Lecture 29 Organic Chemistry 1

Home , Fries rearrangement, Phenols

CHEM 232 University of Illinois Organic Chemistry I at Chicago UIC

Professor Duncan Wardrop April 27, 2010

1 Today’s Lecture

Topics Covered: 1. Phenol - Bonding, Physical Properties and Reactions

2. Electrophilic Aromatic Substitution: Halogen, Nitration, Nitrosation

3. O- and C-Acylation of Phenols: Fries Rearrangement

4. Kolbe-Schmitt Reaction: Carboxylation of Phenols

5. Preparation and Cleavage of Aryl Alkyl Ethers

2 Chapter 24 Phenols

3 24.1 Nomenclature

4 Nomenclature of Phenols

CH3

5-chloro-2-methylphenol Cl

named on basis of phenol as parent substituents listed in alphabetical order lowest numerical sequence: first point of difference rule

5 Nomenclature of Hydroxyphenols

OH OH OH OH

OH OH

1,2-Benzenediol 1,3-Benzenediol 1,4-Benzenediol

(common name: (common name: (common name: pyrocatechol) resorcinol) hydroquinone)

6 Catechols are Biologically Important

NH2 Epinephrine HO is the principal hormone Tyrosine governing the "fight or flight" H response. This hormone also HO N triggers a variety of physiological H events, including increased heart rate. It is biosynthesized from HO Dopamine from the amino acid tyrosine by way of DOPA. OH H HO N http://www.ndrf.org/catechol.htm CH3

HO Epinephrine

7 Nomenclature of Hydroxyphenols

p-Hydroxybenzoic acid

CO2H name on basis of benzoic acid as parent higher oxidation states of carbon outrank hydroxyl group

8 24.2 Structure and Bonding

9 Structure of Phenol

phenol is planar C—O bond distance is 136 pm, which is slightly shorter than that of CH3OH (142 pm)

10 24.3 Physical Properties

11 Hydrogen Bonding in Phenol

O H O

The hydroxyl group of phenols allows hydrogen bonding to other phenol molecules and to water.

12 Physical Properties of Phenol

Compared to compounds of similar size and molecular weight, hydrogen bonding in phenol raises its melting point, boiling point, and solubility in water.

13 Physical Properties of Phenol

C6H5CH3 C6H5OH C6H5F

Molecular weight 92 94 96

Melting point (°C) –95 43 –41

Boiling 111 132 85 point (°C,1 atm)

Solubility in 0.05 8.2 0.2

H2O (g/100 mL,25°C)

14 Carbolic Acid & the History of Antisepsis

15 24.4 Acidity of Phenols

16 Comparative Acidity of Phenol

H O O

Stabilized by H + solvation and resonance

pKa = 10 phenoxide anion

Stabilized by H + H C O H3C O H 3 solvation alone

pKa = 16 alkoxide anion

17 The Phenoxide Anion is Stabilized Through Resonance

O O O H H H

H H H

18 Phenols are Converted to Phenoxide Ions in Aqueous Base

H O O

+ HO H2O + weaker stronger stronger acid weaker acid base base

19 24.5 Substituent Effects on the Acidity of Phenols

20 Electron-Releasing Substituents have Little Effect on the pKa of Phenols

OH OH OH

H CH3 OCH3

pKa 10 pKa 10.3 pKa 10.2

21 Electron-Withdrawing Substituents Lower the pKa of Phenols

OH OH OH

H Cl N+ –O O pKa 10 pKa 9.4 pKa 7.2

22 Effect of Electron-Withdrawing Groups is Most Pronounced at Ortho and Para Positions

OH O OH OH N+ O– O N+ O– N+ –O O

pKa 7.2 pKa 8.4 pKa 7.2

23 Direct Conjugation of the Negatively Charged Group with the Nitro Substituents is Possible

O O O O O O N+ N+ O– O–

N N O O O O

Consequence?

Electron-withdrawing substituents (inc. NO2) have larger effect on the pKa of a phenol group when in an ortho or para relationship

24 Direct Conjugation of the Negatively Charged Group with the Nitro Substituents is not Possible

O O O

O O O + + N+ N N – – O– O O

Consequence?

Electron-withdrawing substituents (inc. NO2) have a smaller effect on the pKa of a phenol group when in a meta relationship

25 The Effect of Electron-Withdrawing Substituents on pKa of Phenols is Cumulative

OH OH OH

NO2 O2N NO2

NO2 NO2 NO2

pKa 7.2 pKa 4.0 pKa 0.4 Picric Acid

26 24.6 Sources of Phenols

27 Phenol - An Industrial Chemical

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.

28 Industrial Preparations Benzene of Phenol

SO3H Cl CH(CH3)2

1. NaOH 1. NaOH heat 1. O2 heat + 2. H 2. H2O, H2SO4 2. H+ OH

29 Preparation of Phenol from Diazonium Salts

N H H N HSO4 N OH

NaNO2 H2O

H2SO4, H2O heat

Me Me Me Me Me Me

Primary Aryl Diazonium Phenol Arylamine Salt

Remember - reaction proceeds via aryl cation

30 24.7 Naturally Occurring Phenols

31 An Antiseptic with a Pleasant Smell

Thymol OH CH3 a major constituent of oil of thyme, was used CH in ancient Egyptian 3 religious ceremonies H3C

32 A Red Pigment Isolated from ‘Young’ Red Wine

OCH3 OH Malvin this phenolic compound HO O belongs to a family of plant OCH3 p i g m e n t s c a l l e d anthocyanins OGlc OGlc

33 A Major Hormone of the Thyroid Gland

I I O NH2 O HO I I OH

Thyroxine is one of the major hormones secreted by the human thyroid gland. Its principle function is to stimulate the metabolism of cells

34 An Antibiotic

OH Me NMe2 H H OH

NH2 OH OH O OH O O

Tetracycline the tetracyclines are a family of antibiotics produced by various strains of microorganisms of the genus Streptomyces. Bacterial resistance to these antibiotics is a major problem

35 24.8 Reactions of Phenols: Electrophilic Aromatic Substitution

36 Electrophilic Aromatic Substitution in Phenols

Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation

37 Electrophilic Aromatic Substitution

H H E -H+ E E

Sigma Complex or Wheland Intermediate

OH groups on benzene rings are ortho, para- directing and strongly activating

38 Halogenation of Phenols - Non-Polar Solvents

OH OH

ClCH2CH2Cl + Br2 0°C (93%) Br

monohalogenation occurs in non-polar solvents (1,2-dichloroethane)

39 Halogenation of Phenols - Polar Solvents

OH OH Br Br H2O + 3 x Br2 25°C F F (95%) Br multiple halogenation in polar solvent (water)

40 Electrophilic Aromatic Substitution in Phenols

Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation

41 Nitration of Phenols

OH OH

NO2 HNO3 acetic acid 5°C (73-77%) CH3 CH3

the OH group is more electron donating than the methyl group and consequently controls the Active Electrophile O N O regiochemistry of this reaction

42 Nitration of Phenols

OH OH

NO2 HNO3

O OH O OH

Hydroxyl groups are ortho, para-directing, while carboxylate groups are meta-directing. In this example, these effects reinforce each other and a single product is obtained

43 Electrophilic Aromatic Substitution in Phenols

Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation

44 Nitrosation of Phenols

NO OH OH NaNO2

H2SO4, H2O 0°C (99%)

only strongly activated rings Active Electrophile O N undergo nitrosation when treated with nitrous acid

45 Electrophilic Aromatic Substitution in Phenols

Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation

46 Sulfonation of Phenols

OH OH

H3C CH3 H3C CH3 H2SO4

100°C (69%) O S O OH

O O Possible H H Active S O O S O Electrophiles O O H

47 Electrophilic Aromatic Substitution in Phenols

Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation

48 Friedel-Crafts Alkylation

OH OH Me OH Me Me Me Me Me Me Me Me

H3PO4 60°C (63%) Me Me BHT (butylated hydroxy toluene)

OH Me Active H+ Electrophile Me Me Me Me Me

49 Phenol-Formaldehyde Resins

OH H H H O HCl O OH H H AcOH H H Friedel-Crafts Alkylation Formaldehyde H+ -H2O OH

OH OH OH OH H H H H H

Friedel-Crafts Alkylations Polymer

50 Bakelite - The First Commerical Synthetic Polymer

OH OH OH OH

HO OH HO

http://www.bakelite.de/eng/

51 Electrophilic Aromatic Substitution in Phenols

Halogenation Nitration Nitrosation Sulfonation Friedel-Crafts Alkylation Friedel-Crafts Acylation

52 24.9 Acylation of Phenols

53 Phenol Acylation: A Question of Regioselectivity and Chemoselectivity

OH O

O R

R O O OH O O-Acylation R X R X via Electrophilic OH2 Aromatic acylating acylating Subsitution agent agent O-Acylation via Nucleophilic Acyl Subsitution

O R Acylation of phenolic compounds can take place either on the ring by electrophilic aromatic substitution or on oxygen by nucleophilic acyl substitution

54 Friedel-Crafts Conditions Yield Aryl Ketones via C-Acylation

O OH OH OH O

H C Cl 3 CH3

AlCl3

(17%) O CH3 (74%)

Active Electrophile H3C C O AlCl4 acylium ion

55 ‘Unactivated’ Acylating Reagents Provide Aryl Esters via O-Acylation

O OH O CH3

H15C7 Cl

(95%)

in the absence of AlCl3, acylation of the hydroxyl group occurs (O-acylation)

56 O-Acylation vs. C-Acylation

O CH3 O-Acylation is kinetically controlled process; Formed faster C-acylation is ('Kinetic Product') thermodynamically controlled AlCl3

OH AlCl3 catalyzes the conversion of the aryl ester to the aryl alkyl More stable ketones; this is called ('Thermodynamic Product')

57 Mechanism of Fries Rearrangement

O Cl O C Cl O R Al C Cl O R

AlCl3

Cl Al OH O Cl O

H O O R O Cl R R C

58 Albuterol Mimics Epinephrine Alleviates the Symptoms of Asthma

OH H OH H

N N CH3 HO CH3 HO H CH3 HO HO Epinephrine Isoprotenerol

OH H

N CH3 HO CH3 CH3 HO Salbutamol

59 Synthesis of Albuterol

O O O

HO AlCl3 HO CH3

O Fries Rearrangement HO

H C O 3 H+ (cat) Aspirin

O O O OH Br HO HBr HO

HO HO

60 Synthesis of Albuterol

Ph Ph O O O O HN Br N HO HO

Substitution HO HO

Carboxylic Acid LiAlH Ketone 4 Reduction Ph OH H OH N N HO H2 HO Pd-C HO Hydrogenolysis HO Salbutamol

61 Difference Between Hydrogenation and Hydrogenolysis

62 24.10 Carboxylation of Phenols

63 Aspirin is Prepared Through O-Acylation of Salicylic Acid

O CH3 O O OH O H3C O CH3 OH OH H2SO4

O O Salicylic Acid Aspirin how is salicylic acid prepared?

64 Aspirin & the Kolbe-Schmitt Reaction

O Na OH OH + CO2 H3O 125 °C O Na OH 100 atm O O Sodium Salicylate Salicylic Phenoxide Anion Acid this process is called the Kolbe-Schmitt reaction acidification converts the sodium salt shown above to salicylic acid

65 Why is the Formation of the Salicylate Anion Thermodynamically Favored? acid-base considerations provide an explanation: stronger base on left; weaker base on right H

O Na O O C O Na O O Sodium Salicylate Phenoxide Anion stronger base: weaker base: pKa of conjugate pKa of conjugate acid = 10 acid = 3

66 Industrial Synthesis of Salicylic Acid

O Na OH CO2 125 °C O Na 100 atm O 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

67 Mechanism of Kolbe-Schmitt Reaction

O O Note the high H charge density at 6 2 the C-2, C-4 and C-6 positions of 4 the phenoxide anion

The alkoxide group O O is a strongly H activating ortho, para-directing group H

68 Mechanism of Ortho Carboxylation

Keto to Enol O Tautomerism! OH O O C O O O H H O O

69 Why is Ortho Carboxylation Preferred? A Question of Regioselectivity

OH O OH

O O

O O weaker base: stronger base: pKa of conjugate acid = 3 pKa of conjugate acid = 4.5

70 Intramolecular Hydrogen Bonding in Salicylate Ion

O H 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.

71 24.11 Preparation of Aryl Ethers

72 Preparation of Aryl Alkyl Ethers O- Alkylation of Phenols

R O M O

SN2 R X + M X electrophile nucleophile this reaction is an example of a Williamson ether synthesis

73 O-Alkylation of Phenols

O Na OCH3

acetone H3C I reflux (95%)

74 O-Alkylation of Phenols

OH O

K2CO3 Br acetone (86%) reflux

Potassium carbonate is sufficiently basic to deprotonate phenol

75 Preparation of Aryl Alkyl Ethers

Nucleophilic Aromatic Substitution (SNAr)

R X O

SNAr R O M + M X nucleophile electrophile

This type of reaction is considerable more demanding than O-alkylation. Nonetheless, for certain aromatic substrates, this can be a useful strategy

76 Two Viable Pathways to Achieve

Nucleophilic Aromatic Substitution (SNAr)

X X H

R X = halogens, R = NO2, F, R + OTs, N2 COR X = halogens, OTs Elimination -HX R O Addition

R O RO X R O -X R R Addition Elimination

Aryne Aryl alkyl ether Meisenheimer-type intermediate

77 Preparation of Aryl Alkyl Ethers Addition- Elimination Substitution

F OCH3

CH3OH + NaOCH3 + NaF 85°C (92%) NO2 NO2 nucleophilic aromatic substitution is effective with nitro-substituted (ortho and/or para) aryl halides

78 Preparation of Aryl Alkyl Ethers Addition- Elimination Substitution

CF3

H CF3 N O K 150°C CH3 CH3 + N O H Cl with regards to nucleophilic aromatic substitution (SNAr), trifluoromethyl groups function Fluoxetine (Prozac) like the nitro groups

79 24.12 Cleavage of Aryl Ethers by Hydrogen Halides

80 Deprotection of Aryl Alkyl Ethers

H Br R Br R H H O O O pKa of HBr = -9.0 R Br

Br Aryl alkyl ethers behave as Brønstead R OH bases

81 Cleavage of Aryl Methyl Ethers

OH OCH3 HBr + CH3Br heat OH OH (57-72%) (85-87%)

82 24.13 Claisen Rearrangement of Allyl Aryl Ethers

83 Claisen Rearrangement of Aryl Allyl Ethers

O OH

200 °C

(86%)

84 Mechanism of Claisen Rearrangement

O O

rewrite as

200 °C

O OH keto -to-enol tautomerism H

85 Sigmatropic Rearrangement

The Claisen rearrangement is an example of a sigmatropic rearrangement. A sigma (σ) bond migrates from one end of a conjugated π electron system to the other.

this α bond breaks during reaction

O O

H “conjugated π electron system” is the allyl group this α bond forms during reaction

86 Pericyclic Reactions Defined

pericyclic reaction a chemical reaction in which concerted reorganization of bonding takes place throughout a cyclic array of continuously bonded atoms. It may be viewed as a reaction proceeding through a fully conjugated cyclic transition state. The number of atoms in the cyclic array is usually six, but other numbers are also possible.

87 Other Pericyclic Reactions in Chem 234

A A B Diels-Alder B [4+2] Reaction Cycloaddition X Y Y X

H O O O Decarboxylation OH Retro-Ene of β-Oxo Acids C Reaction R O R O

O O Os O O O O Dihydroxylation Os [2+3] of Alkenes O O Cycloaddition

88 24.14 Oxidation of Phenols: Quinones

89 Hydroquinones are Oxidized to Quinones

OH O

Na2Cr2O7 H2SO4

H2O (Jones Reag.) OH (76-81%) O

The most common examples of phenol oxidations are the oxidations of 1,2- and 1,4- benzenediols to give quinones.

90 Catechols are Oxidized to Orthoquinones

OH O OH O Ag2O

Et2O (68%) CH3 CH3

91 Many Quinones are Highly Colored

O OH OH

Alizarin is a red dye originally obtained from the root of the common madder plant, Rubia tinctorum. Use of this dye in India Rubia tinctorum predates the 10th century.

92 Biologically Important Quinones

O MeO Me

MeO Me O Me

Ubiquinone (Coenzyme Q) n = 6-10 involved in biological electron transport

93 Biologically Important Quinones

O Me

O Me Me Me Me

Vitamin K (blood-clotting factor)

94 Today’s Lecture

Topics Covered: 1. Phenols - Bonding, Physical Properties and Reactions

2. Electrophilic Aromatic Substitution: Halogen, Nitration, Nitrosation

3. O- and C-Acylation of Phenols: Fries Rearrangement

4. Kolbe-Schmitt Reaction: Carboxylation of Phenols

5. Preparation and Cleavage of Aryl Alkyl Ethers

95 Information & Suggested Problems