Addition-elimination acid-catalyzed

Addition to Double Bonds and Elimination Reactions. Both Lewis and Br nsted acidity of mineral surfaces can promote addition and elimination reactions (37). Equation 14 shows an example for an addition/elimination equilibrium catalyzed by Br nsted acidity ... 

Briefly, the mechanism for formation of an enamine is very similar to that for the formation of an imine. In the first step, nucleophilic addition of the secondary amine to the carbonyl carbon of the aldehyde or ketone followed by proton transfer from nitrogen to oxygen gives a tetrahedral carbonyl addition compound. Acid-catalyzed dehydration gives the enamine. At this stage, enamine formation differs from imine formation. The nitrogen has no proton to lose. Instead, a proton is lost from the a-carbon of the ketone or aldehyde portion of fhe molecule in an elimination reaction. 

The use of a reagent bearing a basic center or the addition of a base to the reaction mixture was recognized as necessary to prevent the acid-catalyzed elimination of the elements of water from the intermediates. Since the publication of this work, a number of similar intermediates have been isolated from thioamides and a-halogeno carbonyl compounds (608, 609, 619, 739, 754, 801), and as a result of kinetic studies, the exact mechanism of this reaction has been well established (739, 821). 

The mechanistic pattern established by study of hydration and alcohol addition reactions of ketones and aldehydes is followed in a number of other reactions of carbonyl compounds. Reactions at carbonyl centers usually involve a series of addition and elimination steps proceeding through tetrahedral intermediates. These steps can be either acid-catalyzed or base-catalyzed. The rate and products of the reaction are determined by the reactivity of these tetrahedral intermediates. 

There are several methods for generation of benzyne in addition to base-catalyzed elimination of hydrogen halide from a halobenzene, and some of these are more generally applicable for preparative work. Probably the most convenient method is diazotization of o-aminobenzoic acid. Concerted loss of nitrogen and carbon dioxide follows diazotization and generates benzyne. Benzyne can be formed in this manner in the presence of a variety of compounds with which it reacts rapidly. 

The final variation of the Feist-Benary furan synthesis encompasses reactions of 1,3-dicarbonyls with 1,2-dibromoethyl acetate (52). For example, treatment of ethyl acetoacetate (9) with sodium hydride followed by addition of 52 at 50°C yields dihydrofuran 53. The product can be easily converted into the corresponding 2-methyl-3-furoate upon acid catalyzed elimination of the acetate, thus providing another strategy for the synthesis of 2,3-disubstituted furans. 

I Elimination reactions are, in a sense, the opposite of addition reactions. They occur when a single reactant splits into two products, often with formation of a small molecule such as wateT or HBr. An example is the acid-catalyzed reaction of an alcohol to yield water and an alkene. 

Acid-catalyzed hydration of isolated double bonds is also uncommon in biological pathways. More frequently, biological hydrations require that the double bond be adjacent to a carbonyl group for reaction to proceed. Fumarate, for instance, is hydrated to give malate as one step in the citric acid cycle of food metabolism. Note that the requirement for an adjacent carbonyl group in the addition of water is the same as that we saw in Section 7.1 for the elimination of water. We ll see the reason for the requirement in Section 19.13, but might note for now that the reaction is not an electrophilic addition but instead occurs... 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

Diels-Alder cycloaddition of 3,4-bis(trifluoromethyl)furan with ethyl propynoate involved addition of two a,/3-unsaturated esters followed by acid-catalyzed ring opening, rearrangement, and elimination of ethanol to give a 6,7-bis(trifluoromethyl)isocoumarin-3-carboxylate [92JFC(56)359]. 

Racemization of some substrates can take place through reversible formation of the substrate via an addition/elimination process. The racemization can be acid or base catalyzed. In this section we vill discuss DKR of cyanohydrins and hemithioacetals. 

Both the exchange and elimination are catalyzed by the addition of a small amount of a weak acid, such as propanoic acid. These reactions are usually conducted at the reflux temperature of the orthoester, which is about 110°C for the trimethyl ester and 140° C for the triethyl ester. Microwave heating has been used and is reported to greatly accelerate orthoester-Claisen rearrangements.232... 

There are, however, serious problems that must be overcome in the application of this reaction to synthesis. The product is a new carbocation that can react further. Repetitive addition to alkene molecules leads to polymerization. Indeed, this is the mechanism of acid-catalyzed polymerization of alkenes. There is also the possibility of rearrangement. A key requirement for adapting the reaction of carbocations with alkenes to the synthesis of small molecules is control of the reactivity of the newly formed carbocation intermediate. Synthetically useful carbocation-alkene reactions require a suitable termination step. We have already encountered one successful strategy in the reaction of alkenyl and allylic silanes and stannanes with electrophilic carbon (see Chapter 9). In those reactions, the silyl or stannyl substituent is eliminated and a stable alkene is formed. The increased reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions because the reactants are more nucleophilic than the product alkenes. 

Clearly, the list can be enlarged by introducing additional steps, whereas the steps leading to the reactive species at the beginning (such as the acid-catalyzed elimination of water from an alcohol to form a carbocation) are not counted. 

Some experimental evidences are in agreement with this proposed mechanism. For example, coordinating solvents like diethyl ether show a deactivating effect certainly due to competition with a Lewis base (149). For the same reason, poor reactivity has been observed for the substrates carrying heteroatoms when an aluminum-based Lewis acid is used. Less efficient hydrovinylation of electron-deficient vinylarenes can be explained by their weaker coordination to the nickel hydride 144, hence metal hydride addition to form key intermediate 146. Isomerization of the final product can be catalyzed by metal hydride through sequential addition/elimination, affording the more stable compound. Finally, chelating phosphines inhibit the hydrovinylation reaction. 

The dissociation of water coordinated to exchangeable cations of clays results in Brtfnsted acidity. At low moisture content, the Brrfnsted sites may produce extreme acidities at the clay surface-As a result, acid-catalyzed reactions, such as hydrolysis, addition, elimination, and hydrogen exchange, are promoted. Base-catalyzed reactions are inhibited and neutral reactions are not influenced. Metal oxides and primary minerals can promote the oxidative polymerization of some substituted phenols to humic acid-like products, probably through OH radicals formed from the reaction between dissolved oxygen and Fe + sites in silicates. In general, clay minerals promote many of the reactions that also occur in homogenous acid or oxidant solutions. However, rates and selectivity may be different and difficult to predict under environmental conditions. This problem merits further study. 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

A-Alkylhydroxylamines react with substituted allyl acetates (e.g. 15, equation 11) in palladium catalyzed addition-elimination reactions giving the corresponding A-alkyl, A-allylhydroxylamines 16. The reaction proceeds with high regioselectivity but complete racemization. A similar reaction with 0-acyl hydroxamic acids has been carried out using allylic a-alkoxycarbonyloxyphosphonates. ... 

Other 0-aUcylation methods are exploited less frequently. 0-Allylation of Af-substituted hydroxamic acids of type 25 with allyl carbonates such as 26 and related compounds has been achieved through palladium catalyzed addition-elimination (equation 16). 

Both the exchange and elimination are catalyzed by addition of a small amount of a weak acid, such as propionic acid. Entries 7-13 in Scheme 6.12 are representative examples. 

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