619 22.26 (a) An alkyl substituent on nitrogen is electron-releasing and base-strengthening: thus methyl amine is a stronger base than ammonia. An aryl substituent is electron-withdrawing and base- weakening and so aniline is a weaker base than ammonia NH3 CHSNH2 Methylamine, Ammonia weakest base 44×10-4K518×10-5K3.8×10-0 pkb 3.4 pK, 4.7 (b) An acetyl group is an electron-withdrawing and base-weakening substituent, especially when bonded directly to nitrogen. Amides are weaker bases than amines, and thus acetanilide is a weaker base than aniline. Alkyl groups are electron-releasing: N-methylaniline is a slightly stronger base than aniline CHSNHCH3 C6H5NH2> C6HsNHCCH3 Aniline k3.8×10 pkb 9.1 pkb.4 pkb 15.0 (c) Chlorine substituents are slightly electron-withdrawing, and methyl groups are slightly electron-releasing. 2, 4-Dimethylaniline is therefore a stronger base than 2, 4-dichloroaniline Nitro groups are strongly electron-withdrawing, their base-weakening effect being especially pronounced when a nitro group is ortho or para to an amino group because the two groups are then directly conjugated. CH H3 NO 2, 4-Dimethylaniline, 2, 4-Dichloroaniline: 2, 4-Dinitroanili kb- pK9.1 pk120 pk18.5 (d) Nitro groups are more electron-withdrawing than chlorine, and the base-weakening effect of a nitro substituent is greater when it is ortho or para to an amino group than when it is meta NO 3.4-Dichloroaniline 4-Chloro2-nitroaniline K8×10-13 pk,=11 pkb 12. pK15.0 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
22.26 (a) An alkyl substituent on nitrogen is electron-releasing and base-strengthening; thus methylamine is a stronger base than ammonia. An aryl substituent is electron-withdrawing and baseweakening, and so aniline is a weaker base than ammonia. (b) An acetyl group is an electron-withdrawing and base-weakening substituent, especially when bonded directly to nitrogen. Amides are weaker bases than amines, and thus acetanilide is a weaker base than aniline. Alkyl groups are electron-releasing; N-methylaniline is a slightly stronger base than aniline. (c) Chlorine substituents are slightly electron-withdrawing, and methyl groups are slightly electron-releasing. 2,4-Dimethylaniline is therefore a stronger base than 2,4-dichloroaniline. Nitro groups are strongly electron-withdrawing, their base-weakening effect being especially pronounced when a nitro group is ortho or para to an amino group because the two groups are then directly conjugated. (d) Nitro groups are more electron-withdrawing than chlorine, and the base-weakening effect of a nitro substituent is greater when it is ortho or para to an amino group than when it is meta to it. NO2 Cl NH2 4-Chloro-2-nitroaniline, weakest base: Kb 1 1015 pKb 15.0 3,4-Dichloroaniline, strongest base: Kb 1011 pKb 11 NH2 Cl Cl 4-Chloro-3-nitroaniline: Kb 8 1013 pKb 12.1 NH2 NO2 Cl CH3 CH3 NH2 2,4-Dimethylaniline, strongest base: Kb 8 1010 pKb 9.1 NH2 Cl Cl 2,4-Dichloroaniline: Kb 1 1012 pKb 12.0 NO2 NO2 NH2 2,4-Dinitroaniline, weakest base: Kb 3 1019 pKb 18.5 N-methylaniline, strongest base: Kb 8 1010 pKb 9.1 C6H5NHCH3 Aniline: Kb 3.8 1010 pKb 9.4 C6H5NH2 Acetanilide, weakest base: Kb 1 1015 pKb 15.0 C6H5NHCCH3 O Methylamine, strongest base: Kb 4.4 104 pKb 3.4 CH3NH2 Ammonia: Kb 1.8 105 pKb 4.7 NH3 Aniline, weakest base: Kb 3.8 1010 pKb 9.4 C6H5NH2 AMINES 619 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
620 AMINES (e) According to the principle applied in part (a)(alkyl groups increase basicity, aryl groups decrease it), the order of decreasing basicity is as show (CH3)2NH CHSNHCH3 >(CHS),NH Dimethylamine, Diphenylamine, Kb5.1×10 K8×10-10 pkb3.3 pk,9.I pkb 13.2 22.27 Nitrogen @is the most basic and the most nucleophilic of the three nitrogen atoms of physostigmine nd is the one that reacts with methyl iodide A 3/H t ChaI OCNHCH OCNHCH “ Physostigmine methiodide” The nitrogen that reacts is the one that is a tertiary alkylamine. Of the other two nitrogens, is attached to an aromatic ring and is much less basic and less nucleophilic. The third nitrogen, is an amide nitrogen; amides are less nucleophilic than amines 22.28 (a) Looking at the problem retrosynthetically, it can be seen that a variety of procedures are avail- able for preparing ethylamine from ethanol. The methods by which a primary amine may be prepared include NCHCH Gabriel synthesis CH3,N3 Reduction of CHICH2NH2 CH CH Reductive CH_CNH2 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(e) According to the principle applied in part (a) (alkyl groups increase basicity, aryl groups decrease it), the order of decreasing basicity is as shown: 22.27 Nitrogen a is the most basic and the most nucleophilic of the three nitrogen atoms of physostigmine and is the one that reacts with methyl iodide. The nitrogen that reacts is the one that is a tertiary alkylamine. Of the other two nitrogens, b is attached to an aromatic ring and is much less basic and less nucleophilic. The third nitrogen, c , is an amide nitrogen; amides are less nucleophilic than amines. 22.28 (a) Looking at the problem retrosynthetically, it can be seen that a variety of procedures are available for preparing ethylamine from ethanol. The methods by which a primary amine may be prepared include NCH2CH3 O O Gabriel synthesis Reduction of an azide CH3CH2N3 CH3CH2NH2 Reductive amination CH3CH O Reduction of an amide CH3CNH2 O Methyl iodide CH3I I Physostigmine CH3 CH3 N N CH3 N OCNHCH3 O b a c “Physostigmine methiodide” H3C CH3 N OCNHCH3 O (CH3)2NH Dimethylamine, strongest base: Kb 5.1 104 pKb 3.3 C6H5NHCH3 N-Methylaniline: Kb 8 1010 pKb 9.1 (C6H5)2NH Diphenylamine, weakest base: Kb 6 1014 pKb 13.2 620 AMINES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
AMINES 621 Two of these methods, the Gabriel synthesis and the preparation and reduction of the corresponding azide, begin with ethyl bromide. CH CH,OH CH3CH B Ethano Ethyl bromide CHaCH Br+ N K NCH.CH H,NNH, CHaCH2NH2 Ethyl N-Ethylphthalimide Ethylamine bromide LiAlH4 CH3CH2Br CHCHN CH CH,NH Ethyl azide Ethylamine bromide To use reductive amination, we must begin with oxidation of ethanol to acetaldehyde CHa CH,OH CH-CH Ethanol Acetaldehvde CHCH CH3 CH,NH Another possibility is reduction of acetamide. This requires an initial oxidation of ethanol to acetic acid CHSCHOOH H,O, heat CH, CO2 2.NH, CH3CNH2 2H0 CH3CHINH2 Ethanol Acetic acid Acetamide Ethylamine (b) Acylation of ethylamine with acetyl chloride, prepared in part (a), gives the desired amide. CHaCCI 2CH, CH,NH2 CH CNHCH, CH3 CH, CH,NH3 CI Ethylamine N-Ethylacetamide Ethylammonium Excess ethylamine can be allowed to react with the hydrogen chloride formed in the acylation reaction. Alternatively, equimolar amounts of acyl chloride and amine can be used in the pres- ence of aqueous hydroxide as the base (c) Reduction of the N-ethylacetamide prepared in part(b)yields dieth 1. LiAlH4 CH: CNHCH, CH3 2. HO CH CHNHCHCH Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
Two of these methods, the Gabriel synthesis and the preparation and reduction of the corresponding azide, begin with ethyl bromide. To use reductive amination, we must begin with oxidation of ethanol to acetaldehyde. Another possibility is reduction of acetamide. This requires an initial oxidation of ethanol to acetic acid. (b) Acylation of ethylamine with acetyl chloride, prepared in part (a), gives the desired amide. Excess ethylamine can be allowed to react with the hydrogen chloride formed in the acylation reaction. Alternatively, equimolar amounts of acyl chloride and amine can be used in the presence of aqueous hydroxide as the base. (c) Reduction of the N-ethylacetamide prepared in part (b) yields diethylamine. N-Ethylacetamide CH3CNHCH2CH3 O Diethylamine CH3CH2NHCH2CH3 1. LiAlH4 2. H2O Ethylamine 2CH3CH2NH2 Acetyl chloride CH3CCl O N-Ethylacetamide CH3CNHCH2CH3 O Ethylammonium chloride CH3CH2NH3 Cl Acetic acid CH3CO2H Ethylamine CH3CH2NH2 K2Cr2O7, H2SO4 H2O, heat Ethanol CH3CH2OH Acetamide CH3CNH2 O 1. SOCl2 2. NH3 1. LiAlH4 2. H2O Ethylamine CH3CH2NH2 NH3, H2, Ni Acetaldehyde CH3CH O Ethanol CH3CH2OH PCC or PDC CH2Cl2 Acetaldehyde CH3CH O Ethyl azide CH3CH2N3 Ethylamine CH3CH2NH2 Ethyl bromide CH3CH2Br NaN3 1. LiAlH4 2. H2O N K O O N-Potassiophthalimide NCH2CH3 O O N-Ethylphthalimide CH3CH2NH2 Ethylamine CH3CH2Br Ethyl bromide H2NNH2 Ethanol CH3CH2OH Ethyl bromide CH3CH2Br PBr3 or HBr AMINES 621 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website