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introduction of the formation of the the Grignard reagent O S OO HOCH2CH2OH Mg Br C CH3 C p-toluenesulfonic L CH LcL L (trace) 3 (See Eq. 19.46) Br LcL protecting group; protonolysis of the inert to Grignard reagents and of the acetal (removal of the protecting group)

O OO OO H2C$ CH2 H2O, H3O| C L C L CH3 L CH3

BrMg BrMg OCH CH LcL |_ 2 2LcL O S HOCH2CH2OH HOCH2CH2 C CH3 (19.54) + LcL L Notice in this synthesis that all steps following acetal formation involve basic or neutral condi- tions. Acid can be used only when destruction of the acetal is desired. Although any acetal group can in principle be used, the five-membered cyclic acetal is fre- quently employed as a protecting group because it forms very rapidly (proximity effect; Sec. 11.7) and it introduces relatively little steric congestion into the protected molecule.

A number of reagents that react with carbonyl groups also react with other functional groups. are commonly used to protect the carbonyl groups of aldehydes and ketones from basic, nucleophilic reagents. Once the protection is no longer needed, the acetal protect- ing group is easily removed, and the re-exposed, by treatment with dilute aqueous acid. Because acetals are unstable in acid, they do not protect carbonyl groups under acidic conditions.

PROBLEM 19.27 Outline a synthesis of the following compound from p-bromoacetophenone and any other reagents. O O S S H3C C C CH3 L LcL L


A. Reaction with Primary Amines and Other Monosubstituted Derivatives of A primary is an organic derivative of ammonia in which only one ammonia is replaced by an or group. An is a analog of an or in which the CAO group is replaced by a CANR group, where R alkyl, aryl, or H. = 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 927


R NH2 $C A O $C A N R L 2 2 2 L primary amine ) ) aldehyde or ketone2 imine ( are sometimes called Schiff bases or Schiff’s bases.) Imines are prepared by the re- action of aldehydes or ketones with primary amines.

heat CH AAO Ph NH2 CH N Ph H2O (19.55) cLL++a primary2 cL 2 L (separates from amine an imine the reaction (84–87% yield) mixture) Formation of imines is reversible and generally takes place with acid or catalysis or with heat. Imine formation is typically driven to completion by precipitation of the imine, re- moval of water, or both. The mechanism of imine formation begins as a to the carbonyl group. In this case, the is the amine, which reacts with the aldehyde or ketone to give an unstable addition product called a carbinolamine. A carbinolamine is a compound with an

amine group ( NH2, NHR, or NR2) and a on the same . L L L O OH S C H2NR "C (19.56a) STUDY GUIDE LINK 19.7 % + 2 L LL Mechanism of % "NH R Carbinolamine 3 L Formation carbinolamine (You should write the detailed mechanism, which is analogous to the mechanism of other re- versible additions.) Carbinolamines are not isolated, but undergo acid-catalyzed dehydration to form imines. This reaction is essentially an dehydration (Sec. 10.1), except that it is typically much faster than dehydration of an ordinary alcohol. OH acid "C NR $C A NR H2O (19.56b) LL2 2 + STUDY GUIDE LINK 19.8 ""H ) Dehydration of imine Carbinolamines carbinolamine (Write the mechanism of this reaction as well.) Typically, the dehydration of the carbinolamine is the rate-limiting step of imine formation. This is why imine formation is catalyzed by . Yet the acid concentration cannot be too high because amines are basic compounds, and because protonated amines cannot act as nu- cleophiles.

| (19.57) RNH2 H3O| RNH3 H2O 2 + 2 + 2 3 of the amine pulls the equilibrium in Eq. 19.56a to the left; consequently, if the acid concentration is high enough, carbinolamine formation cannot occur. For this reason, many imine syntheses are carried out in very dilute acid. To summarize: Imine formation is a sequence of two reactions that have close analogies to familiar reactions—namely, carbonyl addition followed by b-elimination. One use of imines is in the preparation of amines; this is discussed in Sec. 23.7B. Another use, which was more important before the advent of spectroscopy than it is now, is in the char- acterization of aldehydes and ketones. When a new compound was synthesized, it was typically 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 928


characterized by conversion into two or more crystalline compounds called derivatives. These derivatives served as the basis for subsequent identification of the new compound when it was isolated from another source or from a different reaction. It was important to prepare derivatives because they eliminated the ambiguity that could arise if two compounds have very similar melting points or boiling points. It is relatively improbable that two compounds with the same melting or boiling points will give two crystalline derivatives with the same melting points. Certain imines are frequently used as solid derivatives of aldehydes and ketones. These imines, and the amines from which they are derived, are listed in Table 19.3. For example, the 2,4-DNP derivative of acetone is prepared by formation of an imine with 2,4- dintrophenylhydrazine:

NO2 cL

NO2 O cL N NH NO2 S S22L L L dilute H2SO4 H3CCCH3 H2N NH NO2 H3CCCH3 H2O C2H5OH LL + 22L L L LL(precipitates) + 2,4-dinitrophenylhydrazine a 2,4-dinitrophenylhydrazone (2,4-DNP) (2,4-DNP derivative of acetone) (19.58) To illustrate how such derivatives might be used in structure verification, suppose that a chemist has isolated a liquid that could be either 6-methyl-2-cyclohexenone or 2-methyl-2-cy- clohexenone. The boiling points of these compounds are too similar for an unambiguous iden- tification. Yet the melting point of either a 2,4-DNP derivative or a (see Table 19.3) would quickly establish which compound has been isolated. O O S S H3C CH3 M M

boiling point 69–71 °C (18 mm) 69–70 °C (16 mm) semicarbazone, mp 177–178 °C 207–208 °C 2,4-DNP derivative, mp 162–164 °C 207–208 °C

TABLE 19.3 Some N-Substituted Imine Derivatives of Aldehydes and Ketones

Amine Name Carbonyl Derivative Name

H2N OH hydroxylamineR2CNA OH 2 L 2 2 L 2 2 2 H2N NH2 hydrazineR2CA N NH2 2 L 2 2 L 2

H2N NH phenylhydrazineR2CA N NH phenylhydrazone 2 L2 Lc 2 L 2 Lc

NO2 NO2 $ $ 2,4-dinitrophenylhydrazine A 2,4-dinitrophenylhydrazone H2NNH NO2 R2C N NH NO2 2 L2 LcL (2,4-DNP) 2 L 2 LcL (2,4-DNP derivative)

O O S S H2N NH C NH2 semicarbazideR2CNA NH C NH2 semicarbazone 2 L 2 LL2 2 L 2 LL2 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 929


Although the identity of the compound could be readily established today by spectroscopy (explain how), it is important to be familiar with the imine derivatives in Table 19.3 because references to the use of such derivatives are commonplace in the older chemical literature.

PROBLEMS 19.28 Draw the structure of (a) the semicarbazone of cyclohexanone (b) the 2,4-DNP derivative of 2-methylpropanal

(c) the imine formed in the reaction between 2-methylhexanal and (C2H5NH2). 19.29 Write a curved-arrow mechanism for the acid-catalyzed formation of the hydrazone of ac- etaldehyde. 19.30 Write a curved-arrow mechanism for the acid-catalyzed hydrolysis of the imine derived

from benzaldehyde and ethylamine (CH3CH2NH2). Use the principle of microscopic reversibility (p. 171) to guide you.

B. Reaction with Secondary Amines

A secondary amine has the general structure R2NH, in which two ammonia are re- placed by alkyl or aryl groups. An (pronounced e¯n´-e -me¯n˝) has the following gen- eral structure:


$ 2 $ $C A C $

general enamine structure

The name enamine is a contraction of the word amine (a compound of the form R3N) and the suffix ene, which is used for naming . The name recognizes that an amine nitrogen is bonded to a carbon that is part of a (that is, an ). Formation of an enamine occurs when a secondary amine reacts with an aldehyde or ketone, provided that the carbonyl compound has an a-hydrogen. a-hydrogen


% % % % % CH CH A O H N CH3 C A CH N H2O (19.59) L ++L 2 L L 2 (removed as H3C Ph" H3C Ph it is formed) an enamine isobutyraldehyde a secondary amine (87% yield)

O O S O acid N H2O (19.60) + + N 2 (removed as H " it is formed) cyclohexanone 2 (a secondary amine) an enamine (72–80% yield) As Eq. 19.60 illustrates, the two alkyl groups of a secondary amine may be part of a ring. Like imine formation, enamine formation is reversible and must be driven to completion by the removal of one of the reaction products (usually water; see Eq. 19.60). , like imines, revert to the corresponding carbonyl compounds and amines in aqueous acid. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 930


The mechanism of enamine formation begins, like the mechanism of imine formation, as a nucleophilic addition to give a carbinolamine intermediate. (Write the mechanism of this re- action.) O HO NR2 S 2 " " R2NH (19.61a) 2 L +

Because no hydrogen remains on the nitrogen of this carbinolamine, imine formation cannot occur. Instead, dehydration of the carbinolamine involves loss of a hydrogen from an adjacent

carbon. % NR HO NR2 2 H 2 2 " " " acid H OH (19.61b) + L Why don’t primary amines react with aldehydes or ketones to form enamines rather than imines? The answer is the enamines bear the same relationship to imines that bear to ke-

tones. % HNR NR H S

H " " H " (19.62a)

an enamine the isomeric imine

(more stable) % OH O H S

H " " H " (19.62b)

an the isomeric ketone (more stable) Just as most aldehydes and ketones are more stable than their corresponding enols (Sec. 14.5A), most imines are more stable than their corresponding enamines. Because sec- ondary amines cannot form imines, they form enamines instead.

To summarize: Aldehydes and ketones react with primary amines (RNH2) to give imines, and with secondary amines (R2NH) to give enamines. In a third type of amine, a tertiary amine (R3N), all hydrogens of ammonia are replaced by alkyl or aryl groups. Tertiary amines do not react with aldehydes and ketones to form stable derivatives. Although most tertiary amines are good , they have no NH hydrogens and therefore cannot even form carbinolamines. Their adducts with aldehydes and ketones are unstable and can only break down to starting materials.

O O _ 3S3 332 R3N C "C (19.63) 3 + % % L L R3"N| 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 931


PROBLEM 19.31 Give the enamine product formed when each of the following pairs reacts. (a) (b) PhCH2CHA O and (CH3)2NH acetone and H N 2 L 3


The most common reductive transformation of aldehydes or ketones is their conversion into al- cohols (Sec. 19.8). But it is also possible to reduce the carbonyl group of an aldehyde or ketone

completely to a methylene ( CH2 )group.Oneprocedureforeffectingthistransformationin- volves heating the aldehydeL or ketoneL with (H2N NH2)andstrongbase. O L S KOH, heat, 1 h Ph C CH CH H N NH Ph CH CH CH H O N 2 3 2 2 triethylene glycol 2 2 3 2 2 (19.64) LL ++L L + propiophenone hydrazine propylbenzene (85% aqueous (82% yield) solution)


M M M KOH M M (19.65) triethylene glycol CH3O CH3O 3,4-dimethoxybenzaldehyde 3,4-dimethoxytoluene (81% yield) This reaction, called the Wolff–Kishner reduction, typically uses glycol or similar high-boiling compounds as co-. (Triethylene glycol, which has the structure

HOCH2CH2OCH2CH2OCH2CH2OH, and a boiling point of 278 C, is used in Eqs. 19.64 and 19.65.) The high boiling points of these solvents allow the reaction° mixtures to reach the high temperatures required for the reduction to take place at a reasonable rate. The Wolff–Kishner reduction is an extension of imine formation (Sec. 19.11A) because a hydrazone (Table 19.3) is an intermediate in the reaction. A series of Brønsted acid–base re- actions (see Study Guide Link 19.9) lead ultimately to expulsion of dinitrogen gas and forma- tion of the product.

O N NH2 H S S L H O, OH STUDY GUIDE LINK 19.9 C H N NH C 2 _ R "C R´ N (19.66) Mechanism of the 2 2 several steps 2 Wolff–Kishner R R´ + L R R´ LL + % % hydrazine % % Reaction hydrazone "H

H2O + The Wolff–Kishner reduction takes place under strongly basic conditions. The same over- all transformation can be achieved under acidic conditions by a reaction called the Clem- mensen reduction. In this reaction, an aldehyde or ketone is reduced with (a solution of zinc metal in mercury) in the presence of HCl.