Chapter 21

● Phenols and Aryl Halides

Nucleophilic Aromatic Substitution

Ch. 21 - 1

Ch. 21 - 2

1. Structure and Nomenclatureof Phenols

OH OHOH

Phenol 1-Naphthol(α-naphthol)

9-Phenanthrol

Ch. 21 - 3

1A. Nomenclature of Phenols

OH

4-Chlorophenol(p-chlorophenol)

2-Nitrophenol(o-nitrophenol)

3-Methylphenol(m-cresol)

Cl

NO2

OH OH

CH3

Ch. 21 - 4

The benzenediols also have common names

OH

1,2-Benzenediol(catechol)

1,3-Benzenediol(resorcinol)

1,4-Benzenediol(hydroquinone)

OH

OH

OH

OHOH

Ch. 21 - 5

2. Naturally Occurring Phenols

OH

OH

L-Tyrosine Methyl salicylate(oil of wintergreen)

Eugenol(oil of cloves)

HO

O−

O

NH3+H

CO2CH3

OCH3

EstradiolHO

H

H

H

CH3OH

Ch. 21 - 6

3. Physical Properties of Phenols

OH

Phenol

CH3

Toluene

M.W.

B.P. (oC)

94

182

92

110

Ch. 21 - 7

4. Synthesis of Phenols

NH2

R

N2

R

OH

RHONO H2O

Cu2O, Cu2+

4A. Laboratory Synthesis

NH2

1. NaNO2, HCl, 0-5oC

2. Cu2O, Cu2+, H2OCl CH3

OH

Cl CH3

e.g.

Ch. 21 - 8

4B. Industrial Syntheses Hydrolysis of chlorobenzene (Dow

Process)

Cl O Na

OH

2 NaOH

HCl

350oChigh pressure

+ NaCl + H2O

+ NaCl

Ch. 21 - 9

From cumene hydroperoxideH3PO4

O2

95-135oC

250oChigh pressure

+

+(Cumene)

OOH

(Cumenehydroperoxide)

50-90oC

H3O+OHO

Ch. 21 - 10

Mechanism

● Chain initiation

+

H R

R H

Step 1

Ch. 21 - 11

● Chain propagation

O O+O O

O O H+

O O H+

Step 3

Step 2

Ch. 21 - 12

● Chain propagation

O O H+ OH2H

O OH

H

- H2O

OH2OO O

H

H

O OH

H

OH2+

HOO- H3O

+

Ch. 21 - 13

5. Reactions of Phenols as Acids

OH

OHH3C

OHCl

OH

OHO2N

OHO2N

pKa

9.89

10.17

9.20

pKa

7.15

3.96

0.38

O2N

NO2

NO2

NO2

Ch. 21 - 14

OH OH

pKa 18 9.89

OH

H2O+ H3O++

O

(NO resonance stabilization)

Ch. 21 - 15

OH

H2O+

H3O++

O

O O O

Ch. 21 - 16

5B. Distinguishing and SeparatingPhenols from Alcohols andCarboxylic Acids

Question If you are given three unknown samples: one is

benzoic acid; one is phenol; and one is cyclohexyl alcohol; how would you distinguish them by simple chemical tests?● Recall: acidity of

OH

O OH

OH

> >

Ch. 21 - 17

O

R OH Na OH+

O

R O Na+ H2O

(soluble in water)

OH

+ NaOH

OH

+ NaOH

(immisciblewith H2O)

O Na

(soluble in water)

No Reaction

Ch. 21 - 18

O

OH

+ NaHCO3

O

O Na

+ CO2(g) + H2O

(gas evolved)

OH

+ NaHCO3 No Reaction

OH

+ NaHCO3 No Reaction

Ch. 21 - 19

6. Other Reactions of the O–H Group of Phenols

OH O R

O

O

R O R

O

base

O

R Cl

base

Ch. 21 - 20

6A. Phenols in the Williamson Synthesis

OH

R

OH 1. NaOH

2.

O

Br

e.g.

NaOH

O Na

R R X(X = halides,OTs, OMs)

OR

R

Ch. 21 - 21

7. Cleavage of Alkyl Aryl Ethers

O

R

R conc. HX

heat

OH

R

+ RX

Oconc. HCl

heat

OH

+ Cl

e.g.

Ch. 21 - 22

8. Reactions of the Benzene Ring of Phenols

OH

BrominationBr

+ 3 HBr

OH

Br

Br

3 Br2H2O

+ HBr

OH

Br

CS2, 5oC

Br2

(NO Lewis acid required for the brominations)

Ch. 21 - 23

OH

Nitration

NO2

+

OH

20% HNO3

25oC

OH

NO2

(15%)(30-40%)

Ch. 21 - 24

Sulfonation

OH

SO3H

OH

conc. H2SO4

25oC

OH

SO3H

100oC

conc. H2SO4

conc. H2SO4

100oC

Ch. 21 - 25

O Na

Kolbe reaction

COOH

OH

1. CO2

2. H3O+

(Salicylic acid)

Ch. 21 - 26

ONa

O

C

O

● Mechanism

O

C

H

O

O

Na

tautomerization

OH

O

O

Na

Sodium salicylate

OH

O

OH

Salicylic acid

H3O+

Ch. 21 - 27

OH

COOH

(Salicylic acid)

O

R O R

O

CH3COOH

O

O

COOH O

OH+

Acetylsalicylic acid(Aspirin)

Ch. 21 - 28

9. The Claisen Rearrangement

OH 1. NaH

2.

O

Br

OH

200oC

Ch. 21 - 29

O1

2

3

1'

2'

3'

Via a [3,3] sigmatropic rearrangement

O

H

OH

keto-enoltautomerization

Ch. 21 - 30

10. Quinones

OH

- 2 e−

OH

+ 2 e−

O

O

+ 2 H+

Hydroquinone p-Benzoquinone

Ch. 21 - 31

+ 2 e−, + 2 H+

- 2 e−, - 2 H+

O

O

Ubiquinones (n = 6-10)(coenzymes Q)

CH3H3CO

H3CO H

CH3n

OH

OH

Ubiquinol(hydroquinone form)

CH3H3CO

H3CO H

CH3n

Ch. 21 - 32

O

O

1,4-NaphthoquinoneO

O

CH3

3

Vitamin K1

Ch. 21 - 33

11. Aryl Halides and Nucleophilic Aromatic SubstitutionCl

+ NaOH NO substitutionH2O

heat

Cl + NaOH NO substitutionH2O

heat

XNu:

XNO reaction

Ch. 21 - 34

X X X

XX

Ch. 21 - 35

11A. Nucleophilic Aromatic Substitutionby Addition–Elimination:The SNAr Mechanism

NO2

Cl

+ OHH3O

+aq. NaHCO3

130oC

NO2

OH

Nucleophilic aromatic substitution can occur when strong electron-withdrawing groups are ortho or para to the halogen atom

Ch. 21 - 36

NO2

Cl

+ OHH3O

+aq. NaHCO3

130oC

NO2

OH

NO2 NO2

NO2

Cl

+ OH

H3O+

aq. NaHCO3

130oC

NO2

OH

NO2

NO2

O2N

O2N

Ch. 21 - 37

The mechanism that operates in these reactions is an addition–elimination mechanism involving the formation of a carbanion with delocalized electrons, called a Meisenheimer intermediate. The process is called nucleophilic aromatic substitution (SNAr)

Ch. 21 - 38

The SNAr mechanismCl

+ OH

NO2

addition

slow

NO2

Cl OH

eliminationfast

OH

NO2

+ClOH

O

NO2

+HOH

Ch. 21 - 39

HO Cl

NO O

HO Cl

NO O

HO Cl

NO O

HO Cl

NO O

Ch. 21 - 40

11B. Nucleophilic Aromatic Substitution through an Elimination–Addition Mechanism: BenzyneCl

H3O+

350oC

OH

NaOH

ONa

Phenol

Br

-33oC

NH2

K :NH2+ KBr

Aniline

Ch. 21 - 41

The benzyne elimination–addition mechanism

Br

H

NH2

Br(-NH3) (-Br−)

Benzyne(or dehydrobenzene)

NH2NH2NH2

H

+NH2NH3

Ch. 21 - 42

ClK+NH2

− NH2−

NH3

* *

NH2*

*

NH2elimination addition 50%

50%

Ch. 21 - 43

Cl

CF3

NaNH2

NH3

CF3

NH2(-NaCl)

m-(Trifluoromethyl)aniline

CF3

Ch. 21 - 44

NH2

NH2

NH2

CF3

CF3

CF3

NH3

less stablecarbanion

more stablecarbanion

NH2

CF3

+ NH2

>>

X

Ch. 21 - 45

Benzyne intermediates have been “trapped” through the use of Diels–Alder reactions

CO

O

NH3

Anthranilicacid

diazotizationC

O

O

NN

-CO2-N2

Benzyne(trapped in situ)

O

O

Ch. 21 - 46

11C. Phenylation

2 NaNH2

liq. NH3OEt

O O+

Br

OEt

O O

Ch. 21 - 47

12. Spectroscopic Analysis of Phenols and Aryl Halides

Infrared spectra (IR)

●

●

R

OH

O H stretching: 3400-3600 cm-1

R

OH

: characteristic absorptions of the benzene rings

and

R

X

Ch. 21 - 48

1H NMR spectra

OH

δ (ppm) of H

pure phenol:

in CCl4 (1%)

2.55

5.63

OH

O

OH

δ 0.5 – 1.0 ppm

intramolecularhydrogen bonding

Ch. 21 - 49

Y (Y = OH or halides)

H

H

H

H

H

δ 7 – 9 ppm

Ch. 21 - 50

13C NMR spectra

Y (Y = OH or halides)

δ 135 – 170 ppm

Ch. 21 - 51

Mass spectra

● Mass spectra of phenols often display a prominent molecular ion peak, M

● Phenols that have a benzylic hydrogen produce an M – 1 peak that can be larger than the M peak

Ch. 21 - 52

END OF CHAPTER 21