The Reactions of Aldehydes and Ketones with Amines

Aldehydes and Ketones Form Imines with Primary Amines 

An aldehyde or a ketone reacts with a primary amine to form an imine (sometimes called a Schiff base). An imine is a compound with a carbon-nitrogen double bond. The reaction requires a trace amount of acid. Notice that imine formation replaces a C=0 withaC=NR. 

The mechanism for imine formation is shown next. We will see that the pH of the reaction mixture must be carefully controlled. (Recall that HB represents any species in the solution that is capable of donating a proton, and B represents any species in the solution that is capable of removing a proton.) 

Bonding in an imine. The 77 bond is formed by side-to-side overlap of a p orbital of carbon with a p orbital of nitrogen It Is perpendicular to the orange orbitals. 

Notice that the pattern of three tetrahedral intermediates that we saw in the acid-catalyzed mechanisms in Chapter 16 also occurs in this mechanism  

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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. 

Consequently, by choosing proper conditions, especially the ratios of the carbonyl compound to the amino compound, very good yields of the desired amines can be obtained [322, 953]. In catalytic hydrogenations alkylation of amines was also achieved by alcohols under the conditions when they may be dehydrogenated to the carbonyl compounds [803]. The reaction of aldehydes and ketones with ammonia and amines in the presence of hydrogen is carried out on catalysts platinum oxide [957], nickel [803, 958] or Raney nickel [956, 959,960]. Yields range from low (23-35%) to very high (93%). An alternative route is the use of complex borohydrides sodium borohydride [954], lithium cyanoborohydride [955] and sodium cyanoborohydride [103] in aqueous-alcoholic solutions of pH 5-8. 

We now move on to the reaction of aldehydes and ketones with nitrogen and oxygen heteroatoms. Amines, for example, are organic nitrogen compounds that contain a nonbonded eiectron pair on the N atom. Amines are classified as 1°, 2°, or 3° by the number of alkyl groups bonded to the nitrogen atom. 

Both 1 ° and 2° amines react with aldehydes and ketones. We begin by examining the reaction of aldehydes and ketones with 1 ° amines. 

Like acetal formation, the reaction of aldehydes and ketones with primary amines— compounds of the type RNH2 and ArNH2—is a two-stage process. Its first stage is nucleophilic addition of the amine to the carbonyl group to give a carbinolamine. The second stage is the dehydration of the carbinolamine to yield the isolated product of the reaction, an A-alkyl or A-aryl-substituted imine. 

The formation of enamines by the reaction of aldehydes and ketones with secondary amines was described in Section 17.11. As the following equation illustrates, the reaction is reversible. 

The study aids for this chapter include key terms and concepts (which are hyperlinked to the Glossary from the bold, blue terms in the WileyPLUS version of the book at wileyplus.com), Mechanism Summaries regarding reactions of aldehydes and ketones with amines as well as with other nucleophiles, and a Synthetic Connections scheme regarding transformations of aldehydes and ketones. 

Aldimines and ketimines are formed by the reaction of aldehydes and ketones with solutions of primary amines or ammonia, at a hydrogen ion concentration close to the dissociation constant of the amine. With saturated aldehydes (except formaldehyde which shows a more complicated behaviour) and ketones, a well developed wave at about —1-5 V is observed (Fig. 

Reactions of aldehydes and ketones with amines and amine derivatives (Section 17.10) a. Reaction with a primary amine forms an imine. The mechanism is shown on page 811. 

Reductive amination the imines and enamines formed from the reaction of aldehydes and ketones with ammonia and primary and secondary amines are reduced to primary, secondary, and tertiary amines (Section 17.10). 

The most versatile method for preparing enamines involves the condensation of aldehydes and ketones with secondary amines [Eq. (1)]. Mannich and Davidsen (/) discovered that the reaction of secondary amines with aldehydes in the presence of potassium carbonate and at temperatures near 0° gave enamines, while calcium oxide and elevated temperatures were required to cause a reaction between ketones and secondary amines, although usually in poor yield. The introduction by Herr and Heyl 2-4) of the removal of the water produced in the condensation by azeotropic distillation with benzene made possible the facile preparation of enamines from ketones and disubstituted aldehydes. 

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. 

Carmack20 has suggested that thiirenes are intermediates in the classic Willgerodt and Kindler reactions of aldehydes or ketones with amines and sulfur (Scheme 3). 

Aldehydes, ketones, and acetals react with allyltrimethylsilane in the presence of a catalytic amount of BiX3 (X = C1, Br, OTf) to give homoallyl alcohols or homoallyl alkyl ethers (Equation (52)).91-93 The BiX3-catalyzed allylation of aldehydes and sequential intramolecular etherification of the resulting homoallylic silyl ethers are involved in the stereoselective synthesis of polysubstituted tetrahydropyrans (Equation (53)).94,95 Similarly, these Lewis acids catalyze the cyanation of aldehydes and ketones with cyanotrimethylsilane. When a chiral bismuth(m) catalyst is used in the cyanation, cyanohydrines are obtained in up to 72% ee (Equation (54)). a-Aminonitriles are prepared directly from aldehydes, amines, and cyanotrimethysilane by the BiCl3-catalyzed Strecker-type reaction. 

Trioxanes 726 (Z = 0) are trimers of aldehydes or ketones formed by acid-catalyzed condensations of the monomers. 1,3,5-Trithiane 726 (Z = S) is prepared by passing H2S through formaldehyde and hydrochloric acid <1943OSC(2)610>. The reaction of formaldehyde and H2S with amines affords the corresponding thiadiazines 727 (Scheme 311) <2003RCB1817, CHEC-III(9.09.9.3)511>. 

In this process, 3° alcohols react faster than 2° alcohols. Heterolytic bond cleavage of a halide or sulfonate ester (C-X, X = Br, Cl, I, OMs, OTs, etc.) in aqueous solvents (usually with heating) generates tertiary cations easily, secondary alcohols with difficulty, and primary cations with extreme difficulty. Reaction of aldehydes and ketones with an acid catalyst gives the oxygen-stabilized cation (see 1 and 4). Reaction of amines with nitrous acid (HNO2) initially gives a diazonium salt (5, also see sec. 13.9.B) but alkyl diazonium salts readily decompose to cations. ... 

Many steps are nearly the same in acid-catalyzed reactions of aldehydes and ketones with alcohols and amines. Compare the mechanisms vertically to see the similarities and differences. Note differences in completion of the mechanism for each type of product. 

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

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