Reactivity electrophilic substrates

The mercapturic acid pathway metabolites of menadione, the 3-glutathionyl and corresponding N-acetylcysteine conjugate (mercapturic acid) are a result of a detoxicative pathway designed to remove reactive electrophilic substrates from mammalian systems (10). The... 

The Stille reactions of aryl chlorides, as the least reactive electrophilic substrates can be successfully performed by applying a palladium-complex of electron-rich and sterically encumbered Pt-Bus as Pd(0)-stabilizing ligand [78]. The latter increases the electron-density at palladium metallic centre and thus facilitates the oxidative addition step of unreactive electron-rich aryl chlorides to the Pd(Pt-Bu3)2- For instance, even 4-chloroanisole (76), among the least reactive chlorides, was reacted with phenyltri-n-butylstannane (184) to give 4-methoxybiphenyl (78) in 94% yield [78], respectively,... 

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequentiy, an active site nucleophile in close proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via S 2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

There is, however, no direct evidence for the formation of Cl", and it is much more likely that the complex is the active electrophile. The substrate selectivity under catalyzed conditions ( t j = 160fcbenz) is lower than in uncatalyzed chlorinations, as would be expected for a more reactive electrophile. The effect of the Lewis acid is to weaken the Cl—Cl bond, which lowers the activation energy for o-complex formation. 

While A -dimethylaniline is an extremely reactive aromatic substrate and is readily attacked by such weak electrophiles as aiyl diazonium ions and nitrosonium ion, this reactivity is greatly diminished by introduction of an alkyl substituent in the ortho position. Explain. 

Measured activation energies, which are not independent of temperature nor of the acid concentration, vary between 13.3 and 24.2, show a minimum at the acid concentration giving the maximum rate and these fairly low energies for such unreactive substrates are consistent with a highly reactive electrophile. 

Tetraalkylstannanes undergo transmetallation reactions leading to reactive intermediates that may be combined with electrophilic substrates, as shown, for example, in reaction 74325. 

Fig. 14. Manifold of reactive species produced from the reaction of a heme group with oxygen and two reducing equivalents. The rate of conversion of A to B limits the lifetime (and therefore reactivity) of the Fe peroxo anion. The rate of formation of the ferryl species C via the Fe -OOH complex B competes with the intramolecular hydroxylation reaction to give hydroxyheme. Reactions of the Fe -hydroperoxy complex B with exogenous electrophilic substrates must compete with conversion of the intermediate to both C and meso-hydroxyheme. The Fe -OOH complex B can also be formed directly with H2O,.

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

Early studies of these complexes focused primarily on the investigation of their oxygen-atom-transfer reactivity. Relatively little success was achieved, however. The peroxo fragments in these complexes exhibit nucleophilic character, and, therefore, they are generally ineffective oxidants for reactions with synthetically interesting electron-rich substrates such as alkenes and sulfides. Most of the known reactivity involves electrophilic substrates that, in many cases, insert into the Pd-0 bond of peroxopalladium(II) species (Fig. 4) [105,118]. 

New catalysts have been described,646 and ab initio MO calculations have shown that the transformation takes place through a four-center transition state.647 In addition, the anomalous relative reactivities of substrates, specifically, the higher reactivity of alkynes compared to those of alkenes, can be explained by considering the reaction to essentially be a nucleophilic attack by an alkyl anion, rather than an electrophilic one. 

The various ways of forming OH were discussed in Chapter 2. It is a very reactive, electrophilic (9 = -0.41 Anbar et al. 1966a) radical, and with most substrates it reacts at close to diffusion-controlled rates (for a compilation of rate constants, see Buxton et al. 1988). It undergoes mainly three types of reactions (1) addition to C-C and C-N double bonds, (2) H-abstraction and (3) ET. Addition and H-abstraction reactions will be discussed below in some detail, because they are relevant for an OH-attack at the nucleobases and at the sugar moiety in DNA. 

The ease with which these reactions will occur depends to a large extent on the precise structure of the substrate and can be difficult to predict. Low reaction temperatures will generally prolong the half-life of the initially formed carbanions, which might then be trapped intermolecularly with reactive electrophiles before rearrangement can occur [193, 252], Intramolecular trapping of such carbanions can also be used to prevent their rearrangement [253, 491]. 

Monosubstitution is obtained in the photoinitiated reaction of different carb-anions, such as CH(COMe)2, CH(C02Et)2, CH(COMe)C02Me, CMe(COMe) C02Me and CEt(C02Et)2 (60-92%), with electrophilic substrates. Investigations have shown that 4-iodo-l,l,2,2,9,9,10,10-octafluoro[2.2]paracydophane (4) exhibits excellent SRN1 reactivity with some of these stabilized enolates (Scheme 10.12) [24]. 

Vesicants, nerve agents, and phosgene are reactive electrophiles that react covalently with nucleophilic sites on macro molecules. Reactive nucleophilic sites exist on the bases and phosphate groups of DNA molecules. An advantage of DNA as a substrate is that it is present in all tissues of the body. A disadvantage is that repair mechanisms tend to excise the alkylated moiety, resulting in a much shorter lifetime compared to alkylated proteins (for a recent review of mass spectrometry for quantitation of DNA adducts, see Koc and Swen-berg <2>). 

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