity, structural parameters, hydrogen bonds, tunneling and solvent in the reactivity of acids and bases.

The synthesis of novel bicyclic [alpha]-amino acids, exo and endo-1-azabicyclo-[2.2.1]heptane-2-carboxylic acid, 1-azabicyclo[2.2.1]heptane-7-carboxylic acid and 1-azabicyclo[3.2.2]nonane-2-carboxylic acid was carried out to generate neuronal nicotinic receptor ligands. Alkylation of glycine derived Schiff bases for nitroacetates with cyclic ether electrophiles followed by acid-induced ring opening and cyclization in N[H.sub.4]OH, allowed for the preparation of substantial quantities of the three tertiary bicyclic [alpha]-amino acids.

2,3-Disubstituted benzo[b]selenophenes are prepared by the electrophilic cyclization of various 1-(1-alkynyl)-2-(methylseleno)arenes by Br2, NBS, I2, IC1, PhSeCl, PhSeBr, and Hg(OAc)2. This method tolerates a wide variety of functional groups, including alcohol, ester, nitrile, nitro, and silyl groups, and proceeds under exceptionally mild reaction conditions.

Density functional theory based on global and local electrophilicity descriptors are used to study the reliability of local electrophilicity values of the strongest electrophilic sites in generating global intermolecular electrophilicity trends. The values on 15 different organic chlorides show that, for systems having more than one comparatively strong electrophilic site, the local electrophilicity value of the strongest site does not produce a reliable global intermolecular electrophilicity trend.

Reactive intermediates in the Friedel-Crafts acylation of aromatic donors are scrutinized upon their successful isolation and X-ray crystallography at very low temperatures. The X-ray-structure examinations of aliphatic and aromatic acylium electrophiles isolated as crystalline salts that indicate the origins of their electrophilic reactivity are analyzed.

The IR spectroscopy is coupled with the matrix isolation technique to study the reaction of trimethylsilylketene with HCl. Trimethylsilylketene reacts with hydrogen chloride at 50 K, leading to the cleavage of the Si-C bond and the formation of trimethylsilyl chloride and acetyl chloride, through intermediate trimethylsilylacetyl chloride which is identified.

A variety of substituted isoindolin-1-ones are readily prepared in good to excellent yields under very mild reaction conditions by the reaction of o-(1-alkynyl)benzamides with IC1, I(sub 2), and NBS. In a few cases, substituted isoquinolin-1-ones were obtained as the major product instead.

A mechanism for an unusual electrophilic aromatic addition reaction [AD(sub E)Ar)] is reported and proposed. During the preparation of 5,7-dibromo-8-methoxyquinaldine as a key intermediate in the synthesis of 7-bromoquinaldine-5, 8-dione, direct bromination in either acidic or neutral conditions led only to the formation of 5-bromo-8-methoxyquinaldine.

A study demonstrates that the glutathione-gated K(super +) efflux (GGKE) of cytoplasmic K(super +) occurs in activated sludge communities in response to shock loads of industrially relevant electrophilic chemicals. The analysis shows that shock loads of electrophilic chemicals result in very high K(super +) concentrations within the activated sludge floc structure and these K(super +) levels are comparable to that which caused deflocculation by external KCl addition.

A link between the superelectrophilicity of a range of dications and the electrophilicity index of isolated species is presented. The improved electrophilicity is explained by global and local reactivity indexes.

Tetraorganoindates are directly employed as effective nucleophilic cross-coupling parameters in Pd-catalyzed carbonylative cross-coupling reactions with a variety of organic electrophiles such as aryl, and vinyl halide, aryl triflate, benzyl bromide, and benzoyl chloride. The advantages of the present method are described.

N,N-Dichloro-o-nitrobenzenesulfonamide (2-NsNCL2) is an effective electrophilic nitrogen source for the direct diamination of alpha, beta-unsaturated ketones without using any metal catalysts. A simple direct diamination can be carried out by mixing reactants, in a one-pot operation at room temperature.

An absolute scale based on reactivity indexes and an extension of it to describe the local electro-philicity power of molecules was used to evaluate the global electrophilicity pattern of singlet carbenes. Additional information regarding electrophilic activation/deactivation patterns induced by substituent groups in the molecule is provided by the local analysis.