Carbonyl group enolization

We should first consider the open-chain form of glucose 6-phosphate, rather than its pyranose hemiacetal form (see Section 12.2.1). The open-chain aldose has the requirements for enolization, namely a hydrogen a to the aldehyde carbonyl group. Enolization produces in this case an enediol, which can revert to a keto form in two ways, i.e. reforming... 

Claisen condensations always involve esters as the electrophilic partner, but enolates of other carbonyl compounds—ketones, for example—may work equally well as the enol partner. In a reaction with a carbonate, only the ketone can enolize and the reactive carbonate ester is more electrophilic than another molecule of the ketone, A good example is this reaction of cyclooctanone. It does not matter which side of the carbonyl group enolizes—they are both the same, v. 

When the carbonyl group enolized is at a secondary position, the hydrogen can be introduced into four possible adjacent positions, potentially leading to a mixture of four isomers. These possibilities can be decreased if the sugar is held in a rigid conformation so that enolization can take place in one direction only. For example, 1,6-anhydro-2,3-0-isopropylidene-/3-D-lyxo-hexopyranos-4-ulose (10) can-... 

You may also have pointed out that there is an alternative and equally good enol that has the o-i i carbonyl group enolized. These two structures are tautomers of each other and of the keto-ester. 

The carbon which is the chirality center is adjacent to a carbonyl group. Enolization of this carbonyl group makes this carbon sp hybridized with trigonal planar geometry, so it is no longer a chirality center. Protonation of the enol can occur from either side, so both enantiomers of thalidomide are formed. 

The sequential copolymerization of DTC and LLA revealed different polymer microstmctures, depending on the order in which the monomer was polymerized first. When LLA was polymerized first, a random copolymer was formed, whereas the addition of LLA to a living PDTC resulted in a block copolymer. The copolymerization of a mixture of LLA and DTC also resulted in a random copolymer. Based on these results, the following mechanism was proposed by the authors. The PLLA active centers are well stabilized by the adjacent carbonyl group (enol formation) and by the formation of a five-membered cyclic complex including the metallic species. After reaction of the PLLA active centers with DTC, the newly formed active site has a reduced capability of stabilization (Scheme 84). 

So far in this section we have combined enolate anions with other carbonyl compounds by direct attack at the carbonyl group. We can expand the scope of this reaction by using a,p-unsaturated carbonyl compounds as the electrophiles. This is the Michael reaction. Remind yourself of tliis by writing out the mechanism of a Michael reaction such as ... 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

Selective reduction of a benzene ring (W. Grimme, 1970) or a C C double bond (J.E. Cole, 1962) in the presence of protected carbonyl groups (acetals or enol ethers) has been achieved by Birch reduction. Selective reduction of the C—C double bond of an a,ft-unsaturated ketone in the presence of a benzene ring is also possible in aprotic solution, because the benzene ring is redueed only very slowly in the absence of a proton donor (D. Caine, 1976). 

In the preceding chapter you learned that nucleophilic addition to the carbonyl group IS one of the fundamental reaction types of organic chemistry In addition to its own reactivity a carbonyl group can affect the chemical properties of aldehydes and ketones m other ways Aldehydes and ketones having at least one hydrogen on a carbon next to the carbonyl are m equilibrium with their enol isomers... 

A 1 3 arrangement of two carbonyl groups (compounds called P diketones) leads to a situation m which the keto and enol forms are of comparable stability... 

Both enols have their carbon-carbon double bonds conjugated to a carbonyl group and can form an intramolecular hydrogen bond They are of comparable stability... 

Step 1 The aldehyde and its enolate are m equilibrium with each other m basic solution The enolate acts as a nucleophile and adds to the carbonyl group of the aldehyde ... 

An important feature of aldol addition is that carbon-carbon bond formation occurs between the a carbon atom of one aldehyde and the carbonyl group of another This is because carbanion (enolate) generation can involve proton abstraction only from the a carbon atom The overall transformation can be represented schematically as shown m Figure 18 5... 

Now use the negatively charged a carbon of the enolate to form a new carbon-carbon bond to the carbonyl group Proton transfer from the solvent completes the process... 

With certain other nucleophiles addition takes place at the carbon-carbon double bond rather than at the carbonyl group Such reactions proceed via enol intermediates and are described as conjugate addition ox 1 4 addition reactions... 

A reaction of great synthetic val ue for carbon-carbon bond for mation Nucleophilic addition of an enolate ion to a carbonyl group followed by dehydration of the 3 hydroxy aldehyde yields an a p unsaturated aldehyde... 

Esterification of carboxylic acids involves nucleophilic addition to the carbonyl group as a key step In this respect the carbonyl group of a carboxylic acid resembles that of an aldehyde or a ketone Do carboxylic acids resemble aldehydes and ketones m other ways Do they for example form enols and can they be halogenated at their a carbon atom via an enol m the way that aldehydes and ketones can ... 

Step 2 Nucleophilic addition of the ester enolate to the carbonyl group of the neutral ester The product is the anionic form of the tetrahedral intermediate... 

We already know what happens when simple esters are treated with alkoxide bases— they undergo the Claisen condensation (Section 211) Simple esters have s of approximately 22 and give only a small amount of enolate when treated with alkoxide bases The small amount of enolate that is formed reacts by nucleophilic addition to the carbonyl group of the ester... 

As we saw m Chapter 20 thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution They also contain a greater proportion of enol at equilib rmm Both properties are apparent m the properties of acetyl coenzyme A In some reactions it is the carbonyl group of acetyl coenzyme A that reacts m others it is the a carbon atom... 

Conjugation is more important 1 3 Cyclohexanedione exists mainly in its enol form in spite of the fact that intramolecular hydrogen bonding is impossible due to the distance between the carbonyl group and the enohc —OH group... 

Alditol (Section 25 18) The polyol obtained on reduction of the carbonyl group of a carbohydrate Aldol addition (Section 18 9) Nucleophilic addition of an aldehyde or ketone enolate to the carbonyl group of an aide hyde or a ketone The most typical case involves two mole cules of an aldehyde and is usually catalyzed by bases... 

Hydrogen bonding to a carbonyl group causes a shift to lower frequency of 40 to 60 cm k Acids, amides, enolized /3-keto carbonyl systems, and o-hydroxyphenol and o-aminophenyl carbonyl compounds show this effect. All carbonyl compounds tend to give slightly lower values for the carbonyl stretching frequency in the solid state compared with the value for dilute solutions. 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Study of the mechanism of this complex reduction-Hquefaction suggests that part of the mechanism involves formate production from carbonate, dehydration of the vicinal hydroxyl groups in the ceUulosic feed to carbonyl compounds via enols, reduction of the carbonyl group to an alcohol by formate and water, and regeneration of formate (46). In view of the complex nature of the reactants and products, it is likely that a complete understanding of all of the chemical reactions that occur will not be developed. However, the Hquefaction mechanism probably involves catalytic hydrogenation because carbon monoxide would be expected to form at least some hydrogen by the water-gas shift reaction. 

The course of the acid catalyzed dehydration of 1,4-diketones to furans, known as the Paal-Knorr method (1884CB2756), entails the formal addition of the enol of one carbonyl group to the other carbonyl. Examples which illustrate some of the routes used to make the necessary 1,4-diketones are shown in Scheme 13. Few examples are known of the preparation of the other heterocycles by this general approach using isolated intermediates, although some of the ring closures discussed in Section 3.03.3.1.1 are mechanistically equivalent. One example of the preparation of a hydroxypyrrole is included in Scheme 13 <59AC(R)2075). 

The carbonyl group forms a number of other very stable derivatives. They are less used as protective groups because of the greater difficulty involved in their removal. Such derivatives include cyanohydrins, hydrazones, imines, oximes, and semicarbazones. Enol ethers are used to protect one carbonyl group in a 1,2- or 1,3-dicarbonyl compound. 

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