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organic phase organic phase organic phase

CH3(CH2)6CH2 Br CH3(CH2)6CH2 Br CH3(CH2)6CH2 CN

R4P Br R4P CN R4P Br

Na Br Na Br Na CN

aqueous phase aqueous phase aqueous phase (a) (b) (c)

Figure 23.3 Phase-transfer catalysis by a quaternary phosphonium salt.(a) At the beginning of the reaction,the ionic nucleophile (red) is soluble in the aqueous layer. (b) Rapid equilibration of the nucleophile with the counte- rion of the quaternary salt brings the nucleophile into the organic phase. (c) The nucleophile, now in the organic phase, can come into contact with the organic reactant, and a reaction occurs, forming the product and regener- ating the phase-transfer catalyst.


The previous section showed that amines are Brønsted bases. Amines, like many other Brøn- sted bases, are also nucleophiles (Lewis bases). Three reactions of nucleophiles are:

1. SN2reactionwithalkylhalides,sulfonateesters,orepoxides(Secs.9.1,9.4,10.3,and 11.4) 2. addition to , , and a,b-unsaturated carbonyl compounds (Secs. 19.7, 19.11, and 22.8A) 3. nucleophilic acyl substitution at the carbonyl groups of derivatives (Sec. 21.8) This section covers or reviews reactions of amines that fit into each of these categories.

A. Direct Alkylation of Amines Treatment of or an with an halide or other alkylating agent results in alkylation of the .

| R3N H3C I R3N CH3 I_ (23.14) 3 + L L This process is an example of an SN2 reaction in which the amine acts as the nucleophile. The product of the reaction shown in Eq. 23.14 is an alkylammonium ion. If this ammo- nium ion has N H bonds, further can take place to give a complex product mix- ture, as in the followingL example:

| | | (23.15) NH3 CH3I CH3NH3 I_ (CH3)2NH2 I_ (CH3)3NH I_ (CH3)4N| I_ 2 ++++ A mixture of products is formed because the methylammonium ion produced initially is par- tially deprotonated by the ammonia starting material. Because the resulting is also a good nucleophile, it too reacts with methyl iodide. 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1132


| NH3 H3C I H3N CH3 I_ (23.16a) 2 + L L

| | (23.16b) NH3 H NH2 CH3 I_ NH4 I_ H2N CH3 2 + LL + 2 L

| (23.16c) H3C NH2 H3C I (CH3)2NH2 I_ L 2 + L Analogous deprotonation–alkylation reactions give the other products of the mixture shown in Eq. 23.15 (see Problem 23.17). , as well as a,b-unsaturated carbonyl compounds and a,b-unsaturated , also react with amines and ammonia. As the following results show, multiple alkylation can occur with these alkylating agents as well. O

H2O (CH3)3CNH2 H2C$ CH2 (CH3)3CNHCH2CH2 OH (CH3)3CN(CH2CH2OH)2 (23.17) ++L L L

NH3 (excess) H2C A CH CN H2N CH2CH2CN HN(CH2CH2CN)2 (23.18) + L (32%L yield) + (57% yield)

In an alkylation reaction, the exact amount of each product obtained depends on the precise reaction conditions and on the relative amounts of starting amine and alkyl halide. Because a mixture of products results, the utility of alkylation as a preparative method for amines is lim- ited, although, in specific cases, conditions have been worked out to favor particular products. Section 23.11 discusses other methods that are more useful for the preparation of amines.

Quaternization of Amines Amines can be converted into quaternary salts with excess alkyl halide. This process, called quaternization, is one of the most important syn- thetic applications of amine alkylation. The reaction is particularly useful when especially re- active alkyl halides, such as methyl iodide or benzylic halides, are used.

PhCH NMe MeI PhCH N|Me I (23.19) 2 2 EtOH 2 3 _ 2 + benzyldimethylamine benzyltrimethylammonium iodide (94–99% yield)

| (23.20) CH3(CH2)15NMe2 PhCH2 Cl acetone CH3(CH2)15NMe2 Cl_ + L N,N-dimethyl-1-hexadecanamine benzyl chloride "CH2Ph benzylhexadecyldimethylammonium chloride

heat CH CHNHMe MeI (excess) CH CHN|Me I HI (23.21) 3 3 3 _ + + "CH2CH3 "CH2CH3 sec-butylmethylamine sec-butyltrimethylammonium iodide

Conversion of an amine into a quaternary ammonium salt with excess methyl iodide (as in Eqs. 23.19 and 23.21) is called exhaustive . 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1133


B. When primary and secondary amines react with either aldehydes or ketones, they form imines and , respectively (Sec. 19.11). In the presence of a reducing agent, imines and enamines are reduced to amines.

O NEt NHEt S S H , Pt H2O 2 EtNH2 H3CCCH3 - H3CCCH3 30 psi H3CC"H CH3 (23.22) + LLacetoneanLL imine EtOH ethylisopropylamineLL (not isolated)

Reduction of the CAN is analogous to reduction of the CAO double bond (Sec. 19.8). Notice that the imine or does not have to be isolated, but is reduced within the reaction mixture as it forms. Because imines and enamines are reduced more rapidly than car- bonyl compounds, reduction of the carbonyl compound is not a competing reaction. The formation of an amine from the reaction of an or with another amine and a reducing agent is called reductive amination. Two hydride reducing agents, sodium tri-

acetoxyborohydride, NaBH(OAc)3, and , NaBH3CN, find frequent use in reductive amination.

NaBH(OAc)3 HOAc NaOH (23.23) PhCH O + H2N C(CH3)3 1,2-dichloroethane PhCH2NH C(CH3)3 + H2O benzaldehyde tert-butylamine (solvent) N-tert-butylaniline (95% yield)

O Me2N S NaBH3CN " HCl (1 equiv.) KOH Me NH 2 MeOH (23.24) + cyclohexanone N,N-dimethylcyclohexanamine (71% yield)

Both sodium triacetoxyborohydride and sodium cyanoborohydride are commercially avail- able, easily handled solids, and sodium cyanoborohydride can even be used in aqueous solu-

tions above pH 3. Reductive amination with NaBH3CN is known as the Borch reaction, after Richard F. >Borch, a professor of medicinal chemistry and molecular pharmacology at Purdue University, who discovered and developed the reaction while he was a professor of

chemistry at the University of Minnesota in 1971. Like NaBH4 reductions, the Borch reduc- tion requires a protic solvent or one equivalent of acid. A proton source is also required for re- duction with sodium triacetoxyborohydride. In some cases, the water generated in the reaction is adequate for this purpose, and in other situations, a weak acid can be added. (Acetic acid serves this role in Eq. 23.23.) Reductive amination, like catalytic , typically involves the imines or enam-

ines and their conjugate acids as intermediates.

% % % % R R H R O N N| NH S S S 3 H3O 2 | H _BH2CN Na| R NH2 C C C L "CH (23.25) L 2 + % % imine% % % % % %

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The success of reductive amination depends on the discrimination by the reducing agents between the imine intermediate and the of the aldehyde or ketone starting ma-

terial. Each reagent is a (NaBH4) derivative in which one or more of the hydrides have been substituted with electron-withdrawing groups ( OAc or CN). The polar effect of these groups reduces the effective negative charge on theL hydride Land, as a re- sult, each reagent is less reactive than sodium borohydride itself. Each reagent is effectively “tuned” to be just reactive enough to reduce imines, but not reactive enough to reduce alde-

hydes or ketones. When NaCNBH3 is used in protic solvents, -bond donation by the solvent to the imine nitrogen (which is more basic than a carbonyl oxygen) catalyzes the re- duction. Formaldehyde can be reductively aminated with primary and secondary amines using the

Borch reaction. This provides a way to introduce methyl groups to the level of a tertiary amine:

% %

NH2 NaBH3CN N(CH3)2 HOAc KOH H C A O (23.26) 2 CH CN/H O + 3 2 (84% yield)

CH3 NaBH3CN HOAc KOH EtNH CH Ph H C A O Et"N CH Ph (23.27) 2 2 CH CN/H O 2 LL + 3 2 LL benzylethylamine formaldehyde benzylethylmethylamine (80% yield)

(Quaternization does not occur in these reactions. Why?) Neither an imine nor an enamine can be an intermediate in the reaction of a secondary amine with formaldehyde (Eq. 23.27). (Why?) In this case a small amount of a cationic intermediate, an imminium ion, is formed in solution by protonation of a carbinolamine intermediate and loss of water. The imminium ion, which is also a carbocation, is rapidly and irreversibly reduced by its reaction with hydride.

CH2 OH L 2 H OH| 2 1 2 1 2 L R NH R H2COA R "NR2 LL LL 2 2 + carbinolamine 2

CH2 OH| 2 CH| 2 CH2 CH3 L S 1 2 1 2 1 2 H _BH2CN Na| 1 2 R "NR2 R "NR R NR L R "NR LL LL LL LL imminium ion | 2 OH2 2 2 + 2 OH2 (23.28) 2 + 2 Suppose you want to prepare a 2given amine and want to determine whether reductive ami- nation would be a suitable preparative method. How do you determine the required starting materials? Adopt the usual strategy for analyzing a synthesis: Start with the target molecule and mentally reverse the reductive amination process. Mentally break one of the C N bonds and replace it on the nitrogen side with an N H bond. On the side, drop aL hydrogen from the carbon and add a carbonyl oxygen. L 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1135


R2 R2

R1 "NC" R1 "N C reducing agent (23.29) $S LL L L + H O H " H added O added As this analysis shows, the target amine must have a hydrogen on the “disconnected” carbon. This process is applied in Study Problem 23.3.

Study Problem 23.3 Outline a preparation of N-ethyl-N-methylaniline from suitable starting materials using a reduc- tive amination sequence.

N CH3 c L L "CH2CH3 N-ethyl-N-methylaniline

Solution Either the N-methyl or N-ethyl bond can be used for analysis. (The N-phenyl bond cannot be used because the carbon in the C N bond has no hydrogen.) We arbitrarily choose the L N CH3 bond and make the appropriate replacements as indicated in Eq. 23.29 to reveal the fol- lowingL starting materials:

N CH2 H N H O A CH2 c L LL c L L + formaldehyde "CH2CH3 "CH2CH3 N-ethylaniline

Thus, treatment of N-ethylaniline with formaldehyde and NaBH3CN should give the desired amine. (See Problem 23.14 on p. 1136.)

C. Acylation of Amines Amines can be converted into by reaction with acid chlorides, anhydrides, or . These reactions are covered in Sec. 21.8.

O O S S Ј Ј | R C Cl 2R2NHR C NR2 R2NH2 Cl_ (23.30) LL + LL + O O O O S S S S Ј Ј Ј Ј | R C O C R 2R2NHR C NR2 R C O_ R2NH2 (23.31) LLLL + LL ++LL O O S S RЈ C ORЉ R2NHRЈ C NR2 RЉOH (23.32) LL + LL + In this type of reaction, a bond is formed between the amine and a carbonyl carbon. These are all examples of acylation: a reaction involving the transfer of an . 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1136


Recall that the reaction of an amine with an acid chloride or an anhydride requires either two equivalents of the amine or one equivalent of the amine and an additional equivalent of another base such as a tertiary amine or hydroxide ion. These and other aspects of amine acy- lation can be reviewed in Sec. 21.8.

PROBLEMS 23.13 Suggest two syntheses of N-ethylcyclohexanamine by reductive amination. 23.14 Outline a second synthesis of N-ethyl-N-methylaniline (the target molecule in Study Prob- lem 23.3) by reductive amination.

| 23.15 Outline a synthesis of the quaternary ammonium salt (CH3)3NCH2Ph Br_ from each of the following combinations of starting materials. (a) dimethylamine and any other reagents (b) and any other reagents 23.16 (a) A chemist Caleb J. Cookbook heated ammonia with bromobenzene expecting to form tetraphenylammonium bromide. Can Caleb expect this reaction to succeed? Explain. (b) What type of catalyst might be used to bring about this reaction under relatively mild conditions? (See Sec. 23.11C.) 23.17 Continue the sequence of reactions in Eqs. 23.16a–c to show how trimethylammonium io- dide is formed as one of the products in Eq. 23.15. 23.18 Outline a preparation of each of the following from an amine and an acid chloride. (a) N-phenylbenzamide (b) N-benzyl-N-ethylpropanamide


The previous section discussed ways to make carbon–nitrogen bonds. In these reactions, amines react as nucleophiles. The subject of this section is an used to break carbon–nitrogen bonds. In this reaction, which involves quaternary ammonium hydrox-

ides (R4N|_OH) as starting materials, amines act as leaving groups. When a quaternary ammonium hydroxide is heated, a b-elimination reaction takes place to give an , which distills from the reaction mixture.

CH NMe| " 2 3 heat " L A CH2 H OH NMe3 (23.33) H OH ++L 2 _ a quaternary ammonium hydroxide methylenecyclohexane (74% yield)

This type of elimination reaction is called a Hofmann elimination, after August Wilhelm Hofmann (1818–1892), a German chemist who became professor at the Royal College of Chemistry in London and later, at the University of Berlin. Hofmann was particularly noted for his work on amines. A quaternary ammonium hydroxide used as the starting material in Hofmann eliminations is formed by treating a quaternary ammonium salt with silver hydroxide (AgOH), which is es-

sentially a hydrated form of silver (I) oxide (Ag2O).

| | (23.34) CH2NMe3 I_ Ag2O • H2O CH2NMe3 _OH AgI L + L +