chapter 8 to 10.pdf

19-8 nucleophilic addition of amines: imine and enamine formation nucleophiles, R:ⴚ ⴙMgX. Aldehydes give secondary alcohols on reaction with Grignard reagents in ether solution, and ketones give tertiary alcohols. O R C O OH 1. R″MgX 2. H O+ H R 3 Aldehyde C H R R″ 2° Alcohol C OH R′...

19-8 nucleophilic addition of amines: imine and enamine formation nucleophiles, R:ⴚ ⴙMgX. Aldehydes give secondary alcohols on reaction with Grignard reagents in ether solution, and ketones give tertiary alcohols. O R C O OH 1. R″MgX 2. H O+ H R 3 Aldehyde C H R R″ 2° Alcohol C OH R′ 1. R″MgX 2. H O+ R 3 Ketone C R″ R′ 3° Alcohol As shown in FIGURE 19-5, a Grignard reaction begins with an acid–base complexation of Mg2ⴙ to the carbonyl oxygen atom of the aldehyde or ketone, thereby making the carbonyl group a better electrophile. Nucleophilic addition of R:ⴚ then produces a tetrahedral magnesium alkoxide intermediate, and protonation by addition of water or dilute aqueous acid in a separate step yields the neutral alcohol. Like reduction, Grignard additions are effectively irreversible because a carbanion is too poor a leaving group to be expelled in a reversal step. 19-8 Nucleophilic Addition of Amines: Imine and Enamine Formation Primary amines, RNH2, add to aldehydes and ketones to yield imines, R2C P NR. Secondary amines, R2NH, add similarly to yield enamines, R2N O CR P CR2 (ene ⫹ amine ⫽ unsaturated amine). O C H C RNH2 R2NH R H2O C R A ketone or an aldehyde N + H R N + H2O C C C An imine An enamine Imines are particularly common as intermediates in biological pathways, where they are often called Schiff bases. The amino acid alanine, for instance, is metabolized in the body by reaction with the aldehyde pyridoxal phosphate (PLP), a derivative of vitamin B6, to yield a Schiff base that is further degraded. 2–O PO 3 2–O PO 3 H C O H2N +N OH H C CH3 Pyridoxal phosphate C C N CH3 H CO2– H CO2– +N CH3 H + H2O OH H CH3 Alanine An imine (Schiff base) !*#%


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% 619 620 chapter 19 aldehydes and ketones: nucleophilic addition reactions FIGURE 19-6 MECHANISM Mechanism of imine formation by reaction of an aldehyde or ketone with a primary amine. The key step is the initial nucleophilic addition to yield a carbinolamine intermediate, which then loses water to give the imine. O Ketone/aldehyde C 1 Nucleophilic attack on the ketone or aldehyde by the lone-pair electrons of an amine leads to a dipolar tetrahedral intermediate. 1 NH2R O – + NH2R C 2 A proton is then transferred from nitrogen to oxygen, yielding a neutral carbinolamine. 2 Proton transfer OH C NHR Carbinolamine 3 Acid catalyst protonates the hydroxyl oxygen. H3O+ 3 + OH 2 C 4 The nitrogen lone-pair electrons expel water, giving an iminium ion. 4 NHR –H2O R + H N OH2 C Iminium ion 5 Loss of H+ from nitrogen then gives the neutral imine product. 5 R N C + H3O+ Imine !*#%


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% 19-8 nucleophilic addition of amines: imine and enamine formation Imine formation and enamine formation seem different because one leads to a product with a C⫽N bond and the other leads to a product with a C⫽C bond. Actually, though, the reactions are quite similar. Both are typical examples of nucleophilic addition reactions in which water is eliminated from the initially formed tetrahedral intermediate and a new C⫽Nu double bond is formed. Imines are formed in a reversible, acid-catalyzed process (FIGURE 19-6) that begins with nucleophilic addition of the primary amine to the carbonyl group, followed by transfer of a proton from nitrogen to oxygen to yield a neutral amino alcohol, or carbinolamine. Protonation of the carbinolamine oxygen by an acid catalyst then converts the ᎐ OH into a better leaving group ( ᎐ OH2ⴙ), and E1-like loss of water produces an iminium ion. Loss of a proton from nitrogen gives the final product and regenerates the acid catalyst. Imine formation with such reagents as hydroxylamine and 2,4-dinitrophenylhydrazine is sometimes useful because the products of these reactions— oximes and 2,4-dinitrophenylhydrazones (2,4-DNPs), respectively—are often crystalline and easy to handle. Such crystalline derivatives are occasionally prepared as a means of purifying and characterizing liquid ketones or aldehydes. Oxime O N + Cyclohexanone OH NH2OH Hydroxylamine + H2O Cyclohexanone oxime (mp 90 °C) 2,4-Dinitrophenylhydrazone H O C H3C CH3 + H2N NO2 H N N NO2 Acetone 2,4-Dinitrophenylhydrazine H3C C NO2 N + CH3 H2O NO2 Acetone 2,4-dinitrophenylhydrazone (mp 126 °C) Reaction of an aldehyde or ketone with a secondary amine, R 2NH, rather than a primary amine yields an enamine. As shown in FIGURE 19-7, the process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the ␣ carbon), yielding an enamine. !*#%


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% 621 622 chapter 19 aldehydes and ketones: nucleophilic addition reactions FIGURE 19-7 MECHANISM Mechanism for enamine formation by reaction of an aldehyde or ketone with a secondary amine, R2NH. The iminium ion intermediate formed in step 3 has no hydrogen attached to N and so must lose Hⴙ from the carbon two atoms away. O C H C 1 Nucleophilic addition of a secondary amine to the ketone or aldehyde, followed by proton transfer from nitrogen to oxygen, yields an intermediate carbinolamine in the normal way. 1 R2NH OH H C C R2N 2 Protonation of the hydroxyl by acid catalyst converts it into a better leaving group. H3O+ 2 +OH 2 H C C R2N 3 Elimination of water by the lone-pair electrons on nitrogen then yields an intermediate iminium ion. 3 –H2O + R N R C OH2 H C 4 Loss of a proton from the alpha carbon atom yields the enamine product and regenerates the acid catalyst. 4 R N R + C H3O+ C Enamine Imine and enamine formation are slow at both high pH and low pH but reach a maximum rate at a weakly acidic pH around 4 to 5. For example, the profile of pH versus rate shown in FIGURE 19-8 for the reaction between acetone and hydroxylamine, NH2OH, indicates that the maximum reaction rate occurs at pH 4.5. We can explain the observed pH dependence of imine formation by looking at the individual steps in the mechanism. As indicated in Figure 19-7, an acid catalyst is required in step 3 to protonate the intermediate carbinolamine, !*#%


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% 19-8 nucleophilic addition of amines: imine and enamine formation 623 thereby converting the ᎐ OH into a better leaving group. Thus, reaction will be slow if not enough acid is present (that is, at high pH). On the other hand, if too much acid is present (low pH), the basic amine nucleophile is completely protonated, so the initial nucleophilic addition step can’t occur. Reaction rate FIGURE 19-8 Dependence on pH of the rate of reaction between acetone and hydroxylamine: (CH3)2C P O ⫹ NH2OH n (CH3)2C P NOH ⫹ H2O. 1 2 3 4 5 6 7 8 pH Evidently, a pH of 4.5 represents a compromise between the need for some acid to catalyze the rate-limiting dehydration step but not too much acid so as to avoid complete protonation of the amine. Each nucleophilic addition reaction has its own requirements, and reaction conditions must be optimized to obtain maximum reaction rates. Predicting the Product of Reaction between a Ketone and an Amine Wo r k e d E x a m p l e 1 9 - 1 Show the products you would obtain by acid-catalyzed reaction of 3-pentanone with methylamine, CH3NH2, and with dimethylamine, (CH3)2NH. Strategy An aldehyde or ketone reacts with a primary amine, RNH2, to yield an imine, in which the carbonyl oxygen atom has been replaced by the ⫽N ᎐ R group of the amine. Reaction of the same aldehyde or ketone with a secondary amine, R2NH, yields an enamine, in which the oxygen atom has been replaced by the ᎐ NR2 group of the amine and the double bond has moved to a position between the former carbonyl carbon and the neighboring carbon. Solution N CH3CH2 CH3NH2 O C CH3 + H2O CH2CH3 An imine C CH3CH2 CH2CH3 3-Pentanone CH3NCH3 H3C H CH3CH2 N CH3 + C H H2O C CH3 An enamine !*#%


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% 624 chapter 19 aldehydes and ketones: nucleophilic addition reactions PROBLEM 19-10 Show the products you would obtain by acid-catalyzed reaction of cyclohexanone with ethylamine, CH3CH2NH2, and with diethylamine, (CH3CH2)2NH. PROBLEM 19-11 Imine formation is reversible. Show all the steps involved in the acid-catalyzed reaction of an imine with water (hydrolysis) to yield an aldehyde or ketone plus primary amine. PROBLEM 19-12 Draw the following molecule as a skeletal structure, and show how it can be prepared from a ketone and an amine. 19-9 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction A useful variant of the imine-forming reaction just discussed involves the treatment of an aldehyde or ketone with hydrazine, H2NNH2, in the presence of KOH. Called the Wolff–Kishner reaction, the process is a useful and general method for converting an aldehyde or ketone into an alkane, R2C P O n R2CH2. O H C H C CH2CH3 H2NNH2 CH2CH3 KOH C H H2NNH2 H Cyclopropanecarbaldehyde KOH N2 + H2O Propylbenzene (82%) Propiophenone O + H C H + N2 + H2O Methylcyclopropane (72%) As shown in FIGURE 19-9, the Wolff–Kishner reaction involves formation of a hydrazone intermediate, R2CPNNH2, followed by base-catalyzed double-bond !*#%


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% 19-9 nucleophilic addition of hydrazine: the wolff–kishner reaction MECHANISM FIGURE 19-9 Mechanism for the Wolff–Kishner reduction of an aldehyde or ketone to yield an alkane. O + C R 1 Reaction of the aldehyde or ketone with hydrazine yields a hydrazone in the normal way. H2NNH2 R′ 1 H N 2 Base abstracts a weakly acidic N–H proton, yielding a hydrazone anion. This anion has a resonance form that places the negative charge on carbon and the double bond between nitrogens. N – C R R′ H2 O OH 2 N – N H N N C R 3 Protonation of the hydrazone anion takes place on carbon to yield a neutral intermediate. + H R′ R 3 H N C R N C – H R′ O H H – OH H R′ 4 Deprotonation of the remaining weakly acidic N–H occurs with simultaneous loss of nitrogen to give a carbanion . . . 4 – C R H + N2 + HO– R′ 5 . . . which is protonated to give the alkane product. 5 + H2O H2O H R C H R′ migration, loss of N2 gas to give a carbanion, and protonation to give the alkane product. The double-bond migration takes place when a base removes one of the weakly acidic NH protons in step 2 to generate a hydrazone anion, which has an allylic resonance structure that places the double bond between nitrogens and the negative charge on carbon. Reprotonation then occurs on carbon to generate the double-bond rearrangement product. The next step—loss of nitrogen and !*#%


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% 625 626 chapter 19 aldehydes and ketones: nucleophilic addition reactions formation of an alkyl anion—is driven by the large thermodynamic stability of the N2 molecule. Note that the Wolff–Kishner reduction accomplishes the same overall transformation as the catalytic hydrogenation of an acylbenzene to yield an alkylbenzene (Section 16-10). The Wolff–Kishner reduction is more general and more useful than catalytic hydrogenation, however, because it works well with both alkyl and aryl ketones. PROBLEM 19-13 Show how you could prepare the following compounds from 4-methyl-3penten-2-one, (CH3)2C P CHCOCH3. (a) CH3 (b) O CH3CHCH2CCH3 (c) CH3 CH3C CHCH2CH3 CH3 CH3CHCH2CH2CH3 19-10 Nucleophilic Addition of Alcohols: Acetal Formation Aldehydes and ketones react reversibly with 2 equivalents of an alcohol in the presence of an acid catalyst to yield acetals, R2C(OR⬘)2, which are frequently called ketals if derived from a ketone. Cyclohexanone, for instance, reacts with methanol in the presence of HCl to give the corresponding dimethyl acetal. OCH3 OCH3 O 2 CH3OH + HCl catalyst Cyclohexanone H2O Cyclohexanone dimethyl acetal 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 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. ␦– O ␦+ C H + H O O C C+ A A neutral carbonyl group is moderately electrophilic because of the polarity of the C–O bond. H A protonated carbonyl group is strongly electrophilic because of the positive charge on carbon. As shown in FIGURE 19-10, nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. Hemiacetals are formed reversibly, with equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the ᎐ OH group, followed by an E1-like loss of water, leads to an oxonium ion, !*#%


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