1. Chemistry 125: Lecture 63 March 30, 2011 Aromatic Substitution The Friedel-Crafts Reaction Synthetic Accessibility Benzylic Stabilization and Triphenylmethyl This For copyright notice see final page of this file

2. Charles Friedel (1832-1890) James Mason Crafts (1839-1917) AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction

3. Paris (Wurtz - Médicine) Cornell MIT Paris ( Friedel - Mines) President AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction 1877

4. AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction EtI + BuI + 2 Na = Et-Bu + 2 NaI Adolphe Wurtz (1855) On a New Class of Radicals C 4 H 5 I + C 8 H 9 I + 2 Na = + 2 NaI Low Yield (Crossover; Radical or EtNa + BuI or…) The infamous “Wurtz Reaction”

5. ? AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction EtI + BuI + 2 Na = Et-Bu + 2 NaI Might other metals work better? RCl + 3 Al PhH 6 3 R 2 + AlCl 3 + HCl. R-Ph Chem is try! Aromatic Substitution: C for H LOTS initially slow; rate depends on [AlCl 3 ] H R or “S N 1” version via AlCl 4 - R + little not needed completely different from Wurtz Reaction! distillate is high boiling, “poor in hydrogen”

6. AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction R-Cl + H-Ar R-Ar + HCl AlCl 3 “On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877) C 1, C 2, C 5 also Br, I benzene, toluene both previously unknown! “several hundred grams” m.p. 164° (modern, 165°) mol. wt. within 2% by vapor density KMnO 4 cold > 2 months known since 1799 CH 3 Cl 80° “day and night” Friedel-Crafts Alkylation

7. AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction R-Cl + H-Ar R-Ar + HCl AlCl 3 “On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877) C 1, C 2, C 5 also Br, I benzene, toluene AlCl 3 Ph-H + Ph-CH 2 Cl Ph 2 CH 2 3 Ph-H + CHCl 3 AlCl 3 Ph 3 CH 4 Ph-H + CCl 4 AlCl 3 Ph 4 C 200° Ph-H + PhCl AlCl 3 No Reaction 3 Ph-H + CCl 4 AlCl 3 Ph 3 CCl H2OH2O Ph 3 COH known unknown Benzyl but Not Aryl Too Crowded Friedel-Crafts Alkylation

8. AlCl 3 /C-Electrophile: The Friedel-Crafts Reaction R-Cl + H-Ar R-Ar + HCl AlCl 3 “On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877) C 1, C 2, C 5 also Br, I benzene, toluene Benzyl but Not Aryl known AlCl 3 Ph-H + Ph-C-Cl Ph-C-Ph O O known AlCl 3 Ph-H + CH 3 -C-Cl Ph-C-CH 3 O O known + AlCl 3 Ph-H + unknown ? Acyl (R-CO) Friedel-Crafts Alkylation Acylation

9. Warning: PhCH 3 reacts 25 times faster than PhH Rearrangement in Friedel-Crafts Alkylation (e.g. J&F Sec. 14.5) AlCl 3 +? Cl ~45% “yield" of mono substitution 5 hr + 40% : 60% Good News: Bad News: Cl AlCl 3 + H 60% : 40% (-6°C) (35°C) gives n-PrPh product gives i-PrPh product Compared to what? ~15% of C 6 H 6 consumed Ipatieff (1940)

10. Rearrangement in Friedel-Crafts Alkylation (e.g. J&F Sec. 14.5) AlCl 3 + Cl “Clemmensen” Reduction Zn / HCl Stable Acylium Ion No Rearrangement O O Cl AlCl 3 C O + Acylation + 1 eq. AlCl 3 or “Wolff-Kishner” Reduction H 2 N-NH 2 KOH 200°C ! + H 2 O

11. Synthetic Accessibility (e.g. J&F Sec. 14.7) Br Br 2 FeBr 3 NO 2 H 2 SO 4 HNO 3 RC O AlCl 3 RCOCl D D 2 SO 4 R RClAlCl 3 Cl Cl 2 AlCl 3 SO 3 H 2 SO 4 S O OH O CH O HCl AlCl 3 CO H2OH2O 180°C H 2 / Pd / C or Sn / HCl NH 2

12. “aniline yellow” (1861) Synthetic Accessibility (e.g. J&F Sec. 14.7) NO 2 H 2 / Pd / C or Sn / HCl NH 2 i.e. H-O-N=O (nitrous acid) N N Cl - + NaNO 2 HCl, 0°C benzene diazonium chloride Fabulous leaving group N + + N NH 2 N the first of hundreds of azo dyes Bismarck Brown click for sourcesource click for sourcesource

13. Catalysis in these “Sandmeyer” reactions probably involves electron transfer and radical coupling and radical coupling. Diazonium Uses (e.g. J&F Sec. 14.7) Br HBr CuBr Cl HCl / CuCl N + CuCN N C N + + BrCuBr N + CuBrBr from Br - + CuBr very unstable Br -

14. Diazonium Uses (e.g. J&F Sec. 14.7) NO 2 NaNO 2 I KI Cu + H 3 PO 2 H OH H2OH2O Br CuBr Cl CuCl N + CuCN N C Utility? F BF 4 Probably S N 1

15. Preparation Problems NO 2 Cl NO 2 Cl 2 FeCl 3 NO 2 Cl Cl 2 FeCl 3 (Cl + FeCl 4 - ) NH 2 Cl OH Cl “reduction” (Zn/HCl?) H2OH2O 100°C HONO (NaNO 2 /HCl) N2N2 Cl + diazonium salt Cl - or : Hal CN NO 2 H Cl both o,p-directing! HNO 3 H 2 SO 4

16. Yale ‘98S

17. CH 3 H3CH3C NH 2 Indirect Synthesis HNO 3 H 2 SO 4 AlCl 3 CH 3 Cl “reduction” (Zn/HCl) HONO (NaNO 2 /HCl) CH 3 H3CH3C NO 2 CH 3 NH 2 CH 3 CH 3 C O AlCl 3 CH 3 Cl CH 3 C O N2N2 + Cl - CH 3 H3CH3C H 3 PO 2 ! wrong group? wrong place? if necessary stronger o,p-director than CH 3

18. Preparation Problem: NO 2

19. Nucleophilic Aromatic Substitution NO 2 F Sanger’s Regent H 2 N-R NO 2 HN-R Used to visualize fragments with exposed amine groups in chromatography. Amino acid sequence of insulin (1955) NHR F NO 2 + H Why F? (generally a poor leaving group) Slow Step Identify the amino acid at the end of a chain or fragment of a chain 1958 Nobel Prize to Frederick Sanger activated by two NO 2 groups activated by F also won 1980 Nobel for DNA sequencing!

20. NAD +  NADH (e.g. J&F p. 679) (closely enough balanced to run both ways) key molecules in biological Oxidation & Reduction (H - acceptor) (H - donor) + H

21. Benzylic Reactivity - Anion - pK a (e.g. J&F Sec. 13.12) Ph 2 CH-H pK a = 33.5 ~10 9  K a Alkyl-H ~12 kcal/mole from benzylic ~10 8  K a PhCH 2 -H ~11 kcal/mole from 2 nd benzylic 10 2  K a Ph 2 CH-H ~3 kcal/mole from 3 rd benzylic Ph 3 C-H pK a = 31.5 Steric hindrance in triphenylmethyl causes twists that reduce overlap with 2p C by 25% from diphenylmethyl. PhCH 2 -H pK a = 41 H 2 C=CH-CH 2 -H pK a = 43 ~10 7  K a Alkyl-H ~9 kcal/mole from allylic stabilization

22. Triphenylmethyl Free Radical 110 years old

23. Chemistry Metallurgy Geology & Mineralogy Scientific Free-Hand Drawing Chemical Literature in German & French French Rhetoric Logic Psychology Physics Math b. Elizabetgrad, Ukraine (1866)  University of Michigan (1886)  Chicago (1884) Speaker at Dedication of SCL (1923)

24. MG as Student Gomberg in the Analytical Laboratory After freshman year Gomberg averaged 9.5 Chemistry Labs per Week. 2/3 of them were Analytical Labs (not hours!) (no spectroscopy)

25. Adolf v. Baeyer age 61 R. Willstätter age 24 Munich 1896 Moses Gomberg age 30 Johannes Thiele age 31 "Moses Gomberg was Thiele's coworker in the student laboratory. He was very reserved and modest, kept entirely to himself, and never chatted in or out of the laboratory. Some years later the work he carried out in the United States on the triphenylmethyl radical, a case of trivalent carbon, became famous." "This brilliant Experiment, one of the most beautiful in organic chemistry and one which few people credited at first, gave great impetus to chemistry and would have been worthy of any distinction." R. Willstätter

26. Thiele & Heuser (January 1896) Hydrazine Derivatives of Isobutyric Acid AIBN 50% Gomberg ( Ann. 300, 59 ) Under the sponsorship of Prof. Thiele I have followed up these reactions...

27. Victor Meyer 9/8/48 - 8/8/97 “Geliebte Frau! Geliebte Kinder! Lebt wohl! Meine Nerven sind zerstört; ich kann nicht mehr.” Victor Meyer (1848 - 1897) Third Term Heidelberg with who had introduced the idea of Steric Hindrance

28. Friedel-Crafts or Ph 2 Mg Tetraphenylmethane (1897) “I have tried to solve this problem in a completely different way.” ? 8 g 110° Cu 0.3 g Solubility Analysis : C 93.32 (93.75) H 6.36 (6.25) 100 mg for Mol. Wt. : 0.289° 306 (320 calc.) (by solvent b.p. elevation)

29. End of Lecture 63 March 30, 2011 Copyright © J. M. McBride 2011. 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