Sources of Aldehydes and Ketones

As we ll see later in this chapter and the next, aldehydes and ketones are involved in many of the most used reactions in synthetic organic chemistry. Where do aldehydes and ketones themselves come from  

Many aldehydes and ketones are made in the laboratory by reactions that you already know about, summarized in Table 17.1. To the synthetic chemist, the most important of these are the last two the oxidation of primary alcohols to aldehydes and secondary alcohols to ketones. Indeed, when combined with reactions that yield alcohols, the oxidation methods are so versatile that it will not be necessary to introduce any new methods for preparing aldehydes and ketones in this chapter. A few examples will illustrate this point. 

Let s first consider how to prepare an aldehyde from a carboxylic acid. There are no good methods for going from RCO2H to RCHO directly. Instead, we do it indirectly by first reducing the carboxylic acid to the corresponding primary alcohol, then oxidizing the primary alcohol to the aldehyde. 

Can catalytic hydrogenation be used to reduce a carboxylic acid to a primary alcohol in the first step of the sequence RCO2H RCH2OH RCHO  

It is often necessary to prepare ketones by processes involving carbon-carbon bond formation. In such cases the standard method combines addition of a Grignard reagent to an aldehyde with oxidation of the resulting secondary alcohol  

Many are made in the laboratory from alkenes, alkynes, arenes, and alcohols by reactions that you aheady know about and are summarized in Table 17.1. 

Summary of Reactions Discussed in Earlier Chapters That Yield Aldehydes and Ketones 

FIGURE 17.3 Some naturally occurring aldehydes and ketones. 

Alkyl substituents stabilize a carbonyl group in much the same way that they stabilize carbon-carbon double bonds and carbocations—by releasing electrons to p -hybridized carbon. Thus, as their heats of combustion reveal, the ketone 2-butanone is more stable than its aldehyde isomer butanal. 

The carbonyl carbon of a ketone bears two electron-releasing alkyl groups an aldehyde carbonyl has only one. Just as a disubstituted double bond in an alkene is more stable than a monosubstituted double bond, a ketone carbonyl is more stable than an aldehyde carbonyl. We ll see later in this chapter that structural effects on the relative stability of carbonyl groups in aldehydes and ketones are an important factor in their relative reactivity. 

In general, aldehydes and ketones have higher boiling points than alkenes because the dipole-dipole attractive forces between molecules are stronger. But they have lower boiling points than alcohols because, unlike alcohols, two carbonyl groups can t form hydrogen bonds to each other. 

The carbonyl oxygen of aldehydes and ketones can form hydrogen bonds with the protons of OH groups. This makes them more soluble in water than alkenes, but less soluble than 

Sketch the hydrogen bonding between benzaldehyde and water. 

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Because etiolate anions are sources of nucleophilic carbon one potential use m organic syn thesis IS their reaction with alkyl halides to give a alkyl denvahves of aldehydes and ketones... 

Cyanation of aldehydes and ketones is an important chemical process for C C bond formation." " Trimethylsilyl cyanide and/or HCN are commonly used as cyanide sources. The intrinsic toxicity and instability of these reagents are problematic in their applications. Acetyl cyanide and cyanoformates were used as cyanide sources in the enantioselective cyanation of aldehydes catalyzed by a chiral Ti complex and Lewis base (Scheme 5.31)." The Lewis base was necessary for the good yields and selectivities of these reactions. The desired products were obtained in the presence of 10mol% triethyl amine and 5mol% chiral titanium catalyst (Figure 5.14). Various aliphatic and aromatic aldehydes could be used in these reactions. 

The carbonyl of aldehydes and ketones can be transformed into a gem-difluoro group. This transformation can be performed either directly with DAST or in an indirect manner by treating the corresponding thioacetal or hydrazone with an oxidant (NBS, dibromohydantoin, etc.) in the presence of a source of fluoride ions (e.g., HF-pyridin complex or TBABF prepared from TBAF and KHF2). ... 

The first electrophilic source of oxygen introduced for the proline-catalyzed a-oxygenation of aldehydes and ketones was nitrosobenzene, based on the use of this reagent in the asymmetric metal-catalyzed oxidation of tin enolates [12]. A number of research groups, including those of Zhong [12a], MacMillan [13b],... 

One drawback for the direct organocatalytic a-oxidation of aldehydes and ketones is the use of nitrosobenzene, which is an expensive oxygen source . This has led to further investigations in order be able to use other oxidants. Recently, Cordova et al. [20] reported that r-a-methyl proline could incorporate O2 in the a-position of an aldehyde. The presence of tetraphenylporphyrin (TPP) as sensitizer was necessary to promote the formation of singlet 02 as the electrophilic species. Although, the enantioselectivities obtained were only moderate (54-66% ee), this represents undoubtedly a very intriguing alternative to the use of nitrosobenzene in this type of reaction. 

Section 10.14 defined reduction as a decrease in the oxygen content or an increase in the hydrogen content of a compound. Therefore, the conversion of an aldehyde or a ketone to an alcohol, according to the preceding reaction, is a reduction. Aldehydes are reduced to primary alcohols by sources of hydride, and ketones are reduced to secondary alcohols. 

Procter reported a solid-phase variant of Fukuzawa s asymmetric y-butyr-olactone synthesis (see Chapter 5, Section 5.2) that involves the intermolecular reductive coupling of aldehydes and ketones with a,p-unsaturated esters, immobilised using an ephedrine chiral resin 12.44 For example, treatment of acrylate 13 and crotonate 14 with cyclohexanecarboxaldehyde, employing Sml2 in THF, with tert-butanol as a proton source, gave lactones 15 and 16, respectively, in moderate yield and good to high enantiomeric excess (Scheme 7.11).44 The ephedrine resin 12 can be conveniently recovered and recycled.45... 

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