Reactions of Aldehydes and Ketones

Conversion of Carbonyl Croups into Acetals and Analogous Reactions 

This very mild Noyori acetalization has found wide application for the preparation of dialkyl or ethylene acetals of aldehydes and ketones, affording, e.g. with 

For further applications of this Noyori ketalization compare, e.g. Refs. [6-15]. Interesting also are the reactions of silylated 1,3-diols and 1,3,5-triols with l- 

The use of the enolsilyl ether of 1-menthone [16, 19, 21-23] and of some free triflic acid favors the formation of the thermodynamically controlled products as with free 2,2 -dihydroxydiphenyl [22] and only subsequently added HMDS 2 [22]. On reacting silylated alcohols and carbonyl compounds with pure trimethylsilyl triflate 20 under strictly anhydrous conditions no conversion to acetals is observed [24]. Apparently, only addition of minor amounts of humidity to hydrolyze TMSOTf 20 to the much stronger free triflic acid and hexamethyldisiloxane 7 or addition of traces of free triflic acid [18-21, 24, 26] or HCIO4 [25] leads to formation of acetals. 

Introduction. The reactions of aldehydes and ketones can be conveniently divided into three groups (1) reactions involving an addition to the carbonyl group, (2) reactions involving oxidation-reduction of the carbonyl group, and (3) condensation and polymerization reactions. 

A number of addition derivatives may be used in the identification of the carbonyl compounds. Of these the crystalline derivatives formed with phenylhydrazine, C6H6NHNH2, and hydroxylamine, NH2OH, are the most important. The products formed with phenylhydrazine are called phenyUiydrazones, and have the general formula, RRiC=NNHC jls. The products formed with hydroxylamine are called oximes, and have the general formula, RRiC=NOH. Other crystalline addition compounds are formed with sodium bisulfite by aldehydes, and by those ketones which contain a methyl group. The addition compounds with ammonia, except in the case of acetaldehyde and a few other carbonyl compounds, are complex products. 

Condensation reactions involving the carbonyl group are illustrated by the aldol condensation. Under the influence of small amounts of hydroxyl ion two molecules of aldehyde unite to give a more complex molecule. The union occurs between the carbonyl group of one with the alpha carbon atom of another molecule  

Aldehydes that do not have hydrogen atoms on the alpha carbon atom do not undergo the aldol condensation. Such aldehydes undergo the Cannizzaro reaction when treated with strong alkali. For example, formaldehyde with strong sodium hydroxide gives sodium formate and methyl alcohol  

Since two molecules of the aldehyde form one molecule of alcohol and one molecule of acid, it is evident that the reaction is one of auto-oxidation-reduction. One molecule is oxidized and another is reduced. 

Alkylation.—Potassium enolates of aldehydes can be prepared by reaction of the aldehyde with potassium hydride in tetrahydrofuran. Reaction of these enolates with activated primary bromides (allyl or benzyl) and methyl iodide gives rise to C-alkylated products exclusively secondary alkyl iodides afford mixtures of C-and O-alkylated products.  

Powdered sodium hydroxide suspended in benzene containing tetra-n-butyl-ammonium iodide is an effective system for alkylation of isobutyraldehyde and also /S-keto-esters.  

Potassium amyloxide in dimethoxyethane has been recommended as the base for simple monoalkylation of cyclopentanone. Polyalkylation of acyclic and cyclic ketones can be minimized by reaction of the appropriate alkyl iodide and 

Alkylation of 1,5-dimethoxycyclohexa-l,4-diene is a convenient process for the obtention of 2-alkyl- and 2-alkenyl-cyclohexane-l,3-diones [equation (13)].  

Chiral imines of acyclic ketones have been metallated and alkylated also. A pronounced excess of one enantiomer (generally 50%) is only obtained on thermal isomerization of the intermediate lithio-enamines. Asymmetric syntheses of a-substituted ketones (and acids) (optical yields 44—74%) have also been achieved by metallation, alkylation, and further reaction of chiral N,N-disubstituted amides.  

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Table 17 2 summarizes the reactions of aldehydes and ketones that you ve seen m ear her chapters All are valuable tools to the synthetic chemist Carbonyl groups provide access to hydrocarbons by Clemmensen or Wolff-Kishner reduction (Section 12 8) to alcohols by reduction (Section 15 2) or by reaction with Grignard or organolithmm reagents (Sections 14 6 and 14 7)... 

Summary of Reactions of Aldehydes and Ketones Discussed in Earlier Chapters... 

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 of Aldehydes and Ketones That Involve Enol or Enolate Ion Intermediates... 

Scheme 8.2. Addition-Elimination Reactions of Aldehydes and Ketones...

Sections The characteristic reactions of aldehydes and ketones involve nticle-... 

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. 

A class of nitrogen-containing compounds that was omitted from the section just discussed includes imines and their- derivatives. Irnines are formed by the reaction of aldehydes and ketones with ammonia. Imines can be reduced to primary amines by catalytic hydrogenation. 

The initial investigation of the reaction of aldehydes and ketones with complex secondary amine salts was that of Lamchen et al. (11). A few salts had been observed before by Zincke and Wiirker (24), but the reaction was not examined in detail. Lamchen et al. prepared a number of compounds that were presumed to be iminium salts. The amine salts were halostannates, halobismuthates, haloantimonates, and hexahaloplatinates. Among the reported products were N-ethylidenepiperidinium (13) and N-cinnamili-denetetrahydroisoquinolinium (14) salts. 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

Besides the aldol reaction in the true sense, there are several other analogous reactions, where some enolate species adds to a carbonyl compound. Such reactions are often called aldol-type reactions the term aldol reaction is reserved for the reaction of aldehydes and ketones. 

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

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. 

As we saw in A Preview of Carbonyl Compounds, the most general reaction of aldehydes and ketones is the nucleophilic addition reaction. A nucleophile, Nu-, approaches along the C=0 bond from an angle of about 75° to the plane of the carbonyl group and adds to the electrophilic C=0 carbon atom. At the same time, rehybridization of the carbonyl carbon from sp2 to sp3 occurs, an electron pair from the C=0 bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced (Figure 19.1). 

Reaction of Aldehydes and Ketones with Phosphorus Trichloride... 

Jorgensen K. A. Development and application of catalytic highly enantioselective hetero-Diels-Alder reactions of aldehydes and ketones in Curr. Trends Org. Synth.,... 

Reactions 11-22-11-26 involve the introduction of a CH2Z group, where Z is halogen, hydroxyl, amino, or alkylthio. They are all FriedeI-Crafts reactions of aldehydes and ketones and, with respect to the carbonyl compound, additions to the C=0 double bond. They follow mechanisms discussed in Chapter 16. 

Reaction of aldehydes and ketones with methanol or glycols at ambient temperature in the presence of excess trimethylchlorosilane (TCS) 14 to form acetals, hexamethyldisiloxane 7, and HCl is achieved very simply [28]. Thus cyclohexanone and diacetyl react with free glycol and TCS 14 to give the acetals 392 and 405 in 95% yield [28]. Reaction of phenylglyoxal with methanol in the presence of trimethylchlorosilane 14 affords the acetal 406 in 83% yield [28], whereas catechol 79 is converted by pivaldehyde into acetal 407 in 91% yield [29] (Scheme 5.5). 

Alternatively, iminium salts such as 549 or 551 can also be synthesized by reaction of aldehydes and ketones with 0,N- or N,N-acetals in the presence of TMSOTf 20 [121], MejSiCl 14 [122], Me2SiCl2 48, or MeSiClj [123]. The reactions... 

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