Chapter 21

Phenols and Aryl Halides Nucleophilic Aromatic Substitution

Created by Professor William Tam & Dr. Phillis Chang
Ch. 21 - 1

About The Authors

These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

Ch. 21 - 2

1. Structure and Nomenclature of Phenols

OH

OH

OH

Phenol

1-Naphthol (-naphthol)

9-Phenanthrol

Ch. 21 - 3

1A. Nomenclature of Phenols

Cl NO2 OH OH 4-Chlorophenol (p-chlorophenol) 2-Nitrophenol (o-nitrophenol) 3-Methylphenol (m-cresol)
Ch. 21 - 4

CH3

OH

The benzenediols also have common names

OH OH OH OH OH OH

1,2-Benzenediol (catechol)

1,3-Benzenediol (resorcinol)

1,4-Benzenediol (hydroquinone)
Ch. 21 - 5

2. Naturally Occurring Phenols

O O H HO L-Tyrosine OH OCH 3 H H HO Eugenol (oil of cloves) Estradiol
Ch. 21 - 6

CO2CH3 OH

NH3+ Methyl salicylate (oil of wintergreen) CH3 OH

3. Physical Properties of Phenols

OH CH3

Phenol M.W. B.P. (oC) 94 182

Toluene 92 110
Ch. 21 - 7

4. Synthesis of Phenols
4A. Laboratory Synthesis
NH2 HONO R R N2 Cu2O, Cu H2O
2+

OH

e.g.

NH2 1. NaNO2, HCl, 0-5oC

OH

Cl

CH3

2. Cu2O, Cu2+, H2O

Cl

CH3
Ch. 21 - 8

4B. Industrial Syntheses Hydrolysis of chlorobenzene (Dow Process)

Cl 2 NaOH 350 C high pressure HCl OH + NaCl
Ch. 21 - 9
o

O Na + NaCl + H2O

From cumene hydroperoxide

+ H3PO4 250oC high pressure O2 (Cumene)

95-135oC

O +

OH

H3O+ 50-90 C
o

OH

(Cumene hydroperoxide)
Ch. 21 - 10

Mechanism Chain initiation

Step 1
H R + R H

Ch. 21 - 11

Step 2

Chain propagation
+ O O O O

Step 3
O O H

+
Ch. 21 - 12

 Chain propagation
H

+ H

OH2

O H
- H2O

O H

H 2O

OH 2

O H

- H3O

+ O HO
Ch. 21 - 13

5. Reactions of Phenols as Acids

pKa
OH 9.89 O2N OH NO2 H3C OH 10.17 O2N OH NO2 Cl OH 9.20 O2N OH NO2 0.38 3.96

pKa
7.15

Ch. 21 - 14

OH

OH 9.89

pKa

18

O
+ H2O

+ H3O+

(NO resonance stabilization)

Ch. 21 - 15

+ H3O+

+ H2O
O

Ch. 21 - 16

5B. Distinguishing and Separating Phenols from Alcohols and Carboxylic 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
O O H O H O H

>

>
Ch. 21 - 17

O R O H + Na OH
R

O O Na + H2O

(soluable in water)
O

O Na
+ NaOH

(soluble in water)

+ NaOH

No Reaction

(immiscible with H2O)

Ch. 21 - 18

O O H + NaHCO3

O O Na

+ CO2(g) + H2O (gas evolved)

O H

+ NaHCO3

No Reaction

+ NaHCO3

No Reaction
Ch. 21 - 19

6. Other Reactions of the OH Group of Phenols

O R O base O O R

OH
R

O Cl base

Ch. 21 - 20

6A. Phenols in the Williamson Synthesis

OH

O Na NaOH

R X (X = halides, OTs, OMs)

OR

R
e.g. OH 1. NaOH 2. Br
Ch. 21 - 21

7. Cleavage of Alkyl Aryl Ethers

O R conc. HX heat R OH + RX

e.g.

conc. HCl heat

OH + Cl

Ch. 21 - 22

8. Reactions of the Benzene Ring of Phenols

Bromination
3 Br2
OH

OH Br Br + 3 HBr Br
OH

H2O

(NO Lewis acid required for the brominations)

+ HBr

Br2 CS2, 5 C Br
o

Ch. 21 - 23

Nitration
OH
20% HNO3 25 C
o

OH NO2 +

OH

NO2 (30-40%) (15%)

Ch. 21 - 24

Sulfonation
conc. H2SO4 25oC
OH

OH SO3H

conc. H2SO4 100oC

OH conc. H2SO4 100oC SO3H
Ch. 21 - 25

Kolbe reaction
O Na
1. CO2 2. H3O+ (Salicylic acid) OH COOH

Ch. 21 - 26

 Mechanism
Na O O C O
O H C O O Na

tautomerization

OH O H3O+

O O Na
Ch. 21 - 27

Salicylic acid

Sodium salicylate

O
OH COOH

O R

O COOH + O OH

O R CH3COOH

(Salicylic acid)

Acetylsalicylic acid (Aspirin)

Ch. 21 - 28

9. The Claisen Rearrangement

OH 1. NaH 2. Br 200oC OH O

Ch. 21 - 29

Via a [3,3] sigmatropic rearrangement

2 3 3'

1' 2'

keto-enol tautomerization OH

Ch. 21 - 30

10. Quinones
OH - 2 e + 2 e OH Hydroquinone O O + 2 H+

p-Benzoquinone

Ch. 21 - 31

O H3CO H3CO O CH3 Ubiquinones (n = 6-10) (coenzymes Q) CH3 H + 2 e , + 2 H - 2 e , - 2 H OH H3CO H3CO OH CH3 Ubiquinol (hydroquinone form)
Ch. 21 - 32

CH3 H

O 1,4-Naphthoquinone
O

CH3 O Vitamin K1
Ch. 21 - 33

11. Aryl Halides and Nucleophilic Aromatic Substitution

Cl + NaOH H2O heat NO substitution

Cl + NaOH

H2O heat

NO substitution

X
Nu: X

NO reaction
Ch. 21 - 34

Ch. 21 - 35

11A. Nucleophilic Aromatic Substitution by AdditionElimination: The SNAr Mechanism

Nucleophilic aromatic substitution can occur when strong electron-withdrawing groups are ortho or para to the halogen atom
OH NO2 + OH aq. NaHCO3 130oC H3O
+

Cl

NO2

Ch. 21 - 36

Cl NO2 + NO2
Cl O2N NO2 + OH NO2 aq. NaHCO3 130oC H3O
+

OH OH aq. NaHCO3 130oC NO2 H3O

+

NO2

OH O2N NO2

NO2
Ch. 21 - 37

The mechanism that operates in these reactions is an additionelimination 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 mechanism

Cl + OH NO 2

Cl addition slow

OH

NO2
O

elimination fast

OH
OH

HOH

+ NO2

Cl

+ NO2

Ch. 21 - 39

HO

Cl

HO

Cl

HO

Cl

HO

Cl

O
Ch. 21 - 40

11B. Nucleophilic Aromatic Substitution through an EliminationAddition Mechanism: Benzyne

Cl NaOH 350oC Phenol
Br K :NH 2 -33 C Aniline
o

ONa H3O+

OH

NH2 + KBr
Ch. 21 - 41

The benzyne eliminationaddition mechanism

Br H NH2

(-NH3)

Br

(-Br) Benzyne (or dehydrobenzene)

NH2 NH2 + H NH3

NH 2

NH 2

Ch. 21 - 42

* NH2

* Cl

NH2

NH2 NH3

50%

* elimination addition NH2

50%

Ch. 21 - 43

CF3 Cl
NaNH2 NH3 (-NaCl)

CF3

NH2

m-(Trifluoromethyl)aniline

CF3

Ch. 21 - 44

CF3
>

X
CF3 NH2

NH2

less stable carbanion

CF3
>

CF3 NH3 NH2 NH2 + NH2

more stable carbanion

Ch. 21 - 45

Benzyne intermediates have been trapped through the use of Diels Alder reactions
O C
O C N

diazotization

O N

NH 3 Anthranilic acid
O O

-CO2 -N2

Benzyne (trapped in situ)

Ch. 21 - 46

11C. Phenylation
O O + OEt Br 2 NaNH2 liq. NH3 O O OEt

Ch. 21 - 47

12. Spectroscopic Analysis of Phenols and Aryl Halides

Infrared spectra (IR)

OH

R
OH

H stretching: 3400-3600 cm-1

X and : characteristic absorptions of the benzene rings

Ch. 21 - 48

 1H

NMR spectra
(ppm) of H O H pure phenol: in CCl4 (1%) 2.55 5.63

0.5 1.0 ppm

O H O OH
Ch. 21 - 49

intramolecular hydrogen bonding

H H H H Y H (Y = OH or halides)

7 9 ppm

Ch. 21 - 50

 13C

NMR spectra
Y (Y = OH or halides)

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

Ch. 21 - 53