Nucleophilic addition irreversible

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Incorporation of lsO into the ketone occurs hardly at all under these conditions, i.e. at pH 7, but in the presence of a trace of acid or base it occurs [via the hydrate (13)] very rapidly indeed. The fact that a carbonyl compound is hydrated will not influence nucleophilic additions that are irreversible it may, however, influence the position of equilibrium in reversible addition reactions, and also the reaction rate, as... 

Scheme 12 shows a minimal mechanism for solvolysis and isomerization of Me-4- 0C(0)QF5. Values of = 6 X 10 s for the direct nucleophilic addition of solvent to the ion-pair intermediate, and k- = 1.6 X 10 s for the irreversible diffusional separation of the intermediate to free ions have been reported in earlier work. Both of these reactions result, eventually, in formation of the solvent... 

In principle, all carbonyl addition reactions could be reversible but, in practice, many are essentially irreversible. Let us consider mechanisms for the reverse of the nucleophilic addition reactions given above. For the base-catalysed reaction, we would invoke the following mechanism ... 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

Nucleophilic addition of an enzyme group results in irreversible inhibition ... 

The challenge in developing new MCRs involving amines and carbonyls is to identify additional components that do not undergo irreversible nucleophilic addition to the carbonyl component, leading to carbonyl addition products. 

Although this mechanism was widely accepted, later work by Metzler and coworkers167 and by Walsh and coworkers168,169 revealed that, whereas the eneamino aldimine complex is formed in the inhibition process, subsequent elimination produces amino acrylate. Nucleophilic addition of amino acrylate to the Schiff base formed between the enzyme lysine residue and PLP results in irreversible inhibition (Figure 15). Support for this mechanism includes the isolation of the pyruvate derivative 103 (the Schnackerz adduct) upon denaturization. The significance of the reversed polarity pathway as an alternative mechanism is discussed effectively in a review by Walsh170. 

Several hundreds of irreversible MAO inhibitors have been prepared, exemplified by the MAO A-selective clorgyline (134) and the MAO-B selective deprenyl (135). The search for selective MAO B inhibitors has produced a series of mechanism-based inhibitors containing a 3-fluoroallylamine as a critical structural unit (figure 17). The proposed mechanism of inactivation involves nucleophilic addition of the cofactor or of an active site nucleophile to the double bond. Activation of the double bond occurs through M AO-mediated oxidation of the ally lie amine to the electron-deficient iminium species225-227. 

Reaction of the intermediate 2c, X = H, with electrophiles E+ can give interesting cydo-hexadienes 13 (Scheme 2, path c). Indeed, if addition of the nucleophile is irreversible, carbon monoxide can be incorporated into the product, resulting in dearomatization accompanied by the introduction of an acyl group (Scheme 4). For example, complex 9 reacts with an electrophile E+ to give the 18e complex 10a, which can insert CO. A reductive elimination then affords the // -cyclohexadiene 12a, which liberates the free cydohexadiene 13 [li]. 

The kinetically controlled nucleophilic addition of preformed lithium enolates onto carbonyl compounds is reversible with a low activation barrier, and the thermal conditions are likely to have a major impact on the stereoisomeric ratio of the final aldols through the retroaldolization and the thermodynamic equilibration of lithium enolates76. The tendency of aldolates to undergo retroaldolization increases with the stability of enolates, and when going from lithium to potassium. On the other hand, boron enolates usually undergo completely irreversible aldol reaction511,512. 

The ready reversibility of such spectral changes to the spectrum of the cation upon acidification is an important test to rule out irreversible chemical reactions. In general, spectral techniques similar to those extensively used16,19 for the determination of the site of covalent hydration in a heteroaromatic molecule are also applicable to the determination of the site of nucleophilic addition in pseudobase formation. 

The first reduction step provides superoxide anion, which was shown to react with added silanone precursors as is seen fiom the decrease up to a total disappearance of the oxidation peak of O2. Using the ratio of these signals, /p(02 ) tp(02), and the kinetic treatment proposed in [10] for reversible electron transfer followed by an irreversible reaction of ion-radicals and modifying it to pseudo-first order reactions, we determined absolute rate constants of nucleophilic addition of electrogenerated superoxide anion on several silanone precursors (Scheme 5). 

Acid-base complexation of with the carbonyl oxygen atom first serves to make the carbonyl group a better acceptor, and nucleophilic addition of R then produces a tetrahedral magnesium alkoxide intermediate. Protonation by addition of water or dilute aqueous acid in a separate step yields the neutral alcohol (Figure 19.6). Unlike the nucleophilic additions of water and HCN, Grignard additions are irreversible because a carbanion is too poor a leaving group to be expelled in a reversal step. 

There are several published examples of irreversible inhibition of protein kinases, typically involving a Michael addition reaction where there is a nucleophilic addition of a carbanion (such as an enzyme cysteine thiolate in the purine site) to an unsaturated carbonyl compound (Figure 4.4). Compounds working in this way include the EGFR-TK inhibitor, WZ4002 (compound 4.9).17... 

For carboxylic acids, this new type of substitution process occurs best with weakly basic nucleophiles in the pre.sence of an acid catalyst. Strong ba.ses will deprotonate the acid faster than nucleophilic addition can take place, i hcrcfore, if the nucleophile is a strong base and deprotonation is e.s.scn-tially irreversible, nucleophilic addition will be very difficult and will occur only with extraordinarily powerful reagents, such as UAIH4. 

Reversibility, even at low temperatures, has been shown to be fast for stabilized carbanions (e.g., nitrile stabilized carbanions, ester enolates) whereas (most) sulfur stabilized carbanions and simple organo lithium compounds add irreversibly. Nevertheless protonation is more rapid than anion dissociation even for the first category of anions mentioned and nucleophile addition/proto-nation reactions allows efficient conversion to a dearomatized product. 

The sequential trans-addition of a carbon nucleophile and a carbon electrophile across an arene double bond in (arene)Cr(CO)3 was first reported in 1983 [35]. Since then this methodology has undergone extensive development, with recent efforts mainly directed towards enantioenriched products [36]. Anionic (cy-clohexadienyl)Cr(CO)3 complexes are very soft nucleophiles and this places restrictions on the electrophiles that can be used in this sequence. Specifically these reactions are successful when carbanion dissociation from the intermediate anionic cyclohexadienyl complex is slow compared to the reaction with the carbon electrophile. The sequential addition is usually carried out as a one-pot reaction and the proposed reaction sequence is that shown in Scheme 11. In contrast to the nucleophile addition/protonation sequence, products form with excellent 1,2-regioselectivity. It is likely that this is due to an irreversible transfer of the acyl, allyl, or propargyl group to one of the two termini of the cyclohexadienyl ligand. 

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