Deprotonation, irreversible

These factors multiply to ensure that the enolate that forms will be the one with the fewer substituents—provided we now prevent equilibration of the enolate to the more stable, more substituted one. This means keeping the temperature low, typically-78 °C, keeping the reaction time short, and using an excess of strong base to deprotonate irreversibly and ensure that there is no remaining ketone to act as a proton Source. The enolate that we then get is the one that formed faster—the kinetic enolate—and not necessarily the one that is more stable. 

Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. 

The acid-base reactions that occur after the amide bond is broken make the overall hydrolysis irreversible m both cases The amine product is protonated m acid the car boxylic acid is deprotonated m base... 

Section 20 11 Ester hydrolysis m basic solution is called saponification and proceeds through the same tetrahedral intermediate (Figure 20 5) as m acid catalyzed hydrolysis Unlike acid catalyzed hydrolysis saponification is irreversible because the carboxylic acid is deprotonated under the reac tion conditions... 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

The comparatively unreactive complex Mn(CO)3(C5H5BMe) (14) with MeCOCl/AlCl3 produces the 2-acetyl derivative 84 and small amounts of [Mn(CO)3(PhMe)]+ (27). The product ratio is rather insensitive to reaction conditions. It is reasonable to assume a common intermediate 85 (of unspecified stereochemistry at C-6) which under kinetic control may either irreversibly deprotonate to 84 or undergo a rearrangement ultimately leading to the ring-member substitution product (27). 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

The redox and proton transfer reactions undergone by the flavin prosthetic group are summarized in Scheme 5.2. The vertical reactions are oxidations by Q regenerating P. From the standard potential values (V vs. SCE) of the four flavin redox couples that are involved in Scheme 5.2 and those of the mediators (Table 5.1), all four oxidation steps may be regarded as irreversible. The horizontal reactions are deprotonations by the bases present in the buffer. From the pA values of the various flavin acid-base couples indicated in Scheme 5.2 (over or below the horizontal arrows), reactions H2 and H4 may be regarded as irreversible and reactions HI and... 

Allenic amino acids belong to the classical suicide substrates for the irreversible mechanism-based inhibition of enzymes [5], Among the different types of allenic substrates used for enzyme inhibition [128, 129], the deactivation of vitamin B6 (pyr-idoxal phosphate)-dependent decarboxylases by a-allenic a-amino acids plays an important role (Scheme 18.45). In analogy with the corresponding activity of other /3,y-unsaturated amino acids [102,130], it is assumed that the allenic amino acid 139 reacts with the decarboxylase 138 to furnish the imine 140, which is transformed into a Michael acceptor of type 141 by decarboxylation or deprotonation. Subsequent attack of a suitable nucleophilic group of the active site then leads to inhibition of the decarboxylase by irreversible formation of the adduct 142 [131,132]. 

As already mentioned in Chapter 7, Section 2 (Figures 18, 19), the monocation [Co(PP3)(H2)]+ (PP3 = P(CH2CH2PPh2)3), present as non-classical hydride in [Co(PP3)(H2)][PF6], undergoes an irreversible oxidation (Figure 19), which generates the monocation [Co(PP3)H]+, thus suggesting that the oxidation of the dihydrogen complex simply causes deprotonation.83... 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

Irreversibility can be obtained if (1) the equilibrium constant for reaction (3), K = kf/kb, is large, that is, the EGB is a thermodynamically much stronger base than the deprotonated substrate, S . If that is the case, the substrate may be... 

When the EGB is an anion or a dianion, irreversible follow-up reaction of the deprotonated substrate, S , is the only way by which an unfavorable proton transfer equilibrium can be driven toward products. A disadvantage is that when the follow-up reaction of S is with an added electrophile, competing reaction between the EGB and the electrophile is often observed. Or - if the EGB is a dianion - the monoprotonated form may react with the electrophile. 

Providing the deprotonation reaction is kinetically controlled, meaning the intermediates 6 and epi-6 do not interconvert (path A), the enantiomeric ratio Hepi-1 (e.r.) of the trapping products reflects the ratio ks/kg. This is exactly true, if the deprotonation is irreversible and if the reactions of both epimers are complete and stereospecific and proceed with identical yields. (—)-Sparteine 11 proved to be a powerful ligand for the... 

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