Reactions of Benzene & Its Derivatives

Home , Acetophenone, Acylation, Alkylation, Amide, Benzene, Benzenesulfonic acid

Organic Lecture Series

ReactionsReactions ofof BenzeneBenzene && ItsIts DerivativesDerivatives

Chapter 22 1

Organic Lecture Series Reactions of Benzene The most characteristic reaction of aromatic compounds is substitution at a ring carbon:

Halogenation:

FeCl3 H + Cl2 Cl + HCl Chlorobenzene Nitration: H2 SO4 HNO+ HNO3 2 + H2 O Nitrobenzene 2 Organic Lecture Series Reactions of Benzene

Sulfonation:

H 2 SO4 HSO+ SO3 3 H Benzenesulfonic acid

Alkylation:

AlX3 H + RX R + HX

An alkylbenzene

Acylation: O O AlX H + RCX 3 CR + HX

An acylbenzene

Organic Lecture Series

Carbon-Carbon Bond Formations:

R RCl

AlCl3

Arenes Alkylbenzenes

4 Organic Lecture Series Electrophilic Aromatic Substitution • Electrophilic aromatic substitution: a reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile H E + + + E + H

• In this section: – several common types of electrophiles – how each is generated – the mechanism by which each replaces hydrogen 5

Organic Lecture Series EAS: General Mechanism • A general mechanism

slow, rate + determining H Step 1: H + E+ E El e ctro - Resonance-stabilized phile cation intermediate + H fast Step 2: E + H+ E

• Key question: What is the electrophile and how is it generated?

6 Organic Lecture Series

+ +

Organic Lecture Series Chlorination Step 1: formation of a chloronium ion

Cl Cl + + - - Cl Cl+ Fe Cl Cl Cl Fe Cl Cl Fe Cl4 Cl Cl Chlorine Ferric chloride A molecular complex An ion pair (a Lewis (a Lewis with a positive charge containing a base) acid) on ch lorine ch loronium ion Step 2: attack of the chloronium ion on the ring slow, rate determining + Cl + H H H + Cl Cl Cl + Resonance-stabilized cation intermediate; the positive charge is delocalized onto three atoms of the ring 8 Organic Lecture Series Chlorination

Step 3: proton transfer regenerates the aromatic character of the ring

+ H - + fast Cl-FeCl3 Cl + HCl + FeCl3 Cl Cation Chlorobenzene intermediate

Organic Lecture Series Bromination

FeBr 3 + H + Br 2 Br HBr Bromobenzene

This is the general method for Substitution of halogen onto a benzene ring (CANNOT be halogenated by Free Radical Mechanism)

10 Organic Lecture Series

Bromination-Why not addn of Br2?

Regains Aromatic Energy

Organic Lecture Series Nitration + • Generation of the nitronium ion, NO2 – Step 1: proton transfer to nitric acid

O H O HSO3 OH+ HON HSO4 + ON O H O Sulfuric Nitric Co nju gate acid acid pKa= -3 acid pKa= -1.4 of nitric acid

– Step 2: loss of H2O gives the nitronium ion, a very strong electrophile

H O H ON O + ONO H H O The nitronium ion 12 Nitration Organic Lecture Series Step 1: attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile)

HNO 2 H NO2 HNO2 + + + + ONO + Resonance-stabilized cation intermediate

Step 2: proton transfer regenerates the aromatic ring

HHNO NO2 H 2 H O + + + O H H H

Organic Lecture Series Nitration

• A particular value of nitration is that the nitro group can be reduced to a 1° amino group

COOH COOH

Ni + 3H + 2H O 2 (3 atm) 2

NO2 NH2 4-Nitrobenzoic acid 4-Aminobenzoic acid

14 Organic Lecture Series Sulfonation

• Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide

H SO + 2 4 SO3 SO3 H

Benzene B enzenesulfonic acid

(SO3 in H2SO4 is sometimes called “fuming” sulfuric acid.) 15

Organic Lecture Series Friedel-Crafts Alkylation

• Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group

AlCl3 + Cl + HCl

Benzene 2-Chloropropane Cumene (Isopropyl chloride) (Isopropylbenzene)

The electrophilic partner is a carbocation; it will arrange to the most stable ion: allylic>3o>2o>1o 16 Friedel-Crafts Alkylation Organic Lecture Series Step 1: formation of an alkyl cation as an ion pair Cl + Cl - + - RCl+ Al Cl RClAl Cl R AlCl4 Cl Cl A molecular An ion pair containing comp lex a carbocation Step 2: attack of the alkyl cation on the aromatic ring + H H H + R+ + R R R + A resonance-stabilized cation Step 3: proton transfer regenerates the aromatic ring

H + Cl AlCl3 R ++AlCl3 HCl R 17

Friedel-Crafts Alkylation Organic Lecture Series There are two major limitations on Friedel-Crafts alkylations: 1. carbocation rearrangements are common:

AlCl3 + Cl +HCl

Benzene Isobutyl tert-Butylbenzene chloride

CH CH 3 CH3 + 3 - + - CH3 CHCH2 -Cl + AlCl3 CH 3 C- CH2 -Cl-AlCl3 CH3 C AlCl4

H CH 3 I sobutyl chloride amolecular an ion pair complex

18 Organic Lecture Series Friedel-Crafts Alkylation 2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron- withdrawing groups Y

AlCl + RX 3 No reacti on

When Y Equals Any of These Groups, the Benzene Ring Does Not Undergo Friedel-Crafts Alkylation

O O O O O

CH CR COH COR CNH2 + SO3 HNOCN 2 NR3

CF3 CCl3

Organic Lecture Series

20 Organic Lecture Series The “De-activation” of Aromatic Systems

Note: deactivation refers to the rate of EAS

Organic Lecture Series Friedel-Crafts Acylation

• Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group: O O AlCl3 + CH3 CCl + HCl

BenzeneAcetyl Acetophenone ch loride

O Cl O AlCl 3 + HCl

4-Phenylbutanoyl α-Tetralone chlorid e 22 Organic Lecture Series Friedel-Crafts Acylation • The electrophile is an acylium ion

O Cl (1)

•• •• R-C Cl + Al-Cl •• Cl An acyl Aluminum chloride chloride

O O + Cl (2) •• - R-C Cl Al Cl R-C + AlCl - •• 4 Cl A molecular complex A n ion pair with a positive charge containing an charge on chlorine acylium ion

Friedel-Crafts Acylation Organic Lecture Series

– an acylium ion is a resonance hybrid of two major contributing structures

complete valence shells + + : R-C O: : R-C O The more important contributing structure • F-C acylations are free of a major limitation of F-C alkylations; acylium ions do not rearrange.

24 Organic Lecture Series Friedel-Crafts Acylation

A special value of F-C acylations is preparation of unrearranged alkylbenzenes:

O AlCl + Cl 3

2-Methylpropanoyl chloride O

N 2H 4, KOH diethylene 2-Methyl-1- glycol Isobutylbenzene phenyl-1-propanone

Organic Lecture Series Di- and Polysubstitution

Only a trace

26 Organic Lecture Series Di- and Polysubstitution Orientation on nitration of monosubstituted benzenes:

ortho + Substituent ortho meta para para meta - OCH3 44 55 99 trace

CH 3 58 4 38 96 4 Cl 70 - 30 100 trace Br 37 1 62 99 1 COOH 18 80 2 20 80 CN 19 80 1 20 80

NO2 6.4 93.2 0.3 6.7 93.2 27

Organic Lecture Series Di- and Polysubstitution • Orientation: –certain substituents direct preferentially to ortho & para positions; others to meta positions –substituents are classified as either ortho-para directing or meta directing toward further substitution

28 Di- and Polysubstitution Organic Lecture Series • Rate –certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower –substituents are classified as activating or deactivating toward further substitution

Organic Lecture Series

30 Di- and Polysubstitution Organic Lecture Series

– -OCH3 is ortho-para directing:

OCH3 OCH3 OCH3 NO2 + HNO3 + + H2 O CH 3 COOH

NO2 Anisole o-Nitroanisole p-Nitroanisole (44%) (55%) –-CO2H is meta directing COOH COOH COOH COOH NO H2 SO4 2 ++HNO3 + 100°C NO2 Benzoic NO2 acid o-Nitro- m-Nitro- p-Nitro- benzoic benzoic benzoic acid acid acid (18%) (80%) (2%) 31

Organic Lecture Series Di- and Polysubstitution : : : Strongly : :

NH NHR NR OH OR: activating 2 2 :

OOOO: : Moderately : :

NHCR NHCAr OCR: OCAr activating : Weakly activating R :: :: :: : Ortho-para Directing Weakly F: : : : deactivating Cl: Br I

OOO O CH CR COH COR Moderately deactivating O CNH2 SO3 H CN Strongly + Meta Directing deactivating NO2 NH3 CF3 CCl3

32 Di- and Polysubstitution Organic Lecture Series

the order of steps is important:

CH3 COOH HNO 3 K2 Cr2O7 H SO 2 4 H2SO4 CH 3 NO2 NO2 p-Nitrobenzoic acid

COOH COOH HNO K2 Cr 2 O7 3 H SO H2 SO4 2 4 NO2 m-Nitrobenzoic acid 33

Organic Lecture Series Theory of Directing Effects • The rate of EAS is limited by the slowest step in the reaction • For almost every EAS, the rate- determining step is attack of E+ on the aromatic ring to give a resonance- stabilized cation intermediate •The more stable this cation intermediate, the faster the rate- determining step and the faster the overall reaction

34 Organic Lecture Series Theory of Directing Effects • For ortho-para directors, ortho-para attack forms a more stable cation than meta attack – ortho-para products are formed faster than meta products • For meta directors, meta attack forms a more stable cation than ortho-para attack – meta products are formed faster than ortho-para products 35

Theory of Directing Effects Organic Lecture Series Nitration of anisole

-OCH3; examine the meta attack:

OCH3 slow + + NO2

OCH3 OCH3 OCH3 OCH3 + + fast H H H -H+ NO2 NO2 NO2 + NO2 (a) (b) (c)

36 Organic Lecture Series Nitration of anisole

-OCH3: examine the ortho-para attack:

OCH3 OCH3

+ slow + NO2

: +: : : NO : 2 OCH3 ::OCH3 OCH3 OCH3 fast + -H+ + + NO H 2 HNO2 H NO2 H NO2 (d) (e) (f) (g)

This resonance structure accounts for the selectivity 37

Organic Lecture Series Theory of Directing Effects

Nitration of benzoic acid

-NO2; examine the meta attack: COOH

+ slow + NO2

COOH COOH COOH COOH fast H H H -H+ NO2 NO2 NO2 NO2 (a) (b) (c)

38 Organic Lecture Series Nitration of benzoic acid

-NO2: assume ortho-para attack:

COOH

+ slow + NO2

COOH COOH COOH COOH fast -H+ H NO 2 H NO2 H NO2 NO2 (d) (e) (f) The most disfavored contributing structure

This resonance structure accounts for the selectivity 39

Organic Lecture Series Activating-Deactivating

• Any resonance effect,effect such as that of -

NH2, -OH, and -OR, that delocalizes the positive charge on the cation intermediate lowers the activation energy for its formation, and has an activating effect toward further EAS • Any resonance effect,effect such as that of -

NO2, -CN, -CO, and -SO3H, that decreases electron density on the ring deactivates the ring toward further EAS

40 Organic Lecture Series Activating-Deactivating • Any inductive effect,effect such as that of - CH3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS • Any inductive effect,effect such as that of + halogen, -NR3 , -CCl3, or -CF3, that decreases electron density on the ring deactivates the ring toward further EAS

Di- and Polysubstitution Organic Lecture Series • Generalizations: – alkyl, phenyl, and all other substituents in which the atom bonded to the ring has an unshared pair of electrons are ortho- para directing; all other substituents are meta directing – all ortho-para directing groups except the halogens are activating toward further substitution; – the halogens are weakly deactivating

42 Organic Lecture Series Activating-Deactivating ¾for the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger ¾the net effect is that halogens are deactivating but ortho-para directing :: :: H + H + + Cl + ::ClE : Cl: E E

Organic Lecture Series Di- and Polysubstitution : : : Strongly : :

NH NHR NR OH OR: activating 2 2 :

OOOO: : Moderately : :

NHCR NHCAr OCR: OCAr activating : Weakly activating R :: :: :: : Ortho-para Directing Weakly F: : : : deactivating Cl: Br I

OOO O CH CR COH COR Moderately deactivating O CNH2 SO3 H CN Strongly + Meta Directing deactivating NO2 NH3 CF3 CCl3

44 MedicinalOrganic Chemistry Lecture Series BenzodiazepinsBenzodiazepins

1) Sedative-hypnotic

2) Anticonvulsant

3) Muscle relaxant

® Valium 4) Anxiolytic 45

Retrosynthetic Analysis MedicinalOrganic Chemistry Lecture Series

H3C H3C O O N N

NH2 O Cl N Cl

Friedel-Crafts Acylation H3C O NH N 2 O X Cl Cl Cl 46 MedicinalOrganic Chemistry Lecture Series

Short Problem Using EAS: the synthesis of p-Aminochlorobenzene

NH2 NO2

Cl2 HNO3 H2

FeCl3 H2SO4 Pt or Pd

Cl Cl Cl

Separate o from p

MedicinalOrganic Chemistry Lecture Series

The Synthesis of the amide section: O H3C NH2 NH H C O O 3 N CH3 NaH O CH3Br

N Cl Cl Cl

48 MedicinalOrganic Chemistry Lecture Series

Friedel Crafts Acylation:

O H3C H C O 3 N N CH3 O

Cl O Cl

AlCl3

Amide is activating & o p directing

MedicinalOrganic Chemistry Lecture Series

H3C O H3C N O N

Cl O Cl 1) NaOH O Cl

2) O Cl Cl

NH3 H3C H3C O O N N

NH2 O Cl N Cl loss H2O formation of imine

50 MedicinalOrganic Lecture Chemistry Series

Chlorpromazine treatment of schizophrenia and (Thorazine) acute psychotic states and delirium. The introduction (1950) of chlorpromazine into clinical use has been described as the single greatest advance in psychiatric care, dramatically improving the prognosis of patients in psychiatric hospitals worldwide the availability of antipsychotic drugs curtailed indiscriminate use of electroconvulsive therapy and psychosurgery, and was one of the driving forces behind the deinstitutionalization movement.

MedicinalOrganic Lecture Chemistry Series

52 MedicinalOrganic Lecture Chemistry Series

O O O O O 1) LiAlH4 O NH3 NH2 CONH2 COCl + 2) H3O F F F

MedicinalOrganic Lecture Chemistry Series Michael Reaction in Context

O CO2CH3 O 2eq CO2CH3 O O NH2 N CO2CH3

F F

54 MedicinalOrganic Lecture Chemistry Series

Dieckmann Condensation in Context

O CO CH O O 2 3 NaOCH3 O O N N CO2CH3 CO2CH3 CH3OH F F

MedicinalOrganic Lecture Chemistry Series

O 1) NaOH O 2) H O+ O O 3 O O N 3) Δ N CO 2CH3

F F

56 MedicinalOrganic Lecture Chemistry Series

OH O O N O O 1) Cl MgBr Cl N F + 2) H3O F

Haloperidol

Organic Lecture Series O O O + O AlCl3 1)HO OH / H O COOH COCl 2) SOCl F 2 F O F

NH3

O O O O NH 1) LiAlH4 2 CONH2 + 2) H3O F F

2eq CO2CH3

O CO CH O O 2 3 NaOCH3 O O N N CO2CH3 CO2CH3 CH3OH F F 1) NaOH + 2) H3O 3)

O OH O O O 1) Cl MgBr N N Cl + 2) H3O F Haloperidol 58 F