Nucleophilic attack on activated

Both reactions involve nucleophilic attack of tricoordinated phosphorus on tetrahedral carbon and show all the characteristics of non-polar reactants combining through polar transition states although the solvent effects are sometimes quite modest.— Subsequent studies have demonstrated nucleophilic attack on activated alkenes,Z activated alkynes,Z the carbonyl groupZ-Z and halogen , whilst in the Perkow reaction (eqn. 1) all four possible sites in... 

The second example involves nucleophilic attacks on activated bicyclobutane. These attacks occur anti to the central bond, which is cleaved in the course of the reaction. The LUMO of this bond is lower than that of ethylene. Thus, if considered to be an SN2 reaction, the reaction complies with the two aforementioned demands. Unfortunately, data are available (11) for the reaction of this system with CN and CH30 only ... 

The log k values were correlated with two other sets of data. When plotted against the log k for reaction of the [(p-dimethylamino)-phenyl]tropylium ion with nucleophiles, two approximately parallel lines, one for reactions in MeOH and one for reactions with water, were obtained. A plot of log k for the reaction of 9 versus log k for the reaction of 2,4-dinitro-phenyl acetate with several nucleophiles was linear thus, similarities existed in the transition states for nucleophilic attack on activated vinylic and aromatic carbon. 

Several approaches have been taken to the development of efficient hydroam-ination processes and they have led to catalytic reactions that follow three main types of mechanisms (a) nucleophilic attack on activated metal-coordinated alkenes (applied mainly to late transition metals) [218], (b) cycloaddition of an alkyne and a metal imido moiety [219], (c) insertion into an M-N(amido) bond [207,220]. The subject has been reviewed recently [221]. 

Charge diagrams suggest that the 2-amino-5-halothiazoles are less sensitive to nucleophilic attack on 5-position than their thiazole counterpart. Recent kinetic data on this reactivity however, show, that this expectation is not fulfilled (67) the ratio fc.. bron.c.-2-am.noih.azoie/ -biomoth.azoie O"" (reaction with sodium methoxide) emphasizes the very unusual amino activation to nucleophilic substitution. The reason of this activation could lie in the protomeric equilibrium, the reactive species being either under protomeric form 2 or 3 (General Introduction to Protomeric Thiazoles). The reactivity of halothiazoles should, however, be reinvestigated under the point of view of the mechanism (1690). 

The a-amino group of the new aminoacyl-tRNA in the A site carries out a nucleophilic attack on the esterified carboxyl group of the peptidyl-tRNA occupying the P site (peptidyl or polypeptide site). At initiation, this site is occupied by aminoacyl-tRNA mef. This reaction is catalyzed by a peptidyltransferase, a component of the 285 RNA of the 605 ribosomal subunit. This is another example of ribozyme activity and indicates an important—and previously unsuspected—direct role for RNA in protein synthesis (Table 38-3). Because the amino acid on the aminoacyl-tRNA is already activated, no further energy source is required for this reaction. The reaction results in attachment of the growing peptide chain to the tRNA in the A site. 

A. Nucleophilic Attack on Carbon. —(/) Activated Olefins. A study of triarylphosphine-catalysed dimerization of acrylonitrile to 2-methylene-glutaronitrile (26) and 1,4-dicyano-l-butene (27) has established a balance between phosphine nucleophilicity and protolytic strength of the solvent. The reaction of methyl vinyl ketone with triphenylphosphine in triethyl-silanol gave only 3-methylene-2,6-heptadienone (28). 

One of the questions that is commonly addressed in mechanistic proposals is how is the active site water activated for nucleophilic attack on the phosphodi-ester bond Numerous combinations of amino acid side chains and zinc ions have been proposed for this role, but there has been little consensus. Critical to all the general base hypotheses is a quite reasonable assumption about catalysis by PLC5c The nucleophilic attack on the phosphodiester moiety proceeds via an in-line mechanism resulting in stereochemical inversion of configuration at phosphorus [86]. While this assumption is consistent with the position of the active site water molecules in the PLCBc-phosphonate inhibitor complex [45], it has not yet been established experimentally. This structure provides a detailed picture of how the amino acid side chains of Glul46, Glu4, Asp55, and the zinc ions interact with the phosphonate inhibitor (Fig. 12), so mechanistic hypotheses now have a structural basis. 

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

Synthetic organic chemistry applications employing alkane C-H functionalizations are now well established. For example, alkanes can be oxidized to alkyl halides and alcohols by the Shilov system employing electrophilic platinum salts. Much of the Pt(ll)/Pt(rv) alkane activation chemistry discussed earlier has been based on Shilov chemistry. The mechanism has been investigated and is thought to involve the formation of a platinum(ll) alkyl complex, possibly via a (T-complex. The Pt(ll) complex is oxidized to Pt(iv) by electron transfer, and nucleophilic attack on the Pt(iv) intermediate yields the alkyl chloride or alcohol as well as regenerates the Pt(n) catalyst. This process is catalytic in Pt(ll), although a stoichiometric Pt(rv) oxidant is often required (Scheme 6).27,27l 2711... 

Calcineurin is a serine/threonine protein phosphatase widely distributed in the brain, but its role in brain function remains unknown. It is critical for several important cellular processes including T-cell activation, and recent data indicate that it may be involved in hyperphosphorylation of tau in Alzheimer s disease (600, 601). The active site of native calcineurin contains zinc and iron metal ions and three metal-bound water molecules (602), one of which may be involved in nucleophilic attack on the substrate. Compound 119 (FK506, tacroli-... 

A nucleophilic attack on the acetylenic ketone functionality of golfomycin A (184) was proposed as a potential pathway to form the benzannulated enyne-allene 185 (Scheme 20.38) [71]. Subsequent biradical formation has been postulated as a possible mechanism to account for its DNA-cleaving properties and antitumor activity. 

Liebeskind and coworkers have examined the reactivity of (2//-pyran)Mo(CO)2Cp+ cations 210, which may be prepared in optically active form from carbohydrate precursors. Nucleophilic attack on cation 210 occurs at the diene terminus bonded to the ring oxygen to give jr-allyl complexes 51 (Scheme 53)85. Hydride abstraction from 51 gives the cation 54 addition of a second nucleophilie occurs regioselectively to give... 

Fig. 10.5. Catalytic models of epoxide hydrolase (modified from [59]). a) In an earlier model, a basic group in the enzyme activates a H20 molecule during nucleophilic attack on the epoxide, b) A more-elaborate model showing a carboxylate group in the catalytic site that carries out the nucleophilic attack on the substrate to form an ester intermediate. Only in the second step is the intermediate hydrolyzed by an activated H20 molecule, leading to enzyme reactivation and product liberation. 

Molecular dynamics free-energy perturbation simulations utilizing the empirical valence bond model have been used to study the catalytic action of -cyclodextrin in ester hydrolysis. Reaction routes for nucleophilic attack on m-f-butylphenyl acetate (225) by the secondary alkoxide ions 0(2) and 0(3) of cyclodextrin giving the R and S stereoisomers of ester tetrahedral intermediate were examined. Only the reaction path leading to the S isomer at 0(2) shows an activation barrier that is lower (by about 3kcal mol ) than the barrier for the corresponding reference reaction in water. The calculated rate acceleration was in excellent agreement with experimental data. ... 

The mechanism of catalysis by these enzymes has been extensively investigated (for review see ref. 10). Essentially, the active site serine via its side chain hydroxyl group performs a nucleophilic attack on the carbonyl carbon of the scissile peptide bond thus forming a tetrahedral intermediate. A histidine residue in the active site serves as a general base accepting the proton from the serine residue. The acyl enzyme thus formed is broken down via a nucleophilic attack of a water molecule to complete the hydrolysis of the peptide bond. 

The catalytic mechanism in this class is based upon similar chemical principles as the mechanism of the serine proteinases. A cysteine residue in the active site is activated by a histidine imidazolium side chain and carries out a nucleophilic attack on the carbonyl carbon of the scissile peptide bond with the complex going through an acyl intermediate transition state (28,29). Certain members of this class of enzymes have pH optima in the acidic range and... 

Nucleophilic attack on the acyl enzyme p-nitrophenoxycarbonyl-chymotrypsin, where the leaving group has a pATg-value comparable to that of histidine, takes place by a group in the active site which is most probably histidine (Fife et a/., 1972 Hutchins and Fife, 1972 Bender and Wedler, 1972), showing that nucleophilic attack is sterically possible [equation (14)]. p-Nitrophenolate ion is released... 

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