Covalent electrophile

Diels-alder adducts at 0°C. This cation radical-vinylcyclobutane rearrangement is non-stereospecific, thus accounting for the formation of a cis-trans mixture of Diels-Alder adducts. Kinetic studies revealed (Scheme 8) that the ionization of these ethers involves an inner-sphere electron-transfer mechanism involving strong covalent (electrophilic) attachment to the substrate via oxygen (oxonium ion) or carbon (carbocation). 

Acute toxicity to aquatic species can be rationalized mechanistically by one of two types of interactions nonspecific mechanisms (called narcosis) or specific mechanisms. The latter involves specific interactions, such as covalent electrophilic reactions with biological macromolecules, or specific noncovalent interactions that cause toxicity, such as uncoupling of phosphorylative oxidation, among others. Most chemicals that are toxic to aquatic organisms are narcotic. Some have both narcotic and specific mechanisms. A narcotic chemical enters the cellular membranes of the organism and, by its mere presence, causes perturbations in the membranes to the extent that alterations in the function of the membranes occur, resulting in toxicity. 

Winstein et al. [45] first presented evidence for the concept that different types of electrophilic species, each with distinct reactivities, may participate in reactions involving cationic intermediates. As shown in Eq. (36), Winstein et al. proposed that four species are in equilibrium, including covalent electrophiles, contact ion pairs, solvent-separated ion pairs, and free ions. In addition, ion pairs may aggregate in more concentrated solutions- According to this concept, electrophilic species do not react with a continuous spectrum of charge separation, but rather in well-quantified minima in the potential energy diagram. 

In view of this, it is not surprising to find that the majority of modern synthetic methods based on the heterolytic reactions of C-C bond formation rely mainly on the combination of the formally ionic nucleophile and covalent electrophile, with the reverse options being much less common. A notable exception is in the case of electrophilic substitution in the aromatic series (Friedel-Crafts type reactions), which serve as extremely powerful synthetic... 

Thus the utilization of the approach based upon the coupling of neutral nucleophiles with ionic electrophiles, while still not as popular as the coupling of ionic nucleophiles with covalent electrophiles, has already produced a set of results clearly demonstrating its specific merits and promises. 

Figure 46 (a) An JV-bromoacetyl electrophile localized in the major groove by triplex formation proximal to the GC base pair on the duplex target site leads to N7 alkylation of G followed by depurination and strand cleavage, (b) Schematic diagram of target duplex cleavage by covalent electrophiles in the third strand. Reproduced by permission from J. Am. Chem. Soc., 114, 5934 (1992)... 

New Classification of Ionic Polymerization. The polymerization of with cationic initiator provides a novel system of ionic polymerization in which ionic species do not propagate but covalent electrophilic species do propagate Several cyclic monomers are known whose cationic polymerization proceeds via covalent propagating species, but these monomers propagate also via cationic species with changing the initiator. The present monomer is unique in that an electrophilic covalent species is the only species which is able to propagate. 

In the uncatalysed reaction the fact that added nitrate strongly accelerates the rate to the same extent as other salts makes it improbable that the nitronium ion is the effective electrophile. The authors of the work conclude that covalent dinitrogen pentoxide is the electrophilic... 

The Lewis bases that react with electrophiles are called nucleophiles ( nucleus seek ers ) They have an unshared electron pair that they can use m covalent bond formation The nucleophile m Step 3 of Figure 4 6 is chloride ion... 

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. 

The positive bromine which leads to bromonium ion intermediates is softer and also has unshared electron pairs which can permit a total of four electrons to participate in the bridged bromonium ion intermediate. This would be expected to lead to a more strongly bridged and more stable species than is possible in the case of the proton. The bromonium ion can be represented as having two covalent bonds to bromine and is electrophilic but not electron-deficient. 

FIGURE 16.9 Examples of covalent bond formation between enzyme and substrate. In each case, a nucleophilic center (X ) on an enzyme attacks an electrophilic center on a substrate. 

The CC bond distances in cyclopentadienyl anion, C5H5, are all equal, because the anion is aromatic (see Chapter 12, Problem 10). Electrophiles that interact electrostaticaUy with the anion, such as Na", interact equally with all five carbons, and do not disturb the anion s aromatic character. On the other hand, electrophiles that make covalent bonds, such as H", might interact more strongly with one particular carbon and destroy the aromaticity of the ring. 

The pyrylium cation possesses, according to the substituents in positions 2, 4, and 6, a more or less pronounced electrophilic reactivity which enables it to add nucleophiles in these positions. According to the nucleophilic reactivity and the carbon basicity " of the anions, an ion pair (a substituted pyrylium cation and an anion halide, perchlorate, sulfate, fluoroborate, chloroferrate, etc.), or a covalently bonded 2H- or 4//-pyran may be formed. With the more basic anions... 

Crosslinks result from the reaction of a bifunctional electrophilic species with DNA bases and imply a covalent link between two adjacent DNA strands which inhibits DNA replication. Primary targets within bases are N7 and 06 in guanine and N3 in cytosine. The initial lesions are removed by the suicide enzyme alkyltrans-ferase, whereas nucleotide excision repair is needed for frilly established crosslinks. 

Figure 2,40. Schematic of the two extreme conformations of adsorbed atomic oxygen on Ag covalently bonded electrophilic oxygen (a-) and ionically bonded oxygen (P-).98 Reprinted with permission from Academic Press.

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