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23.7 ALKYLATION AND ACYLATION REACTIONS …

ALKYLATION AND ACYLATION REACTIONS OF AND ACYLATION REACTIONS OF AMINESThe previous section showed that amines are Br nsted bases. Amines, like many other Br n-sted bases, are also nucleophiles(Lewis bases). Three REACTIONS of nucleophiles are:1. SN2reactionwithalkylhalides,sulfonateest ers,orepoxides( , , , )2. addition to aldehydes, ketones, and a,b-unsaturated carbonyl compounds (Secs. , , and )3. nucleophilic acyl substitution at the carbonyl groups of carboxylic acid derivatives(Sec. )This section covers or reviews REACTIONS of amines that fit into each of these Direct ALKYLATION of AminesTreatment of ammonia or an amine with an alkyl halide or other alkylating agent results inalkylation of the process is an example of an SN2 reaction in which the amine acts as the product of the reaction shown in Eq. is an alkylammonium ion. If this ammo-nium ion has NLH bonds, further alkylations can take place to give a complex product mix-ture, as in the following example:A mixture of products is formed because the methylammonium ion produced initially is par-tially deprotonated by the ammonia starting material.

23.7 ALKYLATION AND ACYLATION REACTIONS OF AMINES 1133 B. Reductive Amination When primary and secondary amines react with either aldehydes or ketones, they form imines

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Transcription of 23.7 ALKYLATION AND ACYLATION REACTIONS …

1 ALKYLATION AND ACYLATION REACTIONS OF AND ACYLATION REACTIONS OF AMINESThe previous section showed that amines are Br nsted bases. Amines, like many other Br n-sted bases, are also nucleophiles(Lewis bases). Three REACTIONS of nucleophiles are:1. SN2reactionwithalkylhalides,sulfonateest ers,orepoxides( , , , )2. addition to aldehydes, ketones, and a,b-unsaturated carbonyl compounds (Secs. , , and )3. nucleophilic acyl substitution at the carbonyl groups of carboxylic acid derivatives(Sec. )This section covers or reviews REACTIONS of amines that fit into each of these Direct ALKYLATION of AminesTreatment of ammonia or an amine with an alkyl halide or other alkylating agent results inalkylation of the process is an example of an SN2 reaction in which the amine acts as the product of the reaction shown in Eq. is an alkylammonium ion. If this ammo-nium ion has NLH bonds, further alkylations can take place to give a complex product mix-ture, as in the following example:A mixture of products is formed because the methylammonium ion produced initially is par-tially deprotonated by the ammonia starting material.

2 Because the resulting methylamine isalso a good nucleophile, it too reacts with methyl iodide.( )I_++++CH3I|CH3NH3I_I_I_(CH3)4N|NH32(CH3 )2NH2|(CH3)3NH|( )I_CH3|R3NL+3R3NH3 CLIaqueous phaseorganic phaseorganic phaseorganic phaseaqueous phaseaqueous phaseCH3(CH2)6CH2 BrCH3(CH2)6CH2 CNCH3(CH2)6CH2 BrNaCNNaBrNaBrR4P BrR4P BrCNR4P(a)(b)(c)Figure catalysis by a quaternary phosphonium salt. (a) At the beginning of the reaction, theionic 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 organicphase, can come into contact with the organic reactant, and a reaction occurs, forming the product and regener-ating the phase-transfer 12/8/08 1:22 PM Page 11311132 CHAPTER 23 THE CHEMISTRY OF AMINESA nalogous deprotonation ALKYLATION REACTIONS give the other products of the mixtureshown in Eq. (see Problem ).

3 Epoxides, as well as a,b-unsaturated carbonyl compounds and a,b-unsaturated nitriles,also react with amines and ammonia. As the following results show, multiple ALKYLATION canoccur with these alkylating agents as an ALKYLATION reaction, the exact amount of each product obtained depends on the precisereaction conditions and on the relative amounts of starting amine and alkyl halide. Because amixture 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 discusses other methods that are more useful for the preparation of of AminesAmines can be converted into quaternary ammonium saltswith 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 of an amine into a quaternary ammonium salt with excess methyl iodide (as inEqs.)

4 And ) is called exhaustive methylation.( )etherheatsec-butyltrimethylammoniumiodi de+HII_|CH3 CHNMe3"+MeI (excess)sec-butylmethylamineCH3 CHNHMe"CH2CH3CH2CH3( )acetone+N,N-dimethyl-1-hexadecanamineCH 3(CH2)15 NMe2benzyl chloridePhCH2 ClLbenzylhexadecyldimethylammoniumchlori deCl_|CH3(CH2)15 NMe2CH2Ph"( )benzyltrimethylammoniumiodide(94 99% yield)I_|PhCH2 NMe3+MeIbenzyldimethylaminePhCH2 NMe22 EtOH( )(57% yield)HN(CH2CH2CN)2(32% yield)H2 NCH2CH2 CNL+NH3 (excess)H2CL+CHCNA( )(CH3)3 CNH2(CH3)3 CNH(CH3)3CN(CH2CH2OH)2 LOH2 CCH2$$CH2CH2 LOHL++H2O( )I_|(CH3)2NH2+NH22H3CH3 CLLI( )I_|+NH32 HCH3NH2 LLI_NH4+|CH3H2NL2( )I_CH3|H3NL+ 12/8/08 1:22 PM Page ALKYLATION AND ACYLATION REACTIONS OF AMINES1133B. Reductive AminationWhen primary and secondary amines react with either aldehydes or ketones, they form iminesand enamines, respectively (Sec. ). In the presence of a reducing agent, imines andenamines are reduced to of the CAN double bond is analogous to reduction of the CAO double bond ( ).

5 Notice that the imine or enamine does not have to be isolated, but is reduced within thereaction 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 formation of an amine from the reaction of an aldehyde or ketone with another amineand a reducing agent is called reductive h y d r i d e r e d u c i n g a g e n t s , s o d i u m t r i -acetoxyborohydride, NaBH(OAc)3, and sodium cyanoborohydride, NaBH3CN, find frequentuse in reductive amination. 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 atPurdue University, who discovered and developed the reaction while he was a professor ofchemistry at the University of Minnesota in 1971.

6 Like NaBH4reductions, 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 reactionis adequate for this purpose, and in other situations, a weak acid can be added. (Acetic acidserves this role in Eq. )Reductive amination, like catalytic hydrogenation, typically involves the imines or enam-ines and their conjugate acids as intermediates.( )COS%%|CNS%%%%RH+RNH2L2 CHNH%%%R2"H3O|BH2CN Na|_HLCNS3%%%Rimine+ H2O( )NaBH3 CNHCl (1 equiv.)MeOHMe2 NHdimethylamine+cyclohexanoneOSKOHN,N-di methylcyclohexanamine(71% yield)"Me2N( )PhCHO+NaBH(OAc)3 HOAcNaOH1,2-dichloroethane(solvent)C(CH3 )3H2N+PhCH2 NHC(CH3)3H2 Obenzaldehydetert-butylamineN-tert-butyl aniline(95% yield)( )CH3 LLH3 CCHNHEtEtNH2CH3 LLH3 CCOS+-H2OH2, Pt30 psiEtOHCH3 LLH3 CCNEtSan imine(not isolated)" 12/8/08 1:22 PM Page 11331134 CHAPTER 23 THE CHEMISTRY OF AMINESThe success of reductive amination depends on the discrimination by the reducing agentsbetween the imine intermediate and the carbonyl group of the aldehyde or ketone starting ma-terial.

7 Each reagent is a sodium borohydride (NaBH4) derivative in which one or more of thehydrides have been substituted with electron-withdrawing groups (LOAc or LCN). Thepolar effect of these groups reduces the effective negative charge on the hydride and, 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 NaCNBH3is used in protic solvents, hydrogen-bond donation by thesolvent to the imine nitrogen (which is more basic than a carbonyl oxygen) catalyzes the can be reductively aminated with primary and secondary amines using theBorch reaction. This provides a way to introduce methyl groups to the level of a tertiary amine:(Quaternization does not occur in these REACTIONS . Why?)Neither an imine nor an enamine can be an intermediate in the reaction of a secondaryamine with formaldehyde (Eq. ).

8 (Why?) In this case a small amount of a cationicintermediate, an imminium ion,is formed in solution by protonation of a carbinolamineintermediate and loss of water. The imminium ion, which is also a carbocation, is rapidly andirreversibly reduced by its reaction with you want to prepare a given amine and want to determine whether reductive ami-nation would be a suitable preparative method. How do you determine the required startingmaterials? Adopt the usual strategy for analyzing a synthesis: Start with the target moleculeand mentally reverse the reductive amination process. Mentally break one of the CLN bondsand replace it on the nitrogen side with an NLH bond. On the carbon side, drop a hydrogenfrom the carbon and add a carbonyl oxygen.( )BH2CN Na|_HL+OH222+OH222NR2R1 LLOH2|L22CH2"|NR2R1LL2CH2"NR2R1LL2CH3"|N R2R1 LLCH2 Simminium ion+NHR2R1LL2H2 COA|OH2L2 HNR2R1 LLOHL222CH2"carbinolamine( )NaBH3 CNHOAcCH3CN/H2O+KOHH2 COAformaldehydeLLEtCH2 PhNHbenzylethylamineLLEtCH2 PhNCH3"benzylethylmethylamine(80% yield)( )NaBH3 CNHOAcCH3CN/H2O+KOHNH2%(84% yield)N(CH3)2% 12/8/08 1:22 PM Page ALKYLATION AND ACYLATION REACTIONS OF AMINES1135As this analysis shows, the target amine must have a hydrogen on the disconnected process is applied in Study Problem Problem a preparation of N-ethyl-N-methylaniline from suitable starting materials using a reduc-tive amination the N-methyl or N-ethyl bond can be used for analysis.

9 (The N-phenyl bondcannot be used because the carbon in the CLN bond has no hydrogen.) We arbitrarily choose theNLCH3bond and make the appropriate replacements as indicated in Eq. to reveal the fol-lowing starting materials:Thus, treatment of N-ethylaniline with formaldehyde and NaBH3CN should give the desiredamine. (See Problem on p. 1136.)C. ACYLATION of AminesAmines can be converted into amides by reaction with acid chlorides, anhydrides, or REACTIONS are covered in Sec. this type of reaction, a bond is formed between the amine and a carbonyl carbon. These areall examples of ACYLATION :a reaction involving the transfer of an acyl group.( )OR!LLR"COS+R2 NHNR2R!OHLLR"COS+( )OLLR"R"COSLLCOS+2R2 NHNR2 LLR"COS++LLR"COSO_R2NH2|( )ClLLR"COS+2R2 NHNR2 LLR"COS+Cl_R2NH2|cNLCH2 HLLCH2CH3"N-ethylanilinecNLHLCH2CH3"+for maldehydeOACH2N-ethyl-N-methylanilinecNL CH3 LCH2CH3"( )H addedHNR1LR2""NCHR1 LLR2""+reducing agentO added$ 12/8/08 1:22 PM Page 11351136 CHAPTER 23 THE CHEMISTRY OF AMINESR ecall that the reaction of an amine with an acid chloride or an anhydride requires eithertwo equivalentsof the amine or one equivalent of the amine and an additional equivalent ofanother base such as a tertiary amine or hydroxide ion.

10 These and other aspects of amine acy-lation can be reviewed in Sec. ELIMINATION OF QUATERNARY AMMONIUM HYDROXIDESThe previous section discussed ways to makecarbon nitrogen bonds. In these REACTIONS ,amines react as nucleophiles. The subject of this section is an elimination reaction used tobreakcarbon nitrogen bonds. In this reaction, which involves quaternary ammonium hydrox-ides(R4N|_OH) as starting materials, amines act as leaving a quaternary ammonium hydroxide is heated, a b-elimination reaction takes place togive an alkene, which distills from the reaction type of elimination reaction is called a Hofmann elimination,after August WilhelmHofmann (1818 1892), a German chemist who became professor at the Royal College ofChemistry in London and later, at the University of Berlin. Hofmann was particularly notedfor his work on quaternary ammonium hydroxide used as the starting material in Hofmann eliminationsis formed by treating a quaternary ammonium salt with silver hydroxide (AgOH), which is es-sentially a hydrated form of silver (I) oxide (Ag2O).


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