Carbonylation to Aldehydes

The C-N multiple bond of an isocyanide is weaker than the C-O multiple bond in CO. Thus, the insertion of an isocyanide into a C-H bond in a reaction that is analogous to the carbonylation of C-H bonds should be more favorable thermodynamically. An example of this reaction catalyzed by [RhCl(CO)(PMe3)j] under photochemical conditions is shown in Equation 18.34. A more efficient, albeit more complex, reaction of an isocyanide involves intramolecular insertion into the o-methyl group in 2,6-dimefhylphenylisocyanide, whidr leads to an indole product in high yield (Equation 18.35).  

---

The direct catalytic carbonylation of halides to aldehydes is not readily achieved. Aryl, heterocyclic and vinyl halides, for example, in the presence of [Pd(PPh3)2Ch], a stoichiometric quantity of tertiary amine and synthesis gas (CO/H2), are converted to aldehydes, but the conditions are somewhat drastic (80-100 bar, 80-150 Alkyl halides are even less suitable for this reaction as they tend to undergo dehydrohalogenation to form alkenes, rather than carbonylation. However, using the platinum catalyst [PtCh(PPh3)2], primary alkyl iodides can be successfully carbonylated to aldehydes in good yield under moderate conditions (equation 5). °... 

Using poly(methylhydrosiloxane) (PMHS) as the hydrogen donor, aryl and benzyl halides can be carbonylated to aldehydes in the presence of [Pd(PPh3>4] under mild conditions (3 bar, 80 °C). The reaction only works for iodides 4-bromophenyl iodide, for example, is converted to 4-bromobenzaldehyde in 95% yield (equation 6). 

Terminal alkyne anions are popular reagents for the acyl anion synthons (RCHjCO"). If this nucleophile is added to aldehydes or ketones, the triple bond remains. This can be con verted to an alkynemercury(II) complex with mercuric salts and is hydrated with water or acids to form ketones (M.M.T. Khan, 1974). The more substituted carbon atom of the al-kynes is converted preferentially into a carbonyl group. Highly substituted a-hydroxyketones are available by this method (J.A. Katzenellenbogen, 1973). Acetylene itself can react with two molecules of an aldehyde or a ketone (V. jager, 1977). Hydration then leads to 1,4-dihydroxy-2-butanones. The 1,4-diols tend to condense to tetrahydrofuran derivatives in the presence of acids. 

The phenylacetic acid derivative 469 is produced by the carbonylation of the aromatic aldehyde 468 having electron-donating groups[jl26]. The reaction proceeds at 110 C under 50-100 atm of CO with the catalytic system Pd-Ph3P-HCl. The reaction is explained by the successive dicarbonylation of the benzylic chlorides 470 and 471 formed in situ by the addition of HCl to aldehyde to form the malonate 472, followed by decarboxylation. As supporting evidence, mandelic acid is converted into phenylacetic acid under the same reaction conditions[327]. 

Both the Clemmensen and the Wolff-Kishner reductions are designed to carry out a specific functional group transformation the reduction of an aldehyde or ketone carbonyl to a methylene group Neither one will reduce the carbonyl group of a carboxylic acid nor... 

The first stage of the mechanism is exactly the same as for nucleophilic addition to the carbonyl group of an aldehyde or ketone Many of the same nucleophiles that add to aldehydes and ketones—water (Section 17 6) alcohols (Section 17 8) amines (Sections 17 10-17 11)—add to the carbonyl groups of carboxylic acid derivatives... 

This pattern of increased reactivity resulting from carbonyl group prolonalion has been seen before m nucleophilic additions to aldehydes and ketones (Section 17 6) and... 

Although stoichiometric ethynylation of carbonyl compounds with metal acetyUdes was known as early as 1899 (9), Reppe s contribution was the development of catalytic ethynylation. Heavy metal acetyUdes, particularly cuprous acetyUde, were found to cataly2e the addition of acetylene to aldehydes. Although ethynylation of many aldehydes has been described (10), only formaldehyde has been catalyticaHy ethynylated on a commercial scale. Copper acetjlide is not effective as catalyst for ethynylation of ketones. For these, and for higher aldehydes, alkaline promoters have been used. 

A particularly useful reaction has been the selective 1,2-reduction of a, P-unsaturated carbonyl compounds to aHyUc alcohols, accompHshed by NaBH ia the presence of lanthanide haUdes, especially cerium chloride. Initially appHed to ketones (33), it has been broadened to aldehydes (34) and acid chlorides (35). NaBH by itself gives mixtures of the saturated and unsaturated alcohols. 

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 zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Unsaturated compounds undergo ozonization to initially produce highly unstable primary ozonides (15), ie, 1,2,3-trioxolanes, also known as molozonides, which rapidly spHt into carbonyl compounds (aldehydes and ketones) and 1,3-zwitterion (16) intermediates. The carbonyl compound-zwitterion pair then recombines to produce a thermally stable secondary ozonide (17), also known as a 1,2,4-trioxolane (44,64,125,161,162). 

AH ahphatic aldehydes and most ketones react to form cyanohydrins. The lower reactivity of ketones, relative to aldehydes, is attributed to a combination of electron-donating effects and increased steric hindrance of the second alkyl group in the ketones. The magnitude of the equiUbrium constants for the addition of hydrogen cyanide to a carbonyl group is a measure of the stabiUty of the cyanohydrin relative to the carbonyl compound plus hydrogen cyanide ... 

Reductive amination ol aldehydes or ketones by cyanoborohydride (or tnacetoxyborohydride) anion Selective reduction of carbonyls to alcohol, oximes to N alkylhydroxylarmnes, enamines to amines... 

In order to characterize them and more readily separate them from interfering accompanying substances carbonyl compounds (aldehydes, ketones) can be converted to hydrazones at the start. The reagent mainly employed is 2,4-dinitro-phenylhydrazine in acidic solution [70], This yields osazones with aldoses and ketoses. Some examples are listed in Table 15. 

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. 

The presence of a carbonyl group in a molecule makes possible a number of chemical reactions that are of great synthetic, biochemical, and mechanistic importance. This chapter is complementary to the preceding one the two chapters taken together demonstrate the extraordinary range of chemical reactions available to aldehydes and ketones. 

Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form carbinol-amines. These carbinolamines dehydrate under the conditions of their formation to give A/-substituted imines. Secondary amines yield enamines. 

C-C bonds can be formed by reaction with alkyl iodides or more usefully by reaction with metal carbonyls to give aldehydes and ketones e.g. Ni(CO)4 reacts with LiR to form an unstable acyl nickel carbonyl complex which can be attacked by electrophiles such as H+ or R Br to give aldehydes or ketones by solvent-induced reductive elimination ... 

Carboxylic acid derivatives, CH3C(=0)Z, are similar to aldehydes and ketones in that they contain a polar carbonyl group. Therefore, nucleophiles should add to the carbonyl carbon, although the rate of addition may depend on the Z group. 

More recent work has shown that the 2-unsubstituted compound 40 (R = H, R = Pr ) is an effective formyl anion equivalent which reacts at C2 and undergoes both 1,4-addition to a,(3-unsaturated carbonyl compounds and 1,2-addition to aldehydes (93TL3907 96T4719). 

Perhaps the most important reaction of alcohols is their oxidation to carbonyl compounds. Primary alcohols yield either aldehydes or carboxylic acids, secondary alcohols yield ketones, but tertiary alcohols are not normally oxidized. Pyridinium chlorochromate (PCC) in dichloromethane is often used for oxidizing primary alcohols to aldehydes and secondary alcohols to ketones. A solution of Cr03 in aqueous acid is frequently used for oxidizing primary alcohols to carboxylic acids and secondary alcohols to ketones. 

Acetal formation is similar to the hydration reaction discussed in Section 19.5. Like water, alcohols are weak nucleophiles that add to aldehydes and ketones only slowly under neutral conditions. Under acidic conditions, however, the reactivity of the carbonyl group is increased by protonation, so addition of an alcohol occurs rapidly. 

The difference in behavior between aldehydes/ketones and carboxylic acic derivatives is a consequence of structure. Carboxylic acid derivatives have ai acyl carbon bonded to a group -Y that can leave as a stable anion. As soon a the tetrahedral intermediate is formed, the leaving group is expelled to general- a new carbonyl compound. Aldehydes and ketones have no such leaving grouj however, and therefore don t undergo substitution. 

---