More EAS. Lecture 12. Di- and Polysubstitution CH 3 + H + H HNO 2 NO 2. February 25, /25/16 OCH 3 OCH OCH. o-nitro-anisole (31%) Anisole

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1 Lecture 12 More EAS February 25, 2016 Di- and Polysubstitution O O OC OC 3 3 NO 3 2 SO 4 Anisole o-nitro-anisole (31%) m-nitro-anisole (2%) p-nitro-anisole (67%) l -O is ortho-para directing and activating 1

2 Di- and Polysubstitution NO 3 Nitrobenzene 2 SO 4 m-dinitrobenzene (93%) o-dinitrobenzene p-dinitrobenzene Less than 7% combined l - is meta directing and deactivating! l Di- and Polysubstitution Existing groups on a benzene ring influence further substitution in both orientation and rate l Orientation: certain substituents direct preferentially to ortho & para positions; others direct preferentially to meta positions substituents are classified as either Ortho/para directing.. or meta directing l Rate: substituents are classified as Activating More reactive to further substitution Deactivating Less reactive to further substitution 2

3 Relative rates of nitration O C l N O x10-8 Reactivity Nitration: Partial Rate Factors 1 CF x10-6 4x x x x10-6 l l l All ring positions in toluene are more reactive than any position of benzene. Steric hindrance by the methyl group makes each ortho position slightly less reactive than para. All ring positions in trifluoromethylbenzene are less reactive than any position in benzene 3

4 Real Fast Pretty fast Kinda slow Pretty slow Slow Real Slow Effect on Regioselectivity Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Meta directors direct an incoming electrophile to positions meta to themselves. All meta directors are deactivating All ortho-para directors are activating except halogen For EAS, the rate-limiting step is attack of E on the aromatic ring to form a resonance-stabilized cation intermediate 4

5 ortho Nitration of Toluene meta Nitration of Toluene 5

6 Which is more stable? Comparison Ortho/Meta δ δ δ ortho- δ δ meta- δ Adding a Second Substituent Methoxy is is therefore an o-p director 6

7 Adding a Second Substituent Nitro is therefore a meta director Synthesis of m-bromoacetophenone Order of introduction of substituents must be carefully designed to ensure correct orientation Br O C Br O C Which substituent should be introduced first? 7

8 Synthesis of m-bromoacetophenone Br O C Di- and Polysubstitution CO 2 p-nitrobenzoic acid CO 2 m-nitrobenzoic acid 8

9 Multiple Substitution Effects: The Simplest Case O C- O C Al 3 99% All possible EAS sites may be equivalent. Another Straightforward Case Br 2 Br FeBr % Directing effects of substituents reinforce each other. 9

10 The Best Man Wins N N Br 2 Br FeBr 3 87% Regioselectivity is controlled by the most activating substituent When activating effects are similar... NO 3 2 SO 4 C( ) 3 C( ) 3 88% Sterics dominates when activating effects are similar 10

11 Steric effects control regioselectivity when electronic effects are similar NO 3 2 SO 4 NO2 98% O C- Al 3 11

12 Reduction of the Nitro Group Aniline! The Nitro group is easily reduced. Many reducing agents can be employed for this transformation including Sn or Fe in, 2 with Pd/C, etc Diazonium Salts N 2 Na, N 2 Diazonium Salt 12

13 Diazonium Salts l The -N 2 group of an arenediazonium salt can be replaced in a regioselective manner by these groups 2 O Ar-O BF 4, Cu Ar-F Ar- Schiemann reaction Ar-N 2 Br, CuBr KCN, CuCN Ar-Br Ar-CN Sandmeyer reaction KI Ar-I 3 PO 2 Ar- 13

14 Reactions of Diazonium Salts Practice Problems N 2 C N C 2 N 2 N 2 14

15 Practice work backwards????? Br Synthesis Strategy?? 15