22.8 Preparation of amines by alkylation of ammonia TABLE 22.3 Methods for Carbon-Nitrogen Bond Formation Discussed in Earlier Chapters Reaction(section) and comments General equation and specific example Nucleophilic substitution by azide ion on :N=N-N:+ R-x an alkyl halide( Sections 8.1, 8.13)Azide N=N=N一R+X Ion is a very good nucleophile and reacts Alkyl halid Alkyl azide with primary and secondary alkyl halides to give alkyl azides. Phase-transfer cata-CH3CH2CH2CH2CH2Br lysts accelerate the rate of reaction ase-transfer'CH3 CH2 CH2 CH2CH2N3 Pentyl bromide Pentyl azide(89%) Nitration of arenes(Section 12.3)The standard method for introducing a nitro- ArH+ HNO; H2SO gen atom as a substituent on an aromatic Arene Nitric acid Nitroarene Wate ring is nitration with a mixture of nitric acid and sulfuric acid. The reaction pro- O2N ceeds by electrophilic aromatic substitu m-Nitrobenzaldehyde Nucleophilic ring opening of epoxides by ammonia( Section 16. 12) The strained ide is opened HN:+R2C—CR2—>H2N C-OH philic attack by ammonia and amines to give B-amino alcohols. Azide ion also reacts with epoxides; the products are B-Amino alcohol azido aIconoIs H (2R, 3R)-2, 3-Epoxybutane (2R,35)-3-Amino-2-butanol (70%) Nucleophilic addition of amines to alde- hydes and ketones( Sections 17.10, 17.11) Primary amines undergo nucleo- RN →R'CR”+HO philic addition to the carbonyl group of aldehydes and ketones to form carbinol- PrimaryAldehyde Imine Water amines. These carbinolamines dehydrate amine or ketone under the conditions of their formation to give N-substituted imines. Secondary mines yield enamines CH3NH2+ C6HsCH=NCH3 Methylamine (70%) (Continued Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
22.8 Preparation of Amines by Alkylation of Ammonia 873 TABLE 22.3 Methods for Carbon–Nitrogen Bond Formation Discussed in Earlier Chapters Reaction (section) and comments Nitration of arenes (Section 12.3) The standard method for introducing a nitrogen atom as a substituent on an aromatic ring is nitration with a mixture of nitric acid and sulfuric acid. The reaction proceeds by electrophilic aromatic substitution. Nucleophilic substitution by azide ion on an alkyl halide (Sections 8.1, 8.13) Azide ion is a very good nucleophile and reacts with primary and secondary alkyl halides to give alkyl azides. Phase-transfer catalysts accelerate the rate of reaction. Nucleophilic ring opening of epoxides by ammonia (Section 16.12) The strained ring of an epoxide is opened on nucleophilic attack by ammonia and amines to give -amino alcohols. Azide ion also reacts with epoxides; the products are -azido alcohols. Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form carbinolamines. These carbinolamines dehydrate under the conditions of their formation to give N-substituted imines. Secondary amines yield enamines. (Continued) General equation and specific example Pentyl azide (89%) (1-azidopentane) CH3CH2CH2CH2CH2N3 NaN3 phase-transfer catalyst CH3CH2CH2CH2CH2Br Pentyl bromide (1-bromopentane) Nitroarene ArNO2 Water H2O H2SO4 ArH Arene HNO3 Nitric acid Primary amine RNH2 Water H2O Aldehyde or ketone RCR O X Imine RCR X NR Methylamine CH3NH2 N-Benzylidenemethylamine (70%) C6H5CHœNCH3 Benzaldehyde C6H5CH O X Alkyl azide NœNœN±R Alkyl halide R±X X Halide ion Azide ion NœNœN HNO3 H2SO4 CH O X Benzaldehyde O2N CH O X m-Nitrobenzaldehyde (75–84%) Ammonia H3N Epoxide R2C±CR2 O ± ± -Amino alcohol H2N±C±C±OH W W W W R R R R H3C H H3C H O (2R,3R)-2,3-Epoxybutane CH3 CH3 H OH H2N H (2R,3S)-3-Amino-2-butanol (70%) NH3 H2O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-TWo Amines TABLE 22.3 Methods for Carbon-Nitrogen Bond Formation Discussed in Earlier Chapters Reaction(section and comments General equation and specific example Nucleophilic substitution by ammonia on H3N: RCHCO2H-, 2+ NHaX a-halo acids (section 19. 16) The a-halo boxylic acids under conditions of the Ammonia Ammonium Hell-Volhard-Zelinsky reaction are reac- (excess) carboxylic acid tive substrates in nucleophilic substitu tion processes. A standard method for (CH3)2CHCHCO,H T(CH3)2 CHCHcO2 the preparation of a-amino acids is dis- placement of halide from a-halo acids by NH3 nucleophilic substitution using excess aqueous ammonia. 2-Bromo-3-methylbutanoic Aminacid ( 4e489tanor Nucleophilic acyl substitution( Sections 20.3, 20.5, and 20. 11) Acylation of ammo- d amines cyl chloride, acid R2NH+ 2NCR′+HX anhydride, or ester is an exceptiona effective method for the formation of carbon-nitrogen bonds Acyl chloride, Amide Water anhydride, CHaCO NCCH HH Pyrrolidine Acetyl chloride N-Acetylpyrrolidine Pyrrolidi (79%) oride The Hofmann rearrangement(Section 20.17) Amides are converted to amines reaction with bromine in basic media. RCNH An N-bromo amide is an intermediate it Amide A rearranges to an isocyanate. Hydrolysis of the isocyanate yields an amine 2, 2-Dimethylpropanamide tert-Butylamine(64% RX+ NH 2 RNHR NH4 X Al Ammonia Secondary Ammonium halide salt When 1-bromooctane, for example, is allowed to react with ammonia, both the primary amine and the secondary amine are isolated in comparable amounts CHa(CH) CH, Br NH emo CH,(CH)CH,NH,+(CH3(CH)CH,. 1-Bromooctane Octylamine N, N-Dioctylamine (I mol) (43%) In a similar manner, competitive alkylation may continue, resulting in formation of a trialkylamine Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
When 1-bromooctane, for example, is allowed to react with ammonia, both the primary amine and the secondary amine are isolated in comparable amounts. In a similar manner, competitive alkylation may continue, resulting in formation of a trialkylamine. CH3(CH2)6CH2Br 1-Bromooctane (1 mol) CH3(CH2)6CH2NH2 Octylamine (45%) [CH3(CH2)6CH2]2NH N,N-Dioctylamine (43%) NH3 (2 mol) RX Alkyl halide RNH2 Primary amine RNHR Secondary amine NH3 Ammonia NH4 Ammonium halide salt X NH4 874 CHAPTER TWENTY-TWO Amines TABLE 22.3 Methods for Carbon–Nitrogen Bond Formation Discussed in Earlier Chapters (Continued) Reaction (section) and comments Nucleophilic substitution by ammonia on -halo acids (Section 19.16) The -halo acids obtained by halogenation of carboxylic acids under conditions of the Hell–Volhard–Zelinsky reaction are reactive substrates in nucleophilic substitution processes. A standard method for the preparation of -amino acids is displacement of halide from -halo acids by nucleophilic substitution using excess aqueous ammonia. Nucleophilic acyl substitution (Sections 20.3, 20.5, and 20.11) Acylation of ammonia and amines by an acyl chloride, acid anhydride, or ester is an exceptionally effective method for the formation of carbon–nitrogen bonds. The Hofmann rearrangement (Section 20.17) Amides are converted to amines by reaction with bromine in basic media. An N-bromo amide is an intermediate; it rearranges to an isocyanate. Hydrolysis of the isocyanate yields an amine. General equation and specific example Ammonium halide NH4X Ammonia (excess) H3N -Halo carboxylic acid RCHCO2H W X -Amino acid RCHCO2 NH3 W 2-Bromo-3-methylbutanoic acid (CH3)2CHCHCO2H W Br NH3 H2O 2-Amino-3-methylbutanoic acid (47–48%) (CH3)2CHCHCO2 W NH3 Primary or secondary amine, or ammonia R2NH Water RC HX O X ± œ Acyl chloride, acid anhydride, or ester Amide R2NCR O X NCCH3 O X N-Acetylpyrrolidine (79%) 2 N H Pyrrolidine CH3CCl O X Acetyl chloride Cl N H H Pyrrolidine hydrochloride Amine RNH2 Amide RCNH2 O X Br2, HO H2O tert-Butylamine (64%) (CH3)3CNH2 2,2-Dimethylpropanamide (CH3)3CCNH2 O X Br2, HO H2O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
22.9 The Gabriel Synthesis of Primary Alkylamines RX+R2NH+NH3—RN+NH4X halide salt Even the tertiary amine competes with ammonia for the alkylating agent. The product is a quaternary ammonium salt. RX RaN RN X Because alkylation of ammonia can lead to a complex mixture of products, it is used to prepare primary amines only when the starting alkyl halide is not particularly expensive and the desired amine can be easily separated from the other components of the reaction mixture PROBLEM 22.9 Alkylation of ammonia is processes; the resulting mixture of amines is se starting materials for the industrial preparatio a油 employed in industrial ine are propene, chlo- rine, and ammonia. Write a series of equations showing the industrial preparation of allylamine from these starting materials. (Allylamine has a number of uses, including the preparation of the diuretic drugs meralluride and mercaptomerin Ary/ halides do not normally react with ammonia under these conditions. The few exceptions are special cases and will be described in Section 23.5 22.9 THE GABRIEL SYNTHESIS OF PRIMARY ALKYLAMINES A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis. Alkyl halides are converted to primary alkylamines without contam- ination by secondary or tertiary amines. The key reagent is the potassium salt of phthal nide, prepared by the reaction ersity of Berlin in the 1880s. step in the Gabriel synthesi m+m-了 be found n: K+H,O in the october 1975 Journal of Chemical Education(pp. Phthalimide N-Potassiophthalimide Water Phthalimide, with a Ka of 5 x 10(pKa 8.3), can be quantitatively converted to its potassium salt with potassium hydroxide. The potassium salt of phthalimide has a neg atively charged nitrogen atom, which acts as a nucleophile toward primary alkyl halides in a bimolecular nucleophilic substitution(SN2) process DMF is an abbre N, N-dimethylfo HCN(CHa)zDMF is :K++CHCH,CI NCH,C6Hs KCI aprotic solvent(Section 8.12) and an excellent medium for SN2 reactions. N-Potassi phthalimide Benzyl chloride N-Benzylphti Potassium Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Even the tertiary amine competes with ammonia for the alkylating agent. The product is a quaternary ammonium salt. Because alkylation of ammonia can lead to a complex mixture of products, it is used to prepare primary amines only when the starting alkyl halide is not particularly expensive and the desired amine can be easily separated from the other components of the reaction mixture. PROBLEM 22.9 Alkylation of ammonia is sometimes employed in industrial processes; the resulting mixture of amines is separated by distillation. The ultimate starting materials for the industrial preparation of allylamine are propene, chlorine, and ammonia. Write a series of equations showing the industrial preparation of allylamine from these starting materials. (Allylamine has a number of uses, including the preparation of the diuretic drugs meralluride and mercaptomerin.) Aryl halides do not normally react with ammonia under these conditions. The few exceptions are special cases and will be described in Section 23.5. 22.9 THE GABRIEL SYNTHESIS OF PRIMARY ALKYLAMINES A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis. Alkyl halides are converted to primary alkylamines without contamination by secondary or tertiary amines. The key reagent is the potassium salt of phthalimide, prepared by the reaction Phthalimide, with a Ka of 5 109 (pKa 8.3), can be quantitatively converted to its potassium salt with potassium hydroxide. The potassium salt of phthalimide has a negatively charged nitrogen atom, which acts as a nucleophile toward primary alkyl halides in a bimolecular nucleophilic substitution (SN2) process. C6H5CH2Cl Benzyl chloride K O O N N-Potassiophthalimide O O NCH2C6H5 N-Benzylphthalimide (74%) KCl Potassium chloride DMF O O NH Phthalimide KOH K O O N N-Potassiophthalimide H2O Water RX Alkyl halide R3N Tertiary amine Quaternary ammonium salt X R4N RX Alkyl halide R2NH Secondary amine R3N Tertiary amine NH3 Ammonia NH4 Ammonium halide salt X NH4 22.9 The Gabriel Synthesis of Primary Alkylamines 875 The Gabriel synthesis is based on work carried out by Siegmund Gabriel at the University of Berlin in the 1880s. A detailed discussion of each step in the Gabriel synthesis of benzylamine can be found in the October 1975 Journal of Chemical Education (pp. 670–671). DMF is an abbreviation for N,N-dimethylformamide, . DMF is a polar aprotic solvent (Section 8.12) and an excellent medium for SN2 reactions. HCN(CH3)2 O X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-TWo Amines The product of this reaction is an imide(Section 20. 15), a diacyl derivative of an amine. Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine. A more effective method of cleaving the two amide bonds is by acyl transfer to hydrazine NCH,C6H5 H2NN C6HsCH2NH2 NH N-Benzylphthalimide Hydrazine Benzylamine Phthalhydrazide Aryl halides cannot be converted to arylamines by the gabriel synthesis, because they do not undergo nucleophilic substitution with N-potassiophthalimide in the first step of the pro Among compounds other than simple alkyl halides, a-halo ketones and a-halo esters have been employed as substrates in the Gabriel synthesis. Alkyl p-toluenesul onate esters have also been used. Because phthalimide can undergo only a single alky ation, the formation of secondary and tertiary amines does not occur, and the gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines. PROBLEM 22.10 Which of the following amines can be prepared by the gabriel synthesis? Which ones cannot? Write equations showing the successful applica tions of this method (a)Butylamine ( d)2-Phenylethylamine (b) Isobutylamine (e) N-Methylbenzylamine (c) tert-Butylamine (f Aniline SAMPLE SOLUTION (a) The Gabriel synthesis is limited to preparation of amines of the type RCH2NH2, that is, primary alkylamines in which the amino group is bonded to a primary carbon. butylamine may be prepared from butyl bromide by this method CH3CH2 CH2 CH2 Br NCH2 CH2 CH2 CH Butyl bromide N-Potassiophthalimide N-Butylphthalimide H2NNH2 Butylamine Phthalhydrazide Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The product of this reaction is an imide (Section 20.15), a diacyl derivative of an amine. Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine. A more effective method of cleaving the two amide bonds is by acyl transfer to hydrazine: Aryl halides cannot be converted to arylamines by the Gabriel synthesis, because they do not undergo nucleophilic substitution with N-potassiophthalimide in the first step of the procedure. Among compounds other than simple alkyl halides, -halo ketones and -halo esters have been employed as substrates in the Gabriel synthesis. Alkyl p-toluenesulfonate esters have also been used. Because phthalimide can undergo only a single alkylation, the formation of secondary and tertiary amines does not occur, and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines. PROBLEM 22.10 Which of the following amines can be prepared by the Gabriel synthesis? Which ones cannot? Write equations showing the successful applications of this method. (a) Butylamine (d) 2-Phenylethylamine (b) Isobutylamine (e) N-Methylbenzylamine (c) tert-Butylamine (f) Aniline SAMPLE SOLUTION (a) The Gabriel synthesis is limited to preparation of amines of the type RCH2NH2, that is, primary alkylamines in which the amino group is bonded to a primary carbon. Butylamine may be prepared from butyl bromide by this method. CH3CH2CH2CH2Br Butyl bromide O O NK N-Potassiophthalimide N-Butylphthalimide O O NCH2CH2CH2CH3 DMF H2NNH2 CH3CH2CH2CH2NH2 Butylamine NH O NH O Phthalhydrazide H2NNH2 Hydrazine C6H5CH2NH2 Benzylamine (97%) O O NCH2C6H5 N-Benzylphthalimide ethanol Phthalhydrazide NH O NH O 876 CHAPTER TWENTY-TWO Amines Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
22.10 Preparation of Amines by Reduction 22.10 PREPARATION OF AMINES BY REDUCTION compound can be reduced to an amine. The syn thesis of amines then becomes ion of the availability of suitable precursors and the choice of an approp Alkyl azides, prepared by nucleophilic substitution of alkyl halides by sodium azide, as shown in the first entry of Table 22.3, are reduced to alkylamines by a variety of reagents, including lithium aluminum hydride R一N= 一NN= RNH Alkyl azide Primary amine 1. LiAIHa C6HsCH1CH2N3=比→ C6HsCH, CH,NH2 2-Phenylethyl azide 2-Phenylethylamine(89%) atalytic hydrogenation is also effective OH NH 1, 2-Epoxycyclo- trans-2-Azidocyclo- trans-2-Aminocyclo- hexar In its overall design, this procedure is similar to the Gabriel synthesis; a nitrogen ophile is used in a carbon-nitrogen bond-forming operation and then converted to an amIno group in a subsequent transformation. The same reduction methods may be applied to the conversion of nitriles to pri- mary amines RCEN> RCHNH Nitrile F3C CH2CN。,FC CH2CH,? p-(Trifluoromethyl)be 2-p-Trifluoromethy l)pheny lethe CH3CH,CH,,CN CH=CH,CH,CH,CH,NH2 Pentanenitrile I-Pentanamine(56%) Since nitriles can be prepared from alkyl halides by nucleophilic substitution with tanenitrile under phase. cyanide ion, the overall process RX-RC=N-, leads to primary amines described in Section 22. 6 at have one more carbon atom than the starting alkyl halide condr yano groups in cyanohydrins(Section 17.7)are reduced under the same reaction Nitro groups are readily reduced to primary amines by a variety of methods. Cat- alytic hydrogenation over platinum, palladium, or nickel is often used, as is reduction by iron or tin in hydrochloric acid. The ease with which nitro groups are reduced is Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
22.10 PREPARATION OF AMINES BY REDUCTION Almost any nitrogen-containing organic compound can be reduced to an amine. The synthesis of amines then becomes a question of the availability of suitable precursors and the choice of an appropriate reducing agent. Alkyl azides, prepared by nucleophilic substitution of alkyl halides by sodium azide, as shown in the first entry of Table 22.3, are reduced to alkylamines by a variety of reagents, including lithium aluminum hydride. Catalytic hydrogenation is also effective: In its overall design, this procedure is similar to the Gabriel synthesis; a nitrogen nucleophile is used in a carbon–nitrogen bond-forming operation and then converted to an amino group in a subsequent transformation. The same reduction methods may be applied to the conversion of nitriles to primary amines. Since nitriles can be prepared from alkyl halides by nucleophilic substitution with cyanide ion, the overall process RX → RCPN → RCH2NH2 leads to primary amines that have one more carbon atom than the starting alkyl halide. Cyano groups in cyanohydrins (Section 17.7) are reduced under the same reaction conditions. Nitro groups are readily reduced to primary amines by a variety of methods. Catalytic hydrogenation over platinum, palladium, or nickel is often used, as is reduction by iron or tin in hydrochloric acid. The ease with which nitro groups are reduced is LiAlH4 or H2, catalyst RC N Nitrile RCH2NH2 Primary amine 1. LiAlH4, diethyl ether 2. H2O F3C CH2CN p-(Trifluoromethyl)benzyl cyanide F3C CH2CH2NH2 2-(p-Trifluoromethyl)phenylethylamine (53%) H2 (100 atm), Ni diethyl ether CH3CH2CH2CH2CN Pentanenitrile 1-Pentanamine (56%) CH3CH2CH2CH2CH2NH2 NaN3 dioxane–water H2, Pt O 1,2-Epoxycyclohexane OH N3 trans-2-Azidocyclohexanol (61%) OH NH2 trans-2-Aminocyclohexanol (81%) R N N N Alkyl azide RNH2 Primary amine reduce C6H5CH2CH2NH2 2-Phenylethylamine (89%) C6H5CH2CH2N3 2-Phenylethyl azide 1. LiAlH4 diethyl ether 2. H2O 22.10 Preparation of Amines by Reduction 877 The preparation of pentanenitrile under phasetransfer conditions was described in Section 22.6. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website