Ch 16 Synthetic Strategies I.Reactions of Disubstituted Benzenes A.The strongest activator wins 1)Ortho/para directors generally activate the ring, so these substituents should control the reactivity instead of a deactivation meta director 2)Steric considerations also play a role, especially when more than one location is equivalent by activation B.Guidelines for predicting where a third substituent will go 1)The most powerful activator has primary control

2)Substituent groups have been ranked a)Group I = NR 2, OR = most powerful activators b)Group II = X, R c)Group III = all of the other deactivators d)I ~ I > II ~ II > III ~III 3)Ortho attack to a bulky group, or attack between 2 substituents is unlikely

4)The same rules apply for higher substituted benzenes II.Synthetic Strategies for Substituted Benzenes A.Reversibly Interchanging meta and ortho/para directors 1)Nitro (meta) and Amino (ortho/para) Interconversions 2)How could we prepare m-bromoaniline?

3)Use the NH 2 /NO 2 interconversion: 4)Alkanoyl (meta) and Alkyl (ortho/para) Interconversion

5)How can we prepare m-chloroethylbenzene? 6)Use reduction of alkanoyl groups to give monosubstituted alkylbenzenes B.Friedel-Crafts Electrophiles Don’t Attack Deactivated Benzenes NO 2 deactivates ring; electrophile not strong enough to react

C.Use of Reversible Sulfonation for Ortho Disubstitution 1)Para products are usually major when substituting a o,p directed benzene 2)We can block the para position with a sulfonate group. Steric bulk will lead to the para product as major 3)Nitration will then occur only at the original ortho site (meta to NO 2 ) and deprotection yields the desired ortho product

D.Moderation of Highly Activating Groups 1)NH 2 and OH substituents “overactivate” benzene to multiple substitutions 2)The NH 2 and OH groups can also react with electrophiles themselves 3)Amine moderation can be had through an acetyl protecting group 4)Phenols can be protected as the methyl ether 5)Di- or polysubstitution won’t occur with the less-activated derivatives

III.Polycyclic Aromatic Hydrocarbon Reactions A.Naphthalene 1)Naphthalene undergoes electrophilic aromatic substitution very easily 2)Substitution is selective for C-1 3)Resonance forms determine higher reactivity at C-1 a)C-1 attack has 2 resonance structures with benzene rings b)C-2 attack has only 1 resonance structure with a benzene ring c)The most stable intermediate (C-1 attack) gives faster reaction

B.Electrophilic Attack of Substituted Naphthalenes 1)The ring carrying the substituent is most affected a)Activating group puts the next substituent on the same ring b)Deactivating group puts the next substituent on the other ring

2)C-5 and C-8 are the preferred sites for deactivating groups C.Larger PAH’s 1)Use resonance structures to predict substitution 2)Phenanthrene is monosubstituted preferentially at C-9

D.Carcinogenic PAH’s 1)Benzo[a]pyrene is a carcinogen 2)Many carcinogens are alkylating groups that alkylate DNA. This can lead to proliferating (cancerous) cells