Chapter 15 Reactions of Aromatic Compounds Created by

1. Electrophilic Aromatic Substitution Reactions v Overall reaction © 2014 by John Wiley &

© 2014 by John Wiley & Sons, Inc. All rights reserved.

2. A General Mechanism for Electrophilic Aromatic Substitutions v Different chemistry with alkene ©

v Benzene does not undergo electrophilic addition, but it undergoes electrophilic aromatic substitution ©

v Mechanism ● Step 1 © 2014 by John Wiley & Sons, Inc. All

v Mechanism ● Step 2 © 2014 by John Wiley & Sons, Inc. All

3. Halogenation of Benzene v Benzene does not react with Br 2 or Cl

v Examples ● Reactivity: F 2 > Cl 2 > Br 2 > I

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism (Cont’d) © 2014 by John Wiley & Sons, Inc. All rights reserved.

v F 2: too reactive, gives a mixture of mono-, di- and polysubstituted products

v I 2 : very unreactive even in the presence of Lewis acids; usually

4. Nitration of Benzene v Electrophile in this case is NO 2 (nitronium ion)

5. Sulfonation of Benzene v Mechanism ● Step 1 SO 3 is protonated to

● Step 2 SO 3 H+ reacts as an electrophile with the benzene ring

● Step 3 Loss of a proton from the arenium ion restores aromaticity to

v Sulfonation & Desulfonation © 2014 by John Wiley & Sons, Inc. All rights

6. Friedel–Crafts Alkylation v Electrophile in this case is R o o ● R

v Note: Not necessary to start with alkyl halide, other possible functional groups can

7. Friedel–Crafts Acylation v v Acyl group: Electrophile in this case is R–C≡O (acylium

v Acid chlorides (or acyl chlorides) ● Can be prepared by © 2014 by

8. Limitations of Friedel–Crafts Reactions v When the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations that are more stable, it usually does so, and the major products obtained from the reaction are usually those from the more stable carbocations. © 2014 by John Wiley & Sons, Inc. All rights reserved.

v For example (not formed) (How is this formed? ) © 2014 by John

v Reason 1 o cation (not stable) 3 o cation (more stable) © 2014

v Friedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH 2, –NHR, or –NR 2 group. This applies to both alkylations and acylations. These usually give poor yields in Friedel-Crafts reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

v The amino groups, –NH 2, –NHR, and –NR 2, are changed into powerful electronwithdrawing groups by the Lewis acids used to catalyze Friedel-Crafts reactions Does not undergo a Friedel-Crafts reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Aryl and vinylic halides cannot be used as the halide component because they

v Polyalkylations often occur © 2014 by John Wiley & Sons, Inc. All rights

9. Synthetic Applications of Friedel-Crafts Acylations: The Clemmensen Reduction & Wolff–Kishner Reductions Rearrangements of the carbon chain do not occur in Friedel–Crafts acylations v The acylium ion, because it is stabilized by resonance, is more stable than most other carbocations. Thus, there is no driving force for a rearrangement. v © 2014 by John Wiley & Sons, Inc. All rights reserved.

v The carbonyl group of an aryl ketone can be reduced to a CH

9 A. The Clemmensen Reduction © 2014 by John Wiley & Sons, Inc. All

v Clemmensen reduction of ketones ● A very useful reaction for making alkyl benzenes

v Clemmensen reduction of ketones ● Cannot use Friedel-Crafts alkylation © 2014 by John

v Rearrangements of carbon chains do not occur in Friedel-Crafts acylations (no rearrangement of

9 B. The Wolff–Kishner Reduction © 2014 by John Wiley & Sons, Inc. All

10. Substituents Can Affect Both the Reactivity of the Ring and the Orientation of the Incoming Group v Two questions have to be addressed: ● Reactivity ● Regiochemistry © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Reactivity faster or slower than Y = EDG (electron-donating group) or EWG (electron-withdrawing

● Regiochemistry Statistical mixture of o-, m-, pproducts, or any preference? © 2014 by

d+ d- Electrophilic reagent A substituted benzene Arenium ion © 2014 by John Wiley

Z donates electrons Y withdraws electrons The ring is more electron rich and reacts faster with an electrophile The ring is electron poor and reacts more slowly with an electrophile © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Reactivity t Since electrophilic aromatic substitution is electrophilic in nature, and the r. d. s. is the attack of an electrophile (E ) with the benzene p-electrons, an ⊖ increase in e density in the benzene ring will increase the reactivity of the aromatic ring towards attack of an electrophile, and result in a faster reaction. © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Reactivity t On the other hand, a decrease ⊖ in e density in the benzene ring will decrease the reactivity of the aromatic ring towards the attack of an electrophile, and result in a slower reaction. © 2014 by John Wiley & Sons, Inc. All rights reserved.

Increasing activity ● Reactivity Substituent –EDG –H –EWG © 2014 by John Wiley &

● Reactivity t EDG (electron-donating group) on benzene ring q Increases electron density in the benzene ring q More reactive towards electrophilic aromatic substitution © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Reactivity t EWG (electron-withdrawing group) on benzene ring q Decreases electron density in the benzene ring q Less reactive towards electrophilic aromatic substitution © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Reactivity towards electrophilic aromatic substitution © 2014 by John Wiley & Sons, Inc.

v Regiochemistry: directing effect ● General aspects t Either o-, p- directing or mdirecting t Rate-determining step is pelectrons on the benzene ring attacking an electrophile (E ) © 2014 by John Wiley & Sons, Inc. All rights reserved.

v If you look at these resonance structures closely, you will notice that for ortho- or parasubstitution, each has one resonance form with the positive charge attached to the carbon that directly attached to the substituent Y (o-I and p-II) © 2014 by John Wiley & Sons, Inc. All rights reserved.

v When Y = EWG, these resonance forms (o-I and p-II) are highly unstable and unfavorable, thus not favoring the formation of o- and p- regioisomers, and m- product will form preferentially © 2014 by John Wiley & Sons, Inc. All rights reserved.

v On the other hand, if Y = EDG, these resonance forms (o-I and p-II) are extra-stable (due to resonance effect or positive inductive effect of Y), thus favoring the formation of o- and pregioisomers © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Classification of different substituents Y (EDG) –NH 2, –NR 2 Strongly activating –OH, –O o-, p- directing –NHCOR –OR Moderately o-, pactivating directing –R (alkyl) –Ph Weakly activating o-, p- –H NA NA © 2014 by John Wiley & Sons, Inc. All rights reserved. directing

v Classification of different substituents Y (EWG) –Halide (F, Cl, Br, I) Weakly o-, pdeactivating directing –COOR, –COR, Moderately m–CHO, –COOH, deactivating directing –SO 3 H, –CN –CF 3, –CCl 3, –NO 2, –⊕NR 3 Strongly mdeactivating directing © 2014 by John Wiley & Sons, Inc. All rights reserved.

11. How Substituents Affect Electrophilic Aromatic Substitution: A Closer Look © 2014 by John

11 A. Reactivity: The Effect of Electron. Releasing & Electron-Withdrawing Groups v If G is an electron-releasing group (relative to hydrogen), the reaction occurs faster than the corresponding reaction of benzene When G is electron donating, the reaction is faster © 2014 by John Wiley & Sons, Inc. All rights reserved.

v If G is an electron-withdrawing group, the reaction is slower than that of

11 B. Inductive & Resonance Effects: Theory of Orientation v Two types of EDG (i) (ii) by resonance effect (donates electron towards the benzene ring through resonance) by positive inductive effect (donates electron towards the benzene ring through the s bond) © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Two types of EDG ● The resonance effect is usually stronger than the positive inductive effect if the atoms directly attached to the benzene ring are in the same row as carbon in the periodic table © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Similar to an EDG, an EWG can withdraw electrons from the benzene ring by the resonance effect or by the negative inductive effect Deactivate the ring by the resonance effect Deactivate the ring by the negative inductive effect © 2014 by John Wiley & Sons, Inc. All rights reserved.

11 C. Meta-Directing Groups (EWG ≠ halogen) v EWG = –COOR, –CHO, –CF 3,

v For example (highly unstable due to the negative inductive effect of –CF 3)

(highly unstable due to negative inductive effect of –CF 3) © 2014 by John

(positive charge never attaches to the carbon directly attached to the EWG: –CF 3)

11 D. Ortho/Para-Directing Groups v EDG = –NR 2, –OR, –OH, etc. © 2014

v For example (extra resonance structure due to positive mesomeric effect of –OCH 3)

(extra resonance structure due to resonance effect of –OCH 3) © 2014 by John

(3 resonance structures only, no extra stabilization by resonance effect of –OCH 3) less

v For halogens, two opposing effects Negative inductive effect: withdraws electron density from the benzene ring Resonance effect: donates electron density to the benzene ring © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Overall ● Halogens are weak deactivating groups t Negative inductive effect > resonance

v Regiochemistry (extra resonance structure due to resonance effect of –Cl) © 2014 by

(extra resonance structure due to resonance effect of –Cl) © 2014 by John Wiley

(3 resonance structures only, no extra stabilization by the resonance effect of –Cl) less

11 E. Ortho/Para Direction and Reactivity of Alkylbenzenes © 2014 by John Wiley &

v Ortho attack Relatively stable contributor © 2014 by John Wiley & Sons, Inc.

v Meta attack © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Para attack Relatively stable contributor © 2014 by John Wiley & Sons, Inc.

11 F. Summary of Substituent Effects on Orientation and Reactivity Y (EDG) –NH 2, –NR 2 –OH, –O- Strongly activating o-, p- –NHCOR –OR Moderately activating o-, p- –R (alkyl) –Ph Weakly activating o-, p- –H NA NA © 2014 by John Wiley & Sons, Inc. All rights reserved. directing

Y (EWG) –Halide (F, Cl, Br, I) Weakly o-, pdeactivating directing –COOR, –CHO, –COOH, –SO 3 H, –CN Moderately mdeactivating directing –CF 3, –CCl 3, –NO 2, –⊕NR 3 Strongly mdeactivating directing © 2014 by John Wiley & Sons, Inc. All rights reserved.

12. Reactions of the Side Chain of Alkylbenzenes © 2014 by John Wiley &

12 A. Benzylic Radicals and Cations Benzylic radicals are stabilized by resonance © 2014

Benzylic cations are stabilized by resonance © 2014 by John Wiley & Sons, Inc.

12 B. Benzylic Halogenation of the Side Chain © 2014 by John Wiley &

v Mechanism ● Chain initiation ● Chain propagation © 2014 by John Wiley &

● Chain propagation ● Chain termination © 2014 by John Wiley & Sons, Inc.

v e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

13. Alkenylbenzenes 13 A. Stability of Conjugated Alkenylbenzenes v Alkenylbenzenes that have their side-chain double bond conjugated with the benzene ring are more stable than those that do not © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Example (not observed) © 2014 by John Wiley & Sons, Inc. All rights

13 B. Additions to the Double Bond of Alkenylbenzenes © 2014 by John Wiley

v Mechanism (top reaction) © 2014 by John Wiley & Sons, Inc. All rights

v Mechanism (bottom reaction) © 2014 by John Wiley & Sons, Inc. All rights

13 C. Oxidation of the Side Chain © 2014 by John Wiley & Sons,

Using hot alkaline KMn. O 4, alkyl, alkenyl, alkynyl and acyl groups all oxidized to –COOH group o v For alkyl benzene, 3 alkyl groups resist oxidation v ● Need benzylic hydrogen for alkyl group oxidation © 2014 by John Wiley & Sons, Inc. All rights reserved.

13 D. Oxidation of the Benzene Ring © 2014 by John Wiley & Sons,

14. Synthetic Applications © 2014 by John Wiley & Sons, Inc. All rights reserved.

CH 3 group: ortho-, para-directing v NO 2 group: meta-directing v © 2014 by

v If the order is reversed the wrong regioisomer is produced © 2014 by

We do not know how to substitute a hydrogen on a benzene ring with a – COOH group. However, side chain oxidation of alkylbenzene could provide the –COOH group v Both the –COOH group and the NO 2 group are meta-directing v © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Route 1 © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Route 2 © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Which synthetic route is better? ● Recall “Limitations of Friedel-Crafts Reactions, Section 15. 8” Friedel–Crafts reactions usually give poor yields when powerful electronwithdrawing groups are present on the aromatic ring or when the ring bears an –NH 2, –NHR, or –NR 2 group. This applies to both alkylations and acylations t Route 2 is a better route t © 2014 by John Wiley & Sons, Inc. All rights reserved.

Both Br and Et groups are ortho-, paradirecting v How to make them meta to each other? v Recall: an acyl group is meta-directing and can be reduced to an alkyl group by Clemmensen reduction v © 2014 by John Wiley & Sons, Inc. All rights reserved.

14 A. Use of Protecting and Blocking Groups v Protected amino groups ● Example

Problem v Not a selective synthesis, o- and pproducts + dibrominated and tribrominated products

Solution v Introduce a deactivating group on –NH 2 © 2014 by John Wiley

v The amide group is less activating than –NH 2 group ● No problem for over bromination v The steric bulkiness of this group also decreases the formation of the obrominated product © 2014 by John Wiley & Sons, Inc. All rights reserved.

Problem v Difficult to get o-product without getting p-product v Over nitration © 2014

Solution v Use of a –SO 3 H blocking group at the p -position

14 B. Orientation in Disubstituted Benzenes v Directing effect of EDG usually outweighs that of EWG v With two EDGs, the directing effect is usually controlled by the stronger EDG © 2014 by John Wiley & Sons, Inc. All rights reserved.

Examples [only major product(s) shown] © 2014 by John Wiley & Sons, Inc. All

v Substitution does not occur to an appreciable extent between metasubstituents if another position

15. Allylic and Benzylic Halides in Nucleophilic Substitution Reactions © 2014 by John Wiley

v A Summary of Alkyl, Allylic, & Benzylic Halides in SN Reactions ● These halides give mainly SN 2 reactions: ● These halides may give either SN 1 or SN 2 reactions: © 2014 by John Wiley & Sons, Inc. All rights reserved.