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21.9 Reduction of Carboxylic Acid Derivatives

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21.9 Reduction of Carboxylic Acid Derivatives 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1022 1022 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES 21.17 Give the structure of the product in the reaction of each of the following esters with isotopi- 18 STUDY GUIDE LINK 21.5 cally labeled sodium hydroxide, Na| OH_. Esters and Nucleophiles O O S S PhCH2 O S CH3 PhCH2 O C CH3 LLLS L LL O B A 21.18 How would you synthesize each of the following compounds from an acid chloride? (a) Ph (b) O S CH3"CHOSO2 CH3 H3C C O NO2 LL LLL L (c) O (d) O O COA S S O (CH3)3C O C CH2 C O C(CH3)3 L LL LLL 21.9 REDUCTION OF CARBOXYLIC ACID DERIVATIVES A. Reduction of Esters to Primary Alcohols Lithium aluminum hydride reduces all carboxylic acid derivatives. Reduction of esters with this reagent, like the reduction of carboxylic acids, gives primary alcohols. O S H3O| 2CH3CH2 CH C OC2H5 LiAlH4 ether LLL + "CH lithium 3 aluminum ethyl 2-methylbutanoate hydride 3 2CH3CH2 CHCH2 OH 2C2H5OH Li|, Al | salts LL L ++ ethanol "CH3 2-methyl-1-butanol (21.47) (91% yield) Two alcohols are formed in this reaction, one derived from the acyl group of the ester (2- methyl-1-butanol in Eq. 21.47), and one derived from the alkoxy group (ethanol in Eq. 21.47). In most cases, a methyl or ethyl ester is used in this reaction, and the by-product methanol or ethanol is discarded; the alcohol derived from the acyl portion of the ester is typically the prod- uct of interest. As noted several times (Sec. 20.10), the active nucleophile in LiAlH4 reductions is the hy- dride ion (H_) delivered from _AlH4, and this reduction is no exception. Hydride replaces alkoxide at the3 carbonyl group of the ester to give an aldehyde. (Write the mechanism of this reaction, another example of nucleophilic acyl substitution.) O O S S (21.48a) Li| _AlH4 RCOC2H5 RCH Li| C2H5O_ AlH3 +++LL anL aldehydeL 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1023 21.9 REDUCTION OF CARBOXYLIC ACID DERIVATIVES 1023 The aldehyde reacts rapidly with LiAlH4 to give the alcohol after protonolysis (Sec. 19.8). O OH S LiAlH H O RCH 4 3 | RC" H (21.48b) LL LL "H The reduction of esters to alcohols thus involves a nucleophilic acyl substitution reaction fol- lowed by a carbonyl addition reaction. Sodium borohydride (NaBH4), another useful hydride reducing agent, is much less reactive than lithium aluminum hydride. It reduces aldehydes and ketones, but it reacts very sluggishly with most esters; in fact, NaBH4 can be used to reduce aldehydes and ketones selectively in the presence of esters. Acid chlorides and anhydrides also react with LiAlH4 to give primary alcohols. However, because acid chlorides and anhydrides are usually prepared from carboxylic acids, and because carboxylic acids themselves can be reduced to alcohols with LiAlH4 (Sec. 20.10), the reduc- tion of acid chlorides and anhydrides is seldom used. B. Reduction of Amides to Amines Amines are formed when amides are reduced with LiAlH4. O 1) H O S 3 | 2) _OH 3 LiAlH4 2Ph C NH2 2Ph CH2 NH2 Li|, Al | salts 2H2 (21.49) +++LL LL lithium benzamide benzylamine aluminum (80% yield) hydride In the workup conditions, H3O| is followed by _OH. An aqueous acidic solution is often used to carry out the protonolysis step that follows the LiAlH4 reduction (as shown in the following mechanism). The excess of acid that is typically used converts the amine, which is a base, into its conjugate-acid ammonium ion. Hydroxide is then required to neutralize this ammonium salt and thus give the neutral amine. | (21.50) _OH RCH2NH3 RCH2NH2 H2O + conjugate-base amine2 + (pKa 15.7) ammonium ion = (typical pKa 8–11) = Although water itself rather than acid can be used in the protonolysis step, for practical rea- sons the acidic workup is more convenient. Thus, the extra neutralization step is required. Amide reduction can be used not only to prepare primary amines from primary amides, but also to prepare secondary and tertiary amines from secondary and tertiary amides, respec- tively. O 1) H O S 3 | 2) _OH 3 LiAlH4 C N(CH3)2 CH2 N(CH3)2 Li|, Al | salts ++0L L 0L L (88% yield) (21.51) 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1024 1024 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES The reaction of LiAlH4 with an amide differs from its reaction with an ester. In the reduc- tion of an ester, the carboxylate oxygen is lost as a leaving group. If amide reduction were strictly analogous to ester reduction, the nitrogen would be lost, and a primary alcohol would be formed. Instead, it is the carbonyl oxygen that is lost in amide reduction. Ester reduction: the carbonyl oxygen is retained O S LiAlH4 H3O| RCORЈ R CH2OH RЈOH (21.52a) LL L + Amide reduction: the carbonyl oxygen is lost O 1) H O S 3 | LiAlH4 2) _OH RCNRЈ2 R CH2NR2 (21.52b) LL L Let’s consider the reason for this difference, using as a case study the reduction of a secondary amide. (The mechanisms of reduction of primary and tertiary amides are somewhat different, but they have the same result.) In the first step of the mechanism, the weakly acidic amide proton reacts with an equivalent of hydride, a strong base, to give hydrogen gas, AlH3, and the lithium salt of the amide. O Li| O Li| O_ Li| 33S 33S 332 C H H AlH_ 3 C "C AlH3 H2 (21.53a) L _ ++ % N %% % % NR % # NR R % 2 2 2 2 The lithium salt of the amide, a Lewis base, reacts with the Lewis acid AlH3. _ Li| O _ AlH3 Li| O AlH3 332 3 2 L "C "C (21.53b) % # NR % # NR The resulting species is an active hydride2 reagent, conceptually much2 like LiAlH4, and it can deliver hydride to the CAN double bond. reactive hydride H H % _Al % % AlH2 O O .. % % 3 2 H 3 2 RN.. Li "C "C H (21.53c) NR L L % # Li "NR Li |2 L 2 The O AlH group is subsequently lost from the tetrahedral intermediate because it is less _ 2 .. L basic than the other possible leaving group, RN.. Li. The resulting product is an imine (Sec. 19.11). 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1025 21.9 REDUCTION OF CARBOXYLIC ACID DERIVATIVES 1025 AlH2 O % 3 2 "CH CH Li| H2AlO _ (21.53d) L L LSL + 2 3 "NR Li| NR 2 3 _ 2 an 2imine The CAN of the imine, like the CAO of an aldehyde, undergoes nucleophilic addition with “H_” from _AlH4 or from one of the other hydride-containing species in the reaction mixture.3 Addition of acid to the reaction mixture converts the addition intermediate into an amine by protonolysis and then into its conjugate-acid ammonium ion. _ | Li| NR Li| NR HNR H2NR S2 3 2 2 H3O H3O| | C H Al % "C H "C H "C H (21.53e) L L L L L L L L L % + H Al_ % "H "H "H L L % The ammonium ion is neutralized to the free amine when _OH is added in a subsequent step (Eq. 21.52b). C. Reduction of Nitriles to Primary Amines Nitriles are reduced to primary amines by reaction with LiAlH4, followed by the usual protonolysis step. CH CN' CH CH NH 2 1) H3O| 2 2 2 2) OH % _ % 3 2 LiAlH4 2 Li|, Al | salts y ++y lithium 2-(1-cyclohexenyl)ethanenitrilealuminum 2-(1-cyclohexenyl)ethanamine (21.54) hydride (74% yield) As in amide reduction, isolation of the neutral amine requires addition of _OH at the conclu- sion of the reaction. The mechanism of this reaction illustrates again how the C'N and CAO bonds react in similar ways. This reaction probably occurs as two successive nucleophilic additions. Li| Li RC' N RCA N % AlH3 (21.55a) L 3 L 3 + H AlH_ 3 "H L imine salt In the second addition, the imine salt reacts in a similar manner with AlH3 (or another equiv- alent of _AlH4). Li Li Li % % % % RCH A N RCH2 N RCH2 N| (21.55b) L 3 LL3 LL # H AlH2 AlH2 AlH2 L _ 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1026 1026 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES In the resulting derivative, both the N Li and the N Al bonds are very polar, and the nitrogen has a great deal of anionic character.L Both bondsL are susceptible to protonolysis. Hence, an amine, and then an ammonium ion, is formed when aqueous acid is added to the re- action mixture. Li % % H3O H3O RCH2 N | RCH2 NH2 | RCH2 N|H3 (21.55c) L 2 L 2 L Al Li , Al3 salts (neutralization | | with OH gives % + _ " the amine) Nitriles are also reduced to primary amines by catalytic hydrogenation using Raney nickel, a type of nickel–aluminum alloy. Raney Ni ' (21.55d) CH3(CH2)4CN 2H2 2000 psi CH3(CH2)4CH2NH2 + 120–130 °C hexanenitrile 1-hexanamine An intermediate in the reaction is the imine, which is not isolated but is hydrogenated to the amine product. (See also Problem 21.22, p. 1028.) H2, catalyst H2, catalyst RCN' ͓RCH A NH͔ RCH2 NH2 (21.56) L L imine LL The reductions discussed in this and the previous section allow the formation of the amine functional group from amides and nitriles, the nitrogen-containing carboxylic acid derivatives.
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