Electrophilic Aromatic Substitution

Summary

• Phenols are potentially very reactive towards electrophilic aromatic substitution.
• This is because the hydroxy group, -OH,  is a strongly activating, ortho- / para- directing substituent (review)
• Substitution typically occurs para to the hydroxyl group unless the para position is blocked, then ortho substitution occurs.
• The strong activation often means that milder reaction conditions than those used for benzene itself can be used (see table below for a comparison)
• Phenols are so activated that polysubstitution can be a problem  (similar problems occur with anilines)

• Electrophilic Aromatic Substitutions reactions of Benzenes
• Electrophilic Aromatic Substitutions reactions of Aryl Ethers
• Electrophilic Aromatic Substitutions reactions of Aryl Amines

Acylation of Phenols

• Phenols are examples of bidentate nucleophiles, meaning that they can react at two positions:
• on the aromatic ring giving an aryl ketone via C-acylation, a Friedel-Crafts reaction or,
• on the phenolic oxygen giving an ester via O-acylation, an esterification
• Reagents :

C-acylation : acylating agent (acyl chloride or anhydride) and AlCl3

O-acylation : acylating agent (acyl chloride or anhydride)

• The product of C-acylation is more stable and predominates under conditions of thermodynamic control (i.e. when AlCl₃ is present).
• The product of O-acylation forms faster and predominates under conditions of kinetic control
• O-acylation can be promoted by either:
• acid catalysis via protonation of the acylating agent, increasing its' electrophilicity or
• base catalysis via deprotonation of the phenol, increasing its' nucleophilicity.
• It is also known that aryl esters readily rearrange to aryl ketones in the presence of AlCl₃, a reaction known as the Fries rearrangement:

Related reactions

• Friedel-Crafts Acylation of Benzene
• Conversion of Alcohols to Esters
• Reactions of Acyl Halide

Carboxylation of Phenols (Kolbe-Schmitt reaction)

Summary

• Heating the nucleophilic phenolate salt with carbon dioxide under high pressure / temperature results in regioselective ortho-substitution.
• This process is also known as the Kolbe-Schmitt synthesis.
• o-hydroxybenzoic acid is more commonly known as salicyclic acid.

Check out the CHIME image for the intramolecular hydrogen bond by looking the the position of the shared H atom with respect to the two oxygen atoms

Questions
Aspirin is the acetyl ester of salicylic acid (hence ASA),  how would you make aspirin from salicylic acid ? 
Can you think of other reactions of nucleophilic species with carbon dioxide ? 

Study Tip:
Consider the phenolate to be an enolate, hence reactions at the a-C are typically favored.

 

MECHANISM FOR CARBOXYLATION OF PHENOLS
Step 1: The nucleophilic phenolate (reacting like an enolate) reacts with the electrophilic carbon of carbon dioxide in the ortho position (compare this with an Aldol reaction)
Step 2: The non-aromatic cyclohexadienonecarboxylate intermediate tautomerises to the more stable aromatic enol which is further stabilized by an intramolecular hydrogen bond.  An acidic work-up will generate the carboxylic acid.

 

Summary

• Reagents : Use a base such as Na₂CO₃ to prepare the phenoxide, then add the alkyl halide.
• Since the reaction is S_N2, the halide should be methyl or primary alkyl halides (or tosylates).
• This reaction is the Williamson ether synthesis applied to aromatic alcohols.

Question :
Is this method suitable for the preparation of diaryl ethers such as Ph-O-Ph ? 

Related Reactions

• Williamson Ether Synthesis
• Nucleophilic Substitution reactions of Alkyl Halides

Summary

• In general, phenols are more easily oxidized than simple alcohols.
• Oxidation can achieved by reaction with silver oxide (Ag₂O) or chromic acid (Na₂Cr₂O₇), or other oxidizing agents.
• Particularly important are the oxidation of 1,2- and 1,4-benzenediol (pyrocatechol and hydroquinone, respectively) and their derivatives (see examples below):

• These types of systems are important in biological redox-systems such as coenzyme Q and vitamin K.
• Here's a closer look at the two one electron transfers that are believed to take place when hydroquinone is oxidized to benzoquinone

 

	Loss of a proton and an electron generates a phenoxy radical
	Loss of a second proton and a second electron completes the oxidation. Can you draw a curly arrow scheme that shows how the quinone may be formed from a diradical  ?

• Oxidations of Alcohols