Phenols -Acidity, Synthesis & Reactions, cumene oxidation, Kolbe reaction, Reimer-Tiemann reaction,Fries Rearrangement Williamson Synthesis

1. PHENOLS
DR. S. S. HARAK
ASST. PROF. PHARM. CHEM.
GOKHALE EDUCATION SOCIETY’S
SIR DR. M.S.GOSAVI COLLEGE OF PHARMACEUTICAL EDUCATION AND RESEARCH, NASHIK-5

2. LEARNING OBJECTIVES
On completion of this topic you will be able to
 Explain the acidity of phenols.
 Illustrate with help of examples the effect of substituents on acidity of phenols.
 Explain structure and uses of phenol, cresols, resorcinol, naphthols .
 Compare different methods of synthesis of Phenols and their applications.
 Summarize the different reactions of phenols and explain the mechanism for each.

3. PHENOLS
Phenols are compounds of the general formula ArOH, where Ar is
 phenyl,
 substituted phenyl, or
 one of the other aryl groups like naphthyl.
Phenols differ from alcohols in having the OH group attached directly to an aromatic ring

4. DIFFERENT PHENOL DERIVATIVES

5. PHYSICAL PROPERTIES
 The simplest phenols are liquids or low-melting solids;
 because of hydrogen bonding, they have quite high boiling points.
 Phenol itself is somewhat soluble in water (9 g per 100 g of water), presumably because of
hydrogen bonding with the water; most other phenols are essentially insoluble in water.
 Phenols themselves are colorless.
 They are easily oxidized; unless carefully purified, many phenols are colored by oxidation
products.

6. PHENOLS
PHYSICAL
PROPERTIES
Properties vary with
the type of
substitution and also
its position

7. PROPERTIES OF THE NITROPHENOLS
• o-Nitrophenol has a much lower boiling point and much lower solubility in water than its isomers;
• It is the only one of the three that is readily steam-distillable.

8. Meta & Para NITROPHENOLS
 Let us consider first the m- and p-isomers.
 They have very high boiling points because of intermolecular
hydrogen bonding.
 Their solubility in water is due to hydrogen bonding with water
molecules.
 Steam distillation depends upon a substance having an
appreciable vapor pressure at the boiling point of water; by
lowering the vapor pressure, intermolecular hydrogen bonding
inhibits steam distillation of the m- and p-isomers.

9. Ortho NITROPHENOL
 The NO2 and OH groups are located exactly right for the formation of a hydrogen bond within
a single molecule.
 This intramolecular hydrogen bonding takes the place of intramolecular hydrogen bonding
with other phenol molecules and with water molecules;
 therefore o-nitrophenol does not have the low volatility of an associated liquid, nor does it
have the solubility characteristic of a compound that forms hydrogen bonds with water.

10. SALTS OF PHENOLS
 Phenols are fairly acidic compounds, and in this respect differ markedly from alcohols, which
are even more weakly acidic than water.
 Aqueous hydroxides convert phenols into their salts; aqueous mineral acids convert the salts
back into the free phenols.
 The salts being soluble in water and insoluble in organic solvents.
 Most phenols are weaker than carbonic acid, do not dissolve in aqueous bicarbonate
solutions. Indeed, phenols are conveniently liberated from their salts by the action of carbonic
acid.

11. WHY IS PHENOL ACIDIC?
 Compounds like alcohols and phenol which contain an -OH group attached to a hydrocarbon
are very weak acids.
 Alcohols are so weakly acidic that, for normal lab purposes, their acidity can be virtually
ignored.
 However, phenol is sufficiently acidic for it to have recognizably acidic properties - even if it is
still a very weak acid.
 A hydrogen ion can break away from the -OH group and transfer to a base.
 +H3O+
R-OH

12. ACIDITY OF PHENOLS:
 Acidity is Carboxylic acid > Phenol > Water > Alcohol
 Aqueous hydroxides convert Phenols into their salts;
 aqueous mineral acids convert salts back into the free Phenols.
 The acidity of phenols is mainly due to an electrical charge distribution in phenols that causes
the -OH oxygen to be more positive.
 As a result, the proton is held less strongly, and phenols can easily give this loosely held proton
away to form a phenoxide ion as outlined below.

13. COMPARISON OF PHENOL & ALCOHOL ACIDITY

14. SUBSTITUENT EFFECT ON ACIDITY OF PHENOLS:
 Electron-attracting substituents like X or NO2 increase the acidity of phenols,
 Electron-releasing substituents like CH3 decrease acidity.
 Electron-attracting substituents tend to disperse the negative charge of the phenoxide ion,
whereas
 electron-releasing substituents tend to intensify the charge.

15. INDUSTRIAL SOURCE
 Two process are commercially utilized
 The Dow process, in which chlorobenzene is allowed to react with aqueous sodium hydroxide
at a temperature of about 360.
 The air oxidation of Cumene

16. 1. DOW PROCESS
• Aromatic nucleophilic
substitution reaction
• The reaction is carried
out through active
benzyne inter mediate
formation .
• Example of Dow
process is as follows

17. REACTION MECHANISM OF DOW PROCESS

18. 2. AIR OXIDATION
MECHANISM OF
CUMENE
(ISOPROPYL
BENZENE)
Cumene is converted
by air oxidation into
cumene
hydroperoxide, which
is converted by
aqueous acid into
phenol and acetone

19. AIR OXIDATION MECHANISM OF CUMENE (ISOPROPYLBENZENE)

20. NATURALLY OBTAINED PHENOLS

21. NATURALLY OBTAINED PHENOLS

22. LABORATORY PREPARATION OF PHENOLS

23. METHODS OF LABORATORY PREPARATION OF PHENOLS
 Hydrolysis of diazonium salts
 Alkali fusion of sulfonates

24. 1. HYDROLYSIS OF DIAZONIUM SALTS

25. 2. ALKALI FUSION OF SODIUM BENZENE SULPHONATE
 This was the first commercial synthesis of phenol developed in Germany in 1890.
 It can also be used as a laboratory method for synthesis of phenol.
 Sodium benzene sulphonate is fused with sodium hydroxide to give sodium phenoxide
which on acidification yields phenol.

26. OTHER METHODS

27. ALKALINE HYDROLYSIS OF ARYL HALIDES

28. PICRIC ACID

29. REACTIONS OF PHENOL

30. REACTION OF PHENOLS
 There are two type of reaction:
 Reaction of (O–H) bond.
 Reaction of aromatic ring (Electrophilic Aromatic
Substitution).

31. REACTION OF (O–
H) BOND.
1. Acidity of Phenols

32. 2. ETHER
FORMATION
(WILLIAMSON
SYNTHESIS)
• Phenols are converted
into ethers by reaction in
alkaline solution with alkyl
halides.
• An organic reaction that
occurs between an
alkoxide or phenoxide,
derived from the alcohol or
phenol respectively, and
an unhindered alkyl
halide.
• Alexander Williamson in
1850

33. UNDERSTANDING MECHANISM
 William Ether synthesis is an
SN2 reaction
 “X” here is just a good
leaving group, such as Cl,
Br, I, OTs, etc
 F is not used.
 R= aryl/alkyl i.e. phenoxy or
alkoxy nucleophile

34. WILLIAMSON SYNTHESIS EXAMPLES IN ALIPHATICS
 The williamson is the SN2 reaction between
an alkoxide (aro-/RO- ) and an alkyl halide
(R-X)
 The alkoxide or phenoxide is generally
generated in situ and the alkyl halide is
subsequently added to the reaction mixture.
 The reaction occurs through an sn2
mechanism and the alkoxide/phenoxide
serves as the nucleophile and the alkyl
halide the electrophilic substrate.

35. SPECIFIC EXAMPLES

36. SPECIFIC EXAMPLES
 Guaifenesin, an expectorant found in cough syrups and tablets.
 The compound is prepared through the williamson ether synthesis which involves an sn2 mechanism between
the sodium phenoxide salt derived from guaiacol (2-methoxyphenol) and 3-chloro-1,2-propanediol.
 In this experiment, the Williamson ether synthesis is used to prepare guaifenesin. 2-Methoxyphenol (as
referred to as guaiacol) is reacted with sodium hydroxide (NaOH) to generate the phenoxide anion.
 This nucleophilic anion reacts with the primary alkyl chloride carbon of 3-chloro-1,2-propanediol to give the
target product.

37. REACTION FAILURES

38. 2. ETHER FORMATION (WILLIAMSON SYNTHESIS)
 Direct hydrolysis
of alkyl halide
however does not
give the same
result

39. 2. ETHER FORMATION (WILLIAMSON SYNTHESIS)
 Aryl halide must be
containing strong
electron-withdrawing
group to form
corresponding ether.

40. 3. ESTER
FORMATION
Phenols are usually
converted into their esters
by the reaction with
carboxylic acids, acid
chlorides or anhydrides.

41. SPECIFIC EXAMPLES

42. SPECIFIC EXAMPLES

43. 4. FRIES
REARRANGEMENT
When esters of Phenols are
heated with aluminum
chloride, the acyl group
migrates from the Phenolic
oxygen to an ortho or para
position of the ring and yield
a ketone.
This reaction is called the
Fries rearrangement, is
often used to prepare
phenolic ketones.

44. 4. FRIES
REARRANGEMENT
When esters of Phenols are
heated with aluminum
chloride, the acyl group
migrates from the Phenolic
oxygen to an ortho or para
position of the ring and yield
a ketone.
This reaction is called the
Fries rearrangement, is
often used to prepare
phenolic ketones.

45. UNDERSTANDING MECHANISM
 The reaction is catalyzed by Brønsted or Lewis acids such as HF, AlCl3, BF3, TiCl4 or SnCl4.
 The acids are used in excess of the stoichiometric amount, especially the Lewis acids, since they form
complexes with both the starting materials and products.

46. UNDERSTANDING MECHANISM
 The complex can dissociate to form an acylium ion.
 Depending on the solvent, an ion pair can form, and the ionic species can react with each other within
the solvent cage. However, reaction with a more distant molecule is also possible:

47. UNDERSTANDING MECHANISM
 After hydrolysis, the product is liberated.
 The reaction is ortho,para-selective so that, for example, the site of acylation can be regulated by the choice
of temperature. Only sterically unhindered arenes are suitable substrates, since substituents will interfere with
this reaction.
 The reaction is ortho,para-selective so that, for example, the site of acylation can be regulated by the choice
of temperature.
 Only sterically unhindered arenes are suitable substrates, since substituents will interfere with this reaction.

48. FRIES REARRANGEMENT VIA PHOTOCHEMICAL EXCITATION
 An additional option for inducing a Fries Rearrangement is photochemical
excitation, but this method is only feasible in the laboratory.

49. B. REACTION OF AROMATIC RING
ELECTROPHILIC AROMATIC SUBSTITUTION

50. 1. HALOGENATION
(BROMINATION)
Treatment of Phenols
with aqueous solution
of bromine results in
replacement of every
hydrogen ortho or para
to the –OH group

51. EFFECT OF SOLVENT
Polar solvent Low-/Non-Polar solvent

52. OTHER EXAMPLES

53. 2. SULPHONATION
• The orientation of
substituent is
temperature based.
• At low temperatures
ortho product is
obtained which can
reaarange to p-
product if heated to
100 degC.

54. 3. NITRATION
• In dilute acids both
mono nitro (ortho or
para) products are
formed.
• With concentrated
acid trinitro product
is formed.

55. 4. FRIEDEL-
CRAFTS
ALKYLATION
• Alkyl phenols can
be prepared by
Friedel-Crafts
alkylation of
Phenols, but the
yields are often
poor.

56. 5. FRIEDEL-
CRAFTS
ACYLATION
• Phenolic ketones can be
made by direct FC
acylation of Phenols,
• Prepared in two steps by
means of the Fries
rearrangement.

57. 6. NITROSATION:
Nitrous acid converts
Phenols into
nitrosophenols

58. 7. KOLBE
REACTION
• Treatment of the salts of a Phenol with CO2 brings
about substitution of the carboxyl group, -COOH, for
hydrogen of the ring.
• This reaction is known as the Kolbe reaction; its most
important application is in the conversion of Phenol
into o-Hydroxybenzoic acid, known as salicylic acid.
Synthesis of
Phenolic acids

59. KOLBE REACTION
A carboxylation chemical
reaction that proceeds by
heating sodium phenoxide
(the sodium salt of phenol)
with carbon dioxide under
pressure (100 atm, 125
°C), then treating the
product with sulfuric acid.
The final product is an
aromatic hydroxy acid
which is also known as
salicylic acid (the precursor
to aspirin)

60. REIMER-TIEMANN
REACTION
 Treatment of Phenol with chloroform and aqueous
hydroxide introduces an aldehyde group, –CHO, into the
aromatic ring, generally ortho to the –OH.
 This reaction is known as the Reimer-Tiemann reaction.
Synthesis of
Phenolic aldehydes

61. REIMER-TIEMANN REACTION
 The Reimer-Tiemann reaction is an organic reaction used to convert a phenol to an o-
hydroxy benzalde-hyde using chloroform, a base, and acid work-up.
 The mechanism begins with abstraction of the proton from chloroform with the base
to form a trichlorocarbanion which spontaneously loses a chloride ion to form a
neutral dichlorocarbene.
 The base also deprotonates the phenol reagent which then attacks the carbene.
 A series of steps and a final acid work-up result in the o-hydroxy benzaldehyde
product.

62. MECHANISM
 Chloroform (1) reacts with strong
base to form the chloroform
carbanion (2), which will quickly
alpha-eliminate to give
dichlorocarbene (3).
 Dichlorocarbene will react in the
ortho-position of the phenoxide (5)
to give the dichloromethyl
substituted phenol (7).
 After basic hydrolysis, the desired
product (9) is formed.

63. TEST YOUR KNOWLEDGE

64. SET A
Outline the synthesis, from phenols, of:
 -propyl phenyl ether
 phenyl methyl ether
 Phenetole (C6H5OC2H5)
 Resorcinol dimethyl ether (1,3-dimethoxybenzene)

65. SET B
 Three compounds, A, B, and C, have the formula C8H9OBr.
 They are insoluble in water, but are soluble in cold concentrated H2SO4 .
 B is the only one of the three that gives a precipitate when treated with AgNO3.
 The three compounds are unaffected by dilute KMnO4 and Br2/CCl4 .
 Further investigation of their chemical properties leads to the following results:
 What are the probable structures of A, B, and C? Of compounds D through J?
 Write equations for all reactions involved.

66. SET C
p-cresol (4-methylphenol), undergoes the Reimer–Tiemann reaction upon
treatment with chloroform (CHCl3) in alkaline medium. Predict The Product.
?