芳香重氮盐的置换反应

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Chapter 20

20.8 Replacement Reactions of Arenediazonium Salts

芳香重氮盐的置换反应

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Chapter 20

20.8A Synthesis Using Diazonium Salts

F Cl Br

(1) HBF4 (2)

CuCl

+ N N

CuBr KI

I

Arenediazonium salt H2PO2, H2O Cu2O, Cu2+ H2O

H OH

CuCN

CN

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Chapter 20

20.8B The Sandmeyer Reaction: Replacement of the Diazonium Group by –Cl, –Br, or –CN

+ N N Cl + N N Br

+ N N Cl

CuCl HCl, CuBr HBr,

CuCN KCN

Cl + N2

Br + N2

CN + N2

Gatterman reaction

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Chapter 20

Olah Reaction

CH3 35~37 ℃ + N N BCl4 CH3 Cl + N2 + BCl3 77.6% CH3 128~134 ℃ + N N BBr4 CH3 Br + N2 + BBr3 96.5%

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Chapter 20

20.8C Replacement by –I

+ N N HSO4

KI

I

+ N2

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Chapter 20

20.8D Replacement by –F

+ N N Cl

HBF4

+ N N BF4

F + N2

Schiemann reaction

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Chapter 20

20.8E Replacement by –OH

+ N N HSO4

Cu2O Cu , H2O

2+

CH3

CH3

OH

+ N N HSO4

H2O H+

OH + N2

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Chapter 20

20.8F Replacement by Hydrogen: Deamination by Diazotization

+ N N Cl

H3PO2

EtOH / Zn

+ N N Cl

H

+ N2

NH2

NO2

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Example 1

CH3 HNO3

Fe HCl

Ac2O

Cl2

CH3 Cl H3PO2

NHCOCH3

H3O+ HNO2

CH3 Cl

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Example 2

NH2 HNO3 NH2 3Br2 Br Br

Fe HCl

Br N2HSO4 NaNO2/H2SO4 0 ~ 5℃ Br Br

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Br

Br

H3PO2 Br

Br

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Chapter 20

20.9 Coupling Reactions of Arenediazonium Salts

芳香重氮盐的偶联反应

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Arenediazonium ions are weak electrophiles; they react with highly reactive aromatic compounds to yield azo compounds — diazo coupling reaction.

H G NR2 , or

N N N N

+ N N +

G

G= H

OH G

An azo compound

Diazo coupling reaction

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Coupling with phenols

NaOH N N Cl + OH pH 8~10

Benzenediazonium chloride

N N

Phenol

OH

p-(Phenylazo)phenol

HA HA Diazotate ion Arenediazonium Diazohydroxide (does not couple) (does not couple) ion (couples) Department of Chemistry, Xiamen University Ar N N OH Ar N N OH OH Ar N N O

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Coupling with arylamines

N N Cl + HOAc N(CH3)2 pH 5~7

Benzenediazonium chloride

N,N-Dimethylaniline

N N

N(CH3)2

N,N-Dimethyl-p-(phenylazo)aniline

HA

N(CH3)2

OH

N(CH3)2

Amine (couple)

H Aminium salt (does not couple)

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Chapter 20

20.10 Reactions of Amines with Sulfonyl Chlorides

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Primary and secondary amines react with sulfonyl chlorides to form sulfonamides (磺酰胺).

O R NH2 + Ar S Cl HCl O 1°Amine Sulfonyl chloride O Ar S Cl O O R NH S Ar O N-Substituted sulfonamide

R2NH 2°Amine

+

O R2N S Ar HCl O N,N-Disubstituted sulfonamide

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When heated with aqueous acid, sulfonamides are hydrolyzed to amines:

O (1) H3O+, heat R NH S Ar (2) OH O

R NH2

O + O S Ar O

Hydrolysis: carboxamides >> sulfonamides

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20.10A Hinsberg Test

R NH2 + C6H5 1°Amine NaOH O S Cl O HCl HCl O R2N S C6H5 O white Water insoluble No apparent change

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Na O R N S C6H5 O O R2NH + C6H5 S Cl O 2°Amine O S Cl O

O R NH S C6H5 O white Water insoluble

HCl

R3N + 3°Amine

C6H5

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Chapter 20

20.11 The Sulfa Drugs: Sulfanilamide

磺胺药

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Chapter 20

20.11 Chemotherapy (化学疗法)

Chemotherapy is defined as the use of chemical agents selectively to destroy infectious cells without simultaneously destroy the host.

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Chapter 20

20.11B Sulfa Drugs

H2N SO2NHR Sulfonilamide (a sulfa drug) 对氨基苯磺酰胺

N

N N N O CH3

R=

Sulfapyridine Sulfadiazine Sulfamethoxazole 磺胺吡啶(SP) 磺胺嘧啶 (SD) 磺胺甲基异噁唑(SMZ)

N S

Sulfathiazole 磺胺噻唑(ST)

O

Sulfaacetamide CCH3 对乙酰氨基苯磺酰胺 (SA)

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20.11C Essential Nutrients and Antimetabolites

The aromatic amine p-aminobenzoic acid is an essential nutrient for some bacteria that are sensitive to sulfanilamide therapy. Enzymes within these bacteria use p-aminobenzoic acid to synthesize another essential compound called folic acid(叶酸).

H2N N OH Folic acid (叶酸)

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N

N O N CH2 NH C NH C CH2CH2CO2H H CO2H

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Chemicals that inhibit the growth of microbes are called antimetabolites. The sulfanilamides are antimetabolites of those bacterial that require p-aminobenzoic acid.

H N 6.7 H H N 6.9 H

H O

C O

2.3

O S O NHR 2.4

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20.11D Synthesis of Sulfa Drugs

NH2 Ac2O NHCOCH3 ClSO3H 80℃ SO2Cl NH2 (1) dilute HCl, heat (2) HCO3 SO2NHR

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NHCOCH3 RNH2

NHCOCH3

SO2NHR

A sulfonilamide (a sulfa drug) 对氨基苯磺酰胺

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Chapter 20

20.12 Analysis of Amines

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20.12A Chemical Analysis

Basicity

dissolve in dilute aqueous acid pH paper

1°,2°,3° distinguish

Hinsberg test IR

1° Aromatic amine

OH N N Ar OH

Ar NH2

A

r N2

Brightly colored dye

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20.12B Spectroscopic Analysis

IR:

N–H 3330 – 3550 cm-1 (1° give two bands, 2° give one band, 3° none) C–N Aliphatic 1020 – 1220 cm-1 (weak); aromatic 1250 – 1360 cm-1(strong)

1H

NMR:

NMR: α-C δ 42.5, β-C δ 34.0 MS: M+ odd number; α, β -C cleavage

13C

N–H δ 0.5–5 (disappear by adding D2O) CH–CH–NH2 α-H δ 2.2–2.9, β-H δ 1.0–1.7

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Chapter 20

20.13 Eliminations Involving Ammonium Compounds

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Chapter 20

20.13A The Hofmann Elimination

HO H C C heat E2 N(CH3)3 C C + N(CH3)3 + H2O

RCH2CH2N(CH3)3 X + Ag2O A quaternary ammonium halide

H2O

RCH2CH2N(CH3)3 OH A quaternary ammonium hydroxide + AgX

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CH3(CH2)5NH2 Ag2O

CH3I (excess)

CH3(CH2)5N(CH3)3 I

CH3(CH2)5N(CH3)3 OH

CH3CH2CH2CH2CH CH2 + (CH3)3N + H2O

N(CH3)3 OH

CH3CH2CH2CH CH2

CH3CH2CH CHCH3

CH3CH2CH2CHCH3

94 : 6

Hofmann’s rule

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CH3I (excess) N H CH3 N I CH3

Ag2O CH3 Ag2O HO N CH3

CH3I CH3 N (excess) CH3

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20.13B The Cope Elimination

O RCH2CH2N(CH3)2 150°C RCH CH2 + (CH3)2N OH An alkene N,N-Dimethylhydroxylamine

A tertiary amine oxide

O H C C N(CH3)3 C C + HON(CH3)3

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O CH2N(CH3)2 H2O2 CH2N(CH3)2

160℃

CH2 + (CH3)2NOH

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