Chapter 21
● Phenols and Aryl Halides
Nucleophilic Aromatic Substitution
Ch. 21 - 1 1. Structure and Nomenclature of Phenols
OH OH OH
Phenol 1-Naphthol 9-Phenanthrol (α-naphthol)
Ch. 21 - 2 1A. Nomenclature of Phenols
Cl CH3
NO2
OH OH OH
4-Chlorophenol 2-Nitrophenol 3-Methylphenol (p-chlorophenol) (o-nitrophenol) (m-cresol)
Ch. 21 - 3 The benzenediols also have common names
OH OH OH OH
OH OH 1,2-Benzenediol 1,3-Benzenediol 1,4-Benzenediol (catechol) (resorcinol) (hydroquinone)
Ch. 21 - 4 2. Naturally Occurring Phenols O CO2CH3 OH O− H + NH3 HO L-Tyrosine Methyl salicylate (oil of wintergreen) OH OH CH3 OCH3 H
H H HO Eugenol Estradiol (oil of cloves) Ch. 21 - 5 3. Physical Properties of Phenols
OH CH3
Phenol Toluene
M.W. 94 92
B.P. (oC) 182 110
Ch. 21 - 6 4. Synthesis of Phenols 4A. Laboratory Synthesis
NH 2 N2 2+ OH Cu2O, Cu HONO H2O R R R
e.g. NH2 OH
o 1. NaNO2, HCl, 0-5 C 2+ 2. Cu2O, Cu , H2O Cl CH3 Cl CH3
Ch. 21 - 7 4B. Industrial Syntheses Hydrolysis of chlorobenzene (Dow Process)
Cl O Na 2 NaOH + NaCl + H2O 350oC high pressure
HCl
OH + NaCl
Ch. 21 - 8 From cumene hydroperoxide
H3PO4 + 250oC (Cumene) high pressure
O2 95-135oC
O OH + H3O + O 50-90oC OH (Cumene hydroperoxide) Ch. 21 - 9 Mechanism
● Chain initiation
Step 1
H R + R H
Ch. 21 - 10 ● Chain propagation Step 2
O O + O O
Step 3
O O H +
O O H +
Ch. 21 - 11 ● Chain propagation H O O H O O + H OH2 H
- H2O
H O O H2O O H
OH2 + + H - H3O O O O HO H Ch. 21 - 12 5. Reactions of Phenols as Acids
pKa pKa
OH 9.89 O2N OH 7.15
NO2
H3C OH 10.17 O2N OH 3.96
NO2
Cl OH 9.20 O2N OH 0.38
NO2 Ch. 21 - 13 OH OH pKa 18 9.89
O O H + + H2O + H3O
(NO resonance stabilization)
Ch. 21 - 14 O O H + + H3O
+ H2O
O O O
Ch. 21 - 15 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 H H O O O H O > >
Ch. 21 - 16 O O H + Na OH + H2O R O R O Na (soluble in water)
O O Na H + NaOH
(soluble in water)
O H + NaOH No Reaction
(immiscible with H O) 2 Ch. 21 - 17 O O H O O Na + NaHCO3
+ CO2(g) + H2O (gas evolved)
O H + NaHCO3 No Reaction
O H + NaHCO3 No Reaction
Ch. 21 - 18 6. Other Reactions of the O–H Group of Phenols O O
R O R base
O
OH O O R
R Cl
base Ch. 21 - 19 6A. Phenols in the Williamson Synthesis
OH O Na
NaOH R R R X (X = halides, OTs, OMs) OR
R
e.g. OH O 1. NaOH
2. Br Ch. 21 - 20 7. Cleavage of Alkyl Aryl Ethers
O OH R conc. HX + RX heat R R
e.g. O OH conc. HCl + Cl heat
Ch. 21 - 21 8. Reactions of the Benzene Ring of Phenols Bromination OH Br Br 3 Br2 + 3 HBr OH H2O
Br (NO Lewis acid required for the OH brominations)
Br2 + HBr o CS2, 5 C
Br Ch. 21 - 22 Nitration
OH OH OH
NO2 20% HNO3 + 25oC
NO2 (30-40%) (15%)
Ch. 21 - 23 Sulfonation OH
SO3H conc. H2SO4 25oC OH conc. H2SO4 100oC
OH
conc. H2SO4 100oC
SO3H Ch. 21 - 24 Kolbe reaction
O Na OH COOH 1. CO2 + 2. H3O
Ch. 21 - 25 ● Mechanism
Na O O H O O C C Na O O
tautomerization
H H O OH O O
+ O H3O O Na Salicylic acid Sodium salicylate Ch. 21 - 26 O
OH O O O COOH COOH O R O R + CH3COOH OH
(Salicylic acid) Acetylsalicylic acid (Aspirin)
Ch. 21 - 27 9. The Claisen Rearrangement
OH O 1. NaH
2. Br
200oC
OH
Ch. 21 - 28 Via a [3,3] sigmatropic rearrangement
1 2 O O 1'
3 2' 3' H
keto-enol tautomerization
OH
Ch. 21 - 29 10. Quinones
OH O
- 2 e− + 2 H+ + 2 e−
OH O Hydroquinone p-Benzoquinone
Ch. 21 - 30 O
H3CO CH3 + 2 e−, + 2 H+ - 2 e−, - 2 H+ H3CO H n O CH3 OH
Ubiquinones (n = 6-10) H3CO CH3 (coenzymes Q)
H3CO H n OH CH3 Ubiquinol (hydroquinone form)
Ch. 21 - 31 O
O 1,4-Naphthoquinone O
3
CH3 O Vitamin K1
Ch. 21 - 32 11. Aryl Halides and Nucleophilic Aromatic Substitution Cl
H2O + NaOH NO substitution heat
H2O Cl + NaOH NO substitution heat X Nu: X NO reaction
Ch. 21 - 33 X X X
X X
Ch. 21 - 34 11A. Nucleophilic Aromatic Substitution by Addition–Elimination: The SNAr Mechanism
Nucleophilic aromatic substitution can occur when strong electron-withdrawing groups are ortho or para to the halogen atom
Cl OH
NO2 + NO2 aq. NaHCO3 H3O + OH 130oC
Ch. 21 - 35 Cl OH
NO2 + NO2 aq. NaHCO3 H3O + OH 130oC
NO2 NO2 Cl
O2N NO2 aq. NaHCO3 + OH o 130 C OH
+ O2N NO2 NO2 H3O
NO2 Ch. 21 - 36 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 - 37 The SNAr mechanism Cl Cl OH
addition + OH slow elimination NO2 NO2 fast
O OH
OH HOH + Cl +
NO2 NO2 Ch. 21 - 38 HO Cl HO Cl HO Cl
N N N O O O O O O
HO Cl
N O O Ch. 21 - 39 11B. Nucleophilic Aromatic Substitution through an Elimination–Addition Mechanism: Benzyne Cl ONa OH
+ NaOH H3O 350oC
Phenol
Br NH2
K :NH2 + KBr -33oC
Aniline Ch. 21 - 40 The benzyne elimination–addition mechanism
Br Br − (-NH3) (-Br )
H Benzyne (or dehydrobenzene) NH2
NH2 NH2 NH2
NH2 + NH3 H
Ch. 21 - 41 * NH2
Cl 50% * + − * − K NH2 NH2 NH3
*
NH elimination addition 50% 2
Ch. 21 - 42 CF3 CF3 Cl NaNH2
NH3 (-NaCl) NH2 m-(Trifluoromethyl)aniline
CF3
Ch. 21 - 43 CF3 > NH2 X
CF3 less stable carbanion NH2
CF3 CF3 >
NH3
NH2 NH2 more stable + NH carbanion 2 Ch. 21 - 44 Benzyne intermediates have been “trapped” through the use of Diels– Alder reactions O O C C O diazotization O
NH3 N N Anthranilic acid -CO2 O -N2 O
Benzyne (trapped in situ) Ch. 21 - 45 11C. Phenylation
O O Br O O 2 NaNH2 + liq. NH OEt 3 OEt
Ch. 21 - 46 12. Spectroscopic Analysis of Phenols and Aryl Halides
Infrared spectra (IR) OH ● O H stretching: 3400-3600 cm-1 R
OH X ● and : characteristic absorptions of the benzene rings R R Ch. 21 - 47 1H NMR spectra
δ (ppm) of H
O H pure phenol: 2.55
in CCl4 (1%) 5.63
δ 0.5 – 1.0 ppm O H O intramolecular hydrogen bonding OH Ch. 21 - 48 H H Y (Y = OH or halides)
H H H
δ 7 – 9 ppm
Ch. 21 - 49 13C NMR spectra
Y (Y = OH or halides)
δ 135 – 170 ppm
Ch. 21 - 50 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 - 51 END OF CHAPTER 21
Ch. 21 - 52