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23.11 SYNTHESIS OF AMINES 1145

CH3 CH3 OA N NH| Cl (23.52) N)| HNO2 HCl ) _ L ++ L L $CH3 $CH3 N,N-dimethylaniline N,N-dimethyl-4-nitrosoanilinium chloride (89–90% yield)

PROBLEMS 23.26 Design a synthesis of methyl orange (Eq. 23.49) using aniline as the only aromatic starting material. 23.27 What two compounds would react in a diazo coupling reaction to form FD & C Yellow

No. 6? .. .. 23.28 (a) Using the curved-arrow notation, show how the nitrosyl cation, NOA .. , is generated

from HNO2 under acidic conditions. (b) Give a curved-arrow mechanism for the electrophilic aromatic substitution reaction shown in Eq. 23.52.

23.11 SYNTHESIS OF AMINES

Several reactions discussed in previous sections can be used for the synthesis of amines. In this section, four additional methods will be presented, and, in Sec. 23.7D, all of the methods for preparing amines are summarized.

A. Gabriel Synthesis of Primary Amines Recall that direct alkylation of ammonia is generally not a good synthetic method for the preparation of amines because multiple alkylation takes place (Sec. 23.7A). This problem can be avoided by protecting the amine nitrogen so that it can react only once with alkylating

reagents. One approach of this sort begins with the imide phthalimide. Because the pKa of phthalimide is 8.3, its conjugate-base anion is easily formed with KOH or NaOH. This

anion is a good nucleophile, and is alkylated by alkyl halides or sulfonate esters in SN2 reactions.

O O A 1 A KOH CH3CH2CH2CH2 OTs N H N K EtOH _ | L 2 L 2 2 A O A O2

phthalimide O pKa = 8.3 1 A

N CH2CH2CH2CH3 K (23.53a) | _ OTs L + 3 2 A O 2 N-butylphthalimide 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1146

1146 CHAPTER 23 • THE CHEMISTRY OF AMINES

The alkyl halides and sulfonates used in this reaction are primary or unbranched secondary. Because the N-alkylated phthalimide formed in this reaction is really a double amide, it can be converted into the free amine by amide hydrolysis in either strong acid or base.

O

O "S A 1 C OH HBr L N CH CH CH CH 2 H O CH CH CH CH N|H Br 2 2 2 3 2 HOAc 3 2 2 2 3 _ L + + butylammonium bromide "C OH A O SL O N-butylphthalimide (23.53b)

In this example, acidic hydrolysis gives the ammonium salt, which can be converted into the free amine by neutralization with base. The alkylation of phthalimide anion followed by hydrolysis of the alkylated derivative to the primary amine is called the Gabriel synthesis, after Siegmund Gabriel (1851–1924) a profes- sor at the University of Berlin, who developed the reaction in 1887. Because the nitrogen in phthalimide has only one acidic hydrogen, it can be alkylated only once. Although N-alkyl- phthalimides also have a pair of unshared electrons on nitrogen, they do not alkylate further, because neutral imides are much less basic (why?), and therefore less nucleophilic, than the phthalimide anion. Hence, multiple alkylation, which occurs in the direct alkylation of am- monia, is avoided in the Gabriel synthesis.

O O A A R N R RX N| X (23.54) % _ LL+ R 3 alkyl halide % A O A O

PROBLEM 23.29 Which one of the following three amines can be prepared by the Gabriel synthesis: 2,2- dimethyl-1-propanamine, 3-methyl-1-pentanamine, or N-butylaniline? Give an alkyl halide starting material for this synthesis, and explain why the other two amines cannot be pre- pared this way.

B. Reduction of Nitro Compounds Nitro compounds can be reduced easily to amines by catalytic hydrogenation:

NO2 NH2 H , Pd/C % 2 % (23.55) EtOH i i CH O CH O 3 % 3 % "OCH3 "OCH3 1,2-dimethoxy-4-nitrobenzene 3,4-dimethoxyaniline (97% yield) 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1147

23.11 SYNTHESIS OF AMINES 1147

In an older, but nevertheless effective, method, finely divided metal powders and HCl can be used to convert aromatic nitro compounds into aniline derivatives. Iron or tin powder is typ- ically used.

Br Br Sn/HCl or $ Fe/HCl OH $ _ 2 3 (23.56) NO2 NH2 Sn | or Fe | salts vL vL + 1-bromo-3-nitrobenzene m-bromoaniline (80% yield)

In this reaction, the nitro compound is reduced at nitrogen, and the metal, which is oxidized to a metal salt, is the reducing agent. Although the methods shown in both Eqs. 23.55 and 23.56 also work with aliphatic nitro compounds, they are particularly important with aromatic nitro compounds as methods for introducing an amino group into an aromatic ring.

In view of the utility of lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4) as reducing agents for other compounds, what happens when nitro compounds are treated with these reagents? Aromatic nitro compounds do react with LiAlH4, but the reduc- tion products are azobenzenes (Sec. 23.10B), not amines:

LiAlH4 H3O N | i (23.57) 2 NO2 ether cL % 2 # N % i nitrobenzene 2 azobenzene

Nitro groups do not react at all with sodium borohydride under the usual conditions.

NO NO the nitro group 2 2 is not reduced $ NaBH $ A 4 CH O EtOH CH2OH (23.58) vL vL m-nitrobenzaldehyde m-nitrobenzyl alcohol

Hence, LiAlH4 and NaBH4 are not useful in forming aromatic amines from nitro compounds.

PROBLEM 23.30 Outline syntheses of the following compounds from the indicated starting materials. (a) p-iodoanisole from phenol and any other reagents (b) m-bromoiodobenzene from nitrobenzene

C. Amination of Aryl Halides and Aryl Triflates Arylamines can be prepared by the direct amination of aryl chlorides and aryl bromides in the presence of a base and a Pd(0) catalyst. 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1148

1148 CHAPTER 23 • THE CHEMISTRY OF AMINES

CH3 + HN + Na Ot-Bu Pd(0) catalyst toluene H3C Cl pyrrolidine 1,4-dimethyl- 2-chlorobenzene CH3 ++Na Cl t-BuOH (23.59)

H3C N

N-(2,5-dimethylphenyl)pyrrolidine (98% yield)

The direct amination of aryl halides is sometimes called Buchwald–Hartwig amination to recognize the two chemistry professors who led the research groups that developed these re- actions: Stephen L. Buchwald of MIT, and John F. Hartwig of the University of Illinois. A number of different catalysts have been explored for direct amination. These are typi-

cally of the form PdL2, where L is a sterically demanding ligand such as the following:

P(Cy)2 P(t-Bu)2

L = or

(Cy = cyclohexyl)

These catalysts are formed by mixing palladium(II) acetate or other Pd precursors and two equivalents of the ligands. These amination reactions have been shown to operate by more than one mechanism. All of the mechanisms, however, like the mechanisms of the Heck, Suzuki, and Stille reactions (Secs. 18.6A, 18.6B, and 18.10B), involve the key steps of oxidative addition and reductive elimination (Sec. 18.5E). The following scheme summarizes these features.

PdL2 PdL + L Base .. R2NH PdL + ArCl oxidative L Pd Ar ligand L Pd Ar reductive PdL + Ar NR2 (23.60) a 12e– complex addition substitution elimination Cl NR2 Pd(0) a 14e– complex + Base H Pd(II) + Cl

The amine used as the starting material in the amination reaction must lose a hydrogen in the reaction. Consequently, when a tertiary amine is the amination product, it cannot react further. However, when a primary amine is used as the starting material, the product is a secondary amine. It can in principle serve as the starting material in a competing second amination.

Ar RNH2, base, Ar—Cl, base, catalyst catalyst Ar Cl Ar NHR Ar NR (23.61)

The product of this second amination becomes an unwanted by-product. Nevertheless, amina- tion with primary amines is practical if the primary amine is itself an arylamine, or if it has a 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1149

23.11 SYNTHESIS OF AMINES 1149

large or highly branched alkyl group. In such cases, steric hindrance is used to advantage. The catalyst complex leading to the tertiary amine has significant steric repulsions; as a result, the undesired second amination is relatively slow and does not occur to a significant extent. This is one reason that the catalysts involve sterically demanding ligands.

Cl Pd(0) catalyst + H2N CH2(CH2)4CH3 + Na Ot-Bu toluene H3C hexylamine p-chlorotoluene

NHCH2(CH2)4CH3 ++Na Cl t-BuOH

H3C (23.62) N-hexyl-4-methylaniline (85% yield)

As you have learned, reductive amination is another way to prepare tertiary arylamines. (See Eq. 23.23 on p. 1133.) Some tertiary arylamines, however, such those containing nitro- gen heterocycles (Eq. 23.59), would be difficult to prepare by reductive amination. Direct am- ination provides a straightforward route to these amines. Another attractive aspect of direct amination is that it, like other Pd-catalyzed coupling reactions, tolerates a wide variety of other functional groups, as Study Problem 23.5 illustrates.

Study Problem 23.5 Outline a synthesis of p-dipropylaminoacetophenone from chlorobenzene.

Solution Considering the problem retrosynthetically gives the following synthetic pathway, starting with the target molecule:

O O

H3C C NPr2 H3C C Cl Cl

p-dipropylaminoacetophenone

Direct amination of p-chloroacetophenone with dipropylamine and an appropriate Pd(0) catalyst gives the target:

O Pd(0) catalyst, base O Pr2NH H3C C Cl H3C C NPr2

Reductive amination would not have worked, because the acetyl group would have been reduced under conditions of reductive amination. The starting material for the amination, p-chloroacetophenone, can in turn be prepared by a Friedel–Crafts acylation reaction.

O O + AlCl3 H3O Cl + H3C C Cl H3C C Cl 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1150

1150 CHAPTER 23 • THE CHEMISTRY OF AMINES

Aryl triflates can also be used as starting materials in amination. Because aryl triflates can be prepared from the corresponding phenols (Sec. 18.9B), this reaction provides a synthetic path from phenols to arylamines. OTf Pd(0) catalyst + HNBu2 + Na Ot-Bu toluene (CH3)3C dibutylamine p-tert-butylphenyl triflate

NBu2 ++Na OTf t-BuOH (23.63)

(CH3)3C N,N-dibutyl-4-tert-butylaniline (73% yield)

PROBLEM 23.31 Outline a synthesis of each of the following compounds from the indicated starting material and any other reagents. (a) N-(sec-butyl)-N-ethylaniline from chlorobenzene (b) (c) O NH N C

(CH3)3C O from phenol from chlorobenzene

D. Curtius and Hofmann Rearrangements A very useful synthesis of amines starts with a class of compounds called acyl azides. An acyl azide has the following general structure:

O azide group O S S _ R C NN| ' N or RCN3 (23.64) LL2 L 3 anLL acyl azide acyl group 2 (The synthesis of acyl azides is discussed below.) When an acyl azide is heated in an inert sol- vent such as benzene or toluene, it is transformed with loss of nitrogen into an isocyanate, a compound of the general structure R NACAO. L O S heat AA CH3(CH2)10 C N3 benzene CH3(CH2)10 NCO N2 (23.65) LL L + dodecanoyl azide undecyl isocyanate (81–86% yield) This reaction, called the Curtius rearrangement, is a concerted reaction that can be repre- sented as follows: O STUDY GUIDE LINK 23.2 S N Mechanism of 3 3 | 3 the Curtius C N & OAAC NNNR ' (23.66) Rearrangement R _ %N %% 2 2 L + 3 3 2 2 2 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1151

23.11 SYNTHESIS OF AMINES 1151

The rearrangement is named for its discoverer, Theodor Curtius (1857–1928), who was pro- fessor of chemistry at Heidelberg University. The isocyanate product of a Curtius rearrangement can be transformed into an amine by hydration in either acid or base. Hydration involves, first, addition of water across the CAN bond to give a carbamic acid:

O S H3O H OH RNAACO | RNH C OH (23.67) L + Lan isocyanateLLL a carbamic acid

Carbamic acids are among those types of carboxylic acids that spontaneously decarboxylate (see Eq. 20.43, p. 977). Decarboxylation gives the amine, which is protonated under the acidic conditions of the reaction. The free amine is obtained by neutralization:

O S H3O| _OH R NH C OH R NH| 3 R NH2 H2O (23.68) LLL L L + CO2 + The overall transformation that occurs as a result of the Curtius rearrangement followed by

hydration is the loss of the carbonyl carbon of the acyl azide as CO2.

O S STUDY GUIDE LINK 23.3 heat H2O Formation and RNC 3 R N A COA N2 H3O| Decarboxylation of LL - L Carbamic Acids acyl azide isocyanate

O S _OH R NH COH RNH| 3 RNH2 H2O L L L + carbamic acid CO21 amine (unstable) + (23.69)

An important use of the Curtius rearrangement is for the preparation of carbamic acid de- rivatives (see Sec. 21.1G). Such derivatives are produced by allowing the isocyanate products to react with nucleophiles other than water. The reaction of isocyanates with alcohols or phe- nols yields carbamate esters; and the reaction with amines yields ureas. O S RЈOH R NH C ORЈ (alcohol or phenol) LLLa carbamate ester

H2O R N A COA CO2 R NH2 (23.70) (fromL the Curtius an+ amineL rearrangement) O S RЈNH 2 Ј (amine) RNHC NH R LLLa urea L 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1152

1152 CHAPTER 23 • THE CHEMISTRY OF AMINES

The key to the preparation of acyl azides used in the Curtius rearrangement is to recognize that these compounds are carboxylic acid derivatives. The most straightforward preparation is the reaction of an acid chloride with sodium azide.

O O S S Ph CH2 C Cl NaN3 Ph CH2 C N3 NaCl (23.71) L L L + L L L + phenylacetyl chloride phenylacetyl azide (an acyl azide)

Another widely used method is to convert an ethyl ester into an acyl derivative of hydrazine

(H2N NH2) by aminolysis (Sec. 21.8C). The resulting amide, an acyl hydrazide, is then dia- zotizedL with nitrous acid to give the acyl azide.

O O O S S NaNO2, S EtOH HCl PhCH2 C OEt NH2NH2 - Ph CH2 C NHNH2 PhCH2 C N3 L L L + L L L 10 °C L L ethyl phenylacetate hydrazine phenylacetyl hydrazide - phenylacetyl azide (an acyl hydrazide) (80–100% yield) (23.72)

Notice the similarity of this diazotization to the diazotization of alkylamines: Compare:

R CH2 NH2 HONO R CH2 NN| ' L L + L L 3 O O H O S S S H2O ||' _ ' R C NH NH2 HONO R CN" NN R CNN N H3O| LL L + LLLconjugate acid 3 LLL2 3 + of the acyl azide 2 (23.73)

Because the conjugate acid of the acyl azide is quite acidic (why?), it loses a proton from the adjacent nitrogen to the give the neutral acyl azide. A reaction closely related to the Curtius rearrangement is the Hofmann rearrangement or Hofmann hypobromite reaction. The starting material for this reaction is a primary amide rather than an acyl azide. Treatment of an amide with bromine in base gives rise to a re- arrangement.

O S Br2 2 NaOH (CH3)3CCH2 C NH2 (CH3)3CCH2 NH2 OA C A O 2 NaBr H2O +++ LL L ++ 3,3-dimethylbutanamide 2,2-dimethyl-1-propanamine (neopentylamine) (23.74)

The first step in the mechanism of the Hofmann rearrangement is ionization of the amide N H (Sec. 22.1A); the resulting anion is then brominated.

L

1 1 1 O 1 O S S _ RCN H_ OH RCN H2O (23.75a) LLL 3 1 LL3 + 1 "H "H 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1153

23.11 SYNTHESIS OF AMINES 1153

1 O 1 O S S

RCNH_1 Br Br R CNH Br Br_ (23.75b) LL L anL N-bromoamideLL+

(This reaction is analogous to the a-bromination of a ketone in base; Sec. 22.3B.) The

N-bromoamide product is even more acidic than the amide starting material, and it too ionizes.

1 O 1 O S S _ (23.75c) RHC N _ OH RCN H2O LLL 2 3 1 LL2 3 + 1 "Br "Br

The N-bromo anion then rearranges to an isocyanate.

O S3 3 AA (23.75d) C Br OCN R Br _ R N_ L % % % 2 3 2 an isocyanate + 3 2 3 2 2 2 2 2 Notice that the rearrangement2 steps of the Hofmann and Curtius reactions are conceptually identical; the only difference is the leaving group.

O S Br_ Hofmann: C Br _ RN_ % % % 2 2 RNCOA A (23.76) O L S N2 Curtius: C N|2 _ RN_ % % % 2 Because the Hofmann rearrangement2 is carried out in aqueous base, the isocyanate cannot be isolated as it is in the Curtius rearrangement. It spontaneously hydrates to form a carbamate ion, which then decarboxylates to the amine product under the strongly basic reaction condi- tions. (See Study Guide Link 23.3.)

O S OH AA _ (23.77) R NCO _OHRNH C O_ RNH2 CO2 HCO_3 L + LL + isocyanate carbamate ion amine bicarbonate ion

Although the reaction of amines with CO2 is reversible, formation of the amine in the Hofmann rearrangement is driven to completion by the reaction of hydroxide ion with CO2 to form bicar- bonate ion (or carbonate ion) under the strongly basic conditions of the reaction. An interesting and very useful aspect of both the Hofmann and Curtius rearrangements is that they take place with complete retention of stereochemical configuration in the migrating alkyl group: 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1154

1154 CHAPTER 23 • THE CHEMISTRY OF AMINES

1) heat CH2Ph CH2Ph 2) H3O|, H2O 3) _OH H "C N3 H "C (23.78) C % % %NH2 H3C S H3C O (S)-(–)-isomer (S)-(+)-isomer Hence, optically active carboxylic acid derivatives can be used to prepare optically active amines of known stereochemical configuration. (Eq. 23.78 is a further illustration of the fact that there is no smiple correlation between a compound’s absolute configuration and the sign of its optical rotation.) The advantage of the Curtius rearrangement over the Hofmann rearrangement is that the Curtius reaction can be run under mild, neutral conditions, and the isocyanate can be isolated if desired. The disadvantage is that some acyl azides in the pure state can detonate without warning, and extreme caution is required in handling them. Amides, in contrast, are stable and easily handled organic compounds.

PROBLEMS 23.32 (a) Could tert-butylamine be prepared by the Gabriel synthesis? If so, write out the synthe- sis. If not, explain why. (b) Propose a synthesis of tert-butylamine by another route. 23.33 Write a curved-arrow mechanism for each of the following reactions.

(a) ethyl isocyanate (CH3CH2 NACAO) with ethanol to yield ethyl N-ethylcarbamate (b) ethyl isocyanate with ethylamineL to yield N,N9-diethylurea 23.34 What product is formed when 2-methylpropanamide is subjected to the conditions of the Hofmann rearrangement (a) in ethanol solvent? (b) in aqueous NaOH? 23.35 When hexanamide is subjected to the conditions of the Hofmann rearrangement, pen- tanamine (A) is obtained as expected. However, a significant by-product is N,N9-dipentyl- urea (B). Explain the origin of B. (Hint: Neither pentyl isocyanate nor pentanamine has ap- preciable solubility in aqueous base.) O S Br2, NaOH CH3(CH2)4C NH2 H2O L O S CH3(CH2)4 NH2 CH3(CH2)4NH C NH(CH2)4CH3 L + L L AB

E. Synthesis of Amines: Summary The following amine syntheses have been covered in this and previous sections:

1. reduction of amides and nitriles with LiAlH4 (Secs. 21.9B and 21.9C) 2. direct alkylation of amines (Sec. 23.7A). This reaction is of limited utility, but is useful for preparing quaternary ammonium salts. 3. reductive amination (Sec. 23.7B) 4. aromatic substitution reactions of anilines (Sec. 23.9) 5. direct amination of aryl halides (Sec. 23.11C) 6. Gabriel synthesis of primary amines (Sec. 23.11A) 7. reduction of nitro compounds (Sec. 23.11B) 8. Hofmann and Curtius rearrangements (Sec. 23.11D) 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1155

23.12 USE AND OCCURRENCE OF AMINES 1155

Methods 2, 3, 4, and 5 are used to prepare amines from other amines. When an amide used in method 1 is prepared from an amine, this method, too, is a method for obtaining one amine from another. Methods 6–8, as well as nitrile reduction in method 1, are limited to the prepa- ration of primary amines, and methods 1, 3, 7, and 8 can be used for obtaining amines from other functional groups.

PROBLEM 23.36 Show how 2-cyclopentyl-N,N-dimethylethanamine could be synthesized from each of the following starting materials. (a) (b) CH2 CO2H CH2 CN LL LL (c) (d) CH2CH2 CO2H CH2 CH AO (two ways) LL LL

23.12 USE AND OCCURRENCE OF AMINES

A. Industrial Use of Amines and Ammonia Among the relatively few industrially important amines is hexamethylenediamine,

H2N(CH2)6NH2, used in the synthesis of nylon-6,6 (Sec. 21.12A). Ammonia is also an impor- tant “amine” and is a key source of nitrogen in a number of manufacturing processes. In agri- cultural chemistry, for example, liquid ammonia itself and urea, which is made from ammonia

and CO2, are important nitrogen fertilizers. Ammonia is manufactured by the hydrogenation of N2. Although it might not seem that the industrial synthesis of ammonia has anything to do with organic chemistry, the hydrogen used in its manufacture in fact comes from the cracking of alkanes (Eq. 5.71, p. 217). Thus, the availability of ammonia is presently tied to the avail- ability of hydrocarbons. However, there is significant interest in the development of methods

for utilizing solar energy for water splitting—the conversion of water into H2 and O2. Should water splitting become practical, the production of ammonia would be completely uncoupled from the availability of petroleum.

B. Naturally Occurring Amines Alkaloids Among the many types of naturally occurring amines are the alkaloids: nitrogen-containing bases that occur naturally in plants. This simple definition encompasses a highly diverse group of compounds; the structures of a few alkaloids are shown in Fig. 23.4 on p. 1156. Because amines are the most common organic bases, it is not surprising that most al- kaloids are amines, including heterocyclic amines. It is believed that the first alkaloid ever iso- lated and studied was morphine, discovered in 1805. Many alkaloids have biological activity (Fig. 23.4); others have no known activity, and their functions within the plants from which they come are, in many cases, obscure. Investigations dealing with the isolation, structure, and medicinal properties of alkaloids continue to be major research activities in organic chemistry.

PROBLEM 23.37 Illustrate the Brønsted basicity of (a) morphine and (b) mescaline (Fig. 23.4) by giving the structures of their conjugate acids.