Presentation on theme: "16. Chemistry of Benzene: Electrophilic Aromatic Substitution"— Presentation transcript:
1 16. Chemistry of Benzene: Electrophilic Aromatic Substitution
2 Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6 electronsReactions of benzene lead to the retention of the aromatic core
3 Why this Chapter?Continuation of coverage of aromatic compounds in preceding chapter…focus shift to understanding reactionsExamine relationship between aromatic structure and reactivityRelationship critical to understanding of how biological molecules/pharmaceutical agents are synthesized
4 16.1 Electrophilic Aromatic Substitution Reactions (EAS): Reactions typical of addition to alkenes do not work on aromatic double bonds.Need more electrophilic (more positive) halogen in order to break an aromatic double bond.
5 EAS: BrominationEAS occurs in two steps: Addition followed by EliminationFeBr3 acts as a catalyst to polarize the bromine reagent and so make it more positive (more electrophilic)The electrons of the aromatic ring act as a nucleophile toward the now more electrophilic Br2 (in the FeBr3 complex)AdditionThe cationic addition intermediate is called a sigma complex
6 EAS: BrominationEAS occurs in two steps: Addition followed by EliminationThe cationic addition intermediate (sigma complex) transfers a proton to FeBr4- (from Br- and FeBr3)Aromaticity is restored(in contrast with addition in alkenes which is not followed by elimination)AdditionElimination
7 EAS: BrominationEAS occurs in two steps: Addition followed by EliminationThe cationic addition intermediate (sigma complex) transfers a proton to FeBr4- (from Br- and FeBr3)Aromaticity is restored(in contrast with addition in alkenes which is not followed by elimination)Elimination is driven by the stability of becoming aromatic
8 16.2 Other Aromatic Substitutions Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution productsChlorination requires FeCl3Iodine must be oxidized (with Cu+ or peroxide)to form a more powerful I+ species
10 Aromatic NitrationThe combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion)The reaction with benzene produces nitrobenzene
11 Reduction of Nitration Product: To put an amino (NH2) group on an aromatic ringfirst Nitratethen reduce
12 Aromatic SulfonationSubstitution of H by SO3 (sulfonation) with a mixture of sulfuric acid and SO3Reactive species is sulfur trioxide or its conjugate acidReaction is Reversible:Can remove sulfonyl group with H+,H2O, heat
13 Aromatic Hydroxylation Hard to directly add –OH to an aromatic ring in lab.Formation of Electrophile
14 Aromatic Hydroxylation Biological systems use Enzymes to hydroxylate aromatics
15 16.3 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Electrophilic C+ formsAlkylation (substitution of Carbon compounds) among most useful electrophilic aromatic subsitution reactionsAromatic substitution of R+ for H+Aluminum chloride promotes the formation of the carbocationAdditionElimination
16 Friedel-Crafts Alkylation: Limitations Only alkyl halides can be used (F, Cl, I, Br)Aryl halides (Ar-X) and vinylic halides (CH2=CH-X) do not react (their carbocations are too hard to form)Will not work with rings containing an amino group substituent or a strongly electron-withdrawing group
17 Friedel-Crafts Alkylation: Control Problems Multiple alkylations can occur because the first alkylation is activating (makes aromatic ring more nucleophilic so more likely to add again)
18 Friedel-Crafts Alkylation: Control Problems Carbocation RearrangementsSimilar to those that occur during electrophilic additions to alkenesCan involve H or alkyl shifts
20 Friedel-Crafts Acylation Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, CORBenzene with acetyl chloride yields acetophenone
21 Friedel-Crafts Acylation: Mechanism Similar to alkylationReactive electrophile: resonance-stabilized acyl cationAn acyl cation does not rearrangeElectrophilic C+ forms= Acylium ionAdditionElimination
23 16.4 Substituent EffectsNucleophileElectrophileSubstituents that donate electrons make ring more nucleophilicElectron donating groups (edg) activate the ring toward EASSubstitutients that withdraw electrons make less nucleophilicElectron withdrawing groups (ewg) deactivate the ring toward EAS
24 Substituent Effects Substituents influence by induction edg activate the ring toward EASewg deactivate the ring toward EASHalogens, C=O, CN, and NO2 withdraw electrons through s bond connected to ringAlkyl groups donate electrons
25 Substituent Effects Substituents influence by resonance Halogen, OH, alkoxyl (OR), and amino substituents donate electronsedg activate the ring toward EAS
26 Substituent Effects Substituents influence by resonance C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonanceewg deactivate the ring toward EAS
27 Substituent Effects Substituents influence by resonance edgs put negative character at o- and p- positions(make o- and p- positions more nucleophilic)Direct incoming electrophile into o- or p- spotsewgs put positive character at o- and p- positions(make o- and p- positions less nucleophilic)Direct incoming electrophile into m- spots
29 Explanation of Substituent Effects Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation)Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate
30 16.5 Ortho- & Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions ortho and para to themselvesAlkyl group is most effective in the ortho and para positions
31 Ortho- and Para-Directing Activators: OH and NH2 Alkoxyl, and amino groups have a strong, electron-donating resonance effectMost pronounced at the ortho and para positions
32 Ortho- & Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effectResonance effect is only at the ortho and para positions, stabilizing carbocation intermediate
33 Meta-Directing Deactivators Inductive and resonance effects reinforce each otherOrtho and para intermediates destabilized by deactivation of carbocation intermediateResonance cannot produce stabilization
45 Nucleophilic Aromatic Substitution ewg’s o- and p- stabilize the intermediateIntermediate Meisenheimer complex is stabilized by electron-withdrawalHalide ion is lost to give aromatic ring
46 16.8 BenzynePhenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressureElimination reaction gives a triple bond intermediate called benzyne
47 Evidence for BenzyneBromobenzene with 14C* only at C1 gives substitution product with label scrambled between C1 and C2Reaction proceeds through a symmetrical intermediate in which C1 & C2 are equivalent— must be benzyne
48 Structure of Benzyne Benzyne is a highly distorted alkyne The triple bond uses sp2-hybridized carbons, not the usual spThe triple bond has one bond formed by p–p overlap and another by weak sp2–sp2 overlap
49 16.9 Benzylic OxidationAlkyl side chains with a C-H next to the ring can be oxidized to CO2H by strong reagents such asKMnO4 andNa2Cr2O7O2, Co(III)Converts an alkylbenzene into a benzoic acid,ArR ArCO2H
51 Benzylic BrominationReaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain
52 Mechanism of NBS (Radical) Reaction Abstraction of a benzylic hydrogen atom by a bromine radical generates an intermediate benzylic radical which reacts with Br2 to yield productBr· radical cycles back into reaction to carry chain
53 Mechanism of NBS (Radical) Reaction Benzylic radical is stabilized by resonance
54 16.10 Aromatic ReductionsAromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bondsCan selectively reduce an alkene double bond in the presence of an aromatic ring
55 Aromatic ReductionsReduction of aromatic ring requires more powerful reducing conditionshigh pressurerhodium catalysts
56 Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group toward reductionKetone is converted into an alkylbenzene by cat H2/Pd
64 Learning Check:Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.
65 Solution:Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.
66 Learning Check:Which of the following groups is an activator?
67 Solution: Which of the following groups is an activator? Generally and except for the halogens, groups with lone pairs of electrons adjacent to the ring are activators.
68 Learning Check:Which of the following groups is an ortho- para- director?-Cl-CHO-CN-NO2None of the above
69 Solution: Which of the following groups is an ortho- para- director? -Cl-CHO-CN-NO2None of the aboveAlthough –Cl is a deactivator, it’s lone pairs of electrons stabilize electrophilic aromatic substitution reactions and it is an o- p- director.
70 Learning Check:Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation?-NH2-OCH3-O-C(=O)CH3NO2H
71 Solution:Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation?Although the –NH2 group is a stronger activator it complexes with AlCl3 to form a strongly deactivating ammonium group. Consequently, the methoxy is a better activator.-NH2-OCH3-O-C(=O)CH3NO2H
72 Learning Check:Which compound is the major product of the chlorination shown below?
73 Solution:Which compound is the major product of the chlorination shown below?The nitrogen is an activator and o- p- director. The C=O is a deactivator.
74 Learning Check:Which step in the following reaction will cause the proposed synthesis to fail?
75 Solution:Which step in the following reaction will cause the proposed synthesis to fail?Addition of water in step “D” occurs with Markovnikov selectivity.
76 What is the major product of the reaction of nitrobenzene with Br2/FeBr3? 18.104.22.168.5.12345
77 Which of the following compounds would react fastest with HNO3/H2SO4? nitrobenzene (PhNO2)toluene (PhCH3)bromobenzene (PhBr)anisole (PhOCH3)benzoic acid (PhCOOH)
78 Which structure is a major intermediate formed in the electrophilic nitration of chlorobenzene? 22.214.171.124.4.12345
79 Which series of reactions will convert benzene into p-nitrobenzoic acid? CH3Br/AlBr3 followed by HNO3/H2SO4 followed by KMnO4/H2OHNO3/H2SO4 followed by KMnO4/H2O followed by CH3Br/AlBr3KMnO4/H2O followed by CH3Br/FeBr3 followed by HNO3/H2SO4CH3Br/AlBr3 followed by KMnO4/H2O followed by HNO3/H2SO4HNO3/H2SO4 followed by CH3Br/AlBr3 followed by KMnO4/H2O
80 Select the major product of the following reaction. 126.96.36.199.5.12345
81 What is the electrophile in the following aromatic substitution? 188.8.131.52.4.12345
82 What is the best sequence of reactions to synthesize the desired product (Pr = propyl)? Step 1Step 2Step 31HNO3/H2SO4PrMgBr/H3O+H2/Pd2AlCl3/PrBr3AlCl3/PrCl45AlCl3/CH3CH2COClX
83 What are the reagents necessary for step 3 in the following transformation? CH3COCl/AlCl3CH3CH2Br/AlBr3SO3/H2SO4H2/PdSOCl2/AlCl3
84 Which of the following carbons of the benzyl radical has the smallest unpaired electron density? 12345
85 What would be the main product of nitration of benzenesulfonic acid? o-nitrobenzenesulfonic acidp-nitrobenzenesulfonic acid2-nitrobenzoic acidm-nitrobenzenesulfonic acidm-nitrobenzoic acid
86 Fluorine is less deactivating than chlorine in the aromatic electrophilic substitution reactions. What is the main reason for this reactivity trend?Fluorine forms stronger π bonds than chlorine, providing more resonance stabilization.Chlorine is more electronegative than fluorine.Because of it size chlorine has stronger inductive influence than fluorine.Fluorine is smaller, making the entry of electrophiles easier.Chlorine forms complexes with electrophiles, diminishing their reactivity.
87 Which of the following represent the intermediate formed in the reaction between p-chloronitrobenzene and hydroxide ion?184.108.40.206.5.12345
88 Based on the electronic structure, what kind of substituent effect would you expect from the nitroso group?o,p-directing, deactivatingo,p-directing activatingm-directing, activatingm-directing, deactivating
89 Which one is not a limitation of Friedel-Crafts alkylations? carbocation rearrangements may occurpolyalkylation products are possibleonly substrates with selected activating groups can be usedvinyl halides cannot be used to generate electrophilesthe halogen in the aluminum halide must match one in the alkyl halide
90 What is the major product of the following reaction? 220.127.116.11.4.12345
91 What is the result of the reaction between m-bromotoluene and sodium amide? 2-aminotoluene3-aminotoluene4-aminotolueneall of thesenone of these
92 Aromatic compounds can be oxidized to their radical cations by removal of just one electron. Which of the following will be the easiest to oxidize to a radical cation?18.104.22.168.4.12345
93 HNO3/H2SO4 Cl2/FeBr3 I2/CuCl2 SO3/H2SO4 CH3COCl/AlBr3 Which of the following is not a practical method to generate an electrophile for aromatic substitution reaction?HNO3/H2SO4Cl2/FeBr3I2/CuCl2SO3/H2SO4CH3COCl/AlBr3