AMINES 609 (d) The conversion of p-chloronitrobenzene to p-chloroaniline was cited as an example in the text to illustrate reduction of aromatic nitro compounds to arylamines. p-Chloronitrobenzene prepared by nitration of chlorobenzene Cl HNO, H,SO The para isomer accounts for 69% of the product in this reaction (30% is ortho, 1%o meta) Separation of p-chloronitrobenzene and its reduction completes the synthesis Cl Cl 1. Fe. HCl. 2. HO or 1. Sn. HCl: 2. HO N p-Chloronitrobenzene p-Chloroanilin Chlorination of nitrobenzene would not be a suitable route to the required intermediate, because it would produce mainly m-chloronitrobenzene (e) The synthesis of m-aminoacetophenone may be carried out by the scheme shown CH3 Benzene m-Nitroacetophenone The acetyl group is attached to the ring by Friedel-Crafts acylation. It is a meta director, and its nitration gives the proper orientation of substituents. The order of the first two steps cannot reversed, because Friedel-Crafts acylation of nitrobenzene is not possible( Section 12.16) Once prepared, m-nitroacetophenone can be reduced to m-nitroaniline by any of a number of reagents. Indeed, all three reducing combinations described in the text have been employed for this transformation Reducing agent m-Nitroacetophenone m-Aminoacetophenone Sn HCl 82 22.12(b) Dibenzylamine is a secondary amine and can be prepared by reductive amination of benz. HSCH CH-CH2NH, 6H5 Benzaldehyde Benzylamine Dibenzylamine Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(d ) The conversion of p-chloronitrobenzene to p-chloroaniline was cited as an example in the text to illustrate reduction of aromatic nitro compounds to arylamines. p-Chloronitrobenzene is prepared by nitration of chlorobenzene. The para isomer accounts for 69% of the product in this reaction (30% is ortho, 1% meta). Separation of p-chloronitrobenzene and its reduction completes the synthesis. Chlorination of nitrobenzene would not be a suitable route to the required intermediate, because it would produce mainly m-chloronitrobenzene. (e) The synthesis of m-aminoacetophenone may be carried out by the scheme shown: The acetyl group is attached to the ring by Friedel–Crafts acylation. It is a meta director, and its nitration gives the proper orientation of substituents. The order of the first two steps cannot be reversed, because Friedel–Crafts acylation of nitrobenzene is not possible (Section 12.16). Once prepared, m-nitroacetophenone can be reduced to m-nitroaniline by any of a number of reagents. Indeed, all three reducing combinations described in the text have been employed for this transformation. Yield Reducing agent (%) m-Nitroacetophenone H2, Pt 94 ↓ Fe, HCl 84 m-Aminoacetophenone Sn, HCl 82 22.12 (b) Dibenzylamine is a secondary amine and can be prepared by reductive amination of benzaldehyde with benzylamine. H2, Ni C6H5CH O C6H5CH2NH2 C6H5CH2NHCH2C6H5 Benzaldehyde Benzylamine Dibenzylamine Benzene HNO3 H2SO4 reduce AlCl3 CH3CCl O Acetophenone CCH3 O m-Nitroacetophenone NO2 CCH3 O m-Aminoacetophenone NH2 CCH3 O p-Chloroaniline Cl NH2 p-Chloronitrobenzene Cl NO2 1. Fe, HCl; 2. HO or 1. Sn, HCl; 2. HO H2, catalyst; or Benzene Chlorobenzene Cl o-Chloronitrobenzene NO2 Cl p-Chloronitrobenzene Cl NO2 Cl2 FeCl3 HNO3 H2SO4 AMINES 609 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
610 AMINES (c) N,N-Dimethylbenzylamine is a tertiary amine. Its preparation from benzaldehyde requires dimethylamine, a secondary amine. HAN 6HSCH +(CH))NH C6HS CH,N(CH3)2 Benzaldehyde Dimethylamine N, N-Dimethylbenzylamine (d) The preparation of N-butylpiperidine by reductive amination is described in the text in Section 22.11. An analogous procedure is used to prepare N-benzylpiperidine C6HSCH+ CH-CH Piperidine 22.13 (b) First identify the available B hydrogens. Elimination must involve a proton from the carbon atom adjacent to the one that bears the nitrogen. (CH3)3CCH2--C-CH (CH3)3 It is a proton from one of the methyl groups, rather than one from the more sterically hindered methylene, that is lost on elimination (CH3)3CCH2-C-CH2-H OH -(CH3)3CCH,C=CH +(CH3) (1, 1,3,3-Tetramethylbutyl)- 2, 4, 4-Trimethyl-l-pentene Trimethylamine trimethylammonium only alkene formed hydroxid 70% isolated yield) (c) The base may abstract a proton from either of two B carbons. Deprotonation of the B methyl carbon yields ethylene. CH CH2-CH2TNCHCH, CH,CH3 H,C=CH,+(CH,),NCH,CH, CH,CH CH - Ethyl-N, N-dimethy lbutylammonium hydroxide Ethylene N, N-Dimethylbutylamin Deprotonation of the B methylene carbon yields 1-butene C HH-2 CH2CHCH,CH,部,· CH,CH, N(CH,)2+EC=HcH H N-Ethyl-N, N-dimethy lbutylammonium N, N-Dimethylethylamine 1-Butene Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(c) N,N-Dimethylbenzylamine is a tertiary amine. Its preparation from benzaldehyde requires dimethylamine, a secondary amine. (d ) The preparation of N-butylpiperidine by reductive amination is described in the text in Section 22.11. An analogous procedure is used to prepare N-benzylpiperidine. 22.13 (b) First identify the available hydrogens. Elimination must involve a proton from the carbon atom adjacent to the one that bears the nitrogen. It is a proton from one of the methyl groups, rather than one from the more sterically hindered methylene, that is lost on elimination. (c) The base may abstract a proton from either of two carbons. Deprotonation of the methyl carbon yields ethylene. Deprotonation of the methylene carbon yields 1-butene. 1-Butene H2C CHCH2CH3 N-Ethyl-N,N-dimethylbutylammonium hydroxide heat (H2O) N,N-Dimethylethylamine N CH3 CH3 H CH2 CHCH2CH3 OH CH3CH2N(CH3) CH3CH2 2 Ethylene H2C CH2 N-Ethyl-N,N-dimethylbutylammonium hydroxide NCH2CH2CH2CH3 CH3 CH3 OH H CH2 CH2 heat (H2O) N,N-Dimethylbutylamine (CH3)2NCH2CH2CH2CH3 OH (1,1,3,3-Tetramethylbutyl)- trimethylammonium hydroxide (CH3)3CCH2 C H CH2 N(CH3)3 CH3 2,4,4-Trimethyl-1-pentene (only alkene formed, 70% isolated yield) (CH3)3CCH2C CH2 CH3 Trimethylamine (CH3)3N (CH3)3CCH2 C CH3 N(CH3)3 CH3 A methylene group Two equivalent methyl groups H2, Ni C6H5CH O Benzaldehyde Piperidine H N N-Benzylpiperidine C6H5CH2 N H2, Ni C6H5CH O (CH3)2NH C6H5CH2N(CH3) 2 Benzaldehyde Dimethylamine N,N-Dimethylbenzylamine 610 AMINES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
AMINES 611 The preferred order of proton removal in Hofmann elimination reactions is B CH3 B CH2>BCH. Ethylene is the major alkene formed, the observed ratio of ethylene to l-butene 22. 14(b) The pattern of substituents in 2, 4-dinitroaniline suggests that they can be introduced by dini- tration. Since nitration of aniline itself is not practical, the amino group must be protected by conversion to its N-acetyl derivative H NHCCH NHCCH CH.CCI CH,, Acetanilide 4-Dinitroacetanilide Hydrolysis of the amide bond in 2, 4-dinitroacetanilide furnishes the desired 2, 4-dinitroaniline NHCCH H,O HO NO NO, 2.4.Nitroacetanilide 2.4.Dinitroaniline c) Retrosynthetically, p-aminoacetanilide may be derived from p-nitroacetanilide CH CNH A)NH:[ CHCNH--NO p-Aminoacetanilide This suggests the CH. COCCH H,N CH, CNH CH CNH p-Nitroacetanilide arate from ortho iso Fe HC1: 2. HO Sn HCl: 2. HO CH CNH p-Aminoacetanilide Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
The preferred order of proton removal in Hofmann elimination reactions is CH3 CH2 CH. Ethylene is the major alkene formed, the observed ratio of ethylene to 1-butene being 98 : 2. 22.14 (b) The pattern of substituents in 2,4-dinitroaniline suggests that they can be introduced by dinitration. Since nitration of aniline itself is not practical, the amino group must be protected by conversion to its N-acetyl derivative. Hydrolysis of the amide bond in 2,4-dinitroacetanilide furnishes the desired 2,4-dinitroaniline. (c) Retrosynthetically, p-aminoacetanilide may be derived from p-nitroacetanilide. This suggests the sequence HNO3 H2SO4 CH3CNH O Acetanilide H2N Aniline 1. Fe, HCl; 2. HO or 1. Sn, HCl; 2. HO or H2, Pt CH3CNH NO2 O p-Nitroacetanilide (separate from ortho isomer) CH3CNH NH2 O p-Aminoacetanilide CH3COCCH3 O O CH3CNH O NH2 p-Aminoacetanilide CH3CNH O NO2 p-Nitroacetanilide 2,4-Dinitroaniline NH2 NO2 NO2 2,4-Dinitroacetanilide NHCCH3 NO2 NO2 O H2O, HO, or 1. H2O, H 2. HO NH2 Aniline Acetanilide NHCCH3 O 2,4-Dinitroacetanilide NHCCH3 NO2 NO2 O HNO3 H2SO4 CH3CCl O or CH3COCCH3 O O AMINES 611 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
612 AMINES 22.15 The principal resonance forms of N-nitrosodimethylamine are H,CH co: HC、 O: All atoms(except hydrogen) have octets of electrons in each of these structures. Other resonance orms are less stable because they do not have a full complement of electrons around each atom. 22.16 Deamination of 1, 1-dimethylpropylamine gives products that result from 1, 1-dimethylpropyl cation. Because 2, 2-dimethylpropylamine gives the same products, it is likely that 1, I-dimethyl propyl cation is formed from 2, 2-dimethylpropylamine by way of its diazonium ion. A carbocation arrant gement is indicated CH CH3 H CH CCHN CH C-CH CH3 CCH, CH3 2. 2-Dimethylpropylamine . 2-Dimethylpropyldiazo 1, l-Dimethylpropyl Once formed, 1, 1-dimethylpropyl cation loses a proton to form an alkene or is captured by water to give an alcohol CH3 H,C=CCH, CH, +(CH),C=CHCH Methyl-l-butene 2-Methyl-2-butene CH, CCHCH 1, l-Dimethylpropyl (CH3),CCH,CH3 2-Methyl-2-butanol 22.17 Phenols may be prepared by diazotization of the corresponding aniline derivative. The probler simplifies itself, therefore, to the preparation of m-bromoaniline. Recognizing that arylamines are ultimately derived from nitroarenes, we derive the retrosynthetic sequence of intermediates OH NH, NO, Bromophenol Bromoaniline m-bromonitrobenzene Nitrobenzene The desired reaction sequence is straightforward, using reactions that were discussed previously in the text NO NO NH L NaNO. Hs Oa O, 2. H.O. heat Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
22.15 The principal resonance forms of N-nitrosodimethylamine are All atoms (except hydrogen) have octets of electrons in each of these structures. Other resonance forms are less stable because they do not have a full complement of electrons around each atom. 22.16 Deamination of 1,1-dimethylpropylamine gives products that result from 1,1-dimethylpropyl cation. Because 2,2-dimethylpropylamine gives the same products, it is likely that 1,1-dimethylpropyl cation is formed from 2,2-dimethylpropylamine by way of its diazonium ion. A carbocation rearrangement is indicated. Once formed, 1,1-dimethylpropyl cation loses a proton to form an alkene or is captured by water to give an alcohol. 22.17 Phenols may be prepared by diazotization of the corresponding aniline derivative. The problem simplifies itself, therefore, to the preparation of m-bromoaniline. Recognizing that arylamines are ultimately derived from nitroarenes, we derive the retrosynthetic sequence of intermediates: The desired reaction sequence is straightforward, using reactions that were discussed previously in the text. Br OH Br NH2 Br NO2 NO2 HNO3 H2SO4 Br2 Fe 1. Fe, HCl 2. NaOH 2. H2O, heat 1. NaNO2, H2SO4 H2O, 0–5C OH Br Br NH2 Br NO2 NO2 m-Bromophenol m-Bromoaniline m-Bromonitrobenzene Nitrobenzene H H2O CH3CCH2CH3 CH3 1,1-Dimethylpropyl cation (CH3)2CCH2CH3 OH 2-Methyl-2-butanol H2C CCH2CH3 CH3 2-Methyl-1-butene (CH3)2C CHCH3 2-Methyl-2-butene HONO N2 CH3C CH2 N CH3 CH3 N 2,2-Dimethylpropyldiazonium ion CH3CCH2CH3 CH3 1,1-Dimethylpropyl cation CH3CCH2NH2 CH3 CH3 2,2-Dimethylpropylamine N N O H3C H3C N N O H3C H3C 612 AMINES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
AMINES 613 22.18 The key to this problem is to recognize that the iodine substituent in m-bromoiodobenzene is derived from an arylamine by diazotization The preparation of m-bromoaniline from benzene has been described in Problem 22 17. All that remains is to write the equation for its conversion to m-bromoiodobenzene I NaNO, HCl. H, B m-Bromoaniline m-Bromoiodobenzene 22 19 The final step in the preparation of ethyl m-fluorophenyl ketone is shown in the text example im- mediately preceding this problem, therefore all that is necessary is to describe the preparation of 7-aminophenyl ethyl ketone CCHCH CCHCH CCHCH Ethyl m-fluorophenyl aminophenyl ethyl Ethyl m-nitrophenyl Recalling that arylamines are normally prepared by reduction of nitroarenes, we see that ethyl m-nitrophenyl ketone is a pivotal synthetic intermediate. It is prepared by nitration of ethyl phenyl ketone, which is analogous to nitration of acetophenone, shown in Section 12.16 The preparation of ethyl phenyl ketone by Friedel-Crafts acylation of benzene is shown in Sec tion 12.7 CCH.CH CCH,CH3 Ethyl m-nitrophenyl Ethyl phenyl ketone Reversing the order of introduction of the nitro and acyl groups is incorrect. It is possible to nitrate ethyl phenyl ketone but not possible to carry out a Friedel-Crafts acylation on nitrobenzene, owing to the strong deactivating influence of the nitro group 22.20 Direct nitration of the prescribed starting material cumene (isopropylbenzene) is not suitable, because isopropyl is an ortho, para-directing substituent and will give the target molecule Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
22.18 The key to this problem is to recognize that the iodine substituent in m-bromoiodobenzene is derived from an arylamine by diazotization. The preparation of m-bromoaniline from benzene has been described in Problem 22.17. All that remains is to write the equation for its conversion to m-bromoiodobenzene. 22.19 The final step in the preparation of ethyl m-fluorophenyl ketone is shown in the text example immediately preceding this problem, therefore all that is necessary is to describe the preparation of m-aminophenyl ethyl ketone. Recalling that arylamines are normally prepared by reduction of nitroarenes, we see that ethyl m-nitrophenyl ketone is a pivotal synthetic intermediate. It is prepared by nitration of ethyl phenyl ketone, which is analogous to nitration of acetophenone, shown in Section 12.16. The preparation of ethyl phenyl ketone by Friedel–Crafts acylation of benzene is shown in Section 12.7. Reversing the order of introduction of the nitro and acyl groups is incorrect. It is possible to nitrate ethyl phenyl ketone but not possible to carry out a Friedel–Crafts acylation on nitrobenzene, owing to the strong deactivating influence of the nitro group. 22.20 Direct nitration of the prescribed starting material cumene (isopropylbenzene) is not suitable, because isopropyl is an ortho, para-directing substituent and will give the target molecule NO2 CCH2CH3 O Ethyl m-nitrophenyl ketone CCH2CH3 O Ethyl phenyl ketone F CCH2CH3 NH2 NO2 Ethyl m-nitrophenyl ketone Ethyl m-fluorophenyl ketone m-Aminophenyl ethyl ketone CCH2CH3 O CCH2CH3 O O I Br m-Bromoiodobenzene Br NH2 m-Bromoaniline 1. NaNO2, HCl, H2O 2. KI I Br Br NH2 m-Bromoiodobenzene m-Bromoaniline AMINES 613 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website