Chapter 22 Phenols Dr. Wolf's CHM 201 & 202 2

Nomenclature Dr. Wolf's CHM 201 & 202 2

5-Chloro-2-methylphenol Nomenclature OH CH3 Cl 5-Chloro-2-methylphenol named on basis of phenol as parent substituents listed in alphabetical order lowest numerical sequence: first point of difference rule Dr. Wolf's CHM 201 & 202 3

Nomenclature OH OH OH 1,2-Benzenediol 1,3-Benzenediol 1,4-Benzenediol (common name: pyrocatechol) (common name: resorcinol) (common name: hydroquinone) Dr. Wolf's CHM 201 & 202 4

p-Hydroxybenzoic acid Nomenclature OH CO2H p-Hydroxybenzoic acid name on basis of benzoic acid as parent higher oxidation states of carbon outrank hydroxyl group Dr. Wolf's CHM 201 & 202 5

Structure and Bonding Dr. Wolf's CHM 201 & 202 6

Structure of Phenol phenol is planar C—O bond distance is 136 pm, which is slightly shorter than that of CH3OH (142 pm) Dr. Wolf's CHM 201 & 202 7

Physical Properties The OH group of phenols allows hydrogen bonding to other phenol molecules and to water. Dr. Wolf's CHM 201 & 202 8

Hydrogen Bonding in Phenols Dr. Wolf's CHM 201 & 202 7

Physical Properties (Table 24.1) Compared to compounds of similar size and molecular weight, hydrogen bonding in phenol raises its melting point, boiling point, and solubility in water. Dr. Wolf's CHM 201 & 202 10

Physical Properties (Table 24.1) C6H5CH3 C6H5OH C6H5F Molecular weight 92 94 96 Melting point (°C) –95 43 –41 Boiling point (°C,1 atm) 111 132 85 Solubility in H2O (g/100 mL,25°C) 0.05 8.2 0.2 Dr. Wolf's CHM 201 & 202 10

most characteristic property of phenols is their acidity Acidity of Phenols most characteristic property of phenols is their acidity Dr. Wolf's CHM 201 & 202 9

Compare O H O – Ka = 10-10 + H + Ka = 10-16 CH3CH2O – CH3CH2O H + H + • • •• O • • •• – Ka = 10-10 + H + Ka = 10-16 CH3CH2O •• – • • CH3CH2O H •• + H + Dr. Wolf's CHM 201 & 202 10

Delocalized negative charge in phenoxide ion – •• O • • • • H H H H H Dr. Wolf's CHM 201 & 202 11

Delocalized negative charge in phenoxide ion – •• • • O •• H – O • • • • H H H H H Dr. Wolf's CHM 201 & 202 11

Delocalized negative charge in phenoxide ion • • O •• H – Dr. Wolf's CHM 201 & 202 11

Delocalized negative charge in phenoxide ion • • O •• H – • • O •• H – Dr. Wolf's CHM 201 & 202 11

Delocalized negative charge in phenoxide ion • • O •• H – Dr. Wolf's CHM 201 & 202 11

Delocalized negative charge in phenoxide ion • • O •• H – •• O • • H – H •• H H H Dr. Wolf's CHM 201 & 202 11

Phenols are converted to phenoxide ions in aqueous base • • •• O • • •• – HO – + + H2O stronger acid weaker acid Dr. Wolf's CHM 201 & 202 14

Substituent Effects on the Acidity of Phenols Dr. Wolf's CHM 201 & 202 15

Electron-releasing groups have little or no effect OH OH CH3 OH OCH3 Ka: 1 x 10-10 5 x 10-11 6 x 10-11 Dr. Wolf's CHM 201 & 202 16

Electron-withdrawing groups increase acidity OH OH Cl OH NO2 Ka: 1 x 10-10 4 x 10-9 7 x 10-8 Dr. Wolf's CHM 201 & 202 16

Effect of electron-withdrawing groups is most pronounced at ortho and para positions OH NO2 OH NO2 OH NO2 Ka: 6 x 10-8 4 x 10-9 7 x 10-8 Dr. Wolf's CHM 201 & 202 18

Effect of strong electron-withdrawing groups is cumulative OH NO2 OH NO2 OH NO2 O2N Ka: 7 x 10-8 1 x 10-4 4 x 10-1 Dr. Wolf's CHM 201 & 202 19

Resonance Depiction O N H – + O N H – + • • •• • • •• 20 Dr. Wolf's CHM 201 & 202 20

Sources of Phenols Phenol is an important industrial chemical. Major use is in phenolic resins for adhesives and plastics. Annual U.S. production is about 4 billion pounds per year. Dr. Wolf's CHM 201 & 202 1

Industrial Preparations of Phenol SO3H Cl CH(CH3)2 1. NaOH heat 2. H+ 1. O2 1. NaOH heat OH 2. H2O H2SO4 2. H+ Dr. Wolf's CHM 201 & 202 2

Laboratory Synthesis of Phenols from arylamines via diazonium ions O2N NH2 1. NaNO2, H2SO4, H2O 2. H2O, heat O2N OH (81-86%) Dr. Wolf's CHM 201 & 202 3

Naturally Occurring Phenols Many phenols occur naturally Dr. Wolf's CHM 201 & 202 4

Thymol (major constituent of oil of thyme) Example: Thymol OH CH3 CH(CH3)2 Thymol (major constituent of oil of thyme) Dr. Wolf's CHM 201 & 202 5

Example: 2,5-Dichlorophenol OH Cl Cl 2,5-Dichlorophenol (from defensive secretion of a species of grasshopper) Dr. Wolf's CHM 201 & 202 5

Reactions of Phenols: Electrophilic Aromatic Substitution Hydroxyl group strongly activates the ring toward electrophilic aromatic substitution Dr. Wolf's CHM 201 & 202 1

Electrophilic Aromatic Substitution in Phenols Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 2

Halogenation OH OH ClCH2CH2Cl + Br2 0°C Br (93%) monohalogenation in nonpolar solvent (1,2-dichloroethane) Dr. Wolf's CHM 201 & 202 3

Halogenation OH F OH Br F H2O + 3Br2 25°C (95%) multiple halogenation in polar solvent (water) Dr. Wolf's CHM 201 & 202 3

Electrophilic Aromatic Substitution in Phenols Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 2

Nitration OH CH3 OH CH3 NO2 HNO3 acetic acid 5°C (73-77%) OH group controls regiochemistry Dr. Wolf's CHM 201 & 202 3

Electrophilic Aromatic Substitution in Phenols Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 2

Nitrosation NO OH OH NaNO2 H2SO4, H2O 0°C (99%) only strongly activated rings undergo nitrosation when treated with nitrous acid Dr. Wolf's CHM 201 & 202 3

Electrophilic Aromatic Substitution in Phenols Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 2

Sulfonation OH CH3 H3C OH CH3 H3C H2SO4 100°C SO3H (69%) OH group controls regiochemistry (69%) Dr. Wolf's CHM 201 & 202 6

Electrophilic Aromatic Substitution in Phenols Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 2

Friedel-Crafts Alkylation OH CH3 OH C CH3 H3C H3PO4 60°C (CH3)3COH (CH3)3COH reacts with H3PO4 to give (CH3)3C+ (63%) Dr. Wolf's CHM 201 & 202 3

Electrophilic Aromatic Substitution in Phenols Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 2

Acylation of Phenols Acylation can take place either on the ring by electrophilic aromatic substitution or on oxygen by nucleophilic acyl substitution Dr. Wolf's CHM 201 & 202 1

Friedel-Crafts Acylation OH OH C O CH3 CH3CCl O + ortho isomer AlCl3 under Friedel-Crafts conditions, acylation of the ring occurs (C-acylation) (74%) (16%) Dr. Wolf's CHM 201 & 202 3

O-Acylation O OH OC(CH2)6CH3 O + CH3(CH2)6CCl (95%) in the absence of AlCl3, acylation of the hydroxyl group occurs (O-acylation) Dr. Wolf's CHM 201 & 202 3

O- versus C-Acylation OC(CH2)6CH3 O OH C O (CH2)6CH3 AlCl3 formed faster more stable O-Acylation is kinetically controlled process; C-acylation is thermodynamically controlled AlCl3 catalyzes the conversion of the aryl ester to the aryl alkyl ketones; this is called the Fries rearrangement Dr. Wolf's CHM 201 & 202 3

Carboxylation of Phenols COH O OCCH3 Aspirin and the Kolbe-Schmitt Reaction Dr. Wolf's CHM 201 & 202 1

Aspirin is prepared from salicylic acid COH O OCCH3 O CH3COCCH3 COH O OH H2SO4 how is salicylic acid prepared? Dr. Wolf's CHM 201 & 202 2

Preparation of Salicylic Acid ONa CONa O OH CO2 125°C, 100 atm called the Kolbe-Schmitt reaction acidification converts the sodium salt shown above to salicylic acid Dr. Wolf's CHM 201 & 202 3

What Drives the Reaction? acid-base considerations provide an explanation: stronger base on left; weaker base on right O – •• • • O – •• • • C H + CO2 • • stronger base: pKa of conjugate acid = 10 weaker base: pKa of conjugate acid = 3 Dr. Wolf's CHM 201 & 202 3

Preparation of Salicylic Acid ONa CONa O OH CO2 125°C, 100 atm how does carbon-carbon bond form? recall electron delocalization in phenoxide ion negative charge shared by oxygen and by the ring carbons that are ortho and para to oxygen Dr. Wolf's CHM 201 & 202 3

– O O – H H O O – – H H • • •• • • •• • • •• • • •• 11 Dr. Wolf's CHM 201 & 202 11

Mechanism of ortho Carboxylation •• O H •• • • – • • •• C O – •• • • C O • • O • • •• H Dr. Wolf's CHM 201 & 202 5

Mechanism of ortho Carboxylation •• O • • •• – •• C O • • O – •• • • C O •• • • O • • •• H H O – •• • • C H Dr. Wolf's CHM 201 & 202 5

Why ortho? Why not para? •• – O •• O H O H – – C C •• • • • • • • 6 Dr. Wolf's CHM 201 & 202 6

Why ortho? Why not para? •• – O •• O H O H – – C C •• stronger base: • • – O – •• • • C H O •• H C • • – weaker base: pKa of conjugate acid = 3 stronger base: pKa of conjugate acid = 4.5 Dr. Wolf's CHM 201 & 202 6

Intramolecular Hydrogen Bonding in Salicylate Ion – H Hydrogen bonding between carboxylate and hydroxyl group stabilizes salicylate ion. Salicylate is less basic than para isomer and predominates under conditions of thermodynamic control. Dr. Wolf's CHM 201 & 202 7

Preparation of Aryl Ethers Dr. Wolf's CHM 201 & 202 1

Typical Preparation is by Williamson Synthesis ONa SN2 OR + RX + NaX Dr. Wolf's CHM 201 & 202 2

Typical Preparation is by Williamson Synthesis ONa SN2 OR + RX + NaX but the other combination X + RONa fails because aryl halides are normally unreactive toward nucleophilic substitution Dr. Wolf's CHM 201 & 202 2

Example ONa acetone OCH3 + CH3I heat (95%) Dr. Wolf's CHM 201 & 202 3

Example OH + H2C CHCH2Br K2CO3 acetone, heat (86%) OCH2CH CH2 3 Dr. Wolf's CHM 201 & 202 3

Aryl Ethers from Aryl Halides NO2 OCH3 NO2 CH3OH + KOCH3 + KF 25°C (93%) nucleophilic aromatic substitution is effective with nitro-substituted (ortho and/or para) aryl halides Dr. Wolf's CHM 201 & 202 5

Cleavage of Aryl Ethers by Hydrogen Halides Dr. Wolf's CHM 201 & 202 6

Cleavage of Alkyl Aryl Ethers + •• H Br •• • • •• • • Br – •• • • O + + R Dr. Wolf's CHM 201 & 202 7

Cleavage of Alkyl Aryl Ethers + •• •• • • H Br •• • • •• • • Br – O + + R An alkyl halide is formed; never an aryl halide! O Ar •• H R Br •• • • + Dr. Wolf's CHM 201 & 202 7

Example OCH3 OH OH HBr + CH3Br heat (85-87%) (57-72%) 9 Dr. Wolf's CHM 201 & 202 9

Claisen Rearrangement of Allyl Aryl Ethers Dr. Wolf's CHM 201 & 202 1

Allyl Aryl Ethers Rearrange on Heating OCH2CH CH2 allyl group migrates to ortho position 200°C OH CH2CH CH2 (73%) Dr. Wolf's CHM 201 & 202 2

keto-to-enol isomerization Mechanism OCH2CH CH2 O rewrite as keto-to-enol isomerization OH O H Dr. Wolf's CHM 201 & 202 3

Sigmatropic Rearrangement Claisen rearrangement is an example of a sigmatropic rearrangement. A  bond migrates from one end of a conjugated  electron system to the other. this  bond breaks O O H “conjugated  electron system” is the allyl group this  bond forms Dr. Wolf's CHM 201 & 202

Oxidation of Phenols: Quinones Dr. Wolf's CHM 201 & 202 1

Quinones The most common examples of phenol oxidations are the oxidations of 1,2- and 1,4-benzenediols to give quinones. OH O Na2Cr2O7, H2SO4 H2O (76-81%) Dr. Wolf's CHM 201 & 202

Quinones The most common examples of phenol oxidations are the oxidations of 1,2- and 1,4-benzenediols to give quinones. OH CH3 O CH3 O Ag2O diethyl ether (68%) Dr. Wolf's CHM 201 & 202

Alizarin (red pigment) Some quinones are dyes O OH Alizarin (red pigment) Dr. Wolf's CHM 201 & 202

Some quinones are important biomolecules CH3O O CH3 n Ubiquinone (Coenzyme Q) n = 6-10 involved in biological electron transport Dr. Wolf's CHM 201 & 202

Some quinones are important biomolecules CH3 Vitamin K (blood-clotting factor) Dr. Wolf's CHM 201 & 202

Spectroscopic Analysis of Phenols Dr. Wolf's CHM 201 & 202 1

Infrared Spectroscopy infrared spectra of phenols combine features of alcohols and aromatic compounds O—H stretch analogous to alcohols near 3600 cm-1 C—O stretch at 1200-1250 cm-1 Dr. Wolf's CHM 201 & 202

Figure 24.3: Infrared Spectrum of p-Cresol CH3 OH C—H O—H C—O 2000 3500 3000 2500 1000 1500 500 Wave number, cm-1 Dr. Wolf's CHM 201 & 202 8

1H NMR Hydroxyl proton of OH group lies between alcohols and carboxylic acids; range is ca.  4-12 ppm (depends on concentration). For p-cresol the OH proton appears at  5.1 ppm (Figure 24.4). CH3 HO H Dr. Wolf's CHM 201 & 202

H HO CH3 Chemical shift (, ppm) 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Chemical shift (, ppm) Dr. Wolf's CHM 201 & 202 1

13C NMR CH3 OH 139.8 21.3 129.4 112..3 116.1 155.1 121.7 Oxygen of hydroxyl group deshields carbon to which it is directly attached. The most shielded carbons of the ring are those that are ortho and para to the oxygen. Dr. Wolf's CHM 201 & 202

UV-VIS Oxygen substitution on ring shifts max to longer wavelength; effect is greater in phenoxide ion. – OH O max 204 nm 256 nm 210 nm 270 nm 235 nm 287 nm Dr. Wolf's CHM 201 & 202

Mass Spectrometry Prominent peak for molecular ion. Most intense peak in phenol is for molecular ion. OH •+ •• m/z 94 Dr. Wolf's CHM 201 & 202

End of Chapter 22 Dr. Wolf's CHM 201 & 202