Phenols

Dr Md Ashraful Alam

Ar-OHPhenols are compounds with an –OH group attached to an aromatic carbon. Although they share the same functional group with alcohols, where the –OH group is attached to an aliphatic carbon, the chemistry of phenols is very different from that of alcohols.

Nomenclature.

Phenols are usually named as substituted phenols. The methylphenols are given the special name, cresols. Some other phenols are named as hydroxy compounds.

OH

phenol

OH

Br

m-bromophenol

CH3OH

o-cresol

OHCOOH

salicylic acid

OHOH

OH

OH

OH

OH

catechol resorcinol hydroquinone

COOH

OH

p-hydroxybenzoic acid

Physical propertiesThe crystals are hygroscopic and turn pink to red in air

phenols are polar and can hydrogen bond

phenols are water insoluble

phenols are stronger acids than water and will dissolve in 5% NaOH

phenols are weaker acids than carbonic acid and (do not dissolve in 5% NaHCO3 )Phenol:◦is poisonous, corrosive, and flammable.◦affects the central nervous system and targets the liver

and kidneys.◦is mutagenic and possibly teratogenic.

Intramolecular hydrogen bonding is possible in some ortho-substituted phenols. This intramolecular hydrogen bonding reduces water solubility and increases volatility. Thus, o-nitrophenol is steam distillable while the isomeric p-nitrophenol is not.

N

OH

O

O

o-nitrophenolbp 100oC at 100 mm0.2 g / 100 mL watervolatile with steam

OH

NO2

p-nitrophenolbp decomposes1.69 g / 100 mL waternon-volatile with steam

Routes of Exposure: AbsorptionAll forms of phenol cause irritation, and acute

toxic effects of phenol most often occur by skin contact. Even dilute solutions (1 to 2%) may cause severe burns if contact is prolonged.

Due to its local anesthetizing properties, skin burns may be painless.

Phenol vapor and liquid penetrate the skin readily.

Systemic poisoning effects follow skin absorption.

• Discoloration and severe burns may occur, but may be disguised by a loss of pain sensation.

6

Phenol, in low doses, can be found in some consumer products. It is used as a disinfectant, antiseptic and pain reliever

Mostly used in the manufacture of resins and plastics, but it is also found in explosives, fertilizers, paints rubber, textiles, adhesives, drugs, paper, soap, wood preservatives and photographic developers.

Routes of Exposure: Products Containing Phenol

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Synthesis of Phenols

Phenols may be prepared by the hydrolysis of arenediazonium salts:

Since both of the above steps involve mild conditions, most substituted phenols can be prepared by the procedure.

EXAMPLE:

Synthesis of Phenols

Phenols may be prepared by the hydrolysis of arenediazonium salts:

Ar-NH2[HONO]

HXArN2 X-+ Cu2O

Cu2+, H2OAr-OH

an arene-diazonium salt

Since both of the above steps involve mild conditions, most substituted phenols can be prepared by the procedure.EXAMPLE:

NH2

Br

[HONO]HCl

diazotization N2 Cl-

Br

+

Cu2OCu(NO3)2, H2O

hydrolysis OH

Brp-Bromophenol (95%)

Synthesis of Phenols

Phenols may be prepared by the hydrolysis of arenediazonium salts:

Ar-NH2[HONO]

HXArN2 X-+ Cu2O

Cu2+, H2OAr-OH

an arene-diazonium salt

Since both of the above steps involve mild conditions, most substituted phenols can be prepared by the procedure.EXAMPLE:

NH2

Br

[HONO]HCl

diazotization N2 Cl-

Br

+

Cu2OCu(NO3)2, H2O

hydrolysis OH

Brp-Bromophenol (95%)

Industrial Syntheses of Phenol

Phenol is important in the production of soaps, aspirin and plastics. Annual production in the United States is more than 4 billion pounds. There are several commercial syntheses for phenol.

Alkali fusion of sodium benzenesulfonateThis first commercial synthesis was introduced in Germany in 1890 and later in the United States as demand grew for phenol because of the success of Bakelite, a polymer of phenol and formaldehyde.

Industrial Syntheses of Phenol Phenol is important in the production of soaps, aspirin and plastics. Annual production in the United States is more than 4 billion pounds. There are several commercial syntheses for phenol.

Alkali fusion of sodium benzenesulfonate This first commercial synthesis was introduced in Germany in 1890 and later in the United States as demand grew for phenol because of the success of Bakelite, a polymer of phenol and formaldehyde.

O=S=OO- Na+

Sodiumbenzenesulfonate

NaOH350 oC

O- Na+

Sodiumphenoxide

+ Na2SO3 + H2OSodiumsulfite

O- Na+

H3O+OH

Phenol

The Dow Process (1924)

An improved electrochemical synthesis provided a relatively cheap source of chlorine (Cl2) early in the 20th century, and this permitted a variation of the original commercial synthesis of phenol to be developed.

The Dow Process (1924)

An improved electrochemical synthesis provided a relatively cheap source of chlorine (Cl2) early in the 20th century, and this permitted a variation of the original commercial synthesis of phenol to be developed.

Cl

Chlorobenzene

NaOH

350 oC, pressure

O- Na+

+ NaCl + H2O

O- Na+

H3O+OH

Phenol

Oxidation of Cumene (Isopropylbenzene)

This process, originally developed in Germany in 1944, is the preferred way to produce phenol commercially. For each pound of phenol produced, 0.6 pound of acetone (another important industrial chemical) is produced. The overall industrial process begins with two petrochemicals: benzene and propene.

Oxidation of Cumene (Isopropylbenzene)

This process, originally developed in Germany in 1944, is the preferred way to produce phenol commercially. For each pound of phenol produced, 0.6 pound of acetone (another important industrial chemical) is produced. The overall industrial process begins with two petrochemicals: benzene and propene.

+CH3CH=CH2

H+

CHCH3 CH3

Isopropylbenzene(cumene)

O2C-OOH

CH3 CH3Cumene

hydroperoxide

H3O+/H2O

OH

+ CH3CCH3

O=

PhenolAcetone

Synthesis of Cumene: Acid-Catalyzed Alkylation of Benzene

This synthesis is carried out under conditions that minimize thepolyalkylation of benzene:

Synthesis of Cumene: Acid-Catalyzed Alkylation of Benzene

This synthesis is carried out under conditions that minimize the polyalkylation of benzene:

CH3CH=CH2 CH3CHCH3+

H CH(CH3)2

+

(- H+)

H3PO4

250 oC,pressure

CHH3C CH3

Cumene

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Sources of Phenols, Synthesis

14

From aryl diazonium ion

From aryl ketones

Naturally Occurring Phenols. Phenols are common in nature.

resveratrol α-tocopherol (vitamin E)

Resonance of Phenolate ionO O

O O O

Substituents that stabilize an anion enhance the acidity of phenol.Phenol has a pKa = 10; p-nitrophenol has a pKa = 7.1

Picric acid (2,4,6-trinitrophenol)

• 2,4,6-trinitrophenol is so acidic that it is called picric acid; it has a Ka = 10-1 (pKa =1)

• The enhanced acidity compared to phenol itself (Ka = 10-10) is due to the increased resonance stabilization of the conjugate base (phenolate anion) by the nitro groups: O

N

O

O

O

N

O

O

O

N

O

O

Phenols as Acids

Phenols are much more acidic than alcohols, butare weaker acids thancarboxylic acids.

These acidities are explained in terms of the different stabilities of theconjugate bases (A: － ) of the acids (HA) that influence the equilibrium:

An increase in the stability of A: － drives the equilibrium more to the right, increasing the magnitude of Ka.

Phenols as AcidsPhenols are much more acidic than alcohols, but are weaker acids than carboxylic acids.

RCO2H ArOH ROH

pKa 4-5 <11 ~18

These acidities are explained in terms of the different stabilities of the conjugate bases (A:-) of the acids (HA) that influence the equilibrium:

HA + H2O H3O+ + A:-Ka

Ka =[H3O+ ] [A:-]

[HA]

An increase in the stability of A:- drives the equilibrium more to the right, increasing the magnitude of Ka.

Phenols as AcidsPhenols are much more acidic than alcohols, but are weaker acids than carboxylic acids.

RCO2H ArOH ROH

pKa 4-5 <11 ~18

These acidities are explained in terms of the different stabilities of the conjugate bases (A:-) of the acids (HA) that influence the equilibrium:

HA + H2O H3O+ + A:-Ka

Ka =[H3O+ ] [A:-]

[HA]

An increase in the stability of A:- drives the equilibrium more to the right, increasing the magnitude of Ka.

An Example: Cyclohexanol and Phenol

Phenol is a much stronger acid thancyclohexanol.

This difference in acidity is understandable in terms of the difference in stabilities of the conjugate bases. The conjugate base of cyclohexanol is a localized anion. There is no resonance through a series of resonance structures that show it is a delocalized anion. The hybrid structure is stabilized by resonance.

An Example: Cyclohexanol and Phenol

Phenol is a much stronger acid thancyclohexanol.

OH OH

Cyclohexanol PhenolpKa 18 9.89

This difference in acidity is understandable in terms of the difference in stabilities of the conjugate bases. The conjugate base of cyclohexanol is a localized anion. There is no resonance stabilization. The conjugate base of phenol may be represented through a series of resonance structures that show it is a delocalized anion. The hybrid structure is stabilized by resonance.

:O:

:

:O:

:- --

:O

-

:O:

:

-:O:

Resonance structures for the phenoxide ion

....

:

An Example: Cyclohexanol and Phenol

Phenol is a much stronger acid thancyclohexanol.

OH OH

Cyclohexanol PhenolpKa 18 9.89

This difference in acidity is understandable in terms of the difference in stabilities of the conjugate bases. The conjugate base of cyclohexanol is a localized anion. There is no resonance stabilization. The conjugate base of phenol may be represented through a series of resonance structures that show it is a delocalized anion. The hybrid structure is stabilized by resonance.

:O:

:

:O:

:- --

:O

-

:O:

:

-:O:

Resonance structures for the phenoxide ion

....

:

Carboxylic Acids and Phenols: Solubilities

A standard way to separate water-insoluble carboxylic acids and phenols is by extraction with an aqueous solution of sodium bicarbonate. Carboxylic acids are soluble in the aqueous phase through their salts, while the less acidic phenols remain in the organic phase. Relative acidities:

Consider the following equilibria:

Bicarbonate ion will selectively deprotonate carboxylic acids in the presence of phenols because of the above equilibria.

Carboxylic Acids and Phenols: Solubilities A standard way to separate water-insoluble carboxylic acids and phenols is by extraction with an aqueous solution of sodium bicarbonate. Carboxylic acids are soluble in the aqueous phase through their salts, while the less acidic phenols remain in the organic phase. Relative acidities:

RCO2H HOCOH ArOHO=

pKa 4-5 6.4 ~10Consider the following equilibria:

RCO2H + Na+ HCO3- RCO2

- Na+ + H2CO3stronger acid

stronger base

weaker base

weaker acid

water soluble

ArOH + Na+ HCO3- ArO- Na+ + H2CO3

stronger acid

stronger base

weaker base

weaker acid

water solubleBicarbonate ion will selectively deprotonate carboxylic acids in the presence of phenols because of the above equilibria.

Carboxylic Acids and Phenols: Solubilities A standard way to separate water-insoluble carboxylic acids and phenols is by extraction with an aqueous solution of sodium bicarbonate. Carboxylic acids are soluble in the aqueous phase through their salts, while the less acidic phenols remain in the organic phase. Relative acidities:

RCO2H HOCOH ArOHO=

pKa 4-5 6.4 ~10Consider the following equilibria:

RCO2H + Na+ HCO3- RCO2

- Na+ + H2CO3stronger acid

stronger base

weaker base

weaker acid

water soluble

ArOH + Na+ HCO3- ArO- Na+ + H2CO3

stronger acid

stronger base

weaker base

weaker acid

water solubleBicarbonate ion will selectively deprotonate carboxylic acids in the presence of phenols because of the above equilibria.

Separation of Phenols and Alcohols

Mixtures of water-insoluble phenols and alcohols may be separated by extraction with an aqueous solution of hydroxide ion. Because of the greater acidity of the phenols, they rapidly react with hydroxide ions to produce water-soluble phenoxide ions.

Hydroxide ion will deprotonate phenols selectively in the presence of most alcohols. With the exception of methanol, alcohols are slightly less acidic than water.

Separation of Phenols and Alcohols Mixtures of water-insoluble phenols and alcohols may be separated by extraction with an aqueous solution of hydroxide ion. Because of the greater acidity of the phenols, they rapidly react with hydroxide ions to produce water-soluble phenoxide ions.

Relative acidities: ArOH HOH ROH

pKa ~10 15.7 ~18

Consider the equilibria:ArOH + Na+ -OH ArO- Na+ + H2Ostronger acid

stronger base

weakerbase

weaker acid

water soluble

ROH + Na+ -OH RO- Na+ + H2Ostronger acid

stronger base

weakerbase

weaker acid

water soluble Hydroxide ion will deprotonate phenols selectively in the presence of most alcohols. With the exception of methanol, alcohols are slightly less acidic than water.

Phenols, reactions1. as acids

2. ester formation

3. ether formation

4. EAS

a) nitration

b) coupling with diaz salts

c) halogenation

d) Friedel-Crafts alkylation

as acids:

with active metals:

with bases: CH4 < NH3 < HCCH < ROH < H2O < phenols < H2CO3 < RCOOH < HF

OHNa

ONa

sodium phenoxide

+ H2(g)

OH

+ NaOH

ONa

+ H2O

SA SB WB WA

2. ester formation (similar to alcohols)

OHCH3

+ CH3CH2CO

OH

H+

CH3CH2CO

O

H3C

+ H2O

OHCOOH

salicyclic acid

+ (CH3CO)2O

OCOOH

CH3CO

aspirin

Reactions of Phenols

Acylation of the Hydroxyl Group

Acylation is the introduction of the acyl group, The hydroxyl group in phenols may be acylated by either of twogeneral procedures:

Reactions of PhenolsAcylation of the Hydroxyl Group

Acylation is the introduction of the acyl group, RC-O=

The hydroxyl group in phenols may be acylated by either of two general procedures:

OH + RCOCRO

acid anhydride

base OCR + RCOH

OH + RCClbase

acyl chloride+ HCl

O O O

OOCR

O

Reactions of PhenolsAcylation of the Hydroxyl Group

Acylation is the introduction of the acyl group, RC-O=

The hydroxyl group in phenols may be acylated by either of two general procedures:

OH + RCOCRO

acid anhydride

base OCR + RCOH

OH + RCClbase

acyl chloride+ HCl

O O O

OOCR

O

3. ether formation (Williamson Synthesis)

Ar-O-Na+ + R-X Ar-O-R + NaX

note: R-X must be 1o or CH3

Because phenols are more acidic than water, it is possible to generate the phenoxide using NaOH.

OH

CH3

+ CH3CH2Br, NaOH

OCH2CH3

CH3

Phenols in the Williamson Synthesis of EthersBecause of their acidity (pKa~10), phenols are easily converted into their phenoxide ions with sodium or potassium hydroxide. The nucleophilic phenoxide ions react with alkyl halides (or equivalent compounds) by an SN2 mechanism to yield aryl alkyl ethers.

Phenols in the Williamson Synthesis of Ethers Because of their acidity (pKa ~10), phenols are easily converted into their phenoxide ions with sodium or potassium hydroxide. The nucleophilic phenoxide ions react with alkyl halides (or equivalent compounds) by an SN2 mechanism to yield aryl alkyl ethers.

ArOH HO-ArO-

phenoxideion

RX(where X = Cl, Br, I

or OSO2R or OSO2OR)

ArOR

via Ar-O:

::

-C X:

::

All the usual structural limitations of the SN2 mechanism apply.

ExamplesOH

Brp-Bromophenol

NaOH

O- Na+

BrSodium

p-bromophenoxide

CH3IOCH3

Br

+ NaI

p-Bromoanisole

CH3OSOCH3

O=

O

=

(Dimethyl sulfate)

OCH3

Brp-Bromoanisole

Na+ -OSOCH3

O=

O

=+

Cleavage of Aryl Alkyl Ethers

Reaction with HI or HBr cleaves these ethers in a specific direction:

Nucleophilic attack does not occur on the aromatic ring.

Cleavage of Aryl Alkyl EthersReaction with HI or HBr cleaves these ethers in a specific direction:

O-CH3

:: + H-Br O-CH3:

H++ Br-

better leaving group

fast and reversible protonation

O-CH3:

H+ + Br- OH

:: + CH3Br

cleavage by nucleophilic attack

Nucleophilic attack does not occur on the aromatic ring.

4. Electrophilic Aromatic Substitution

The –OH group is a powerful activating group in EAS and an ortho/para director.

a) nitration

OH OHNO2

NO2

O2Npolynitration!

OH

dilute HNO3

OH OH

NO2

NO2

+

HNO3

OHBr2 (aq.)

OHBr

Br

Br no catalyst required

use polar solvent

polyhalogenation!

OH

Br2, CCl4

OH OHBr

Br

+

non-polar solvent

b) halogenation

c) Friedel-Crafts alkylation.

OH

+ H3C C CH3

CH3

Cl

AlCl3

OH

C CH3CH3

H3C

d) Friedel-Crafts acylation

f) coupling with diazonium salts

(EAS with the weak electrophile diazonium)

OHCH3

+

N2 Cl

benzenediazoniumchloride

CH3

OH

NN

an azo dye

g) Kolbe reaction (carbonation)

ONa

+ CO2125oC, 4-7 atm.

OHCOONa

sodium salicylate

H+

OHCOOH

salicylic acid

EAS by the weaklyelectrophilic CO2

O C O

h) Reimer-Tiemann reaction

OH

CHCl3, aq. NaOH70oC

H+

OHCHO

salicylaldehyde

The salicylaldehyde can be easily oxidized to salicylic acid

Quiz 1

The order of acidity (strongest to weakest) of the oxygen acids below isQuiz 21.01

The order of acidity (strongest to weakest) of the oxygen acids below is

COOH OH OH OH

NO2

I II III IV

> > >I IV III II

Quiz 2

Provide the structures of the products of the reactions below.Quiz 21.02

Provide the structures of the products of the reactions below.

OH

+ CH3CClO=

Et3N as base

OH

CH3

+ Br2 0 oC, CCl4

OCCH3

O=

BrOH

CH3

Quiz 3

Provide the missing structures in the scheme below.

Quiz 21.03

Provide the missing structures in the scheme below.

CH3

NH2

(1) NaNO2, HBr, H2O, 0 oC

(2) Cu2O, Cu(NO3)2, H2O

(1) CO2, pressure; then heat

(2) H3O+

CH3

OH

CH3

OHCOOH

Quiz 4

In a nucleophilic aromatic substitution reaction like that above,which of the aryl chlorides below would be the most reactive?

Quiz 21.04

In a nucleophilic aromatic substitution reaction like that above, which of the aryl chlorides below would be the most reactive?

Ar-ClNaOCH3

CH3OHAr-OCH3

Cl

CH3H3C

Cl

NO2O2N

ClNO2

NO2I II III

Quiz 21.04

In a nucleophilic aromatic substitution reaction like that above, which of the aryl chlorides below would be the most reactive?

Ar-ClNaOCH3

CH3OHAr-OCH3

Cl

CH3H3C

Cl

NO2O2N

ClNO2

NO2I II III

Quiz 5

Provide the structures for the key intermediate and the product(s) in the reactions below.

Quiz 21.05

Provide the structures for the key intermediate and the product(s) in the reaction below.

BrCH3

CH3

KNH2liq NH3

CH3

CH3

CH3

CH3

NH2CH3

CH3

H2N

+