1. Chemistry 125: Lecture 62 March 29, 2010 Electrophilic Aromatic Substitution This For copyright notice see final page of this file

2. Electrophilic Aromatic Substitution

3. H HH H H H D 2 SO 4 H HH H D H Sec. 14.4 H HH H H H D A/D via intermediate + D 2 SO 4 C6D6C6D6 etc. Observable! Or other electrophiles in place of D + e.g. NO 2 +, Br +, HOSO 2, R +, R-C=O R-C=O + HOSO 2 + In electrophilic addition to alkenes, a nucleophile would add in the next step, but here it is easier to lose H + and recover aromatic stabilization.

4. 1 H vs. 1 H correlation in time 0.3 sec 40°C CACA DBDB Remember

5. + + + SHMo2 (Simple H ü ckel Molecular Orbital Program) BenzenePentadienyl Cation addition converts  ring to  chain. H HH H H H D+D+ H HH H H H D + Locus of odd electron in radical, + charge (LUMO) in cation. - charge (HOMO) in anion, SOMO (nonbonding) Cf. Sec. 14.4b

6. LUMO X NO 2 + ++ ++ ++ H O2NO2N X + ++ ++ ++ H O2NO2N X ++ ++ ++ H Substituent Effects on Rate (sec. 14.9-14.10) X O2NO2N X O2NO2N XX NO 2 + + + (from HONO 2 /H 2 SO 4 ) X Relative Rate (overall) H[1] Cl0.03 NO 2 6  10 -8 CH 3 25 OH1000 (CH 3 ) 3 N + 1  10 -8  donation /  withdrawal  (or  ) e-donation eases formation of cation intermediates  (or  ) e-withdrawal retards formation of cation intermediates HO H + Note: + NO 2 is O=C=O with an extra proton in the center products intermediates Cf. Table 14.2

7. Why is -NO 2 e-Withdrawing when -OH is e-Donating? -NO 2 6  10 -8  e-withdrawal retards formation of cation intermediates -OH1000  e-donation eases N OO O H pCpC  C=C  p O 0 High HOMO; Good Overlap with Phenyl Low OMO; Good Overlap with Phenyl (but poor E-match) High HOMO; Low LUMO; Good Overlap with Phenyl OH is a  Donor NO 2 is a  Acceptor No Overlap with Phenyl NO 2 is allylic (willing but not able)

8. Substituent Effects on Orientation (sec. 14.9-14.10) X NO 2 + (from HONO 2 /H 2 SO 4 ) X- Relative Rate (per replaceable H) H-[1] Cl-0.00080.030.13 O 2 N- 9  10 -8 0.6  10 -8 0.03  10 -8 H 3 C-13946 (CH 3 ) 3 C-4672 Directing Activating Deactivating Act Deact  (CH 3 ) 3 N- 3  10 -8 0.6  10 -8 + _ orthometapara EtOC=O 0.0060.0006 - 0.003 o/po/p m o/po/p “e-donating” “e-withdrawing” (steric hindrance) ? X NO 2 + ++ ++ ++ H O2NO2N X + ++ ++ ++ H O2NO2N X ++ ++ ++ H intermediates

9. Activate the Electrophile Halogenation (sec. 14.4f) “Cl +” H +29 +38 AlCl 3 “Lewis acid” catalyst AlCl 5 Cl 2 vs. LUMOsSurface Potentials (Al, like B, has an empty valence AO) AlCl 4 leaving group

10. Activate the Nucleophile H OH C O O H NH 2 100 atm 125°C Self-Igniting Rocket Fuel (1944) C O H3CH3C N O O + Salicylic Acid Kolbe (1860) OH C O H+H+ Aspirin lowered HOMO raised HOMO Acetylation of aniline makes its nitration controllable.

11. Taming Aniline Nitration

12. Friedel-Crafts Alkylation (sec. 14.5)

13. Friedel-Crafts Acylation (sec. 14.6)

14. Synthetic Accessibility (sec. 14.7)

15. End of Lecture 62 March 29, 2010 Copyright © J. M. McBride 2010. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0