Chapter 17 Amines ( 胺 )17.1 Amine Nomenclature 17.2 Structures of amines 17.3 Basicity of amines 17.4 Preparation of amines 17.4.1 Preparation of amines by alkylation of ammonia 17.4.2 The Gabriel synthesis of primary amines 17.4.3 Preparation of amines by reduction17.5 Reactions of amines17.5.1 Alkylation of amines17.5.2 Acylation of amines17.5.3 The Hofmann Elimination

17.5.4 Reactions of amines with nitrous acid(A) Reactions of primary aliphatic amines with nitrous acid(B) Reactions of primary arylamines with nitrous acid(C) Reactions of secondary amines with nitrous acid (D) Reactions of tertiary amines with nitrous acid 17.5.5 Synthetic transformations of aryl diazonium salt (A) Replacement of the diazonium group by － OH

(B) Replacement of the diazonium group by － X, － CN(c) Replacement of the diazonium group by － H 17.5.6 Azo coupling 17.6 Spectroscopic analysis of amines

17.1 Amine Nomenclature

R N NHH

H

Organic derivatives of ammonia

Alkylamines ArylaminesNAr

CH3NH2 CH2NH2CH3 CHCH2NH2CH3

Methylamine( 甲胺）

Isobutylamine( 异丁胺 )

2-Methylpropylamine（ 2- 甲基丙胺）

Benzylamine( 苄胺）

Primary amines （伯胺） :

P380P380

Aniline( 苯胺 )

NHH

NCH3

CH3CH2

H (CH3CH2)2NH

Ethylmethylamine（甲乙胺）

N-Methylethylamine(N- 甲基乙胺）

Diethylamine（二乙胺）

Secondary amines:( 仲胺）

TrimethylamineN,N-Dimethylmethylamine

（三甲胺）（ N,N- 二甲基甲胺）

N,N-Dimethyl-aniline

(N,N- 二甲基苯胺 )

Tertiary amines:（叔胺） (CH3)3N

N CH3H3C

NH2Cyclohexylamine

( 环己胺 )

H2NCH2CH2NH21,2-Ethyldiamine

（ 1,2- 乙二胺）

Diamines:

Ammonium ions（铵离子）

Aminium salts（铵盐）

NH3 Cl C16H33N(C4H9)3 Br

Anilinium chloride（盐酸苯胺）

Quaternaryammonium

salts （季铵盐）HOCH2CH2NH2

2-Aminoethanol（ 2- 氨基乙醇）

NH3C CH2CH3

N-Ethyl-N-methylcyclohexylamine(N- 甲基 -N- 乙基环己胺 )

Heterocyclic amine:( 杂环胺 )

Pyridine( 吡啶 )

Pyrrole( 吡咯 )

Quinoline( 喹啉 )

Indole( 吲哚 )

N N N N

H

Pyrrolidine ( 吡咯烷 )( 四氢吡咯 )

Piperidine ( 哌啶 )

N

H

N

H

17.2 Structures of amines

sp3-hybrid

sp3-sp3 hybridized orbitals overlapC － N ：

N － H ： sp3hybridized -1s orbitals overlap

N

R'R''

R'''

NR'

R''

R'''

Tertiary amines with 3 different groups:

Interconversion of amine enantiomers

NCH

N: 1s22s22px12py

12pz1N: 1s22s22px

12py12pz

1

P383,12.2P383,12.2

Pyramid( 棱锥型 )

17.3 Basicity of amines

N

CH3

Et C6H5

CH2CH CH2

X

N

CH3

C6H5CH2 CHCH2

Et

X(S) (R)

Quarternary ammonium salt:

RNH2 + H2O RNH3 + OH

Weak bases

Kb =[ RNH3 ] [ OH ]

[ RNH2 ]pKb = - log Kb

P384,12.3

P384,12.3

Amines pKb

NH3

CH3NH2

(CH3)2NH

(CH3)3NNH2

NH2O2N

NH2CH3O

4.7

3.4

3.3

4.3

9.4

13

8.7

Table 1 Basic strength of some aminesP385,Table12.1

P385,Table12.1

1. All amines are weak bases:H2O < RNH2 < < OH -

2. RNH2 > NH3 > NH2

Alkylamines are slightly stronger bases than ammonia; Arylamines are much weakerbases than ammonia and alkylamines.

R NH2 +I p -πconjugationDelocalization of nitrogen lone-pairelectrons

Decreasing the electron density at nitrogen.

P384,12.3

P384,12.3

NH

H

NH2 NH2 NH2 NH2 NH2

NH3 CH3 NH3pKa = 4.63 pKa = 10.66

R NH3 + H2O R NH2 + H3O

Ka =[RNH2][H3O+]

[RNH3+]

pKa = -logKa

pKa + pKb = 14

Weaker base:Smaller pKa for ammonium ionStronger base: Larger pKa for ammonium ionWeaker base:Smaller pKa for ammonium ionStronger base: Larger pKa for ammonium ion

3. R2NH > RNH2 > R3N >NH3

NR

RR

H Poorer solvation

+ HCl NH3ClNH2

Separation of amines from neutral organic compounds

17.4 Preparation of amines17.4.1 Preparation of amines by alkylation of ammonia

R X R NH3X NaOH R NH2NH3 (excess) +

P384,12.3

P384,12.3

Anilinium ionAnilinium ion

R NH2R X R2NH

2. OH

1. R X

2. OHR3N1.

17.4.2 The Gabriel synthesis of primary amines

R X R NH2

Reagent:C

CN

O

O

K

Potassium salt of Phthalimide

（邻苯二甲酰胺钾盐）

C

CN

O

O

HKOH C

CN

O

O

KR X C

CN

O

O

RDMF

Imide（酰亚胺）

Ch.P436Ch.P436

Primary alkyl halide, SN2Primary alkyl halide, SN2

RX: CHCR'

O

X

CHCOR'

O

X

ROTs

, ,ArX

17.4.3 Preparation of amines by reduction

CH2C N + 2 H2Raney Ni

140¡æ CH2CH2NH2

(71%)

LiAlH4

Reduction of nitriles to amines

C

C

O

O

N RNaOH, H2O

R NH2 +C

C

O

O

O

O

Siegmund Gabriel(1851-1924)

Siegmund Gabriel was born in Berlin,Germany,and received his Ph.D. in1874 at the University of Berlin,working with August von Hofmann. After furtherwork with Robert Bunsen,he became Professor of Chemistry at the Univ. of Berlin.

 

Robert Wilhelm Bunsen

1811-1899

poohbah.cem.msu.edu/Portraits/

Gabriel Synthesis. Gabriel, Ber. 20, 2224(1887). M. S. Gibson, R. W. Bradshaw, Angew. Chem. Int. Ed. 7, 919 (1968); B. Dietrich et al., J. Am. Chem. Soc. 103, 1282 (1981); O. Mitsunobu, Comp. Org. Syn. 6, 79-85 (1991). Modified conditions: S. E. Sen, S. L. Roach, Synthesis 1994, 756; M. N. Khan, J. Org. Chem. 61, 8063 (1996). Stereoselectivity: A. Kubo et al., Tetrahedron Letters 37, 4957 (1996).

Ar H HNO3 Ar NO2[ H]

Ar NH2H2SO4

Reduction of nitro compounds to arylamines

NO21) Fe, HCl

2) OH

NH2H2, cat

Reduction of amides to amines:

N

CH3

CCH3

O

+ LiAlH4Et2O

2) H2ON CH2CH3

CH3

1)

P389P389

Reductive amination:

CR

(R')H O + NH3(or R''NH2)

-H2O CR

(R')H NH(R'')

Imine（亚胺）H2, Ni

CHR

(R')H

NH2(R'')

C O

H

+ NH3H2, Ni90 atm

40 ~ 70¡æ

CH2NH2(89%)

(CH3)2C O + H2NCH2CH2OHH2, Ni, EtOH

95£¥(CH3)2CNHCH2CH2OH

Ch.P435Ch.P435

17.5 Reactions of amines

NUnshared electron pair of nitrogen:

Basicity: N + H X

Nucleophilicity:

N + C O

17.5.1 Alkylation of amines

RNH2R'CH2X RNHCH2R'

R'CH2X RN(CH2R')2

R'CH2X RN(CH2R')3X

CH2NH2 + 3 CH3IMeOH

heatCH2N(CH3)3 I

(Cyclohexyl-methyl)-

amine

(Cyclohexyl-methyl)-

amineMethyliodideMethyliodide

(cyclohexylmethyl)-trimethyl-

ammonium iodide(99%)

(cyclohexylmethyl)-trimethyl-

ammonium iodide(99%)

17.5.2 Acylation of aminesAcylating agents: acyl chlorides, carboxylic acid anhydrides

Cl NO21) NaOH, H2O

2) H3+O

HO NO2H2, Ni

HO NH2(CH3CO)2O

HO NHCCH3

O

Synthesis of Paracetamol （扑热息痛） :

17.5.3 The Hofmann Elimination

Decreasing the activity of aryl ring or Protecting amino groups :

NH2(CH3CO)2O

NHCOCH3

Br2, ¡÷

NHCOCH3

Br

H2O,OH- ,¡÷

NH2

Br

RNH2 C C

Methylation of an amine by excess CH3I:CH3CH2CH2CH2CH2CH2NH2

CH3Iexcess

CH3CH2CH2CH2CH2CH2N(CH3)3IHexylamine

Hexyltrimethylammonium iodide

Ch.P448

( 六 )Ch.P448

( 六 )

Quaternary ammonium hydroxides （氢氧化季铵碱） can be prepared from Quaternary ammonium halides:2 RCH2CH2N(CH3)3X + Ag2O + H2O 2 RCH2CH2N(CH3)3OH

+ 2AgX

CH2N(CH3)3 I Ag2OH2O, CH3OH

CH2N(CH3)3 OH

Quaternary ammonium hydroxidesheat β- Elimination to form alkenes

and an amineCH2H

N(CH3)3

OH

160¡æ CH2 + (CH3)3N + H2O

Methylenecyclohexane（亚甲基环己烷）

(69%)

RCH CH2

N(CH3)3

HHO¦Ä

¦Ä

Transition stateThe base attacks the mostacidic hydrogen or least hinder hydrogen.

E2 Reaction

Anti relationship

Regioselectivity of Hofmann elimination:

To give a less substituted alkene.

C C

N(CH3)3+

HHO E2 reactionC C + N(CH3)3 + H2O

HO

CH3CH2CHNH2

CH31) 3CH3I

2) AgOHCH3 CH

H

CH

H2C H

N(CH3)3OH

CH3CH2CH CH2 CH3CH CHCH3(95%) (5%)

¡÷ +

H

HHN(CH3)3

CH3CH2 H

HO

-H2O-N(CH3)3 H

HCH3CH2

H

H

HHN(CH3)3

CH3CH2 H

HO

-H2O-N(CH3)3 H

HCH3CH2

H N(CH3)3

H CH3

H

CH3H

HO

-H2O

-N(CH3)3

H CH3

CH3 HN(CH3)3

H CH3

H

CH3H

HO

-H2O

-N(CH3)3

H CH3

CH3 H

Hofmann rule is opposed to the Zaitsev rule.C1–C2

C2–C3

August Wilhelm von1818–1892

August Wilhelm von , 1818–1892,German organic chemist. He wasProfessor at the Univ. of Berlin from 1865 and was a founder (1868) of the German ChemicalSociety. He studied the constitu-tion of aniline and was the firstto prepare rosaniline and its derivatives, thereby laying the basis for the aniline dye industry. He also discovered a reaction forderiving amines from amides anddeveloped the Hofmann methodof finding the vapor densities, and from these the molecular weights, of liquids. He also helped topopularize the concept of valence(the word comes from his termquantivalence

17.5.4 Reactions of amines with nitrous acid (Nitrosation 亚硝化反应 )

(A) Reactions of primary aliphatic amines with nitrous acid

NaNO2 + HCl1/2 H2SO4

HNO2 + NaCl1/2 Na2SO4

Nitrosating agent:

Primary aliphatic amines Nitrous acidto yield unstable aliphatic diazonium salt ( 重氮盐 )Diazotization ( 重氮化反应 )Aliphatic diazonium salts decompose to formcarbocations and nitrogen:

CH3CH2CH2NH2NaNO2, HCl

CH3CH2CH2N NCl

CH3CH2CH2 + N2 + HCl

Alkene, alcohol, alkyl halide

(B) Reactions of primary arylamines with nitrous acid

Primary arylamines form diazonium salt on nitrosation:

NH2 + NaNO2 + 2 HCl 0 ~ 5¡æ N N Cl + H2O + NaCl

Aryl diazoniumsalts are stable below 5℃

P390P390

(C) Reactions of secondary amines with nitrous acidSecondary amines: both aryl amines and alkyl amines react with nitrous acid to yieldN-nitrosoamines （亚硝胺）

+ NaNO2 + 2 HCl NN

CH3

ONHCH3

N-nitrosoamines are usually separated from the reaction mixture as oily yellow liquids(D) Reactions of tertiary amines with nitrous acid

R3N NaNO2, HCl

No reaction

Tertiary aryl amines react with nitrous acid to form C-nitroso aromatic compounds:

N(CH3)2NaNO2, HCl

N(CH3)2ON

Electrophilic aromatic substitution

17.5.5 Synthetic transformations of aryl diazonium saltThe diazonium group （重氮基） may be replaced by other atomes or groups: －X, － OH, － CN and － H.

( )

P391P391

:Electron-withdrawing group

ArH ArNO2 ArNH2 ArN N

Aryl diazonium salts can be prepared from arene:

(A) Replacement of the diazonium group by － OH

Aryl diazonium ion is converted to phenols( 酚 ) (CH3)2CH NH2

1. NaNO2, H2SO4, H2O2. H2O, heat

(CH3)2CH OH

Sulfuric acid is usually used instead of hydrochloric acidQuestion: Design a synsthesis of

OH

Br

Hydrolysis N2+

p-Isopropylaniline p-Isopropylphenol (73%)

(B) Replacement of the diazonium group by － X, － CN

NO2

NH2

H2SO4, NaNO2

H2O, 0 ~ 5¡æ

NO2

N2+HSO4

KI

NO2

I

+ N2

The preparation of aryl iodides

The preparation of aryl fluorides:Treating the diazonium salt with fluoboricacid (HBF4)

CH3

NH2

1) NaNO2, H+

2) HBF4

CH3

N2+BF4

¡÷

CH3

F+ N2 + BF3

(69%)

(81%)

The Sandmeyer reaction:Aryl diazonium salts react with cuprouschloride, cuprous bromide, cuprous cyanide

£ N2 -X or -CN

NH2

Cl

HBr, NaNO2

H2O0 ~ 5¡æ

N2+ Br -

Cl

CuBr

100¡æ

Br

Cl

+ N2

NO2

NH2HCl, NaNO2

H2O(r.t)

NO2N2

+Cl CuCN

90 ~ 100¡æ

NO2CN

+ N2

(70% overall)

(65% overall)

Born inWettingen near Zurich, and lived in the Zurich area for nearly all of his life. He trained as a precision instrument-maker, but became interested in chemistry. Self-educated in chemistry, he carried out chemical experiments in his kitchen. In 1881, he became a lecture assistant to Victor Meyer (1848-1897). He followed Meyer to Göttingen in 1886, but soon returned to Zurich and worked for Arthur Hantzsch (1857-1935). Sandmeyer joined Geigy as a research scientist in 1888, and eventually became a director of the firm. He discovered the decomposition of aryl diazonium Chlorides to chloroarenes in the presence of copper (I) chloride in 1884. He also worked on the triphenylmethane dyes and the synthesisof isatin. Many years before, he had suggested to Victor Meyer an impurity in commerical benzene was responsible for the isatin reaction with sulphuric acid, thereby paving the way for Meyer's discovery of thiophen.

Traugott Sandmeyer (1854-1922).

(C) Replacement of the diazonium group by － H Aryl diazonium salts react with hypophosphorous acid (H3PO2) ( 次磷酸）or ethanol to yield the product:

£ N2Ar £ HAr

CH3

NH2

(CH3CO)2O

CH3

NHCOCH3

1) Br2

2) OH -, H2O,¡÷

CH3

NH2

Br

H2SO4, NaNO2

H2O, 0 ~ 5¡æ

CH3

N2+

Br

H2PO2

H2Or.t

CH3

Br

Deamination（脱氨基作用）

(85%)

P392P392

The value of diazonium salts in synthesis:1. Substituents that are otherwise accessible only with difficulty, such as － F, － I, － CN, － OH, may be introduced onto a benzene ring.2. Compounds that have substitution patterns not directly available by electrophilic aromatic substitution can be prepared

Br

Br

BrNH2 Br2

H2O

Br

Br

BrNH2 NaNO2, H2SO4

H2O

EtOH

Aniline 2,4,6-Tribromoaniline(100%)

1,3,5-Tribromo-Benzene(74-77%)

17.5.6 Azo coupling ( 偶氮偶合反应 )Aryl diazonium salts are weak electrophiles, they react with highly reactive aromatic compounds, to yield azo compounds

N2+Cl + N(CH3)2

CH3COO -Na+

0¡æH2O

N N N(CH3)2

OH OpH = ~ 8

Azo dyes （偶氮染料）

OHN N SO3 NaOrange II ：

P393P393

Alkaline solution

17. 6 Spectroscopic analysis of aminesIR ：N H: Streching

vibration Primary amine3000-3500 cm-1

two peaks

Secondary amines 3280 cm-1

one peakTertiary amines No peak

C N: Streching vibration

1020-1220 cm-1Aliphaticamines

Aromaticamines 1250-1360 cm-1

Ch.P437( 四 )Ch.P437( 四 )

Infrared spectrum of isobutylamineCH3

CH3CH CH2 N H

H

C–N Stretchingvibration

C–N Stretchingvibration

N–H Stretchingvibration

N–H Stretchingvibration

N- 甲基苯胺的红外光谱

N-H伸缩 C-N

伸缩

苯环伸缩

1H NMR

N - H δ： 0. 6 ~ 5 ppm

C NR2

Hδ： 2.2 ~ 2.8 ppm

Problems to Chapter 17

P40212.21 (a), (d),(e)12.22 (a), (c),(f)12.24 酶斯卡灵，一种 高效的致幻剂。从 仙人掌中得来。12.27(b), (d),12.29(b), (c)12.30 (a)12.31(b), (c)12.3712.39

12.4112.4212.4812.5112.52

Additional Problems to Chapter 17

11. What are the major products you would expect from Hofmann elimination of the following amines? Show the reactions.

(a)N-Methylcyclopentylamine(c)

CH3CHCHCH2CH2CH3

CH3

NH2

2. Predict the product(s) of the following reactions.Give the major product.

N

H

(CH3)3I

excessA? Ag2O, H2O

B?heat

C?

(3) How would you prepare the following compounds from toluene? A diaonio ( 重氮盐 )replacement reaction is needed in some instances.

H3C

NH2(a) (b)

CH3

CH2NH2 (c)I C

OCH3

O

(4) Ch.P464 ( 十六 ), ( 十七 )