Chapter 9Phenols and Aryl Halides: Nucleophilic Aromatic Substitution

Lecture Notes in Chem. 206(Organic Chemistry II )Assoc. Prof. Joel R. Salazar

Structure and Nomenclature of Phenols Phenols have hydroxyl groups bonded directly to a

benzene ring Naphthols and phenanthrols have a hydroxyl group bonded

to a polycyclic benzenoid ring

Synthesis of Phenols Laboratory Synthesis

Phenols can be made by hydrolysis of arenediazonium salts

Industrial Syntheses 1. Hydrolysis of Chlorobenzene (Dow Process)

Chlorobenzene is heated with sodium hydroxide under high pressure

The reaction probably proceeds through a benzyne intermediate

2. Alkali Fusion of Sodium Benzenesulfonate Sodium benzenesulfonate is melted with sodium hydroxide

3. From Cumene Hydroperoxide Benzene and propene are the starting materials for a three-step

sequence that produces phenol and acetone Most industrially synthesized phenol is made by this method

The first reaction is a Friedel-Crafts alkylation

The second reaction is a radical chain reaction with a 3o benzylic radical as the chain carrier

The third reaction is a hydrolytic rearrangement (similar to a carbocation rearrangement) that produces acetone and phenol A phenyl group migrates to a cationic oxygen group

Reactions of Phenols as Acids Strength of Phenols as Acids

Phenols are much stronger acids than alcohols

Phenol is much more acidic than cyclohexanol

Experimental results show that the oxygen of a phenol is more positive and this makes the attached hydrogen more acidic The oxygen of phenol is more positive because it is attached

to an electronegative sp2 carbon of the benzene ring Resonance contributors to the phenol molecule also make

the oxygen more positive

Distinguishing and Separating Phenols from Alcohols and Carboxylic Acids Phenols are soluble in aqueous sodium hydroxide because of their relatively

high acidity Most alcohols are not soluble in aqueous sodium hydroxide A water-insoluble alcohol can be separated from a phenol by extracting the phenol into

aqueous sodium hydroxide

Phenols are not acidic enough to be soluble in aqueous sodium bicarbonate (NaHCO3) Carboxylic acids are soluble in aqueous sodium bicarbonate Carboxylic acids can be separated from phenols by extracting the carboxylic acid into

aqueous sodium bicarbonate

Other Reactions of the O-H Group of Phenols

Phenols can be acylated with acid chlorides and anhydrides

Phenols in the Williamson Ether Synthesis Phenoxides (phenol anions) react with primary alkyl

halides to form ethers by an SN2 mechanism

Cleavage of Alkyl Aryl Ethers Reaction of alkyl aryl ethers with HI or HBr leads to

an alkyl halide and a phenol

Recall that when a dialkyl ether is reacted, two alkyl halides are produced

Reaction of the Benzene Ring of Phenols (electrophilic aromatic substitution) Bromination

The hydroxyl group is a powerful activating group (ortho - para director)in electrophilic aromatic substitution and usually the tribromide is obtained Monobromination can be achieved in the presence of carbon

disulfide at low temperature

Nitration Nitration produces o- and p-nitrophenol

Low yields occur because of competing oxidation of the ring

Sulfonation Sulfonation gives mainly the the ortho (kinetic)

product at low temperature and the para (thermodynamic) product at high temperature

The Kolbe Reaction Carbon dioxide is the electrophile for an electrophilic

aromatic substitution with phenoxide anion The phenoxide anion reacts as an enolate The initial keto intermediate undergoes tautomerization to

the phenol product Kolbe reaction of sodium phenoxide results in salicyclic

acid, a synthetic precursor to acetylsalicylic acid (aspirin)

Aryl Halides and Nucleophilic Aromatic Substitution

Simple aryl and vinyl halides do not undergo nucleophilic substitution

Back-side attack required for SN2 reaction is blocked in aryl halides

SN2 reaction also doesn’t occur in aryl (and vinyl halides) because the carbon-halide bond is shorter and stronger than in alkyl halides Bonds to sp2-hybridized carbons are shorter, and therefore

stronger, than to sp3-hybridized carbons

Resonance gives the carbon-halogen bond some double bond character

Nucleophilic Aromatic Substitution by Addition-Elimination: The SNAr Mechanism Nucleophilic substitution can occur on benzene rings

when strong electron-withdrawing groups are ortho or para to the halogen atom The more electron-withdrawing groups on the ring, the

lower the temperature required for the reaction to proceed

The reaction occurs through an addition-elimination mechanism A Meisenheimer complex, which is a delocalized carbanion,

is an intermediate The mechanism is called nucleophilic aromatic substitution

(SNAr)

The carbanion is stabilized by electron-withdrawing groups in the ortho and para positions

Nucleophilic Aromatic Substitution through an Elimination-Addition Mechanism: Benzyne Under forcing conditions, chlorobenzene can undergo

an apparent nucleophilic substitution with hydroxide Bromobenzene can react with the powerful base amide

The reaction proceeds by an elimination-addition mechanism through the intermediacy of a benzyne (benzene containing a triple bond)

When chlorobenzene labeled at the carbon bearing chlorine reacts with potassium amide, the label is divided equally between the C-1 and C-2 positions of the product This is strong evidence for an elimination-addition

mechanism and against a straightforward SN2 mechanism

Sample problem Explain why the meta product is more stable

NaNH2/ NH3

========

CF3

Cl

CF3

NH2

Benzyne can be generated from anthranilic acid by diazotization The resulting compound spontaneously loses CO2 and N2 to

yield benzyne The benzyne can then be trapped in situ using a Diels-Alder

reaction

Reactions of the Side Chain of Alkylbenzenes Benzylic Radicals and Cations

When toluene undergoes hydrogen abstraction from its methyl group it produces a benzyl radical A benzylic radical is a radical in which the carbon bearing

the unpaired electron is directly bonded to an aromatic ring

Departure of a leaving group by an SN1 process from a benzylic position leads to formation of a benzylic cation

Benzylic radicals and cations are stabilized by resonance delocalization of the radical and positive charge, respectively

Halogenation of the Side Chain: Benzylic Radicals Benzylic halogenation takes place under conditions

which favor radical reactions Reaction of N-bromosuccinamide with toluene in the

presence of light leads to allylic bromination Recall N-bromosuccinamide produces a low concentration of

bromine which favors radical reaction

Reaction of toluene with excess chlorine can produce multiple benzylic chlorinations

When ethylbenzene or propylbenzene react under radical conditions, halogenation occurs primarily at the benzylic position

Alkenylbenzenes

Additions to the Double Bond of Alkenylbenzenes Additions proceed through the most stable

benzylic radical or benzylic cation intermediates

Oxidation of the Side Chain Alkyl and unsaturated side chains of aromatic rings

can be oxidized to the carboxylic acid using hot KMnO4

Reduction of Aromatic Compounds Aromatic rings are inert to catalytic hydrogenation under

conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the

presence of an aromatic ring

Reduction of Aromatic Compounds

Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium catalysts)

Reduction of Aryl Alkyl Ketones

Aromatic ring activates neighboring carbonyl group toward reduction

Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst