16. Chemistry of Benzene: Electrophilic Aromatic Substitution
Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6 electrons Reactions of benzene lead to the retention of the aromatic core
Why this Chapter? Continuation of coverage of aromatic compounds in preceding chapter…focus shift to understanding reactions Examine relationship between aromatic structure and reactivity Relationship critical to understanding of how biological molecules/pharmaceutical agents are synthesized
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.
EAS: Bromination EAS occurs in two steps: Addition followed by Elimination FeBr3 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) Addition The cationic addition intermediate is called a sigma complex
EAS: Bromination EAS occurs in two steps: Addition followed by Elimination The 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) Addition Elimination
EAS: Bromination EAS occurs in two steps: Addition followed by Elimination The 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
16.2 Other Aromatic Substitutions Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution products Chlorination requires FeCl3 Iodine must be oxidized (with Cu+ or peroxide) to form a more powerful I+ species
Example: A common Amino Acid
Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion) The reaction with benzene produces nitrobenzene
Reduction of Nitration Product: To put an amino (NH2) group on an aromatic ring first Nitrate then reduce
Aromatic Sulfonation Substitution of H by SO3 (sulfonation) with a mixture of sulfuric acid and SO3 Reactive species is sulfur trioxide or its conjugate acid Reaction is Reversible: Can remove sulfonyl group with H+,H2O, heat
Aromatic Hydroxylation Hard to directly add –OH to an aromatic ring in lab. Formation of Electrophile
Aromatic Hydroxylation Biological systems use Enzymes to hydroxylate aromatics
16.3 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Electrophilic C+ forms Alkylation (substitution of Carbon compounds) among most useful electrophilic aromatic subsitution reactions Aromatic substitution of R+ for H+ Aluminum chloride promotes the formation of the carbocation Addition Elimination
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
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)
Friedel-Crafts Alkylation: Control Problems Carbocation Rearrangements Similar to those that occur during electrophilic additions to alkenes Can involve H or alkyl shifts
Example:
Friedel-Crafts Acylation Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, COR Benzene with acetyl chloride yields acetophenone
Friedel-Crafts Acylation: Mechanism Similar to alkylation Reactive electrophile: resonance-stabilized acyl cation An acyl cation does not rearrange Electrophilic C+ forms = Acylium ion Addition Elimination
EAS: Summary
16.4 Substituent Effects Nucleophile Electrophile Substituents that donate electrons make ring more nucleophilic Electron donating groups (edg) activate the ring toward EAS Substitutients that withdraw electrons make less nucleophilic Electron withdrawing groups (ewg) deactivate the ring toward EAS
Substituent Effects Substituents influence by induction edg activate the ring toward EAS ewg deactivate the ring toward EAS Halogens, C=O, CN, and NO2 withdraw electrons through s bond connected to ring Alkyl groups donate electrons
Substituent Effects Substituents influence by resonance Halogen, OH, alkoxyl (OR), and amino substituents donate electrons edg activate the ring toward EAS
Substituent Effects Substituents influence by resonance C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance ewg deactivate the ring toward EAS
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- spots ewgs put positive character at o- and p- positions (make o- and p- positions less nucleophilic) Direct incoming electrophile into m- spots
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
16.5 Ortho- & Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions ortho and para to themselves Alkyl group is most effective in the ortho and para positions
Ortho- and Para-Directing Activators: OH and NH2 Alkoxyl, and amino groups have a strong, electron-donating resonance effect Most pronounced at the ortho and para positions
Ortho- & Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate
Meta-Directing Deactivators Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by deactivation of carbocation intermediate Resonance cannot produce stabilization
Summary:
Another Summary:
16.6 Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive
Learning Check: Br2, FeBr3 ?
Solution: Br2, FeBr3 ?
Substituents with Opposite Effects If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome Usually gives mixtures of products
Meta-Disubstituted Compounds The reaction site is too hindered To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound
16.7 Nucleophilic Aromatic Substitution Aryl halides with ewg’s o- and p- react with nucleophiles Sanger’s reagent: For labeling proteins in biochemistry
Nucleophilic Aromatic Substitution
Nucleophilic Aromatic Substitution
Nucleophilic Aromatic Substitution ewg’s o- and p- stabilize the intermediate Intermediate Meisenheimer complex is stabilized by electron-withdrawal Halide ion is lost to give aromatic ring
16.8 Benzyne Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure Elimination reaction gives a triple bond intermediate called benzyne
Evidence for Benzyne Bromobenzene with 14C* only at C1 gives substitution product with label scrambled between C1 and C2 Reaction proceeds through a symmetrical intermediate in which C1 & C2 are equivalent— must be benzyne
Structure of Benzyne Benzyne is a highly distorted alkyne The triple bond uses sp2-hybridized carbons, not the usual sp The triple bond has one bond formed by p–p overlap and another by weak sp2–sp2 overlap
16.9 Benzylic Oxidation Alkyl side chains with a C-H next to the ring can be oxidized to CO2H by strong reagents such as KMnO4 and Na2Cr2O7 O2, Co(III) Converts an alkylbenzene into a benzoic acid, ArR ArCO2H
Examples:
Benzylic Bromination Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain
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 product Br· radical cycles back into reaction to carry chain
Mechanism of NBS (Radical) Reaction Benzylic radical is stabilized by resonance
16.10 Aromatic Reductions Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the presence of an aromatic ring
Aromatic Reductions Reduction of aromatic ring requires more powerful reducing conditions high pressure rhodium catalysts
Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group toward reduction Ketone is converted into an alkylbenzene by cat H2/Pd
Examples:
Learning Check: Synthesize para-chlorobenzoic acid from benzene. Synthesize meta-chlorobenzoic acid from benzene.
Solution: Synthesize para-chlorobenzoic acid from benzene. Synthesize meta-chlorobenzoic acid from benzene.
16.11 Synthesis of Trisubstituted Benzenes plan a sequence of reactions in right order is valuable to synthesis of substituted aromatic rings
Synthesis of Trisubstituted Benzenes Work Backwards
Synthesis of Trisubstituted Benzenes Work Backwards
Synthesis of Trisubstituted Benzenes
Learning Check: Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.
Solution: Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.
Learning Check: Which of the following groups is an activator?
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.
Learning Check: Which of the following groups is an ortho- para- director? -Cl -CHO -CN -NO2 None of the above
Solution: Which of the following groups is an ortho- para- director? -Cl -CHO -CN -NO2 None of the above Although –Cl is a deactivator, it’s lone pairs of electrons stabilize electrophilic aromatic substitution reactions and it is an o- p- director.
Learning Check: Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation? -NH2 -OCH3 -O-C(=O)CH3 NO2 H
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)CH3 NO2 H
Learning Check: Which compound is the major product of the chlorination shown below?
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.
Learning Check: Which step in the following reaction will cause the proposed synthesis to fail?
Solution: Which step in the following reaction will cause the proposed synthesis to fail? Addition of water in step “D” occurs with Markovnikov selectivity.
What is the major product of the reaction of nitrobenzene with Br2/FeBr3? 1. 2. 3. 4. 5. 1 2 3 4 5
Which of the following compounds would react fastest with HNO3/H2SO4? nitrobenzene (PhNO2) toluene (PhCH3) bromobenzene (PhBr) anisole (PhOCH3) benzoic acid (PhCOOH)
Which structure is a major intermediate formed in the electrophilic nitration of chlorobenzene? 1. 2. 3. 5. 4. 1 2 3 4 5
Which series of reactions will convert benzene into p-nitrobenzoic acid? CH3Br/AlBr3 followed by HNO3/H2SO4 followed by KMnO4/H2O HNO3/H2SO4 followed by KMnO4/H2O followed by CH3Br/AlBr3 KMnO4/H2O followed by CH3Br/FeBr3 followed by HNO3/H2SO4 CH3Br/AlBr3 followed by KMnO4/H2O followed by HNO3/H2SO4 HNO3/H2SO4 followed by CH3Br/AlBr3 followed by KMnO4/H2O
Select the major product of the following reaction. 1. 2. 3. 4. 5. 1 2 3 4 5
What is the electrophile in the following aromatic substitution? 2. 1. 3. 5. 4. 1 2 3 4 5
What is the best sequence of reactions to synthesize the desired product (Pr = propyl)? Step 1 Step 2 Step 3 1 HNO3/H2SO4 PrMgBr/H3O+ H2/Pd 2 AlCl3/PrBr 3 AlCl3/PrCl 4 5 AlCl3/CH3CH2COCl X
What are the reagents necessary for step 3 in the following transformation? CH3COCl/AlCl3 CH3CH2Br/AlBr3 SO3/H2SO4 H2/Pd SOCl2/AlCl3
Which of the following carbons of the benzyl radical has the smallest unpaired electron density? 1 2 3 4 5
What would be the main product of nitration of benzenesulfonic acid? o-nitrobenzenesulfonic acid p-nitrobenzenesulfonic acid 2-nitrobenzoic acid m-nitrobenzenesulfonic acid m-nitrobenzoic acid
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.
Which of the following represent the intermediate formed in the reaction between p-chloronitrobenzene and hydroxide ion? 1. 2. 3. 4. 5. 1 2 3 4 5
Based on the electronic structure, what kind of substituent effect would you expect from the nitroso group? o,p-directing, deactivating o,p-directing activating m-directing, activating m-directing, deactivating
Which one is not a limitation of Friedel-Crafts alkylations? carbocation rearrangements may occur polyalkylation products are possible only substrates with selected activating groups can be used vinyl halides cannot be used to generate electrophiles the halogen in the aluminum halide must match one in the alkyl halide
What is the major product of the following reaction? 1. 2. 3. 5. 4. 1 2 3 4 5
What is the result of the reaction between m-bromotoluene and sodium amide? 2-aminotoluene 3-aminotoluene 4-aminotoluene all of these none of these
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? 1. 2. 3. 5. 4. 1 2 3 4 5
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/H2SO4 Cl2/FeBr3 I2/CuCl2 SO3/H2SO4 CH3COCl/AlBr3