21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1022


21.17 Give the structure of the product in the reaction of each of the following with isotopi- 18 STUDY GUIDE LINK 21.5 cally labeled sodium , Na| OH_. Esters and 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


A. Reduction of Esters to Primary Lithium aluminum hydride reduces all carboxylic acid derivatives. Reduction of esters with this reagent, like the reduction of carboxylic , gives primary alcohols.

O S H3O| 2CH3CH2 CH C OC2H5 LiAlH4 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 of the (2- methyl-1-butanol in Eq. 21.47), and one derived from the (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 derived from the acyl portion of the ester is typically the prod- uct of interest.

As noted several times (Sec. 20.10), the active in LiAlH4 reductions is the hy- dride ion (H_) delivered from _AlH4, and this reduction is no exception. Hydride replaces at the3 of the ester to give an . (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


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 fol- lowed by a carbonyl .

Sodium borohydride (NaBH4), another useful hydride reducing agent, is much less reactive than lithium aluminum hydride. It reduces and , 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 to

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 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 , which is a , into its conjugate-acid 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 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. 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


The reaction of LiAlH4 with an amide differs from its reaction with an ester. In the reduc- tion of an ester, the carboxylate is lost as a leaving group. If amide reduction were strictly analogous to ester reduction, the 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 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 .

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 (Sec. 19.11). 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 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

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 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


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 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 from amides and nitriles, the nitrogen-containing carboxylic acid derivatives. Hence, any synthesis of a carboxylic acid can be used as part of an amine synthesis, but it is important to notice that the amine prepared by these methods must have the following form:

RNCH2 ) LL $ CA O or C' N of the carboxylic acid derivative

As this diagram shows, the carbon of the carbonyl group or cyano group in the carboxylic acid

derivative ends up as a CH2 group adjacent to the amine nitrogen. L L Study Problem 21.1 Outline a synthesis of (cyclohexylmethyl)methylamine from cyclohexanecarboxylic acid. O S C CH2 NHCH3 OH ? L % % %

cyclohexanecarboxylic acid (cyclohexylmethyl)methylamine

Solution Any carboxylic acid derivative used to prepare the amine must contain nitrogen; the two such derivatives are amides and nitriles. However, the only type of amine that can be prepared di-

rectly by reduction is a primary amine of the form CH2NH2. Because the desired product is not a primary amine, the reduction of nitriles must be rejectedL as an approach to this target. 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1027


The amide that could be reduced to the desired amine is N-methylcyclohexanecarboxamide:

O S 1) LiAlH C 4 CH NHCH 2) H3O| 2 3 NHCH 3) OH L % % 3 _ %


This amide can be prepared, in turn, by reaction of the appropriate amine, in this case methy- lamine, with an acid chloride:

O O S S H2NCH3 C methylamine C Cl (excess) NHCH % % % % 3 | H3NCH3 Cl_ +

cyclohexanecarbonyl chloride

Finally, the acid chloride is prepared from the carboxylic acid (Sec. 20.9A).

D. Reduction of Acid Chlorides to Aldehydes Acid chlorides can be reduced to aldehydes by either of two procedures. In the first, the acid chloride is hydrogenated over a catalyst that has been deactivated, or poisoned, with an amine, such as , that has been heated with sulfur. (Amines and sulfides are catalyst poisons.) This reaction is called the Rosenmund reduction.

O O S S CH3O C Cl Pd/C CH3O C H L 50 psi L % % H2 % % HCl (21.57) CH O + CH O + 3 % 3 % N "OCH3 quinoline "OCH3 sulfur 3,4,5-trimethoxybenzoyl chloride 3,4,5-trimethoxybenzaldehyde (54–83% yield)

The poisoning of the catalyst prevents further reduction of the aldehyde product. A second method of converting acid chlorides into aldehydes is the reaction of an acid chlo-

ride at low temperature with a “cousin” of LiAlH4, lithium tri(tert-butoxy)aluminum hydride. O S 78 °C H3O (CH ) CC Cl Li H Al[OC(CH_ ) ] | 3 3 | 3 3 3 _diglyme LL + L 2,2-dimethylpropanoyl lithium tri(tert-butoxy)aluminum hydride chloride O S HOC(CH ) 3 (21.58) (CH3)3C C H 33 3 LiCl Al | salts L L + ++ 2,2-dimethylpropanal 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1028


The hydride reagent used in this reduction is derived by the replacement of three of

lithium aluminum hydride by tert-butoxy groups. As the hydrides of LiAlH4 are replaced suc- cessively with alkoxy groups, less reactive reagents are obtained. In fact, the preparation of

LiAlH[OC(CH3)3]3 owes its success to the poor reactivity of its hydride: the reaction of LiAlH4 with tert-butyl alcohol stops after three moles of alcohol have been consumed.

_ H H (21.59) Li| _AlH4 3(CH3)3COH Li| H Al͓O C(CH3)3͔3 3 + LL L L + L The one remaining hydride reduces only the most reactive functional groups. Because acid chlo- rides are more reactive than aldehydes toward nucleophiles, the reagent reacts preferentially with the acid chloride reactant rather than with the product aldehyde. In contrast, lithium alu- minum hydride is so reactive that it fails to discriminate to a useful degree between the aldehyde and acid chloride groups, and it thus reduces acid chlorides to primary alcohols. The reduction of acid chlorides adds another synthesis of aldehydes and ketones to those given in Sec. 19.4. A complete list of methods for preparing aldehydes and ketones is given in Appendix V.

PROBLEMS 21.19 Show how can be converted into each of the following compounds. (a) benzaldehyde (b) PhCH2 N L 21.20 Complete the following reactions by giving the principal organic product(s). (a) Raney Ni PhCH CH' N 2 2 heat + (b) O 1) H3O| S LiAlH 2) OH C H OC CH CN 4 _ 2 5 2 (excess) LL L (c) O S OC CH3 LL H3O| Ph"CH CO2C2H5 LiAlH4 (excess) L L + 21.21 Give the structures of two compounds that would give the amine

(CH3)2CHCH2CH2CH2 NH2 after LiAlH4 reduction. 21.22 (a) In the catalytic hydrogenation of some nitriles to primary amines, secondary amines are obtained as by-products:

H2 (catalyst) R CN' RCH2NH2 (RCH2)2NH L +secondary amine

Suggest a mechanism for the formation of this by-product. (Hint: What is the intermedi- ate in the reduction? How can this intermediate react with an amine?) (b) Explain why added to the reaction mixture prevents the formation of this by- product.

E. Relative Reactivities of Carbonyl Compounds Recall that the reaction of lithium aluminum hydride with a carboxylic acid (Sec. 20.10) or ester (Sec. 21.9A) involves an aldehyde intermediate. But the product of such a reaction is a 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1029


primary alcohol, not an aldehyde, because the aldehyde intermediate is more reactive than the acid or ester. The instant a small amount of aldehyde is formed, it is in competition with the

remaining acid or ester for the LiAlH4 reagent. Because it is more reactive, the aldehyde re- acts faster than the remaining ester reacts. Hence, the aldehyde cannot be isolated under such circumstances. On the other hand, the lithium tri(tert-butoxy)aluminum hydride reduction of acid chlorides can be stopped at the aldehyde because acid chlorides are more reactive than aldehydes. When the aldehyde is formed as a product, it is in competition with the remaining acid chloride for the hydride reagent. Because the acid chloride is more reactive, it is con- sumed before the aldehyde has a chance to react. These examples show that the outcomes of many reactions of carboxylic acid derivatives are determined by the relative reactivities of carbonyl compounds toward nucleophilic reagents, which can be summarized as follows. (Nitriles are included as “honorary carbonyl compounds.”)

Relative reactivities of carbonyl compounds:

nitriles < amides < esters, acids << ketones < aldehydes < acid chlorides

increasing reactivity (21.60)

The explanation of this reactivity order is the same one used in Sec. 21.7E. Relative reactivity is determined by the stability of each type of carbonyl compound relative to its transition state for addition or substitution. The more a compound is stabilized, the less reactive it is; the more a transition state for nucleophilic addition or substitution is stabilized, the more reactive the compound is (Fig. 21.6, p. 1012). For example, esters are stabilized by (Eq. 21.28, p. 1014) in a way that aldehydes and ketones are not. Hence, esters are less reactive than alde- hydes. In contrast, resonance stabilization of acid chlorides is much less important, and acid chlorides are destabilized by the electron-attracting polar effect of the chlorine. Moreover, the transition-state energies for nucleophilic substitution reactions of acid chlorides are lowered by favorable leaving-group properties of chlorine. For these reasons, acid chlorides are more reactive than aldehydes, in which these effects of the chlorine are absent.


A. Reaction of Esters with Grignard Reagents Most carboxylic acid derivatives react with Grignard or organolithium reagents. One of the most important reactions of this type is the reaction of esters with Grignard reagents. In this reaction, a tertiary alcohol is formed after protonolysis. (Secondary alcohols are formed from esters of formic acid; see Problem 21.24a, p. 1032.)

O OH S H O (CH ) CHC OC H 2 CH MgI 3 | (CH ) CH"C CH C H OH Mg2 salts 3 2 2 5 3 ether 3 2 3 2 5 | LL + L L ++ ethyl 2-methylpropanoate methylmagnesium "CH iodide 3 2,3-dimethyl-2-butanol (21.61) (92% yield)