Chapter 12 Reactions of Arenes: Electrophilic and NucleophilicAromatic Substitution + Y + – X Nu + :Nu- :X- Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1

12.1 Representative Electrophilic Aromatic Substitution Reactions of Benzene + Y + – 3

Electrophilic aromatic substitutions (EAS) include: + Y + – Electrophilic aromatic substitutions (EAS) include: 1. Halogenation 2. Nitration 3. Sulfonation 4. Friedel-Crafts Alkylation 5. Friedel-Crafts Acylation 5

Table 12.1: Halogenation of Benzene FeBr3 Br + Br2 + HBr heat Bromobenzene (65-75%) Note: This reaction does not go via a radical mechanism like halogenation of alkanes nor does it proceed spontaneously like halogenation of alkenes, it requires a Lewis acid catalyst and heat. 6

Table 12.1: Nitration of Benzene H H2SO4 NO2 + HONO2 + H2O heat Nitrobenzene (95%) 6

Table 12.1: Sulfonation of Benzene H heat SO2OH + HOSO2OH + H2O fuming Benzenesulfonic acid (100%) Note: fuming H2SO4 contains dissolved SO3. 6

Table 12.1: Friedel-Crafts Alkylation of Benzene H AlCl3 C(CH3)3 + (CH3)3CCl + HCl ~00 C tert-Butylbenzene (60%) Note: Once attached, the alkyl group activates the ring. 6

Table 12.1: Friedel-Crafts Acylation of Benzene CCH2CH3 O O CH3CH2CCl H AlCl3 + + HCl ~00 C 1-Phenyl-1-propanone (88%) Note: Once attached, the alkyl group deactivates the ring. 6

12.2 Mechanistic Principles of Electrophilic Aromatic Substitution 11

Step 1: Attack of Electrophile on -electron System of Aromatic Ring + A highly endothermic step (need to overcome the resonance energy of the ring). The carbocation is allylic, but the ring has lost aromatic character. 12

Step 2: Loss of a Proton from the Carbocation Intermediate + H H H H H H+ The second step is highly exothermic; this step restores the aromatic character of the ring and the resonance energy is regained. In this step, the proton is always removed from the carbon to which the electrophile added. 12

Energy diagram for the two step EAS reaction. + H + E+ E H + H+ 6

Based on this General Mechanism: Identify the electrophile in each EAS reaction: nitration, sulfonation, halogenation, Friedel-Crafts alkylation, and Friedel-Crafts acylation. Establish the mechanism of each specific electrophilic aromatic substitution reaction. 14

12.3 Nitration of Benzene 15

Electrophile is nitronium ion. O N + Nitration of Benzene H H2SO4 NO2 + HONO2 + H2O heat Electrophile is nitronium ion. O N •• + • 6

Where does Nitronium Ion Come From ? •• + • H O N H + •• • – O N H + •• • – H2SO4 H2SO4 is a stronger acid than HNO3 and forces it to take a proton. 21

Step 2: Loss of a Proton from the Carbocation Intermediate Step 1: Attack of Nitronium Cation on the -electron system of the Aromatic Ring H NO2+ H NO2 + Step 2: Loss of a Proton from the Carbocation Intermediate H H NO2 H H H H NO2 + H H H H H H+ 12

12.4 Sulfonation of Benzene 22

Sulfonation of Benzene H heat SO2OH + HOSO2OH + H2O The major electrophile is sulfur trioxide, SO3. O S + •• • – 6

Step 2: Loss of a Proton from the Carbocation Intermediate Step 1: Attack of Sulfur Trioxide on the -electron system of the Aromatic Ring H SO3 H SO3– + Step 2: Loss of a Proton from the Carbocation Intermediate H H SO3– H SO3– H+ H + H H H 12

Step 3: Protonation of the Benzenesulfonate Ion SO3– H2SO4 H SO3H This is the only EAS reaction that is reversible. 12

12.5 Halogenation of Benzene (See the note on slide 4.) 24

Halogenation of Benzene FeBr3 Br + Br2 + HBr heat Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2. 6

The Br2-FeBr3 complex is more electrophilic than Br2 alone. • •• FeBr3 – + Complex • Br •• + FeBr3 Lewis base Lewis acid The Br2-FeBr3 complex is more electrophilic than Br2 alone. 21

Step 2: Loss of a Proton from the Carbocation Intermediate Step 1: Attack of Br2-FeBr3 Complex on the -electron System of the Aromatic Ring + – Br Br FeBr3 H Br + H H H H H H + FeBr4– Step 2: Loss of a Proton from the Carbocation Intermediate H H Br H H H H Br + H H H H H H+ 12

12.6 Friedel-Crafts Alkylation of Benzene 27

Friedel-Crafts Alkylation of Benzene H AlCl3 C(CH3)3 + (CH3)3CCl + HCl Electrophile is tert-butyl cation. C CH3 H3C + 6

AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide. Role of AlCl3 AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide. + (CH3)3C Cl •• AlCl3 – •• (CH3)3C • Cl + AlCl3 •• (CH3)3C + Cl •• AlCl3 – • 29

Step 2: Loss of a Proton from the Carbocation Intermediate Step 1: Attack of tert-Butyl carbocation on the -electron System of the Aromatic Ring C(CH3)3 + H C(CH3)3 + H H H H H H Step 2: Loss of a Proton from the Carbocation Intermediate H H C(CH3)3 H C(CH3)3 H+ H + H H H 12

Rearrangements in Friedel-Crafts Alkylation Carbocations are intermediates in this mechanism, therefore, rearrangements can occur. Here, isobutyl chloride is the alkyl halide, but tert-butyl cation is the electrophile due to rearrangement. H (CH3)2CHCH2Cl AlCl3 Isobutyl chloride tert-Butylbenzene (66%) C(CH3)3 + 34

Rearrangements in Friedel-Crafts Alkylation Alkyl halide:AlCl3 complex. •• C CH2 H3C CH3 H Cl AlCl3 + – C CH2 H3C CH3 H + Cl •• AlCl3 – • Rearranged alkyl carbocation. 35

Reactions Related to Friedel-Crafts Alkylation H H2SO4 + Cyclohexylbenzene (65-68%) Cyclohexene is protonated by sulfuric acid, to give the cyclohexyl carbocation which attacks the benzene ring. 38

12.7 Friedel-Crafts Acylation of Benzene 39

Friedel-Crafts Acylation of Benzene H AlCl3 CCH2CH3 + CH3CH2CCl + HCl Electrophile is an acyl carbocation (an acylium ion). •• CH3CH2C O • + 6

AlCl3 acts as a Lewis acid to promote ionization of the acyl halide. Step 1: Attack of the acyl carbocation on the -electron System of the Aromatic Ring AlCl3 acts as a Lewis acid to promote ionization of the acyl halide. O CCH2CH3 + H + O CCH2CH3 H H H H H H 12

Step 2: Loss of a Proton from the Carbocation Intermediate + O CCH2CH3 H H+ O CCH2CH3 12

Anhydrides can be used instead of acyl chlorides. O Acid Anhydrides Anhydrides can be used instead of acyl chlorides. O CCH3 O CH3COCCH3 H AlCl3 + Acetophenone (76-83%) O CH3COH + 43

12.8 Synthesis of Alkylbenzenes by Acylation-Reduction 4 4

Acylation-Reduction Permits monosubstitution of primary alkyl groups on an aromatic ring in acid media. O CR O H RCCl AlCl3 Zn(Hg), HCl CH2R Reduction of aldehyde and ketone carbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction. 45

Acylation-Reduction Permits monosubstitution of primary alkyl groups on an aromatic ring in basic media. O CR O H RCCl H2NNH2, KOH, triethylene glycol, heat AlCl3 Reduction of aldehyde and ketone carbonyl groups by heating with H2NNH2 and KOH is called the Wolff-Kishner reduction. CH2R 45

Example: Prepare Isobutylbenzene This does not work ! (CH3)2CHCH2Cl CH2CH(CH3)3 AlCl3 No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement. 46

tert-Butylbenzene (66%) Recall rearrangement ! C(CH3)3 AlCl3 + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene (66%) Note that although alkyl carbocations may rearrange, acylium ions do not. 34

So, Use Acylation-Reduction Instead (CH3)2CHCCl O + AlCl3 CH2CH(CH3)2 Zn(Hg) HCl O CCH(CH3)2 34

12.9 Rate and Regioselectivity in Electrophilic Aromatic Substitution A substituent already present on the ring can affect both the rate and regioselectivity of electrophilic aromatic substitution. 4 4

Effect on Rate Activating substituents increase the rate of EAS compared to that of benzene. Activating substituents are typically electron donating groups. Deactivating substituents decrease the rate of EAS compared to benzene. Deactivating substituents are typically electron withdrawing groups. 2

Toluene undergoes nitration 20-25 times faster than benzene. Methyl Group CH3 Toluene undergoes nitration 20-25 times faster than benzene. A methyl group is an activating substituent. CF3 (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene. A trifluoromethyl group is a deactivating substituent. 3

Effect on Regioselectivity Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Ortho-para directors are typically electron donating groups. Meta directors direct an incoming electrophile to positions meta to themselves. Meta directors are typically electron withdrawing groups. 5

O- and p-nitrotoluene together comprise 97% of the product. Nitration of Toluene CH3 CH3 NO2 CH3 NO2 CH3 NO2 acetic anhydride HNO3 + + 63% 3% 34% O- and p-nitrotoluene together comprise 97% of the product. A methyl group is an ortho-para director. 6

Nitration of (Trifluoromethyl)benzene CF3 NO2 CF3 NO2 CF3 NO2 CF3 HNO3 H2SO4 + + 6% 91% 3% M-nitro(trifluoromethyl)benzene comprises 91% of the product. A trifluoromethyl group is a meta director. 6

12.10 Rate and Regioselectivity in the Nitration of Toluene 4 4

Carbocation Stability Controls Regioselectivity Which intermediate leads to product ? more stable less stable + H CH3 NO2 + H NO2 CH3 + H NO2 CH3 gives ortho gives para gives meta 10

ortho Nitration of Toluene CH3 H CH3 NO2 + H CH3 NO2 + + NO2 H H H H H The last resonance structure is a 3o carbocation and is the rate-determining intermediate in the ortho nitration of toluene. 12

para Nitration of Toluene H NO2 CH3 H NO2 CH3 H NO2 CH3 + + + The center resonance structure is a 3o carbocation and is the rate-determining intermediate in the para nitration of toluene. 12

meta Nitration of Toluene H NO2 CH3 H NO2 CH3 + H NO2 CH3 + + All the resonance forms of the rate-determining intermediates in the meta nitration of toluene are 2o carbocations and none is adjacent to the electron donating substituent. 14

Nitration of Toluene: Interpretation The rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation and it is next to the electron donating group. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations and none are next to the electron donating group. 15

Nitration of Toluene: Interpretation Tertiary carbocations, being more stable, are formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. So, the major products are o- and p-nitrotoluene. 15

Nitration of Toluene: Partial Rate Factors The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions. Expressed as a numerical value, a partial rate factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene. 15

Nitration of Toluene: Partial Rate Factors CH3 1 1 1 42 42 1 1 2.5 2.5 1 58 All of the available ring positions in toluene are more reactive than a single position of benzene. A methyl group activates all of the ring positions, but the effect is greatest at the ortho and para positons. Steric hindrance by the methyl group makes each ortho position slightly less reactive than para. 15

Nitration of Toluene vs. tert-Butylbenzene CH3 75 3 4.5 C H3C CH3 42 2.5 58 tert-Butyl is activating and ortho-para directing. tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions. 15

Generalization All alkyl groups are activating, ortho-para directing and electron donating. Note: The rate and regioselectivity effects in EAS of substituted benzenes is controlled by the substituent on the ring. The attacking electrophile has no influence on these effects. 17

12.11 Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 4 4

A methyl group is electron-donating and stabilizes a carbocation. A Key Point C + H3C C + F3C A methyl group is electron-donating and stabilizes a carbocation. Because F is so electronegative, a CF3 group destabilizes a carbocation. 17

Carbocation Stability Controls Regioselectivity Which intermediate leads to product ? less stable more stable + H CF3 NO2 gives ortho + H NO2 CF3 gives para + H NO2 CF3 gives meta more destabilized less destabilized 10

ortho Nitration of (Trifluoromethyl)benzene CF3 CF3 CF3 NO2 NO2 NO2 + H H H + H H H + H H H H H H H H H The resonance form on the right of the rate-determining intermediate in the ortho nitration of (trifluoromethyl)benzene is strongly destabilized next to the e-withdrawing group. 12

para Nitration of (Trifluoromethyl)benzene CF3 H NO2 CF3 H NO2 CF + + + The center of the resonance forms of the rate-determining intermediate in the para nitration of (trifluoromethyl)benzene is strongly destabilized next to the e-withdrawing group. 12

meta Nitration of (Trifluoromethyl)benzene + H NO2 CF3 H NO2 CF3 + H NO2 CF3 + None of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)-benzene have their positive charge on the carbon that bears the CF3 group. Meta is least destabilized. 14

Nitration of (Trifluoromethyl)benzene: Interpretation The rate-determining intermediates for ortho and para nitration each have a resonance form in which the positive charge is on a carbon that bears a CF3 group. Such a resonance structure is strongly destabilized. The intermediate in meta nitration avoids such a structure. It is the least unstable of three unstable intermediates and is the one from which most of the product is formed. 15

Nitration of (Trifluoromethyl)benzene: Partial Rate Factors CF3 4.5 x 10-6 67 x 10-6 All of the available ring positions in (trifluoromethyl)-benzene are much less reactive than a single position of benzene. A CF3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons. 15

12.12 Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents 4 4

Very strongly activating VSA Strongly activating SA Activating A Table 12.2 Classification of Substituents in Electrophilic Aromatic Substitution Reactions Very strongly activating VSA Strongly activating SA Activating A Standard of comparison is Benzene Deactivating D Strongly deactivating SD Very strongly deactivating VSD 1

Table 12.2 Classification of Substituents in Electrophilic Aromatic Substitution Reactions 1

Important Generalizations 1. All activating substituents are ortho-para directors. 2. Halogen substituents are slightly deactivating, but ortho-para directing. 3. Strongly deactivating substituents are meta directors. 23

Electron-Releasing Groups (ERGs) ERGs are ortho-para directing and activating. ERG ERGs include —R (alkyl), —Ar (aryl), and —C=C. 25

ERGs such as —OH, and —OR are strongly activating. Nitration of Phenol ERGs such as —OH, and —OR are strongly activating. OH OH NO2 OH NO2 HNO3 + 44% This occurs about 1000 times faster than nitration of benzene. 56% 26

Bromination of Anisole -OCH3 is such a strong activator that the FeBr3 catalyst not necessary. OCH3 OCH3 Br Br2 acetic acid 90% 26

Oxygen Lone Pair Stabilizes Intermediate H Br + OCH3 •• • OCH3 •• • H Br + OCH3 •• + H H H H H Br All atoms have octets. 26

Electron-Releasing Groups (ERGs) • ERG ERGs with a lone pair on the atom directly attached to the ring are ortho-para directing and strongly activating. 25

Examples O OH OR OCR ERG = NHCR O NH2 NHR NR2 •• OR • •• OCR • •• ERG = • • NHCR • O • NH2 • NHR • NR2 All of these are ortho-para directing and strongly to very strongly activating. 25

Lone Pair Stabilizes Intermediates for ortho and para Substitution X + ERG H X + ERG Comparable stabilization not possible for intermediate leading to meta substitution. 26

12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents 4 4

Remember: ERGs Stabilize Intermediates for ortho and para Substitution X + ERG • H X + ERG • 26

Electron-withdrawing Groups (EWGs) Destabilize Intermediates for ortho and para Substitution X H H H + + H H H H H H X H —CF3 is a powerful EWG. It is strongly deactivating and meta directing. 26

Many EWGs Have a Carbonyl Group Attached Directly to the Ring —CR —EWG = O —COH O —COR O —CH - O —CCl O —CH + All of these are meta directing and strongly deactivating. 25

All of these are meta directing and strongly deactivating. Other EWGs Include: —EWG = —NO2 —SO3H —C N All of these are meta directing and strongly deactivating. 25

Nitration of Benzaldehyde CH O O2N CH O HNO3 H2SO4 75-84% 26

Problem 12.17(a) Chlorination of benzoylchloride Cl CCl O CCl O Cl2 FeCl3 62% 26

Disulfonation of Benzene HO3S SO3 SO3H H2SO4 90% 26

Bromination of Nitrobenzene Fe 60-75% 26

F, Cl, Br, and I are ortho-para directing, but deactivating. 12.14 Substituent Effects in Electrophilic Aromatic Substitution: Halogens F, Cl, Br, and I are ortho-para directing, but deactivating. 4 4

Nitration of Chlorobenzene Cl NO2 Cl NO2 Cl NO2 Cl HNO3 + + H2SO4 30% 1% 69% The rate of nitration of chlorobenzene is about 30 times slower than that of benzene but directs ortho/para. 6

Nitration of Toluene vs. Chlorobenzene 42 2.5 58 0.137 0.009 0.029 Cl Rate factors (compared to benzene) for the nitration of various positions in these two compounds. 15

Electron withdrawing via induction. Halogen Substituents Electron withdrawing via induction. X X Electron releasing via resonance. For the halogens, the inductive effect outweighs the resonance effect. The weak releasing effect stabilizes the carbocations from o- and p-attack. 26

12.15 Multiple Substituent Effects 4 4

Here, all possible EAS sites are equivalent. The Simplest Case Here, all possible EAS sites are equivalent. CH3 O AlCl3 CH3COCCH3 + CH3 CCH3 99% 2

Another Straightforward Case CH3 NO2 CH3 NO2 Br 86-90% Br2 Fe Directing effects of these substituents reinforce each other: substitution takes place ortho to the methyl group and meta to the nitro group. 2

Regioselectivity is controlled by the stronger activating substituent. Example strongly activating NHCH3 Cl acetic acid Br2 87% NHCH3 Cl Br Regioselectivity is controlled by the stronger activating substituent. 2

When activating effects are similar... CH3 C(CH3)3 CH3 C(CH3)3 NO2 HNO3 H2SO4 88% Substitution occurs ortho to the smaller group. 5

Steric effects control regioselectivity when electronic effects are similar CH3 HNO3 H2SO4 98% NO2 CH3 The position between two substituents is last position to be substituted for steric reasons. 5

12.16 Regioselective Synthesis of Disubstituted Aromatic Compounds 4 4

Synthesis of m-Bromoacetophenone Introduce substituents in the order that ensures the correct orientation in the product. Br Which substituent should be introduced first ? CCH3 O 8

Synthesis of m-Bromoacetophenone Introduce substituents in the order that ensures the correct orientation in the product. Br para If bromine is introduced first, p-bromoacetophenone is major product. CCH3 O meta 8

Synthesis of m-Bromoacetophenone AlCl3 CCH3 O Br If the acetyl group is first, then m-bromoacetophenone is the major product. O CH3COCCH3 CCH3 O AlCl3 8

Synthesis of m-Nitroacetophenone Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics. NO2 Which substituent should be introduced first ? CCH3 O 8

Synthesis of m-Nitroacetophenone Introduce substituents in the order that ensures the correct orientation in the product. NO2 If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails. CCH3 O 8

Synthesis of m-Nitroacetophenone HNO3 H2SO4 CCH3 O If the acetyl group is first, then m-nitroacetophenone is the major product. O CH3COCCH3 CCH3 O AlCl3 8

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H Sometimes electrophilic aromatic substitution must be combined with a functional group transformation. CH3 NO2 CH3 Which first ? (oxidation of methyl group or nitration of ring) 8

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H nitration gives m-nitrobenzoic acid CH3 NO2 CH3 oxidation gives p-nitrobenzoic acid 8

Synthesis of p-Nitrobenzoic Acid from Toluene So, one would elect to nitrate first and then oxidize. NO2 CO2H Na2Cr2O7, H2O H2SO4, heat CH3 NO2 CH3 HNO3 H2SO4 8

12.17 Substitution in Naphthalene 4 4

Two sites are possible for electrophilic aromatic substitution. Naphthalene H H 1 H H 2 H H H H Two sites are possible for electrophilic aromatic substitution. All other sites at which substitution can occur are equivalent to 1 and 2. 2

Reaction is faster at C-1 than at C-2. EAS in Naphthalene CCH3 O O CH3CCl AlCl3 90% Reaction is faster at C-1 than at C-2. 2

EAS in Naphthalene E H E H + + When attack is at C-1 the carbocation is stabilized by allylic resonance and benzenoid character of other ring is maintained. 2

EAS in Naphthalene E H + E H + When attack is at C-2, in order for the carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is lost. 2

Sulfonation of Naphthalene SO3H H2SO4 SO3 At 0°C SO3H Kinetic vs. thermodynamic control! At 160°C 2

12.18 Substitution in Heterocyclic Aromatic Compounds 4 4

Generalization There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible. Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive... 2

Pyridine N Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes  electrons to be held more strongly than in benzene. 2

Pyridine can be sulfonated at high temperature. SO3, H2SO4 SO3H N N HgSO4, 230°C 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3. 2

Pyrrole, Furan, and Thiophene •• O •• S •• Have 1 less ring atom than benzene or pyridine to hold same number of  electrons (6). The  electrons are held less strongly. These compounds are relatively reactive toward EAS. 31

Furan undergoes EAS readily and C-2 is most reactive position. Example: Furan O CH3COCCH3 O BF3 + CCH3 O O 75-92% Furan undergoes EAS readily and C-2 is most reactive position. 2

12.19 Nucleophilic Aromatic Substitution 4 4

Nucleophilic Aromatic Substitution LG Nu + :Nu- :LG- Because the carbon-halogen bond is stronger (where LG = halide), aryl halides react more slowly than alkyl halides when carbon-halogen bond breaking is rate determining. 6

Reactions of Aryl Halides We have not yet seen any nucleophilic substitution reactions of aryl halides. Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required. This goes by the benzyne mechanism (elimination-addition). 1. NaOH, H2O 370°C Cl OH 2. H+/HOH (97%)

Reactions of Aryl Halides In this mechanism, the base causes elimination of HCl to form benzyne. Here, addition of NH3 to either carbon of the benzyne yields product. NaNH2, NH3(l) -33°C Cl NH2

Reasons for Low Reactivity Cl + – SN1 not reasonable because: 1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process 2) aryl cations are less stable than alkyl cations

Reasons for Low Reactivity SN2 not reasonable because ring blocks attack of nucleophile from side opposite bond to the leaving group.

12.20 Nucleophilic Substitution in Nitro-Substituted Aryl Halides 4 4

But... Nitro-substituted aryl halides undergo nucleophilic aromatic substitution more readily. Cl NO2 + NaOCH3 CH3OH 85°C OCH3 NO2 NaCl (92%) 2

Effect of nitro group is cumulative especially when nitro group is ortho and/or para to leaving group Cl Cl NO2 Cl NO2 Cl NO2 O2N 1.0 7 x 1010 2.4 x 1015 too fast to measure 7

follows second-order rate law: rate = k[aryl halide][nucleophile] Kinetics follows second-order rate law: rate = k[aryl halide][nucleophile] inference: both the aryl halide and the nucleophile are involved in rate-determining step. 9

Effect of leaving group unusual order: F > Cl > Br > I Based on electronegativity rather than basicity. X Relative Rate* F Cl Br I 312 1.0 0.8 0.4 *NaOCH3, CH3OH, 50°C X NO2 8

General Conclusions About Mechanism bimolecular rate-determining step in which nucleophile attacks aryl halide rate-determining step precedes carbon-halogen bond cleavage rate-determining transition state is stabilized by electron-withdrawing groups (such as NO2) 9

12.21 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution 4 4

Addition-Elimination Mechanism Two step mechanism: Step 1) nucleophile attacks aryl halide and bonds to the carbon that bears the halogen (slow: aromaticity of ring lost in this step) Step 2) intermediate formed in first step loses halide (fast: aromaticity of ring restored in this step) 9

Reaction F NO2 OCH3 NO2 CH3OH + NaOCH3 + NaF 85°C (93%) 2

Mechanism Step 1 NO2 F H OCH3 – F OCH3 H H – slow H H NO2 •• •• •• • • Bimolecular; consistent with second-order kinetics; first order in aryl halide, first order in nucleophile, intermediate is negatively charged, formed faster when ring bears electron-withdrawing groups such as NO2. 13

Stabilization of Rate-Determining Intermediate by Nitro Group •• • • N F H OCH3 O + – •• • • N F H OCH3 O + – – 17

Regeneration of aromatic character in the ring. Mechanism Step 2 fast • • OCH3 •• NO2 H F – •• •• F OCH3 • • • • • • H H – •• H H NO2 Regeneration of aromatic character in the ring. 13

F > Cl > Br > I is unusual, but consistent with mechanism Leaving Group Effects F > Cl > Br > I is unusual, but consistent with mechanism Carbon-halogen bond breaking does not occur until after the rate-determining step. Electronegative F stabilizes negatively charged intermediate. 18

12.22 Related Nucleophilic Substitution Reactions 4 4

Example: 2-Chloropyridine Cl N OCH3 N NaOCH3 CH3OH 50°C 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions. 20

Example: 2-Chloropyridine Cl N •• • • OCH3 – •• Cl N OCH3 – Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed. 20

End of Chapter 12 Reactions of Arenes: Electrophilic and NucleophilicAromatic Substitution 4 4