24.6 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.

1. NaOH heat 2. H + 1. NaOH heat 2. H + 1. O 2 2. H 2 O H 2 SO 4 Industrial Preparations of Phenol SO 3 H Cl CH(CH 3 ) 2 OH

(81-86%) O2NO2NO2NO2N NH2NH2NH2NH2 O2NO2NO2NO2N OHOHOHOH 1.NaNO 2, H 2 SO 4, H 2 O 2.H 2 O, heat Laboratory Synthesis of Phenols from arylamines via diazonium ions

24.7 Naturally Occurring Phenols Many phenols occur naturally

CH(CH 3 ) 2 OH CH 3 Thymol (major constituent of oil of thyme) Example: Thymol

Cl OH Cl 2,5-Dichlorophenol (from defensive secretion of a species of grasshopper) Example: 2,5-Dichlorophenol

24.8 Reactions of Phenols: Electrophilic Aromatic Substitution Hydroxyl group strongly activates the ring toward electrophilic aromatic substitution

HalogenationNitrationNitrosationSulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution in Phenols

HalogenationHalogenation monohalogenation in nonpolar solvent (1,2-dichloroethane) + Br 2 ClCH 2 CH 2 Cl 0°C OHOHOHOH OHOHOHOHBr (93%)

HalogenationHalogenation multiple halogenation in polar solvent (water) + 3Br 2 H2OH2OH2OH2O 25°C OHOHOHOHF OHOHOHOHBr BrBr F (95%)

HalogenationNitrationNitrosationSulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution in Phenols

NitrationNitration HNO 3 acetic acid 5°C (73-77%) OH group controls regiochemistry OHOHOHOH CH 3 OHOHOHOH NO2NO2NO2NO2

HalogenationNitrationNitrosationSulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution in Phenols

NitrosationNitrosation NaNO 2 H 2 SO 4, H 2 O 0°C OHOHOHOH NONONONO (99%) only strongly activated rings undergo nitrosation when treated with nitrous acid OHOHOHOH

HalogenationNitrationNitrosationSulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution in Phenols

OHOHOHOH CH 3 H3CH3CH3CH3C SO 3 H (69%) H 2 SO 4 100°C SulfonationSulfonation OHOHOHOH CH 3 H3CH3CH3CH3C OH group controls regiochemistry

HalogenationNitrationNitrosationSulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution in Phenols

Friedel-Crafts Alkylation (63%) (CH 3 ) 3 COH reacts with H 3 PO 4 to give (CH 3 ) 3 C + OHOHOHOHC CH 3 H3CH3CH3CH3C H 3 PO 4 60°C (CH 3 ) 3 COH OHOHOHOH CH 3

HalogenationNitrationNitrosationSulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation Electrophilic Aromatic Substitution in Phenols

24.9 Acylation of Phenols Acylation can take place either on the ring by electrophilic aromatic substitution or on oxygen by nucleophilic acyl substitution

Friedel-Crafts Acylation AlCl 3 OHOHOHOH(74%) CH 3 CCl O OHOHOHOHC O CH 3 + ortho isomer (16%) under Friedel-Crafts conditions, acylation of the ring occurs (C-acylation)

O-AcylationO-Acylation (95%) in the absence of AlCl 3, acylation of the hydroxyl group occurs (O-acylation) OHOHOHOH CH 3 (CH 2 ) 6 CCl O + OC(CH 2 ) 6 CH 3 O

O- versus C-Acylation OC(CH 2 ) 6 CH 3 O OHOHOHOHC O CH 3 AlCl 3 formed faster more stable O-Acylation is kinetically controlled process; C-acylation is thermodynamically controlled AlCl 3 catalyzes the conversion of the aryl ester to the aryl alkyl ketones; this is called the Fries rearrangement

24.10 Carboxylation of Phenols Aspirin and the Kolbe-Schmitt Reaction COH O OCCH 3 O

how is salicylic acid prepared? Aspirin is prepared from salicylic acid COH O OCCH 3 O H 2 SO 4 COH O OHOHOHOH O CH 3 COCCH 3 O

called the Kolbe-Schmitt reaction acidification converts the sodium salt shown above to salicylic acid Preparation of Salicylic Acid CO 2 125°C, 100 atm CONa OOH ONa

acid-base considerations provide an explanation: stronger base on left; weaker base on right What Drives the Reaction? + CO 2 O – stronger base: pK a of conjugate acid = 10 weaker base: pK a of conjugate acid = 3 O – C O O H

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 Preparation of Salicylic Acid CO 2 125°C, 100 atm CONa OOH ONa

O H H H H H – OH H H H H – OH H H H H – OH H H H H –

O C Mechanism of ortho Carboxylation OO H – O H – C O O

O C Mechanism of ortho Carboxylation O O H – O H – C O O O – C O O H

Why ortho? Why not para? O – O – C O O H O H C O O –

weaker base: pK a of conjugate acid = 3 Why ortho? Why not para? O – O – C O O H stronger base: pK a of conjugate acid = 4.5 O H C O O –

Hydrogen bonding between carboxylate and hydroxyl group stabilizes salicylate ion. Salicylate is less basic than para isomer and predominates under conditions of thermodynamic control. Intramolecular Hydrogen Bonding in Salicylate Ion OOC O – H