Organic Chemistry III

Home , Hofmann elimination, Hofmann rearrangement, Mannich base

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 950 CHAPTER 21 Amines and Their Derivatives

Exercise 21-9 The cleavage of an N-alkyl-1,2-benzenedicarboximide (N-alkyl phthalimide) is frequently carried out with base or with hydrazine, H2NNH2. The respective products of these two treatments are the 1,2-benzenedicarboxylate A or the hydrazide B. Write mechanisms for these two transformations. (Hint: Review Section 20-6.)

O O COOϪ ϪOH H NNH NH NR 2 2 A ϪRNH2 ϪRNH2 NH COOϪ O O AB

Exercise 21-10 Show how you would apply the Gabriel method to the synthesis of each of the following amines: (a) 1-hexanamine; (b) 3-methylpentanamine; (c) cyclohexanamine; (d) H2NCH2CO2H, the amino acid glycine. (Caution: In the synthesis of glycine, you need to watch out for the carboxylic acid function. Can you see why?) For each of these four syntheses, would the azide displacement– reduction method be equally good, better, or worse?

In Summary Amines can be made from ammonia or other amines by simple alkylation, but this method gives mixtures and poor yields. Primary amines are better made in stepwise fashion, employing nitrile and azide groups, or protected systems, such as 1,2-benzenedicarboxylic imide (phthalimide) in the Gabriel synthesis.

21-6 SYNTHESIS OF AMINES BY REDUCTIVE AMINATION 21-6 SYNTHESIS OF AMINES BY REDUCTIVE AMINATION Reductive amination of aldehydes and ketones, allows the construction of primary, secondary,A moreand generaltertiary methodamines of amine. synthesis, called reductive amination of aldehydes and ketones, allows the construction of primary, secondary, and tertiary amines. In this process, In thistheprocess, carbonylthe compoundcarbonyl iscompound exposed to is anexposed amine containingto an amine at leastcontaining one N–H at bondleast (NHone3, N–H primary, secondary amines) and a reducing agent to furnish a new alkylated amine directly bond (NH3, primary, secondary amines) and a reducing agent to furnish a new alkylated amine(adirectly primary,(a secondary,primary, secondary,or tertiary amine,or tertiary respectively).amine, Therespectively) new C–N bond. is formed to the carbonyl carbon of the aldehyde or ketone. The new C–N bond is formed to the carbonyl carbon of the aldehyde or ketone.

General Reductive Amination R H ␦ϩ f i Reduction i f OPCCðNOH ~ ONð i f R ; i RЈ RЈ

2 The sequence begins by the initial condensation of the amine with the carbonyl component (Section 17-9) to produce the corresponding imine (for NH3 and primary amines) or iminium ion (secondary amines). Similar to the carbon–oxygen double bond in aldehydes and ketones, the carbon–nitrogen double bond in these intermediates is then reduced by simultaneous catalytic hydrogenation or by added special hydride reagents. The sequence begins by the initial condensation of the amine with the carbonyl component to produce the corresponding imine (for NH3 and primary amines) or iminium ion (secondary amines).

Similar to the carbon–oxygen double bond in aldehydes and ketones, the carbon– nitrogen double bond in these intermediates21-6 Synthesisis ofthen Aminesreduced by Reductiveby simultaneous AminationcatalyticCHAPTER 21 951 hydrogenation or by added special hydride reagents.

Reductive Amination of a Ketone with a Primary Amine R R RЉ G G D CPO ϩ H2NRЉ CPN ϩ H2O D Condensation D RЈ RЈ

R RЉ R G D A Animation CPN RЈOOC NHRЉ D Reduction A ANIMATED MECHANISM: RЈ H Reductive amination

This reaction succeeds because of the selectivity of the reducing agents: either 3 N hydrogen gas in the presence of a catalyst (Section 12-2) or sodium cyanoborohydride, c 12 ␦ϩ Electron Na BH3CN. Both react faster with the imine double bond than with the carbonyl group C withdrawing under the conditions employed. With Na12BH CN, the conditions are relatively acidic A 3 ϪB (pH 5 2–3), activating the imine double bond by protonation on nitrogen and thus E ~ H & H facilitating hydride attack at carbon. As shown in the margin, the relative stability of H the modi! ed borohydride reagent at such low pH (at which NaBH4 hydrolyzes; Section Diminished ability of H to 8-6) is due to the presence of the electron-withdrawing cyano group, which renders the leave as :HϪ, hence reagent ϩ hydrogens less basic (hydridic). In a typical procedure, the carbonyl component and the is less sensitive to H amine are allowed to equilibrate with the imine and water in the presence of the reducing agent. In this way, ammonia furnishes primary amines, and primary amines result in secondary amines.

Amine Synthesis by Reductive Amination

CH3 CH3 CH3 C ϪH2O C H2, Ni, CH3OH, 90°C, 100 atm C B ϩ NH3 B A A A

ϩH2O H O N H NA H H Phenyl-2-propanone Not isolated Amphetamine (Industrial production)

H O NCH3 H NCH3

NaBH3CN, ϪH2O CH3CH2OH, pH ϭ 2–3 ϩ CH3NH2 ϩH2O

78% Cyclohexanone Not isolated N-Methylcyclohexanamine

Similarly, reductive aminations with secondary amines give tertiary amines.

H O H3C H3C N(CH3)2

(CH3)2NH, NaBH3CN, CH3OH

H3C CH3 H3C CH3 89% 760 CHAPTER 17 Aldehydes and Ketones

OH Exercise 17-11 Try It Yourself O Show how the starting material for Exercise 17-10 may be converted into the alcohol in the O margin.

Thioacetals are desulfurized to the corresponding hydrocarbon by treatment with Raney nickel (Section 12-2). Thioacetal generation followed by desulfurization is used to convert a carbonyl into a methylene group under neutral conditions.

H H Raney Ni, H SS 2 65%

Exercise 17-12

Suggest a possible synthesis of cyclodecane from .

(Caution: Simple hydrogenation will not do. Hint: See Section 12-12.)

In Summary Acetals and thioacetals are useful protecting groups for aldehydes and ketones. Acetals are21-6 formed Synthesis under acidic of conditions Amines andby areReductive stable toward Amination bases and nucleophiles.CHAPTER They 21 951 are hydrolyzed by aqueous acid. Thioacetals are usually prepared using Lewis acid catalysts 21-6and Synthesis are stable toof both Amines aqueous by baseReductive and acid. Amination Mercuric salts CHAPTER are required for 21 thioacetal 951 Reductivehydrolysis. Amination Thioacetals of a Ketonemay also with be desulfurizeda Primary Amineto hydrocarbons with Raney nickel. R R RЉ ReductiveG Amination of a Ketone with a Primary AmineG D CPO ϩ H2NRЉ CPN ϩ H2O R D 17-9 NUCLEOPHILICCondensationR RЉ ADDITIOND OF AMMONIA AND ITS G RЈ G D RЈ CPO ϩ H2NRЉ DERIVATIVESCPN ϩ H2O Condensation D R RЉ D R RЈ RЈ A Animation AmmoniaG andD the amines may be regarded as nitrogen analogs of water and alcohols. Do HHD R D H CPN RЈOOC NHRЉ G G ReductionR šN šN R theyRЉ D add to aldehydes and ketones? InA fact, they do, giving products correspondingAnimationANIMATED to MECHANISM: those A A G DjustRЈ studied. We shall seeA one importantH difference, however. The products of addition of H H CPN RЈOOC NHRЉ Reductive amination amines Reduction and their derivatives lose water, furnishing either of two new derivatives of the Ammonia Primary amineD A ANIMATED MECHANISM: RЈ original carbonyl compounds:H imines and enamines. Reductive amination This reaction succeeds because of the selectivity of the reducing agents: either N hydrogen gas in the presenceAmmonia of a andcatalyst primary (Section amines 12-2) or sodiumform iminescyanoborohydride, c 12 ␦ϩ Electron This reactionNa BH succeeds3CN. Both because reactUpon faster ofexposure the with selectivity to the an imineamine, of double aldehydes the reducing bond and than ketones agents: with initially the either carbonyl form hemiaminals, group N the nitrogenC withdrawing ReactionR 12 A hydrogen gasunder in thethe presenceconditions of employed.a catalyst (SectionWith Na 12-2)BH or3CN, sodium the conditions cyanoborohydride, are relatively acidic c Ϫ 12 analogs of hemiacetals. In a subsequent, slower step, hemiaminals of primary␦ϩ aminesElectron loseB Na BH3CN.(pH Both 5 2–3), react fasteractivating with the imineimine doubledouble bond bond than by withprotonation the carbonyl on nitrogengroup and thus C withdrawingE ~ water to form12 a carbon–nitrogen double bond. This function is called an imine (an H older & H under the conditions employed. With Na BH CN, the conditions are relatively acidic A facilitating hydride attackname isat Schiff*carbon. 3base As) shownand is thein thenitrogen margin, analog the of relative a carbonyl stability group. of ϪB H (pH 5 2–3), activating the imine double bond by protonation on nitrogen and thus E ~ the modi! ed borohydride reagent at such low pH (at which NaBH4 hydrolyzes; SectionH & HDiminished ability of H to facilitating8-6) hydride is due attack to the at presencecarbon. Asof theshown electron-withdrawing in the margin, the cyanorelative group, stability which of renders the H leave as :HϪ, hence reagent is less sensitive to Hϩ the modi! edhydrogens borohydride less reagentbasicImine (hydridic). at Formation such low In pHafrom typical (at Amines which procedure, andNaBH Aldehydes4 thehydrolyzes; carbonyl or Ketones Sectioncomponent and Diminishedthe ability of H to 8-6) is due to the presence of the electron-withdrawing cyano group, which renders the leave as :HϪ, hence reagent amine are allowed to equilibrate with the imine and water in the presence of theElimination reduc- ϩ hydrogens less basic (hydridic). In a HHtypical procedure, theDeprotonation carbonyl at N, componentH and the of water is less sensitive to H ing agent. In thisAddition way, ammonia furnishes primaryreprotonation amines, at O and Aprimary aminesϪ resultH O

amine are allowed to equilibrate with theA ϩ imineA and water in the presence of the reduc- 2 ) š RONšH2 ϩin secondaryC š"O amines. N šOðϪ "N šOH N C E H " E H " ϩH2O R ing agent. In this way, ammonia furnishesR primaryC O amines, and primaryR aminesC resultO in secondary amines. Rate determining Amine Synthesis by ReductiveA hemiaminal Amination An imine

CH3 Amine Synthesis by Reductive AminationCH3 CH3 C ϪH2O C H2, Ni, CH3OH, 90°C, 100 atm C

B *Professorϩ NH Hugo Schiff (1834–1915), UniversityB of Florence, Italy. A A A

CH3 3 CH3 CH3 ϩH2O H H NA C O ϪH2O C N C H2, Ni,H CH3OH, 90°C, 100 atm B ϩ NH3 B A A A

ϩH2O H H O N H NA Phenyl-2-propanone HNot isolated Amphetamine (IndustrialH production) Phenyl-2-propanone Not isolated Amphetamine (Industrial production) H O NCH3 H NCH H 3 O NCH 3 NaBH3CN, H NCH3 ϪH2O CH3CH2OH, pH ϭ 2–3 ϩ CH3NH2 NaBH3CN, ϩH O ϪH2O 2 CH3CH2OH, pH ϭ 2–3 ϩ CH3NH2 ϩH2O 78% Cyclohexanone Not isolated 78%N-Methylcyclohexanamine 4 Cyclohexanone Not isolated N-Methylcyclohexanamine

Similarly, reductive aminations with secondary amines give tertiary amines. Similarly, reductive aminations with secondary amines give tertiary amines.

H O H3C H3C H O N(CH3)2 H3C H3C N(CH3)2 (CH3)2NH, NaBH3CN, CH3OH

(CH3)2NH, NaBH3CN, CH3OH

H3C CH3 H3C CH3 H3C CH3 H3C CH3 89% 89% 21-6 Synthesis of Amines by Reductive Amination CHAPTER 21 951

Reductive Amination of a Ketone with a Primary Amine R R RЉ G This reaction succeeds becauseG of theD selectivity of the reducing agents: either hydrogen CPO gasϩ inHthe2NRpresenceЉ of a catalystCorPsodiumN cyanoborohydride,ϩ H2O Na+ –BH CN. D Condensation D 3 RЈ RЈ Both react faster with the imine double bond than with the carbonyl group under the +R– conditionsR RemployedЉ . With Na BH3CN, the conditions are relatively acidic (pH = 2–3), G D A Animation activatingCPN the imine doubleRbondЈOOC byNHRprotonationЉ on nitrogen and thus facilitating hydride attackD at carbon. Reduction A ANIMATED MECHANISM: RЈ H Reductive amination The relative stability of the modified borohydride reagent at such low pH (at which NaBH4 hydrolyzes) is due to the presence of the electron-withdrawing cyano group, which renders This reaction succeedsthe hydrogens because less of thebasic selectivity(hydridic) of. the reducing agents: either N hydrogen gas in the presence of a catalyst (Section 12-2) or sodium cyanoborohydride, c 12 ␦ϩ Electron Na BH3CN. Both react faster with the imine double bond than with the carbonyl group C withdrawing under the conditions employed. With Na12BH CN, the conditions are relatively acidic A In a typical procedure, the3 carbonyl component and the amine are ϪB (pH 5 2–3), activating the imine double bond by protonation on nitrogen and thus E ~ allowed to equilibrate with the imine and water in the presence of the H & H facilitating hydride attackreducing at carbon.agent. AsIn thisshownway, in ammoniathe margin,furnishes the relativeprimary stabilityamines, of and H the modi! ed borohydrideprimary reagentamines at suchresult lowin pHsecondary (at whichamines NaBH4. hydrolyzes; Section Diminished ability of H to 8-6) is due to the presence of the electron-withdrawing cyano group, which renders the leave as :HϪ, hence reagent is less sensitive to Hϩ hydrogens less basic (hydridic). In a typical procedure, the carbonyl component and the 5 amine are allowed to equilibrate with the imine and water in the presence of the reducing agent. In this way, ammonia furnishes primary amines, and primary amines result in secondary amines.

Amine Synthesis by Reductive Amination

CH3 CH3 CH3 C ϪH2O C H2, Ni, CH3OH, 90°C, 100 atm C B ϩ NH3 B A A A

ϩH2O H O N H NA H H Phenyl-2-propanone Not isolated Amphetamine (Industrial production)

H O NCH3 H NCH3

NaBH3CN, ϪH2O CH3CH2OH, pH ϭ 2–3 ϩ CH3NH2 ϩH2O

78% Cyclohexanone Not isolated N-Methylcyclohexanamine

Similarly, reductive aminations with secondary amines give tertiary amines.

H O H3C H3C N(CH3)2

(CH3)2NH, NaBH3CN, CH3OH

H3C CH3 H3C CH3 89% 21-6 Synthesis of Amines by Reductive Amination CHAPTER 21 951

Reductive Amination of a Ketone with a Primary Amine R R RЉ G G D CPO ϩ H2NRЉ CPN ϩ H2O D Condensation D RЈ RЈ

R RЉ R G D A Animation CPN RЈOOC NHRЉ D Reduction A ANIMATED MECHANISM: RЈ H Reductive amination

This reaction succeeds because of the selectivity of the reducing agents: either N hydrogen gas in the presence of a catalyst (Section 12-2) or sodium cyanoborohydride, c 12 ␦ϩ Electron Na BH3CN. Both react faster with the imine double bond than with the carbonyl group C withdrawing under the conditions employed. With Na12BH CN, the conditions are relatively acidic A 3 ϪB (pH 5 2–3), activating the imine double bond by protonation on nitrogen and thus E ~ H & H facilitating hydride attack at carbon. As shown in the margin, the relative stability of H the modi! ed borohydride reagent at such low pH (at which NaBH4 hydrolyzes; Section Diminished ability of H to 8-6) is due to the presence of the electron-withdrawing cyano group, which renders the leave as :HϪ, hence reagent ϩ hydrogens less basic (hydridic). In a typical procedure, the carbonyl component and the is less sensitive to H amine are allowed to equilibrate with the imine and water in the presence of the reducing agent. In this way, ammonia furnishes primary amines, and primary amines result in secondary amines.

Amine Synthesis by Reductive Amination

CH3 CH3 CH3 C ϪH2O C H2, Ni, CH3OH, 90°C, 100 atm C B ϩ NH3 B A A A

ϩH2O H O N H NA H H Phenyl-2-propanone Not isolated Amphetamine (Industrial production)

H O NCH3 H NCH3

NaBH3CN, ϪH2O CH3CH2OH, pH ϭ 2–3 ϩ CH3NH2 ϩH2O

78% Cyclohexanone Not isolated N-Methylcyclohexanamine

Similarly, reductive aminations with secondary amines give tertiary amines. Similarly, reductive aminations with secondary amines give tertiary amines.

H O H3C H3C N(CH3)2

(CH3)2NH, NaBH3CN, CH3OH

H C CH H C CH 952 CHAPTER3 213 Amines and Their Derivatives 3 3 89%

Secondary amines cannotSecondaryform aminesimines cannotwith formaldehydes imines with aldehydesand ketones, and ketones,but are but arein equilibriumin equilibrium – with the correspondingwith Nthe,N corresponding-dialkyliminium N,N-dialkyliminiumions, which ionsare (Sectionreduced 17-9),by whichaddition are reducedof H byfrom addi- cyanoborohydride. tion of H2 from cyanoborohydride.

NaBH3CN, CH3OH CH2 O ϩ ϩ N C6H5 N C6H5 N C6H5

H CH2 HCH2 100% N-(Phenylmethyl)- Iminium ion N-Methyl-N-(phenylmethyl)- cyclopentanamine cyclopentanamine (Benzylcyclopentylamine) (Benzylcyclopentylmethylamine) 6

Exercise 21-11 Formulate a mechanism for the reductive amination with the secondary amine shown in the pre- ceding example.

Working with the Concepts: Applying Reductive Solved Exercise 21-12 Amination Explain the following transformation by a mechanism. Remember WHIP O O What NaBH3CN, CH3OH H H How N NH Information 2 35% Proceed Strategy As usual, you need to take an inventory of the functionalities present in the starting material, the reagent, and the product (an amine). The result is that we are dealing with an intramolecular variant of reductive amination. This realization should be the starting point for retrosynthetic analysis. Solution • First, write down the generic process retrosynthetically:

ONC CPO ϩ ONH A H • Thus, the retrosynthetic disconnection from the product is OO

N N HH OH H NH2 • The mechanism of the forward reaction follows accordingly (not all intermediates are shown): O O CK CK H H ϩ ϩ NH H NaBH3CN # 2 NOH ϪH2O C CH i B H O

CH B

O ϩ H NaBH3CN ðNH Nϩ N ϪH2O Â 952 CHAPTER 21 Amines and Their Derivatives

Secondary amines cannot form imines with aldehydes and ketones, but are in equilibrium with the corresponding N,N-dialkyliminium ions (Section 17-9), which are reduced by addition of H2 from cyanoborohydride.

NaBH3CN, CH3OH CH2 O ϩ ϩ N C6H5 N C6H5 N C6H5

H CH2 HCH2 100% N-(Phenylmethyl)- Iminium ion N-Methyl-N-(phenylmethyl)- cyclopentanamine cyclopentanamine (Benzylcyclopentylamine) (Benzylcyclopentylmethylamine)

Exercise 21-11 Formulate a mechanism for the reductive amination with the secondary amine shown in the pre- ceding example.

Working with the Concepts: Applying Reductive Solved Exercise 21-12 Solved Exercise 21-12 ExplainAminationthe following transformation by a mechanism. Explain the following transformation by a mechanism. Remember WHIP O O What NaBH3CN, CH3OH H H How N NH Information 2 35% Proceed Strategy As usual, you need to take an inventory of the functionalities present in the starting material, the reagent, and the product (an amine). The result is that we are dealing with an intramolecular variant of reductive amination. This realization should be the starting point for retrosynthetic analysis. Solution • First, write down the generic process retrosynthetically:

ONC CPO ϩ ONH A H • Thus, the retrosynthetic disconnection from the product is 7 OO

N N HH OH H NH2 • The mechanism of the forward reaction follows accordingly (not all intermediates are shown): O O CK CK H H ϩ ϩ NH H NaBH3CN # 2 NOH ϪH2O C CH i B H O

CH B

O ϩ H NaBH3CN ðNH Nϩ N ϪH2O Â 952 CHAPTER 21 Amines and Their Derivatives

NaBH3CN, CH3OH CH2 O ϩ ϩ N C6H5 N C6H5 N C6H5

H CH2 HCH2 100% N-(Phenylmethyl)- Iminium ion N-Methyl-N-(phenylmethyl)- cyclopentanamine cyclopentanamine (Benzylcyclopentylamine) (Benzylcyclopentylmethylamine)

Exercise 21-11 Formulate a mechanism for the reductive amination with the secondary amine shown in the pre- ceding example.

ONC CPO ϩ ONH A H • Thus, the retrosynthetic disconnection from the product is OO

N N HH OH H NH2 • The mechanism of the forward reaction follows accordingly (not all intermediates are shown): O O CK CK H H ϩ ϩ NH H NaBH3CN # 2 NOH ϪH2O C CH i B H O

CH B

O ϩ H NaBH3CN ðNH Nϩ N ϪH2O Â 8 21-7 Synthesis of Amines from Carboxylic Amides CHAPTER 21 953

Exercise 21-13 Try It Yourself21-7 Synthesis of Amines from Carboxylic Amides CHAPTER 21 953 Treatment of aldehyde A with the modi! ed sodium cyanoborohydride reagent shown gave the natural product bu" avine, a bioactive constituent of the bulbs of the Boophane ! ava plant from southernExercise Africa. 21-13 Its massTry spectral It Yourself molecular ion occurs at m͞z 5 283. Suggest a structure.

Treatment of aldehydeH3CO A with the modi! ed sodium cyanoborohydride reagent shown gave the natural product bu" avine, a bioactive constituent of the bulbs of the Boophane ! ava plant from southern Africa.H3CO Its mass spectral molecularH ion occurs at m͞z 5 283. Suggest a structure.

H3CO O O B H3CO HH NaBH(OCCH3)3 N Buflavine 35% CH3 O O A B H NaBH(OCCH3)3 The Boophane plant. N Buflavine 35% CH3 In Summary Reductive aminationA furnishes alkanamines by reductive condensation of The Boophane plant. amines with aldehydes and ketones.

In Summary Reductive amination furnishes alkanamines by reductive condensation of 21-7amines withSYNTHESIS aldehydes and OF ketones. AMINES FROM CARBOXYLIC AMIDES

Carboxylic amides can be versatile precursors of amines by reduction of the carbonyl unit (Section21-7 20-6). SinceSYNTHESIS amides are OF in AMINESturn readily FROM available CARBOXYLIC by reaction of acyl AMIDES halides with amines (Section 20-2), the sequence acylation–reduction constitutes a controlled mono- 21-7alkylationSYNTHESISCarboxylic of amines. amidesOF AMINES can be versatileFROM CARBOXYLICprecursors of aminesAMIDES by reduction of the carbonyl unit (Section 20-6). Since amides are in turn readily available by reaction of acyl halides with Carboxylicaminesamides (Sectioncan 20-2),be versatile the sequenceprecursors acylation–reductionof amines by constitutesreduction a controlledof the carbonyl mono- unit. Since amidesalkylationare of inamines.turn readilyUtility ofavailable Amides inby Aminereaction Synthesisof acyl halides with amines, the sequence acylationO –reduction constitutesOa controlled mono-alkylation of amines. B ! Base B! LiAlH , (CH CH ) O ! RCCl ϩ H NRЈ Utility of AmidesRCNHR inЈ Amine 4Synthesis3 2 2 RCH NHRЈ 2 ϪHCl 2 O O B B ! Base ! LiAlH4, (CH3CH2)2O ! RCCl ϩ H2NRЈ RCNHRЈ RCH2NHRЈ Primary amides can also be turnedϪHCl into amines by oxidation with bromine or chlorine in the presence of sodium hydroxide—in other words, by the Hofmann rearrangement (Sec- Primary amides can also be turned into amines by oxidation with bromine or chlorine in the tion 20-7). Recall that in this transformation the carbonyl group is extruded as carbon presence of sodium hydroxide (Hofmann rearrangement). Recall that in this transformation dioxide,Primary so the resultingamides can amine also bearsbe turned one carboninto amines less thanby oxidation the starting with material. bromine or chlorine the carbonylin the presencegroup is ofextruded sodium hydroxide—inas carbon dioxide, other words,so the by theresulting Hofmannamine rearrangementbears one (Sec-carbon less thantionthe 20-7).starting Recallmaterial that in. this transformation the carbonyl group is extruded as carbon dioxide, so the resultingAmines amine bybears Hofmann one carbon Rearrangement less than the starting material. O B B AminesBr2, NaOH, by H Hofmann2O RearrangementB RCNH2 RNH2 ϩ O C O O 9 H3C B B Br2, NaOH, H2O B NH RCNH2 RNH2 ϩ O C O Exercise 21-14 H3C NH Show three reactions from any starting materials that would make the C–N bond in N-methyl- hexanamineExercise (margin) 21-14 according to the indicated retrosynthetic disconnection ( ). Show three reactions from any starting materials that would make the C–N bond in N-methyl- hexanamine (margin) according to the indicated retrosynthetic disconnection ( ). In Summary Amides can be reduced to amines by treatment with lithium aluminum hydride. The Hofmann rearrangement converts amides into amines with loss of the carbonyl group. In Summary Amides can be reduced to amines by treatment with lithium aluminum hydride. The Hofmann rearrangement converts amides into amines with loss of the carbonyl group. 954 CHAPTER 21 Amines and Their Derivatives

21-8 REACTIONS OF QUATERNARY AMMONIUM SALTS: HOFMANN ELIMINATION

Much like the protonation of alcohols, which turns the –OH into the better leaving group 1 –OH2 (Section 9-2), protonation of amines might render the resulting ammonium salts subject to nucleophilic attack. In practice, however, amines are not suf! ciently good leaving groups (they are more basic than water) to partake in substitution reactions. Nevertheless, they can function as such in the Hofmann* elimination, in which a tetraalkylammonium 21-8 REACTIONSsalt is convertedOF QUATERNARY to an alkene by a AMMONIUMstrong base. SALTS: HOFMANN ELIMINATION Section 21-5 described how complete alkylation of amines leads to the corresponding Much likequaternarythe protonation alkylammoniumof alcohols, salts. Thesewhich speciesturns arethe unstable–OH ininto the presencethe better of strongleaving base,group + OH2, protonationbecause of a ofbimolecularamines eliminationmight render reactionthe that furnishesresulting alkenesammonium (Section 7-7).salts Thesubject base to nucleophilicattacksattack the. hydrogen in the ␤-position with respect to the nitrogen, and a trialkylamine departs as a neutral leaving group. In practice, amines are not sufficiently good leaving groups (they are more basic than water) to partake in substitution reactions. In the Hofmann elimination, tetraalkylammonium salt is converted to an alkene by a strong base. Bimolecular Elimination of Quaternary Ammonium Ions

GNR3 GCOC C C ϩ HOH ϩ ðNR3 H Alkene Ϫ ðOH"š The quaternary alkylammonium salts are unstable in the presence of strong base, because of a bimolecular elimination reaction that furnishes alkenes. The base attacks the hydrogen in the �-position with respect to the nitrogen, and a trialkylamine departs as a neutral leaving groupIn. the procedure of Hofmann elimination, the amine is ! rst completely methylated with excess iodomethane (exhaustive methylation) and then treated with wet silver 10 oxide (a source of HO2) to produce the ammonium hydroxide. Heating degrades this salt to the alkene. When more than one regioisomer is possible, Hofmann elimination, in contrast to most E2 processes, tends to give less substituted alkenes as the major products. Recall that this result adheres to Hofmann’s rule (Section 11-6) and appears to be caused by the bulk of the ammonium group, which directs the base to the less hindered protons in the molecule.

Hofmann Elimination of 1-Butanamine ϩ Excess CH3I, K2CO3, H2O Ϫ Ag2O, H2O CH3CH2CH2CH2NH2 CH3CH2CH2CH2N(CH3)3 I 1-Butanamine 1-Butyltrimethylammonium ϪAgI iodide

HO"šð

H G H

& H ⌬

C G CC G CH3CH2CH PCH2 ϩ HOH ϩ N(CH3)3 H ( ϩ CH3CH2 N(CH3)3 1-Butyltrimethylammonium 1-Butene hydroxide

*This is the Hofmann of the Hofmann rule for E2 reactions (Section 11-6) and the Hofmann rearrangement (Section 20-7). 954 CHAPTER 21 Amines and Their Derivatives

21-8 REACTIONS OF QUATERNARY AMMONIUM SALTS: HOFMANN ELIMINATION

Bimolecular Elimination of Quaternary Ammonium Ions

GNR3 GCOC C C ϩ HOH ϩ ðNR3 H Alkene Ϫ ðOH"š

In the procedure of Hofmann elimination, the amine is ! rst completely methylated with excess iodomethane (exhaustive methylation) and then treated with wet silver 2 In theoxideprocedure (a sourceof ofHofmann HO ) toelimination, produce the the ammoniumamine hydroxide.is first completely Heating degradesmethylated this with excesssaltiodomethane to the alkene.(exhaustive When more thanmethylation) one regioisomerand then is possible,treated Hofmannwith wet elimination,silver oxide (a sourcein of contrastHO–) to to mostproduce E2 processes,the ammonium tends tohydroxide give less . substitutedHeating degrades alkenes asthis the salt majorto the products. Recall that this result adheres to Hofmann’s rule (Section 11-6) and appears alkene. to be caused by the bulk of the ammonium group, which directs the base to the less hindered protons in the molecule. When more than one regioisomer is possible, Hofmann elimination, in contrast to most E2 processes, tends to give less substituted alkenes as the major products (the less hindered protons in the molecule). Hofmann Elimination of 1-Butanamine ϩ Excess CH3I, K2CO3, H2O Ϫ Ag2O, H2O CH3CH2CH2CH2NH2 CH3CH2CH2CH2N(CH3)3 I 1-Butanamine 1-Butyltrimethylammonium ϪAgI iodide

HO"šð

H G H

& H ⌬

C G CC G CH3CH2CH PCH2 ϩ HOH ϩ N(CH3)3 H ( ϩ CH3CH2 N(CH3)3 1-Butyltrimethylammonium 1-Butene hydroxide 11

*This is the Hofmann of the Hofmann rule for E2 reactions (Section 11-6) and the Hofmann rearrangement (Section 20-7). 21-9 Mannich Reaction CHAPTER 21 955

Exercise 21-15 Give the structures of the possible alkene products of the Hofmann elimination of The(a) HofmannN-ethylpropanamineelimination (ethylpropylamine)of amines and has(b) 2-butanamine.been used (Caution:to elucidate In the Hofmannthe elim-structure of nitrogen- containingination of 2-butanamine,natural products, you need tosuch consideras severalalkaloids products.. Hint: Review Section 11-6).

Each sequence of exhaustive methylation and Hofmann elimination cleaves one C–N The Hofmann elimination of amines has been used to elucidate the structure of nitrogen- bondcontaining. natural products, such as alkaloids (Section 25-8). Each sequence of exhaustive methylation and Hofmann elimination cleaves one C–N bond. Repeated cycles allow the Repeatedheteroatom tocycles be preciselyallow located,the heteroatom particularly ifto itbe is partprecisely of a ring.located, In this case,particularly the ! rst if it is part of a ringcarbon–nitrogen. In this case, bondthe cleavagefirst carbon opens the–nitrogen ring. bond cleavage opens the ring.

1. CH3I 1. CH3I 2. Ag2O, H2O 2. Ag2O, H2O H H 3. ⌬ H 3. ⌬ ϩ N(CH3)3

N N(CH3)2 A CH3 N-Methylazacycloheptane N,N-Dimethyl-5-hexenamine 1,5-Hexadiene

Exercise 21-16 Why is exhaustive methylation and not, say, ethylation used in Hofmann eliminations for structure 12 elucidation? (Hint: Look for other possible elimination pathways.)

Exercise 21-17

13 An unknown amine of the molecular formula C7H13N has a C NMR spectrum containing only three lines of ␦ 5 21.0, 26.8, and 47.8 ppm. Three cycles of Hofmann elimination are required to form 3-ethenyl-1,4-pentadiene (trivinylmethane; margin) and its double-bond isomers (as side products arising from base-catalyzed isomerization). Propose a structure for 3-Ethenyl-1,4-pentadiene the unknown.

In Summary Quaternary methyl ammonium salts, synthesized by amine methylation, undergo bimolecular elimination in the presence of base to give alkenes.

21-9 MANNICH REACTION: ALKYLATION OF ENOLS BY IMINIUM IONS

In the aldol reaction, an enolate ion attacks the carbonyl group of an aldehyde or ketone (Section 18-5) to furnish a ␤-hydroxycarbonyl product. A process that is quite analogous is the Mannich* reaction. Here, however, it is an enol that functions as the nucleophile and an iminium ion, derived by condensation of a second carbonyl component with an amine, as the substrate. The outcome is a ␤-aminocarbonyl product. To differentiate the reactivity of the three components of the Mannich reaction, it is usually carried out with (1) a ketone or aldehyde; (2) a relatively more reactive aldehyde (often formaldehyde, CH2PO, see Section 17-6); and (3) the amine, all in an alcohol solvent containing HCl. These conditions give the hydrochloride salt of the product. The free amine, called a Mannich base, can be obtained upon treatment with base.

*Professor Carl U. F. Mannich (1877–1947), University of Berlin. 21-9 MANNICH REACTION: ALKYLATION OF ENOLS BY IMINIUM IONS

In the aldol reaction, an enolate ion attacks the carbonyl group of an aldehyde or ketone to furnish a �-hydroxycarbonyl product. A process that is quite analogous is the Mannich reaction.

Here, it is an enol that functions as the nucleophile and an iminium ion, derived by condensation of a second carbonyl component with an amine, as the substrate. The outcome is a �-aminocarbonyl product.

To differentiate the reactivity of the three components of the Mannich reaction, it is usually carried out with (1) a ketone or aldehyde; (2) a relatively more reactive aldehyde (often formaldehyde, CH2=O); and (3) the amine, all in an alcohol solvent containing HCl.

These conditions give the hydrochloride salt of the product. The free amine, called a Mannich base, can be obtained upon treatment with base.

13 956 CHAPTER 21 Amines and Their Derivatives

Mannich Reaction OO ϩ ReactionR Ϫ CH2N(CH3)2 Cl HCl, CH3CH2OH, ⌬ A ϩ CH2PO ϩ (CH3)2NH H

85% Ketone More reactive Amine Salt of Mannich base aldehyde CH CH 3 1. HCl, CH3CH2OH, ⌬ 3 A Ϫ A 2. HO , H2O CH3CHCHPO ϩ CH2PO ϩ CH3NH2 CH3C PO OCH Animation 2-Methylpropanal A CH2NHCH3 ANIMATED MECHANISM: 70% The Mannich reaction Aldehyde More reactive Amine 2-Methyl-2-(N-methyl- aldehyde aminomethyl)propanal Again, we depict only the Mannich base mechanism that leads to product. You can formulateThe mechanismThe mechanismof this process of this processstarts startswith withiminium iminium ionion formationformation betweenbetween the aldehydethe aldehyde multiple alternative reactions(e.g. , formaldehyde)(e.g., formaldehyde)and the andamine, the amine,and onenolization the one hand, ofandthe enolizationketone of. the ketone, on the steps (protonations; enol, other. The electrostatic potential maps in the margin illustrate the electron de! ciency of the iminium ion (blue) and the contrasting relative electron abundance (red and yellow) of hemiacetal, and heminaminalAs soon as the enol is formed, it undergoes nucleophilic attack on the electrophilic iminium formations; aldol additions), the enol. One can also recognize that the electron density is greater at the ␣-carbon (yellow) all of which are reversiblecarbon, andnextthe to resulting the hydroxy-bearingspecies carbonconverts (green).to Asthe soonMannich as the enolsalt isby formed,proton it undergoestransfer from the dead ends, making the carbonyl oxygennucleophilicto the attackamino on thegroup electrophilic. iminium carbon, and the resulting species converts 14 Mannich reaction possible. to the Mannich salt by proton transfer from the carbonyl oxygen to the amino group.

Mechanism of the Mannich Reaction Step 1. Iminium ion formation

ϩ ϩ Mechanism Ϫ Ϫ CH2PO ϩ (CH3)2NH2 Cl CH2PN(CH3)2 Cl ϩ H2O

Step 2. Enolization

Oðð HšOð

Hϩ

Step 3. Carbon–carbon bond formation

H ClϪ Iminium ion H HšOð šOϩ Ϫ Cl CH2šN(CH3)2 ϩ CH2PN(CH3)2

Step 4. Proton transfer

H ClϪ H šOϩ Oðð ϩ Ϫ CH2šN(CH3)2 CH2N(CH3)2 Cl Enol A H

Salt of Mannich base 956 CHAPTER 21 Amines and Their Derivatives

956 CHAPTER 21 Amines and Their Derivatives Mannich Reaction OO Mannich Reaction ϩ ReactionR Ϫ CH2N(CH3)2 Cl OOHCl, CH3CH2OH, ⌬ A ϩ ϩCH PO ϩ (CH ) NH ReactionR 2 Ϫ 3 2 H CH2N(CH3)2 Cl HCl, CH3CH2OH, ⌬ A ϩ CH2PO ϩ (CH3)2NH H 85% Ketone More reactive Amine Salt of Mannich base aldehyde 85% CH3 CH3 Ketone More reactive Amine Salt of Mannich base 1. HCl, CH3CH2OH, ⌬ A Ϫ A aldehyde 2. HO , H2O CH3CHCHPO ϩ CH2PO ϩ CH3NH2 CH3C PO OCH CH Animation 2-MethylpropanalCH A 3 1. HCl, CH3CH2OH, ⌬ 3 A Ϫ A CH2NHCH3 ANIMATED MECHANISM: 2. HO , H2O Animation CH3CHCHPO ϩ CH2PO ϩ CH3NH2 CH3C PO OCH 70% 2-Methylpropanal The Mannich reaction Aldehyde A More reactive Amine 2-Methyl-2-(N-methyl- CH2NHCHaldehyde3 aminomethyl)propanal ANIMATED MECHANISM: 70% Mannich base The Mannich reaction Again, we depict only the Aldehyde More reactivemechanismAmine that leads to 2-Methyl-2-(N-methyl- aldehyde product. You can formulate Theaminomethyl)propanal mechanism of this process starts with iminium ion formation between the aldehyde Mannich base Again, we depict only the multiple alternative reactions (e.g., formaldehyde) and the amine, on the one hand, and enolization of the ketone, on the mechanism that leads to steps (protonations; enol, other. The electrostatic potential maps in the margin illustrate the electron de! ciency of product. You can formulate The mechanism of this processhemiacetal, starts with and heminaminaliminium ion formationthe iminium between ion the (blue) aldehyde and the contrasting relative electron abundance (red and yellow) of multiple alternative reactions (e.g., formaldehyde) and the amine,formations; on the aldol one additions), hand, and enolizationthe enol. of theOne ketone, can also on recognize the that the electron density is greater at the ␣-carbon (yellow) steps (protonations; enol, other. The electrostatic potentialall maps of which in are the reversible margin illustrate next the electron to the hydroxy-bearing de! ciency of carbon (green). As soon as the enol is formed, it undergoes hemiacetal, and heminaminal the iminium ion (blue) and the contrastingdead ends, making relative the electron abundancenucleophilic (red and attack yellow) on the of electrophilic iminium carbon, and the resulting species converts formations; aldol additions), the enol. One can also recognizeMannich that the reaction electron possible. density is greaterto theat the Mannich ␣-carbon salt (yellow)by proton transfer from the carbonyl oxygen to the amino group. all of which are reversible next to the hydroxy-bearing carbon (green). As soon as the enol is formed, it undergoes dead ends, making the nucleophilic attack on the electrophilic iminium carbon, and the resulting species convertsMechanism of the Mannich Reaction Mannich reaction possible. to the Mannich salt by proton transfer from the carbonyl oxygen to the amino group. Step 1. Iminium ion formation

ϩ ϩ Mechanism of the MechanismMannich Reaction Ϫ Ϫ Mechanism of the MannichCH2PO Reactionϩ (CH3)2NH2 Cl CH2PN(CH3)2 Cl ϩ H2O Step 1. Iminium ion formation Step 2. Enolization ϩ ϩ Mechanism Ϫ Ϫ CH2PO ϩ (CH3)2NH2 Cl CH2PN(CH3)2 Cl ϩ H2O Oðð HšOð

Step 2. Enolization Hϩ Oðð HšOð

Hϩ Step 3. Carbon–carbon bond formation

H ClϪ Iminium ion H HšOð šOϩ Step 3. Carbon–carbon bond formation Ϫ Cl CH2šN(CH3)2 ϩ H ClϪ CH2PN(CH3)2 Iminium ion H HšOð šOϩ Ϫ Cl CHStep2šN(CH 4. Proton3)2 transfer ϩ CH PN(CH ) 2 3 2 H ClϪ H šOϩ Oðð ϩ Ϫ Step 4. Proton transfer CH2šN(CH3)2 CH2N(CH3)2 Cl Enol A H H ClϪ H ϩ šO Oðð 15 ϩ Salt of Mannich base Ϫ CH2šN(CH3)2 CH2N(CH3)2 Cl Enol A H

Salt of Mannich base The following example shows the Mannich reaction in natural product synthesis. In this instance, one ring is formed by condensation21-9of Mannichthe amino Reactiongroup withCHAPTERone of the 21two 957 carbonyl functions.

The following example shows the Mannich reaction in natural product synthesis. In this CH OH Mannich reaction of the resulting iminium salt with the enol form of the otherHO carbonylH 2 instance, one ring is formed by condensation of the amino group with one of the two car- * ´ bonyl functions.function Mannichfollows reaction. of the resulting iminium salt with the enol form of the 21-9 Mannich Reaction CHAPTER 21 957 other carbonyl function follows. The product has the framework of retronecine (see margin), N an alkaloidThe thatproduct is presenthas in manythe framework shrubs and isof hepatotoxicretronecine, (causesan liveralkaloid damage)that to isgraz-present in many shrubs ing livestock.and is hepatotoxic (causes liver damage) to grazing livestock. The following example shows the Mannich reaction in natural product synthesis. In this HO CH2OH O instance, one ring is formed by condensation of the amino group with one of the two car- H * ´ O bonyl functions. Mannich reaction ofMannich the resulting Reaction iminium in Synthesis salt with the enol form of the other carbonyl function follows.CHO The product has the frameworkCHO of retronecine (see margin),CHO N an alkaloid that is present in many shrubs and is hepatotoxic (causes liver damage) to graz- ϩ ing livestock. CHO H N ϩ N ϪH2O N ϪH N O A ϩ Mannich Reaction in Synthesis 52% O H Retronecine CHO CHO CHO

16 ϩ CHO H N Working with the Concepts:ϩ Practicing the Solved Exercise 21-18ϪH2O ϪH N MannichN Reaction N A ϩ 52% WriteH the product of the Mannich reaction of ammonia, formaldehyde, and cyclopentanone. Retronecine What we need to do is to determine the product of a reaction. Such problems are often relatively straightforward. In the Mannich reaction, however, we have three organic components, a complication that requiresWorking more with care the in crafting Concepts: a solution. Practicing the Solved Exercise 21-18 How to begin? To predictMannich the outcome Reaction of a Mannich process, it is necessary to follow its mechanism. Several steps are involved, and formulating them in the correct order is essential. Write theInformation product of needed?the Mannich The Mannichreaction ofreaction ammonia, features formaldehyde, the two carbonyl and cyclopentanone. compounds and either ammonia or an amine (see the text section). In particular, we have to identify the more reac- What we need to do is to determine the product of a reaction. Such problems are often relatively tive of the carbonyl components, because the process starts by its initial condensation with straightforward. In the Mannich reaction, however, we have three organic components, a the amine. The resulting iminium species is then attacked by the enol isomer of the less complication that requires more care in crafting a solution. reactive carbonyl partner. How to begin? To predict the outcome of a Mannich process, it is necessary to follow its mech- Proceed. We follow the above steps of the mechanism. Thus: anism. Several steps are involved, and formulating them in the correct order is essential. Information• The needed? more reactive The Mannich carbonyl reaction species features is formaldehyde. the two carbonyl compounds and either ammonia or an amine (see the text section). In particular,H weH have to identify the more reactive of the carbonyl components, because the processi startsϩf by its initial condensation with the amine.• Formaldehyde The resulting and iminium ammonia species condense is thento attackedCPN .by the enol isomer of the less f i reactive carbonyl partner. H H Proceed. We follow the above steps of the mechanism. Thus: ðšOH • The more reactive carbonyl species is formaldehyde. • The enol tautomer of cyclopentanone is . H H i f • Formaldehyde and ammonia condense to CPNϩ . • Reaction of the two species occurs byf attacki of the electron-rich enol on the positively polar- ized iminium ion, and deprotonationH on basicH work-up ! nishes the job. ðšOH H ϩ ðšOH H H šO ððO • The enol tautomer of cyclopentanonei f is . CPNϩ f i šN H šN H H H • Reaction of the two species occurs by attack of the electron-rich enol on the positively polar- H H ized iminium ion, and deprotonation on basic work-up ! nishes the job.

H ϩ ðšOH H H šO ððO i f Exercise 21-19CPNϩ Try It Yourself f i šN H šN H H H Write the products of each of the following Mannich reactions: (a) 1-hexanamine 1 formaldehyde 1 H H 2-methylpropanal; (b) N-methylmethanamine 1 formaldehyde 1 acetone; (c) cyclohexanamine 1 formaldehyde 1 cyclohexanone.

Exercise 21-19 Try It Yourself Write the products of each of the following Mannich reactions: (a) 1-hexanamine 1 formaldehyde 1 2-methylpropanal; (b) N-methylmethanamine 1 formaldehyde 1 acetone; (c) cyclohexanamine 1 formaldehyde 1 cyclohexanone. 958 CHAPTER 21 Amines and Their Derivatives 958 CHAPTER 21 Amines and Their Derivatives

Exercise 21-20 Exercise 21-20 ␤-Dialkylamino alcohols and their esters are useful local anesthetics. Suggest a synthesis of ␤-Dialkylamino alcoholsthe anesthetic and their Tutocaine esters are hydrochloride, useful local beginninganesthetics. with Suggest 2-butanone a synthesis and using of any other organic the anesthetic Tutocainecompounds. hydrochloride, (Hint: Identifybeginning the with embedded 2-butanone four-carbon and using unit any of other 2-butanone organic in the product and compounds. (Hint:apply Identify retrosynthetic the embedded disconnections four-carbon from unit it.)of 2-butanone in the product and apply retrosynthetic disconnections from it.) O O O O

NH2 NH2 ϩ ϩ (H3C)2N ClϪ (H3C)2N ClϪ H H Tutocaine hydrochloride Tutocaine hydrochloride

In Summary Condensation of aldehydes (e.g., formaldehyde) with amines furnishes imin- In Summary Condensationium ions, which of aldehydes are electrophilic (e.g., formaldehyde) and may be with attacked amines by furnishes the enols imin- of ketones (or other ium ions, which arealdehydes) electrophilic in the andMannich may bereaction. attacked The by products the enols are of ␤ -aminocarbonyl ketones (or other compounds. aldehydes) in the Mannich reaction. The products are ␤-aminocarbonyl compounds.

21-10 NITROSATION OF AMINES 21-10 NITROSATION OF AMINES Amines react with nitrous acid, through nucleophilic attack on the nitrosyl cation, NO1. 21-10 NITROSATION OF AMINES 1 Amines react withThe nitrous product acid, depends through very nucleophilic much on whether attack onthe thereactant nitrosyl is an cation, alkanamine NO .or a benzenamine The product depends very much on whether the reactant is an alkanamine or a benzenamine (aniline) and on whether it is primary, secondary, or tertiary. This + section deals with Amines react with nitrous(aniline) acid, and onthrough alkanamines; whether nucleophilic it is aromatic primary, amines secondary,attack will on be or considered the tertiary.nitrosyl This in the section cation,next chapter. dealsNO with. The product dependsalkanamines;very mucharomaticon amineswhether will be1 consideredthe reactant in the nextis chapter.an alkanamine or a 1To generate NO , we must ! rst prepare the unstable nitrous acid by the treatment of benzenamine (aniline) andTo generateon whether NOsodium, weit nitriteis mustprimary, ! with rst prepare aqueoussecondary, the HCl. unstable Inor such tertiary nitrous an acid acid. solution, by the treatment an equilibrium of is established sodium nitrite withwith aqueous the nitrosyl HCl. In cation. such (Compare an acid solution, this sequence an equilibrium with the is preparation established of the nitronium with the nitrosyl cation. (Compare this sequence with the preparation of the nitronium + cation from nitric acid; Section 15-10.) To generate NO , thecationunstable from nitricnitrous acid; acidSectionprepares 15-10.) by the treatment of sodium nitrite with aqueous HCl. Nitrosyl Cation from Nitrous Acid Nitrosyl Cation from Nitrous Acid H

ϩ ϩ

HCl H H O ϩ ϩ ϩϪ ϩ ϩ O

Na HðCl#šOOšP#šON HH#šOOšNPO #šO šOOššϩP#ON ðNP#šOϩ ððqON ϩ H2#šO ϩϪ ϪNaCl O Na ð#šOOšP#šON H#šOOšNP#šO šOOššP#ON ðNP#šO ððqON ϩ H2#šO ϪNaCl H Sodium nitrite NitrousH acid Nitrosyl cation Sodium nitrite Nitrous acid Nitrosyl cation The nitrosyl cation is electrophilic and is attacked by amines to form an N-nitrosammonium salt. The nitrosyl cation is electrophilic and is attacked by amines to form an N-nitrosammonium salt.

Nð ϩ ϩššPON Oϩ ššPONN ϩ #ϩ # The nitrosyl cation is electrophilic and isNattackedð ϩ ššP#ON OššP#ONN by amines to form an N-nitrosammonium salt. N-Nitrosammonium N-Nitrosammonium salt salt 17 The course of the reaction now depends on whether the amine nitrogen bears zero, one, or The course of twothe reaction hydrogens. now Tertiarydepends Non-nitrosammonium whether the amine salts nitrogen are stable bears onlyzero, atone, low or temperatures and R2N O NPtwoO hydrogens. Tertiarydecompose N-nitrosammonium upon heating to give salts a aremixture stable of onlycompounds. at low Secondary temperatures N-nitrosammonium and salts R N N O 2 O P N-Nitrosaminedecompose upon heatingare simply to give deprotonated a mixture toof furnishcompounds. the relatively Secondary stable N-nitrosammonium N-nitrosamines saltsas the major products. N-Nitrosamine are simply deprotonated to furnish the relatively stable N-nitrosamines as the major products. H H3C H A NaNO2, HCl, H2O, 0ЊC H3C i A ϩ Ϫ NaNO(CH2, HCl,3) 2HN2O,H 0ЊC (CH3)2 ONN PO Cl i NO PON ϩ Ϫ ϪHCl (CH3)2NH (CH3)2 ONN PO Cl NO PON ϪHCl f f H3C H C 3 88–90% 88–90% N-Nitrosodimethylamine N-Nitrosodimethylamine 958 CHAPTER 21 Amines and Their Derivatives 958 CHAPTER 21 Amines and Their Derivatives

Exercise 21-20 Exercise 21-20 ␤-Dialkylamino alcohols and their esters are useful local anesthetics. Suggest a synthesis of ␤-Dialkylamino alcohols and their esters are useful local anesthetics. Suggest a synthesis of the anesthetic Tutocaine hydrochloride, beginning with 2-butanone and using any other organic the anesthetic Tutocaine hydrochloride, beginning with 2-butanone and using any other organic compounds. (Hint: Identify the embedded four-carbon unit of 2-butanone in the product and compounds. (Hint: Identify the embedded four-carbon unit of 2-butanone in the product and apply retrosynthetic disconnections from it.) apply retrosynthetic disconnections from it.) O O

O O

NH2 NH2

ϩ ϩ (H C) N Ϫ 3 2 Cl (H3C)2N ClϪ H H Tutocaine hydrochloride Tutocaine hydrochloride

In Summary Condensation of aldehydes (e.g., formaldehyde) with amines furnishes iminium ions, which are electrophilic and may be attacked by the enols of ketones (or other In Summary Condensation of aldehydes (e.g., formaldehyde) with amines furnishes imin- aldehydes) in the Mannich reaction. The products are ␤-aminocarbonyl compounds. ium ions, which are electrophilic and may be attacked by the enols of ketones (or other aldehydes) in the Mannich reaction. The products are ␤-aminocarbonyl compounds.

21-10 NITROSATION OF AMINES 21-10 NITROSATION OF AMINES Amines react with nitrous acid, through nucleophilic attack on the nitrosyl cation, NO1. The product depends very much on whether the reactant is an alkanamine or a benzenamine Amines react with nitrous acid, through nucleophilic attack on the nitrosyl cation, NO1. (aniline) and on whether it is primary, secondary, or tertiary. This section deals with The product depends very much on whether the reactant is an alkanamine or a benzenamine alkanamines; aromatic amines will be considered in the next chapter. (aniline) and on whether it is primary, secondary, or tertiary. This section deals with To generate NO1, we must ! rst prepare the unstable nitrous acid by the treatment of alkanamines; aromatic amines will be considered in the next chapter. sodium nitrite with aqueous HCl. In such an acid solution, an equilibrium is established 1 with the nitrosyl cation. (Compare this sequence with the preparation of the nitronium To generate NO , we must ! rst prepare the unstable nitrous acid by the treatment of cation from nitric acid; Section 15-10.) sodium nitrite with aqueous HCl. In such an acid solution, an equilibrium is established with the nitrosyl cation. (Compare this sequence with the preparation of the nitronium Nitrosyl Cation from Nitrous Acid cation from nitric acid; Section 15-10.) H ϩ ϩ

HCl H O ϩ ϩ Nitrosyl Cation from Nitrous Acid ϩϪ O Na ð#šOOšP#šON H#šOOšNP#šO šOOššP#ON ðNP#šO ððqON ϩ H2#šO ϪNaCl H

ϩ ϩ

H HCl H O ϩ ϩ Sodium nitrite Nitrous acid Nitrosyl cation ϩϪ O Na ðšOOšPšON HšOOšNPšO šOOššPON ðNPšO ððqON ϩ H2šO # # ϪNaCl # # # # # The nitrosyl cation is electrophilic and is attacked by amines to form an N-nitrosammonium salt. H Sodium nitrite Nitrous acid Nitrosyl cation ϩ ϩšš ϩ šš Nð P#ON O P#ONN The nitrosyl cation is electrophilic and is attacked by amines to form an N-nitrosammonium salt. The course of the reaction now depends on whether the amine nitrogen bears zero, one, or two hydrogens. Tertiary N-nitrosammoniumN-Nitrosammoniumsalts are stable only at low temperatures and salt ϩ ϩ decompose upon heating to give a mixture of compounds. Nð ϩ ššP#ON OššP#ONN The course of the reaction now depends on whether the amine nitrogen bears zero, one, or two hydrogens. Tertiary N-nitrosammonium salts are stable only at low temperatures and Secondary N-nitrosammonium salts are simply deprotonated to furnish the relatively stable N-Nitrosammonium R2N O NPO decompose upon heating to give a mixture of compounds. Secondary N-nitrosammonium salts salt N-Nitrosamine Nare-nitrosamines simply deprotonatedas tothe furnishmajor the productsrelatively stable. N-nitrosamines as the major products. The course of the reaction now depends on whether the amine nitrogen bears zero, one, or H H3C two hydrogens. Tertiary N-nitrosammonium salts are stable only at low temperatures and A NaNO2, HCl, H2O, 0ЊC i ϩ Ϫ R2N O NPO decompose upon heating to give a mixture of compounds. Secondary N-nitrosammonium salts (CH3)2NH (CH3)2 ONN PO Cl NO PON ϪHCl f N-Nitrosamine are simply deprotonated to furnish the relatively stable N-nitrosamines as the major products. H3C H H3C 88–90% A NaNO2, HCl, H2O, 0ЊC i N-Nitrosodimethylamine ϩ Ϫ (CH3)2NH (CH3)2 ONN PO Cl NO PON ϪHCl f Similar treatment of primary amines initially gives the analogous monoalkyl-N-nitrosamines. H3C However, these products are unstable because of the remaining proton on the nitrogen. 88–90% N-Nitrosodimethylamine By a series of hydrogen shifts, they first rearrange to the corresponding diazohydroxides. + Then protonation, followed by loss of water, gives highly reactive diazonium ions, R–N2 .

18 960 CHAPTER 21 Amines and Their Derivatives

Similar treatment of primary amines initially gives the analogous monoalkyl-N-nitrosamines. However, these products are unstable because of the remaining proton on the nitrogen. By a series of hydrogen shifts, they ! rst rearrange to the corresponding diazohydroxides. Then 1 protonation, followed by loss of water, gives highly reactive diazonium ions, R–N2 . When R is a secondary or a tertiary alkyl group, these ions lose molecular nitrogen, N2, and form the corresponding carbocations, which may rearrange, deprotonate, or undergo nucleophilic trapping (Section 9-3) to yield the observed mixtures of compounds.

MechanismMechanism of Decompositionof Decomposition of Primaryof PrimaryN-NitrosaminesN-Nitrosamines Step 1. Rearrangement to a diazohydroxide Reminder In the adjacent scheme, free R R R ϩ H1 does not exist in solution, G ϩHϩ G Gϩ ϪHϩ šNOšNPšO šNOššNNPOH PšNOšOH šNR PšNOO šOH but is attached to any available " ϩ " ϩ " D ϪH D D ϩH electron pair, mostly the H H H oxygen of the solvent water. Diazohydroxide

Step 2. Loss of water to give a diazonium ion

ϩ ϩ ϩH ϪH2O ϩ šNR PšNOO šOH OšNR PšNOšOH2 O qNNR ð " ϩ ϪH ϩH2O Diazonium cation

Step 3. Nitrogen loss to give a carbocation H@ ϩ

& D RO qNN ð Rϩ product mixtures CH3CH2CH2OC G ϪN2 NH 2 When R is a secondary or a tertiary alkyl group, these ions lose molecular nitrogen, N2, Pure R enantiomer and form the corresponding carbocations, which may rearrange, deprotonate, or undergo Exercise 21-21 19 NaNO2, nucleophilic trapping to yield the observed mixtures of compounds. HCl,

H2O The mechanism just shown pertains to the decomposition of diazonium ions in which the alkyl

groups R are secondary or tertiary. The result depicted in the margin was reported in 1991 and

H@ addresses the pathway chosen in the case of R ϭ primary alkyl. Is the mechanism the same?

D& GCOCH2 CH2CH3 HO 100% The nitrosyl cation also attacks the nitrogen of N-methylamides. The products, N- Pure S enantiomer methyl-N-nitrosamides, are precursors to useful synthetic intermediates.

Nitrosation of an N-Methylamide O O B NOϩ B

RCNHCH3 ϩ RCNCH3 ϪH A NO N-Methylamide N-Methyl-N-nitrosamide

Solved Exercise 21-22 Working with the Concepts: Applying Basic Principles: A New Reaction of NO؉ The ketone shown below undergoes nitrosation to the corresponding oxime (for oximes, see Section 17-9). Explain by a mechanism.

O O

NaNO2, HCl N HOH 960 CHAPTER 21 Amines and Their Derivatives

Mechanism of Decomposition of Primary N-Nitrosamines Step 1. Rearrangement to a diazohydroxide Reminder In the adjacent scheme, free R R R ϩ H1 does not exist in solution, G ϩHϩ G Gϩ ϪHϩ šNOšNPšO šNOššNNPOH PšNOšOH šNR PšNOO šOH but is attached to any available " ϩ " ϩ " D ϪH D D ϩH electron pair, mostly the H H H oxygen of the solvent water. Diazohydroxide

Step 2. Loss of water to give a diazonium ion

ϩ ϩ ϩH ϪH2O ϩ šNR PšNOO šOH OšNR PšNOšOH2 O qNNR ð " ϩ ϪH ϩH2O Diazonium cation

Step 3. Nitrogen loss to give a carbocation H@ ϩ

& D RO qNN ð Rϩ product mixtures CH3CH2CH2OC G ϪN2

NH2 Pure R enantiomer Exercise 21-21 NaNO2, HCl,

H2O The mechanism just shown pertains to the decomposition of diazonium ions in which the alkyl

groups R are secondary or tertiary. The result depicted in the margin was reported in 1991 and

H@ addresses the pathway chosen in the case of R ϭ primary alkyl. Is the mechanism the same? D& The nitrosyl cation also attacks the nitrogen of N-methylamides. The products, N-methyl-

GCOCH2 CH2CH3 N-nitrosamides, are precursors to useful synthetic intermediates. HO 100% The nitrosyl cation also attacks the nitrogen of N-methylamides. The products, N- N-Methyl-N-nitrosamides are converted into diazomethane, CH N , upon treatment with Pure S enantiomer methyl-N-nitrosamides, are precursors to useful synthetic intermediates.2 2 aqueous base. Nitrosation of an N-Methylamide 964 CHAPTER 21 Amines and Their Derivatives O O B NOϩ B

RCNHCH3 ϩ RCNCH3 ϪH A Base treatment of N-methyl-N-nitrosamidesNO gives diazomethane N-Methyl-N-nitrosamidesN-Methylamide are convertedN- Methyl into diazomethane,-N-nitrosamide CH2N2, upon treatment with aqueous base.

O Making Diazomethane ؉ Solved Exercise 21-22 Working with theB Concepts: Applying Basic Principles: A New Reaction of NO H3C A C A A The ketone shown below undergoes nitrosationN to theNH corresponding2 KOH, H2O, oxime(CH3CH2 )(for2O, 0° Coximes, see Sectionϩ 17-9). Explain by a mechanism. Ϫ A CH2PNPšNð ϩ NH3 ϩ K2CO3 ϩ H2O N O P O O N-Methyl-N-nitrosourea Diazomethane

NaNO2, HCl 20 Diazomethane is used in the synthesis of methyl esters from carboxylic acids. However, NH it is exceedingly toxic and highlyOH explosive in the gaseous state (b.p. 2248C) and in concentrated solutions. It is therefore usually generated in dilute ether solution and immediately allowed to react with the acid. This method is very mild and permits esteri! cation of molecules possessing acid- and base-sensitive functional groups, as shown in the following example.

H H O N OH O N OCH3 CH2N2, (CH3CH2)2O, CH3OH O O O O O NH2 O NH2

75%

When it is irradiated or exposed to catalytic amounts of copper, diazomethane evolves nitrogen to generate the reactive carbene methylene, H2C: Methylene reacts with alkenes by addition to form cyclopropanes stereospeci! cally (Section 12-9).

Exercise 21-24 Formulate a mechanism for the methyl esteri! cation by diazomethane. (Hint: Review the reso- nance structures for CH2N2 in Section 1-5.)

In Summary Nitrous acid attacks amines, thereby causing N-nitrosation. Secondary amines give N-nitrosamines, which are notorious for their carcinogenicity. N-Nitrosamines derived from primary amines decompose through SN1 or SN2 processes to a variety of products. N-Nitrosation of N-methylamides results in the corresponding N-nitrosamides, which liber- ate diazomethane upon treatment with hydroxide. Diazomethane is a reactive substance used in the methylesteri! cation of carboxylic acids and as a source of methylene for the cyclo- propanation of alkenes.

THE BIG PICTURE We have seen the role of the amine function as a base or nucleophile at various points of the text. As early as in Sections 1-3 and 1-8, we learned about its valence electron count and hybridization, using NH3 as an example. In Section 2-2, we saw its first use as a base or nucleophile, and a resulting practical application in the resolution of ammonium tartrates was featured in Section 5-8. Amine nucleophilicity was an essential part of Chapters 6 and 7, elaborated in its synthetic aspects in Sections 17-9, 18-4, 18-9, 19-10, 20-6, and 20-7. The present chapter summarizes, reinforces, and extends this material. In particular, it points out the similarities and differences between the amines and the alcohols. Thus, nitrogen is located immediately to the left of oxygen in the periodic table. It therefore 960 CHAPTER 21 Amines and Their Derivatives

Step 2. Loss of water to give a diazonium ion

ϩ ϩ Exercise 21-21 ϩH ϪH2O ϩ šNR PšNOO šOH OšNR PšNOšOH2 O qNNR ð " ϩ ϪH ϩH2O The mechanism just shown pertains to the decomposition of diazonium ions in which the Diazonium cation alkyl groups R are secondary or tertiary. The result depicted in the margin was reported in 1991 and addresses the pathway chosen in the case of RStep= primary 3. Nitrogenalkyl loss. Is tothe give a carbocation

mechanism the same? H@ ϩ

& D RO qNN ð Rϩ product mixtures CH3CH2CH2OC G ϪN2

NH2 Pure R enantiomer Exercise 21-21 NaNO2, HCl,

H2O The mechanism just shown pertains to the decomposition of diazonium ions in which the alkyl

groups R are secondary or tertiary. The result depicted in the margin was reported in 1991 and

H@ addresses the pathway chosen in the case of R ϭ primary alkyl. Is the mechanism the same?

D& GCOCH2 CH2CH3 HO 100% The nitrosyl cation also attacks the nitrogen of N-methylamides. The products, N- Pure S enantiomer methyl-N-nitrosamides, are precursors to useful synthetic intermediates. 21 Nitrosation of an N-Methylamide O O B NOϩ B

RCNHCH3 ϩ RCNCH3 ϪH A NO N-Methylamide N-Methyl-N-nitrosamide

O O

NaNO2, HCl N HOH 964 CHAPTER 21 Amines and Their Derivatives

Base treatment of N-methyl-N-nitrosamides gives diazomethane

N-Methyl-N-nitrosamides are converted into diazomethane, CH2N2, upon treatment with aqueous base.

O Making Diazomethane B H3C A C A A N NH2 KOH, H2O, (CH3CH2)2O, 0°C ϩ Ϫ A CH2PNPšNð ϩ NH3 ϩ K2CO3 ϩ H2O DiazomethaneN is used in the synthesis of methyl esters from carboxylic acids. However, it is exceedinglyO P toxic and highly explosive in the gaseous state (b.p. –24 oC) and in concentratedN-Methyl-N-nitrosoureasolutions. Diazomethane Diazomethane is used in the synthesis of methyl esters from carboxylic acids. However, It is thereforeit usually is exceedinglygenerated toxic andin highlydilute explosiveether insolution the gaseousand stateimmediately (b.p. 2248C) allowed and in to react with the acid.concentrated solutions. It is therefore usually generated in dilute ether solution and immediately allowed to react with the acid. This method is very mild and permits esteri! cation This method ofis moleculesvery mild possessingand acid-permits and base-sensitiveesterification functionalof groups,molecules as shownpossessing in the follow- acid- and base-sensitiveingfunctional example. groups, as shown in the following example. H H O N OH O N OCH3 CH2N2, (CH3CH2)2O, CH3OH O O O O O NH2 O NH2

75%

When it is irradiatedWhen it is or irradiatedexposed or exposedto catalytic to catalyticamounts amounts ofof copper,copper, diazomethanediazomethane evolves evolves nitrogen to generatenitrogen to generatethe reactive the reactive carbene carbene methylene,methylene, H2C: MethyleneH2C: reactsMethylene with alkenesreacts with alkenes by additionby additionto toform form cyclopropanescyclopropanes stereospecistereospecifically! cally (Section 12-9)..

22 Exercise 21-24 Formulate a mechanism for the methyl esteri! cation by diazomethane. (Hint: Review the reso- nance structures for CH2N2 in Section 1-5.)