Addition reactions to aldehydes and ketones

The earliest studies on allenylzinc reagents were mainly concerned with the regioselec-tivity of addition reactions to aldehydes and ketones. Moreau and Gaudemar converted... 

Boron enolates are important intermediates for the aldol reaction, since the transition states of their addition reactions to aldehydes and ketones appear tightly organized, transmitting well the spatial arrangement to the aldol product. The reaction has been reviewed.674,675... 

Organocerium derivatives possess low basicity. 5-Pyrimidylcerium dichlorides (e.g., 904) are available via low-temperature metalmetal exchange using cerium trichloride and 5-lithiated pyrimidines. The 5-pyrimidinylcerium dichloride is superior to its 5-lithio analogue in addition reactions to aldehydes and ketones, especially in reactions when the carbonyl compound is enolizable. 

In accordance with the above discussion, general base catalysis is not found in thiol addition reactions to aldehydes and ketones only specific base catalysis is prevalent (Lienhard and Jencks, 1966). This is in contrast to the general base-catalyzed hydration of ketones or aldehydes. The reactions of the carbonyl group at the carboxylic acid level of oxidation have much in common with the reactions of the carbonyl group at the aldehyde or ketone level of oxidation. In an excellent review on simple carbonyl addition reactions Jencks (1964) has discussed in detail the mechanisms of catalyzed additions to the carbonyl group of ketones and aldehydes. For general base-catalj ed additions the mechanism... 

In the aldol reaction, we saw an enolate anion acting as a nucleophile leading to an addition reaction with aldehydes and ketones. 

The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly novel. The compounds do, however, prove a means of introducing a variety of functional groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can only occur readily when there is no alternative site for the metal. Therefore, only N-substituted imidazoles are of synthetic utility, and it may be necessary to select an N-substituent which can be removed later. For this reason, benzyl (removed by reductive or oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium) groups have proved useful in this context. A typical reaction sequence is shown in Scheme 136 <78JOC438l, 77JHC517). In addition, reactions with aldehydes and ketones (to form alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form carboxylic acids) have found application (B-76MI40701). 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

Other organo-silanes and -stannanes are relatively inert, and addition reactions to aldehydes or ketones have been quite limited. However, there seems to be no reason why these organometals should not find applications in the future through the development of appropriate promoters. Actually, several examples appear in the literature. Aryl- or vinyl-silanes, which possess sp C—Si bonds, add to chloral in the presence of AICI3 (Scheme 2). The intramolecular addition reactions of alkylstannanes to ketones proceed with TiCU (equations 13 and 14). ... 

P-Hydroxy selenides are conveniently prepared from epoxides by treatment with sodium phenylse-lenide (Scheme 32) and by the addition of benzeneselenenic acid and its derivatives to alkenes (Scheme 33), - -" although in some cases these reactions are not regioselective. Useful phenylseleno -etherification and -lactonization reactions have been developed which can be regioselective (equation 42 and Schemes 34 and 35). -" " Selenide- and selenoxide-stabilized carbanions have been used in addition reactions with aldehydes and ketones, - and the reduction of a-seleno ketones also provides a route to P-hydroxy selenides. ... 

Nucleophilic addition is the characteristic mechanism for addition reactions of aldehydes and ketones. It can be base-initiated in which a negative or neutral nucleophile attacks the carbonyl carbon generating a negative carbonyl oxygen that is subsequently neutralized. In the acid-initiated mechanism, hydrogen ion bonds to the carbonyl oxygen a carbocation results which is neutralized by the nucleophile. 

Alcohols also undergo reversible addition reactions with aldehydes and ketones. The product of addition of one mole of alcohol to an aldehyde or ketone is referred to as a hemiacetal or hemiketal, respectively. Dehydration and addition of a second mole of alcohol gives an acetal or ketal. This second phase of the process can be catalyzed only by acids, since a necessary step is elimination of hydroxide ion from a tetrahedral intermediate. There is no low-energy mechanism for base assistance of this elimination step. For this reason, acetals and ketals are stable toward hydrolysis in alkaline aqueous solution. 

Other reactions of carbohydrates include those of alcohols, carboxylic acids, and their derivatives. Alkylation of carbohydrate hydroxyl groups leads to ethers. Acylation of their hydroxyl groups produces esters. Alkylation and acylation reactions are sometimes used to protect carbohydrate hydroxyl groups from reaction while a transformation occurs elsewhere. Hydrolysis reactions are involved in converting ester and lactone derivatives of carbohydrates back to their polyhydroxy form. Enolization of aldehydes and ketones leads to epimerization and interconversion of aldoses and ketoses. Addition reactions of aldehydes and ketones are useful, too, such as the addition of ammonia derivatives in osazone formation, and of cyanide in the Kiliani-Fischer synthesis. Hydrolysis of nitriles from the Kiliani-Fischer synthesis leads to carboxylic acids. 

Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions. 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

The mechanism of a nucleophilic addition reaction of aldehydes and ketones under both basic and acidic conditions, (a) Under basic conditions, a negatively charged nucleophile adds to the carbonyl group to give an alkoxide ion intermediate, which is subsequently protonated. (b) Under acidic conditions, protonation of the carbonyl group occurs first, followed by addition of a neutral nucleophile and subsequent deprotonation. 

The first step in the reduction of the carboxylate is a hydride addition reaction to the carbonyl group. This reaction is. similar to the addition reaction of aldehydes and ketones. A subsequent elimination reaction forms an aldehyde. This reaction is analogous to the ehmination reaction of a hemiacetal, which also has two oxygen atoms bonded to the same carbon atom, to give the more stable carbonyl compound. 

Some imine-forming reactions are shown in Figure 14.30—all of these were part of longer synthetic sequences. Imines undergo many of the same types of addition reactions as aldehydes and ketones. A particularly useful example of this is their reaction with cyanide ion, the Strecker reaction (Figure 14.31). When a carbonyl compound is treated with ammonia and sodium or KCN, the ammonia adds to the carbonyl to give an unstable imine. This is attacked by cyanide to give the a-aminocyanide. Since the cyanide can be hydrolyzed to a carboxylic acid, this constitutes a simple amino acid synthesis. 

An ability to form carbon-carbon bonds is fundamental to organic synthesis The addition of Grignard reagents to aldehydes and ketones is one of the most frequently used reactions m synthetic organic chemistry Not only does it permit the extension of carbon chains but because the product is an alcohol a wide variety of subsequent func tional group transformations is possible... 

The next section explores the mechanism of nucleophilic addition to aldehydes and ketones There we 11 discuss their hydration a reaction m which water adds to the C=0 group After we use this reaction to develop some general principles we 11 then survey a number of related reactions of synthetic mechanistic or biological interest... 

With this as background let us now examine how the principles of nucleophilic addition apply to the characteristic reactions of aldehydes and ketones We 11 begin with the addition of hydrogen cyanide... 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

The characteristic reactions of aldehydes and ketones involve nude ophihc addition to the carbonyl group and are summarized m Table 17 5 Reagents of the type HY react according to the general equation... 

Reactions with Aldehydes and Ketones. The base-catalyzed self-addition of acetaldehyde leads to formation of the dimer, acetaldol [107-89-1/, which can be hydrogenated to form 1,3-butanediol [107-88-0] or dehydrated to form crotonaldehyde [4170-30-3]. Crotonaldehyde can also be made directiy by the vapor-phase condensation of acetaldehyde over a catalyst (53). 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

The in situ cyanosilylation of p-an1saldehyde is only one example of the reaction which can be applied to aldehydes and ketones in general. - The simplicity of this one-pot procedure coupled with the use of inexpensive reagents are important advantages over previous methods. The silylated cyanohydrins shown in the Table were prepared under conditions similar to those described here. Enolizable ketones and aldehydes have a tendency to produce silyl enol ethers as by-products in addition to the desired cyanohydrins. The... 

Although the present chapter includes the usual collection of topics designed to acquaint us with a particular class of compounds, its central theme is a fundfflnental reaction type, nucleophilic addition to carbonyl groups. The principles of nucleophilic addition to aldehydes and ketones developed here will be seen to have broad applicability in later chapters when transfonnations of various derivatives of carboxylic acids are discussed. 

Other than nucleophilic addition to the carbonyl group, the most important reactions of aldehydes and ketones involve replacing an a hydrogen. A par ticularly well studied exfflnple is halogenation of aldehydes and ketones. 

The most common reaction of aldehydes and ketones is the nucleophilic addition reaction, in which a nucleophile, Nu , adds to the electrophilic carbon of the carbonyl group. Since the nucleophile uses an electron pair to form a new bond to carbon, two electrons from the carbon-oxygen double bond must move toward the electronegative oxygen atom to give an alkoxide anion. The carbonyl carbon rehybridizes from sp2 to sp3 during the reaction, and the alkoxide ion product therefore has tetrahedral geometry. 

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