Reac%ons of Benzene and Subs%tuted Benzenes

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1 Reac%ons of Benzene and Subs%tuted Benzenes

2 This Chapter Begins the Discussion of the Families of Compounds in Group IV

3 Many Subs%tuted Benzenes are Found in Nature

4 The Nomenclature of Subs%tuted Benzenes some monosubs%tuted benzenes have names that incorporate the subs%tuent

5 Subs%tu%on Reac%ons of Benzene and Its Deriva%ves Benzene is aroma%c: a cyclic conjugated compound with 6 π electrons Reac%ons of benzene lead to the reten%on of the aroma%c core

6 The Way Benzene Reacts Aroma%c compounds such as benzene undergo electrophilic aroma%c subs%tu%on reac%ons. The π electrons above and below the ring make benzene a nucleophile.

7 Benzene Undergoes Subs%tu%on, Not Addi%on Aroma%city is restored in the product from electrophilic subs%tu%on

8 Benzene Undergoes Subs%tu%on, Not Addi%on The reac%on of benzene with an electrophile forms the aroma%c subs%tu%on product, not the nonaroma%c addi%on product.

9 The Mechanism for Electrophilic Aroma%c Subs%tu%on

10 Electrophilic Aroma%c Subs%tu%on Reac%ons: Bromina%on or Chlorina%on Bromina%on or chlorina%on of benzene requires a Lewis acid catalyst because benzene s aroma%city causes it to be less reac%ve than an alkene. Ferric bromide (FeBr 3 ) or ferric chloride (FeCl 3 ) is usually used. FeBr 3 is added as a catalyst to polarize the bromine reagent Benzene s π electrons par%cipate as a Lewis base in reac%ons with Lewis acids The product is formed by loss of a proton, which is replaced by bromine

11 Addi%on Intermediate in Bromina%on The intermediate is not aroma%c and therefore high in energy

12 Forma%on of Product from Intermediate The ca%onic addi%on intermediate transfers a proton to FeBr 4 - (from Br - and FeBr 3 ) This restores aroma%city (in contrast with addi%on in alkenes)

other reagents to promote the reac%on Chlorina%on requires FeCl 3

13 Other Aroma%c Subs%tu%ons Chlorine and iodine (but not fluorine, which is too reac%ve) can produce aroma%c subs%tu%on with the addi%on of other reagents to promote the reac%on Chlorina%on requires FeCl 3 Iodine must be oxidized to form a more powerful I + species (with Cu + or peroxide)

14 Aroma%c Nitra%on The combina%on of nitric acid and sulfuric acid produces NO 2 + (nitronium ion) The reac%on with benzene produces nitrobenzene

15 Aroma%c Sulfona%on Subs%tu%on of H by SO 3 H (sulfona%on) Reac%on with sulfuric acid and heat, or a mixture of sulfuric acid and SO 3 Reac%ve species is sulfur trioxide or its conjugate acid

16 Alkali Fusion of Aroma%c Sulfonates SO 3 H OH 1) NaOH 2) H 3 O + Benzensulfonic Acid Phenol

17 Sulfona%on of Benzene is Reversible If benzenesulfonic acid is heated in dilute acid, an H + adds to the ring and the sulfonic acid group comes off the ring. The Mechanism for Desulfona%on:

18 Aroma%c Hydroxyla%on Direct hydroxyla%on of an aroma%c ring difficult in the laboratory Usually occurs via an enzyme in biological pathways

19 Friedel Craas Subs%tu%ons Two electrophilic subs%tu%ons are named for the chemists Charles Friedel and James Craas Friedel Craas acyla%on places an acyl group on a benzene ring Friedel Craas alkyla%on places an alkyl group on a benzene ring.

20 Alkyla%on among most useful electrophilic aroma%c subsitu%on reac%ons Aroma%c subs%tu%on of R + for H + Aluminum chloride promotes the forma%on of the carboca%on Alkyla%on of Aroma%c Rings: The Friedel Craas Reac%on

21 Limita%ons of the Friedel- Craas Alkyla%on Only alkyl halides can be used (F, Cl, I, Br) Aryl halides and vinylic halides do not react (their carboca%ons are too hard to form) Will not work with rings containing an amino group subs%tuent or a strongly electron- withdrawing group

22 Control Problems Mul%ple alkyla%ons can occur because the first alkyla%on is ac%va%ng

23 Carboca%on Rearrangements During Alkyla%on Similar to those that occur during electrophilic addi%ons to alkenes Can involve H or alkyl shias

24 Acyla%on of Aroma%c Rings Reac%on of an acid chloride (RCOCl) and an aroma%c ring in the presence of AlCl 3 introduces acyl group, COR Benzene with acetyl chloride yields acetophenone

25 Mechanism: Friedel Craas Acyla%on

26 Mechanism of Friedel- Craas Acyla%on Similar to alkyla%on Reac%ve electrophile: resonance- stabilized acyl ca%on An acyl ca%on does not rearrange

27 The Gaderman Koch Reac%on Benzaldehyde cannot be made by a Friedel Craas acyla%on because the needed acyl chloride (formyl chloride) is unstable Formyl chloride is generated in the reac%on mixture

28 Electrophilic Aroma%c Subs%tu%on Reac%on Pufng a Straight Chain Alkyl Group on a Ring

29 Other Ways to Convert a Carbonyl Group to a Methylene Group Mechanism for the Wolff Kishner Reduc%on

30 Coupling Reac%ons Can Be Used to Put a Straight Chain Alkyl Group on a Benzene Ring

31 Why it is Important to Have More Than One Way to Carry Out a Reac%on Cataly%c hydrogena%on reduces aroma%c nitro groups and carbonyl groups. Wolff Kishner reduc%on reduces only the carbonyl group.

32 Reduc%on of Benzene THE BIRCH REDUCTION: Aromatic rings are inert to catalyzed hydrogenation except under industrially extreme conditions. A useful alternative to hydrogenation is the BIRCH REDUCTION. The resulting diene can then be readily hydrogenated to the corresponding alkene or alkane using H 2 /Pd. H Li(0) NH 3, EtOH O H H Li(0) H O Li(0) H H

Reduc%on of Aroma%c Compounds Aroma%c rings are inert to cataly%c hydrogena%on under condi%ons that reduce alkene double bonds Can selec%vely reduce an

33 Reduc%on of Aroma%c Compounds Aroma%c rings are inert to cataly%c hydrogena%on under condi%ons that reduce alkene double bonds Can selec%vely reduce an alkene double bond in the presence of an aroma%c ring Reduc%on of an aroma%c ring requires more powerful reducing condi%ons (high pressure or rhodium catalysts)

34 Reduc%on of Aryl Alkyl Ketones Aroma%c ring ac%vates neighboring carbonyl group toward reduc%on Ketone is converted into an alkylbenzene by cataly%c hydrogena%on over Pd catalyst

35 Subs%tuents on a Benzene Ring Can Be Chemically Changed Bromine will selec%vely subs%tute for a benzylic hydrogen in a radical subs%tu%on reac%on. A halogen at the benzylic posi%on can lead to subs%tu%on or elimina%on.

36 Bromina%on of Alkylbenzene Side Chains Reac%on of an alkylbenzene with N- bromo- succinimide (NBS) and benzoyl peroxide (radical ini%ator) introduces Br into the side chain

37 Mechanism of NBS (Radical) Reac%on Abstrac%on of a benzylic hydrogen atom generates an intermediate benzylic radical Reacts with Br 2 to yield product Br radical cycles back into reac%on to carry chain Br 2 produced from reac%on of HBr with NBS

38 The Benzene Ring is Reduced Only at High Temperature and Pressure

39 Alkyl Subs%tuents are Oxidized to Carboxyl Groups

40 Oxida%on of Aroma%c Compounds Alkyl side chains can be oxidized to CO 2 H by strong reagents such as KMnO 4 and Na 2 Cr 2 O 7 if they have a C H next to the ring Converts an alkylbenzene into a benzoic acid, Ar R Ar CO 2 H

41 Nitro Subs%tuents are Reduced by Cataly%c Hydrogena%on

The Effect of Subs%tuents on Reac%vity Subs%tuents that donate electron density to the benzene ring increase benzene s nucleophilicity and stabilize the

42 The Effect of Subs%tuents on Reac%vity Subs%tuents that donate electron density to the benzene ring increase benzene s nucleophilicity and stabilize the carboca%on intermediate. Subs%tuents that withdraw electron density to the benzene ring decrease benzene s nucleophilicity and destabilize the carboca%on intermediate.

Subs%tuent Effects in Subs%tuted Aroma%c Rings Subs%tuents can cause a compound to be (much) more or (much) less reac%ve than benzene Subs%tuents affect the orienta%on of

43 Subs%tuent Effects in Subs%tuted Aroma%c Rings Subs%tuents can cause a compound to be (much) more or (much) less reac%ve than benzene Subs%tuents affect the orienta%on of the reac%on the posi%onal rela%onship is controlled ortho- and para- direc%ng ac%vators, ortho- and para- direc%ng deac%vators, and meta- direc%ng deac%vators (Table 16.1)

44 Origins of Subs%tuent Effects An interplay of induc4ve effects and resonance effects Induc%ve effect - withdrawal or dona%on of electrons through a σ bond Resonance effect - withdrawal or dona%on of electrons through a π bond due to the overlap of a p orbital on the subs%tuent with a p orbital on the aroma%c ring

45 Induc%ve Effects Controlled by electronega%vity and the polarity of bonds in func%onal groups Halogens, C=O, CN, and NO 2 withdraw electrons through σ bond connected to ring Alkyl groups donate electrons

46 Resonance Effects Electron Withdrawal C=O, CN, NO 2 subs%tuents withdraw electrons from the aroma%c ring by resonance π electrons flow from the rings to the subs%tuents

47 Resonance Effects Electron Dona%on Halogen, OH, alkoxyl (OR), and amino subs%tuents donate electrons π electrons flow from the subs%tuents to the ring Effect is greatest at ortho and para

48 Strongly Ac%va%ng Subs%tuents All the strongly ac%va%ng subs%tuents donate electrons by resonance. All the strongly ac%va%ng subs%tuents withdraw electrons induc%vely. Because the subs%tuents are ac%va%ng, electron dona%on by resonance is more significant than induc%ve electron withdrawal.

49 Moderately Ac%va%ng Subs%tuents Moderately ac%va%ng subs%tuents donate electrons by resonance.

intermediate (carboca%on) Deac%va%ng groups withdraw

51 An Explana%on of Subs%tuent Effects Ac%va%ng groups donate electrons to the ring, stabilizing the Wheland intermediate (carboca%on) Deac%va%ng groups withdraw electrons from the ring, destabilizing the Wheland intermediate

52 Ortho- and Para- Direc%ng Ac%vators: Alkyl Groups Alkyl groups ac%vate: direct further subs%tu%on to posi%ons ortho and para to themselves Alkyl group is most effec%ve in the ortho and para posi%ons

53 Ortho- and Para- Direc%ng Ac%vators: OH and NH 2 Alkoxyl, and amino groups have a strong, electron- dona%ng resonance effect Most pronounced at the ortho and para posi%ons

dona%ng resonance effect Resonance effect is only at the

54 Ortho- and Para- Direc%ng Deac%vators: Halogens Electron- withdrawing induc%ve effect outweighs weaker electron- dona%ng resonance effect Resonance effect is only at the ortho and para posi%ons, stabilizing carboca%on intermediate

55 Meta- Direc%ng Deac%vators Induc%ve and resonance effects reinforce each other Ortho and para intermediates destabilized by deac%va%on of carboca%on intermediate Resonance cannot produce stabiliza%on

56 Summary Table: Effect of Subs%tuents in Aroma%c Subs%tu%on

57 Subs%tuents on the Benzene Ring Affect the pka electron dona%ng groups decrease the acidity (destabilize the conjugate base) electron withdrawing groups increase the acidity (stabilize the conjugate base)

58 Subs%tuents on the Benzene Ring Affect the pka

59 Reac%ons of Monosubs%tuted Benzene

60 Halogena%on with a Strongly Ac%va%ng Group Present

61 Friedel Craas Reac%ons Do Not Occur with Meta Directors

62 Aniline Must Be Protected in Order to Be Nitrated Aniline cannot be nitrated directly because nitric acid will oxidize an NH 2 group. If the amino group is protected by acetyla%on, the ring can be nitrated. An acetyl group is removed by acid- catalyzed hydrolysis.

63 Synthesis OH

64 The Order of the Reac%ons is Important

65 Trisubs%tuted Benzenes: Addi%vity of Effects If the direc%ng effects of the two groups are the same, the result is addi%ve

66 Subs%tuents with Opposite Effects If the direc%ng effects of two groups oppose each other, the more powerful ac%va%ng group decides the principal outcome Usually gives mixtures of products

67 Meta- Disubs%tuted Compounds The reac%on site is too hindered To make aroma%c rings with three adjacent subs%tuents, it is best to start with an ortho- disubs%tuted compound

68 Nucleophilic Aroma%c Subs%tu%on Aryl halides do not react with nucleophiles because a nucleophile is repelled by the π electron cloud. Two different pathways are available for nucleophilic aroma%c subs%tu%on: 1) Bimolecular displacement mechanism for ac%vated aryl halides 2) Elimina%on- addi%on mechanism (Benzyne intermediate forma%on)

69 Nucleophilic Aroma%c Subs%tu%on Bimolecular Displacement Mechanism X Nu Nu +##X G G G#=#SO 3 H,#COOH,#COR,#NR 3 +,#NO 2,#NO,#CN#located#ortho#or#para#to#halogen# (leaving#group) In#nucleophilic#aromatic#substitution#reactions, ####!electron!withdrawing!group#causes#activation#(stabalizes#carbanion) #####electron!donating!group#causes#deactivation#(destabalizes#carbanion) ####OPPOSITE#TO#ELECTROPHILIC#AROMATIC#SUBSTITUTION

70 Nucleophilic Aroma%c Subs%tu%on Bimolecular Displacement Mechanism

71 The Mechanism for Nucleophilic Aroma%c Subs%tu%on The nucleophile adacks the carbon bonded to the leaving group from a trajectory that is nearly perpendicular to the aroma%c ring. The leaving group is eliminated, reestablishing the aroma%city of the ring.

72 Why the Electron Withdrawing Groups Must Be Ortho or Para to the Site of Adack Electrons can be delocalized onto ortho and para subs%tuents. Electrons cannot be delocalized onto a meta subs%tuent.

Form addi%on intermediate (Meisenheimer complex) that is

73 Nucleophilic Aroma%c Subs%tu%on Aryl halides with electron- withdrawing subs%tuents ortho and para react with nucleophiles Form addi%on intermediate (Meisenheimer complex) that is stabilized by electron- withdrawal Halide ion is lost to give aroma%c ring

74 Many Nucleophiles Can Engage in Nucleophilic Aroma%c Subs%tu%on The nucleophile must be a stronger base than the leaving group.

75 Nucleophilic Aroma%c Subs%tu%on Elimina%on- addi%on method Needs a strong base, and must have Hydrogen ortho to a leaving group (halogen) Forms benzyne intermediate

76 Benzyne Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340 C under high pressure The reac%on involves an elimina%on reac%on that gives a triple bond The intermediate is called benzyne

77 Structure of Benzyne Benzyne is a highly distorted alkyne The triple bond uses sp 2 - hybridized carbons, not the usual sp The triple bond has one π bond formed by p p overlap and another by weak sp 2 sp 2 overlap

78 Evidence for Benzyne as an Intermediate Bromobenzene with 14 C only at C1 gives subs%tu%on product with label scrambled between C1 and C2 Reac%on proceeds through a symmetrical intermediate in which C1 and C2 are equivalent must be benzyne

79 Synthesis of an Arenediazonium Salt The synthesis and denitrifica%on of diazonium salts is one of the most effec%ve methods for introducing a nucleophile to a benzene ring. The condi%ons are milder than those for nucleophilic aroma%c subs%tu%on and yields are generally good. NH 2 HNO 2,&H 2 SO 4 N N Nu 0& C +""HSO 4 """"+""2"H 2 O Nu +&&N 2

80 Mechanism for Forma%on of the Nitrosonium Ion Hydrochloric acid protonates the nitrite ion, forming nitrous acid. Hydrochloric acid protonates nitrous acid. Protonated nitrous acid loses water to form the nitrosonium ion. The nitrosonium ion is the electrophile required to form a diazonium ion.

81 Sandmeyer Reac%ons

82 Mechanism for Diazonium Ion Forma%on

83 The Sandmeyer Reac%on Can Be a Useful Alterna%ve for Halogena%on Chlorina%on of ethylbenzene leads to a mixture of ortho and para isomers A Sandmeyer reac%on forms only the para product.

84 Aryl Fluorides and Iodides Can Be Made from Arenediazonium Salts

85 Phenols Can Be Made from Arenediazonium Salts An acidic aqueous solu%on of a diazonium salt that warms up forms a phenol. Copper(I) oxide and copper(ii) nitrate can be added to get a higher yield of a phenol.

86 A Diazonium Group Can Be Replaced by a Hydrogen

87 The Arenediazonium Ion Reacts as an Electrophile with Highly Ac%vated Rings The product of the reac%on is an azo compound. The N N linkage is called an azo linkage.

88 The Mechanism The electrophile adds to the benzene ring. A base in the solu%on removes the proton from the carbon that formed the bond with the electrophile.

89 Azo Compounds Have Geometric Isomers

Chapter 16- Chemistry of Benzene: Electrophilic Aromatic Substitution

Chapter 16- Chemistry of Benzene: Electrophilic Aromatic Substitution Ashley Piekarski, Ph.D. Substitution Reactions of Benzene and Its Derivatives Benzene is aroma%c What does aromatic mean? Reac9ons