Electrophilic Aromatic Substitution Electrophile substitutes for a hydrogen on the benzene ring. => Chapter 17

Mechanism => Chapter 17

Energy Diagram for Bromination => Chapter 17

Bromination of Benzene Requires a stronger electrophile than Br2. Use a strong Lewis acid catalyst, FeBr3. Chapter 17

Chlorination and Iodination Chlorination is similar to bromination. Use AlCl3 as the Lewis acid catalyst. Iodination requires an acidic oxidizing agent, like nitric acid, which oxidizes the iodine to an iodonium ion. => Chapter 17

Nitration of Benzene Use sulfuric acid with nitric acid to form the nitronium ion electrophile. NO2+ then forms a sigma complex with benzene, loses H+ to form nitrobenzene. => Chapter 17

Sulfonation Sulfur trioxide, SO3, in fuming sulfuric acid is the electrophile. => Chapter 17

Desulfonation All steps are reversible, so sulfonic acid group can be removed by heating in dilute sulfuric acid. This process is used to place deuterium in place of hydrogen on benzene ring. Benzene-d6 => Chapter 17

Nitration of Toluene Toluene reacts 25 times faster than benzene. The methyl group is an activator. The product mix contains mostly ortho and para substituted molecules. => Chapter 17

Sigma Complex Intermediate is more stable if nitration occurs at the ortho or para position. => Chapter 17

Energy Diagram => Chapter 17

Activating, O-, P- Directing Substituents Alkyl groups stabilize the sigma complex by induction, donating electron density through the sigma bond. Substituents with a lone pair of electrons stabilize the sigma complex by resonance. => Chapter 17

NITRATION OF ANISOLE

Nitration of Anisole ortho meta para activated ring actual products + para

: ortho EXTRA! meta para : EXTRA!

Energy Profiles meta ortho para Ea ortho-para director NITRATION OF ANISOLE benzenium intermediate RECALL: HAMMOND POSTULATE Ea meta benzenium intermediates have more resonance ortho para ortho-para director

X BENZENIUM IONS GIVE ELIMINATION INSTEAD OF ADDITION ADDITION REACTION doesn’t happen resonance would be lost X ELIMINATION REACTION restores aromatic ring resonance ( 36 Kcal / mole )

The Amino Group Aniline reacts with bromine water (without a catalyst) to yield the tribromide. Sodium bicarbonate is added to neutralize the HBr that’s also formed. => Chapter 17

Summary of Activators => Chapter 17

Deactivating Meta- Directing Substituents Electrophilic substitution reactions for nitrobenzene are 100,000 times slower than for benzene. The product mix contains mostly the meta isomer, only small amounts of the ortho and para isomers. Meta-directors deactivate all positions on the ring, but the meta position is less deactivated. => Chapter 17

Ortho Substitution on Nitrobenzene => Chapter 17

Para Substitution on Nitrobenzene => Chapter 17

Meta Substitution on Nitrobenzene => Chapter 17

Energy Diagram => Chapter 17

Structure of Meta- Directing Deactivators The atom attached to the aromatic ring will have a partial positive charge. Electron density is withdrawn inductively along the sigma bond, so the ring is less electron-rich than benzene. => Chapter 17

Summary of Deactivators => Chapter 17

More Deactivators => Chapter 17

Halobenzenes Halogens are deactivating toward electrophilic substitution, but are ortho, para-directing! Since halogens are very electronegative, they withdraw electron density from the ring inductively along the sigma bond. But halogens have lone pairs of electrons that can stabilize the sigma complex by resonance. => Chapter 17

Sigma Complex for Bromobenzene Ortho and para attacks produce a bromonium ion and other resonance structures. => No bromonium ion possible with meta attack. Chapter 17

Energy Diagram => Chapter 17

Summary of Directing Effects => Chapter 17

DIRECTIVITY OF SINGLE GROUPS

ortho, para - Directing Groups Groups that donate electron density to the ring. PROFILE: : E+ increased reactivity +I Substituent +R Substituent .. These groups also “activate” the ring, or make it more reactive. CH3-O- CH3- .. .. R- CH3-N- .. -NH2 .. The +R groups activate the ring more strongly than +I groups. -O-H ..

meta - Directing Groups Groups that withdraw electron density from the ring. PROFILE: d+ d- E+ decreased reactivity -I Substituent -R Substituent These groups also “deactivate” the ring, or make it less reactive. + + - -SO3H

Halides - o,p Directors / Deactivating THE EXCEPTION Halides - o,p Directors / Deactivating Halides represent a special case: .. : : They are o,p directing groups that are deactivating E+ They are o,p directors (+R effect ) They are deactivating ( -I effect ) Most other other substituents fall into one of these four categories: +R / -I / o,p / deactivating 1) +R / o,p / activating -F -Cl -Br -I 2) +I / o,p / activating 3) -R / m / deactivating 4) -I / m / deactivating

PREDICT ! o,p m o,p m

DIRECTIVITY OF MULTIPLE GROUPS

GROUPS ACTING IN CONCERT steric crowding o,p director m-director very little formed HNO3 H2SO4 When groups direct to the same positions it is easy to predict the product. major product

GROUPS COMPETING X o,p-directing groups win over m-directing groups too crowded X HNO3 + H2SO4

RESONANCE VERSUS INDUCTIVE EFFECT HNO3 H2SO4 major product +I resonance effects are more important than inductive effects

SOME GENERAL RULES 1) Activating (o,p) groups (+R, +I) win over deactivating (m) groups (-R,-I). 2) Resonance groups (+R) win over inductive (+I) groups. 3) 1,2,3-Trisubstituted products rarely form due to excessive steric crowding. 4) With bulky directing groups, there will usually be more p-substitution than o-substitution. 5) The incoming group replaces a hydrogen, it will not usually displace a substituent already in place.

HOW CAN YOU MAKE ... only, no para

BROMINE - WATER REAGENT PHENOLS AND ANILINES

BROMINE IN WATER .. .. .. .. .. .. - : : : : : .. .. .. .. .. .. : .. This reagent works only with highly-activated rings such as phenols, anisoles and anilines. .. .. .. .. .. .. - : : : : : .. .. .. .. + .. .. : + .. + bromonium ion etc

PHENOLS AND ANILINES REACT Br2 H2O All available positions are bromiated. Br2 H2O

Friedel-Crafts Alkylation Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl3. Reactions of alkyl halide with Lewis acid produces a carbocation which is the electrophile. Other sources of carbocations: alkenes + HF or alcohols + BF3. => Chapter 17

Examples of Carbocation Formation => Chapter 17

Formation of Alkyl Benzene => + - Chapter 17

Limitations of Friedel-Crafts Reaction fails if benzene has a substituent that is more deactivating than halogen. Carbocations rearrange. Reaction of benzene with n-propyl chloride and AlCl3 produces isopropylbenzene. The alkylbenzene product is more reactive than benzene, so polyalkylation occurs. => Chapter 17

Friedel-Crafts Acylation Acyl chloride is used in place of alkyl chloride. The acylium ion intermediate is resonance stabilized and does not rearrange like a carbocation. The product is a phenyl ketone that is less reactive than benzene. => Chapter 17

Mechanism of Acylation => Chapter 17

Clemmensen Reduction Acylbenzenes can be converted to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc. => Chapter 17

Gatterman-Koch Formylation Formyl chloride is unstable. Use a high pressure mixture of CO, HCl, and catalyst. Product is benzaldehyde. => Chapter 17

Chlorination of Benzene Addition to the benzene ring may occur with high heat and pressure (or light). The first Cl2 addition is difficult, but the next 2 moles add rapidly. The product, benzene hexachloride, is an insecticide. => Chapter 17

Catalytic Hydrogenation Elevated heat and pressure is required. Possible catalysts: Pt, Pd, Ni, Ru, Rh. Reduction cannot be stopped at an intermediate stage. => Chapter 17

Birch Reduction: Regiospecific A carbon with an e--withdrawing group is reduced. A carbon with an e--releasing group is not reduced. => Chapter 17

Birch Mechanism => Chapter 17

Side-Chain Oxidation Alkylbenzenes are oxidized to benzoic acid by hot KMnO4 or Na2Cr2O7/H2SO4. => Chapter 17

Side-Chain Halogenation Benzylic position is the most reactive. Chlorination is not as selective as bromination, results in mixtures. Br2 reacts only at the benzylic position. => Chapter 17