Carbonyl groups, 40. addition reversibility

Despite the lower reactivity of the azomethine group as compared with the carbonyl group, intramolecular reversible nucleophilic additions of OH, NH, or SH groups to the C=N bond often proceed. The intramolecular addition of nucleophilic groups to the C=N bond can occur along two pathways (endo and exo), depending on the orientation of the azomethine group in the molecule. 

Additions of alkyl radicals onto carbonyl groups are reversible and energetically unfavorable because of strong n bond strengths of carbonyl bonds. Fragmentation reactions of oxy radicals are faster than additions to carbonyl groups. Thus, it is anticipated that carbonyl derivatives cannot be used as elficient radical traps. Only several carbonyl derivatives are effective to some extent in radical cyclizations. The intermolecular addition of alkyl radicals to carboxylic acid derivatives represents a radical acylation reaction in which carboxylic acid derivatives are required to be... 

We know how stabilized carbanions such as enols and enolated enamines are key intermediates in biological isomerization reactions and in carbon-carbon bond-forming and bond-breaking events. In this chapter, we will look at two more important reaction types, called Michael additions and -eliminations, which involve stabilized carbanion species as intermediates. In a Michael addition, a nucleophile and a proton are added to the two carbons of an alkene that is conjugated to a carbonyl group. The reverse of a Michael addition is called a -elimination. 

Cyanohydrin formation is reversible and the position of equilibrium depends on the steric and electronic factors governing nucleophilic addition to carbonyl groups described m the preceding section Aldehydes and unhindered ketones give good yields of cyanohydrins... 

The reversible addition of sodium bisulfite to carbonyl groups is used ia the purification of aldehydes. Sodium bisulfite also is employed ia polymer and synthetic fiber manufacture ia several ways. In free-radical polymerization of vinyl and diene monomers, sodium bisulfite or metabisulfite is frequentiy used as the reduciag component of a so-called redox initiator (see Initiators). Sodium bisulfite is also used as a color preventative and is added as such during the coagulation of crepe mbber. 

There are two distinct groups of aldolases. Type I aldolases, found in higher plants and animals, require no metal cofactor and catalyze aldol addition via Schiff base formation between the lysiae S-amino group of the enzyme and a carbonyl group of the substrate. Class II aldolases are found primarily ia microorganisms and utilize a divalent ziac to activate the electrophilic component of the reaction. The most studied aldolases are fmctose-1,6-diphosphate (FDP) enzymes from rabbit muscle, rabbit muscle adolase (RAMA), and a Zn " -containing aldolase from E. coli. In vivo these enzymes catalyze the reversible reaction of D-glyceraldehyde-3-phosphate [591-57-1] (G-3-P) and dihydroxyacetone phosphate [57-04-5] (DHAP). 

Aldehyde oxidations occur through intermediate l/l-diols, or hydrates, which are formed by a reversible nucleophilic addition of water to the carbonyl group. Even though formed to only a small extent at equilibrium, the hydrate reacts like any typical primary or secondary alcohol and is oxidized to a carbonyl compound (Section 17.7). 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. HcmiacetaJs are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the -OH group, followed by an El-like loss of water, leads to an oxonium ion, R2C=OR+, which undergoes a second nucleophilic addition of alcohol to yield the acetal. The mechanism is shown in Figure 19.12. 

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. 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

Just as the Kiliani-Fischer synthesis lengthens an aldose chain by one carbon, the Wohl degradation shortens an aldose chain by one carbon. The Wohl degradation is almost the exact opposite of the Kiliani-Fischer sequence. That is, the aldose aldehyde carbonyl group is first converted into a nitrile, and the resulting cyanohydrin loses HCN under basic conditions—the reverse of a nucleophilic addition reaction. 

On the other hand, in the presence of Lewis acids such as titanium(lV) chloride or eerium(TIT) chloride, the (S)-e s-conformer predominates via chelation of the two carbonyl groups and a reversed stereochemistry of the addition reaction is observed1 °. 

N-Acetylneuraminic acid aldolase (or sialic acid aldolase, NeuA EC 4.1.3.3) catalyzes the reversible addition of pyruvate (2) to N-acetyl-D-mannosamine (ManNAc (1)) in the degradation of the parent sialic acid (3) (Figure 10.4). The NeuA lyases found in both bacteria and animals are type I enzymes that form a Schiff base/enamine intermediate with pyruvate and promote a si-face attack to the aldehyde carbonyl group with formation of a (4S) configured stereocenter. The enzyme is commercially available and it has a broad pH optimum around 7.5 and useful stability in solution at ambient temperature [36]. 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

The obvious choice for a reagent is again a sulphur ylid, but how are we to control the regioselectivity of the addition The more reactive sulphur ylids, notably (26) and (27), add directly to the carbonyl group (kinetic control, cf p T 117 ) giving epoxides (29) while the more stable ylid (28), which combines the anion-stabilisations of (26) and (27), adds reversibly and gives the thermodynamic product (25). 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

This comparison suggests that of these two similar reactions, only alkene additions are likely to be a part of an efficient radical chain sequence. Radical additions to carbon-carbon double bonds can be further enhanced by radical stabilizing groups. Addition to a carbonyl group, in contrast, is endothermic. In fact, the reverse fragmentation reaction is commonly observed (see Section 10.3.6) A comparison can also be made between abstraction of hydrogen from carbon as opposed to oxygen. 

Although the high reactivity of metal-chalcogen double bonds of isolated heavy ketones is somewhat suppressed by the steric protecting groups, Tbt-substituted heavy ketones allow the examination of their intermolecular reactions with relatively small substrates. The most important feature in the reactivity of a carbonyl functionality is reversibility in reactions across its carbon-oxygen double bond (addition-elimination mechanism via a tetracoordinate intermediate) as is observed, for example, in reactions with water and alcohols. The energetic basis... 

Hydroperoxides undergo reversible addition across the carbonyl group of a ketone with the formation of a new peroxide. 

In proton-catalyzed hydrolysis (specific acid catalyzed hydrolysis), protonation of the carbonyl O-atom leads to polarization of the carbonyl group, facilitating addition of the nucleophile, i. e., a H20 molecule (Fig. 3.1, Pathway a). The acid-catalyzed hydrolysis of esters is reversible because the neutral alcohol or phenol released is nucleophilic, whereas hydrolysis of amides is irreversible because the amine released is protonated in the acidic medium and, hence, has considerably reduced nucleophilicity. 

This reaction represents the simplest example of the important class of reversible additions to the carbonyl group. The present review... 

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