1. Chemistry 125: Lecture 63 March 31, 2010 Aromatic Substitution and Triphenylmethyl This For copyright notice see final page of this file

2. an important intermediate for aromatic synthesis How to make it? N 2 is a spectacular leaving group. Diazotization I: N-Nitrosoamine (sec. 14.7) (anhydride) H-O-N=O (nitrous acid) Why not cut out the middle man? Slow Fast at modest acidity Rate  [HONO] 2 [PhNH 2 ] 0 [PhNH 2 ] 0 2 0 rate-determining step

3. Diazotization II: Higher Acidity “allylic” proton Fast at higher acidity Rate  [HONO] 2 [PhNH 2 ] 1 H + Slower 1 Slow depends on small concentration of free aniline rate-determining step

4. Diazotization II: Higher Acidity increasing acidity Complex! Shifts of rate-determining step, and even of mechanism. Many roads lead to benzenediazonium. Allylic Rearrangement

5. Diazonium Uses (sec. 14.7)

6. What use is this reaction? Good way to make toluene?

7. Preparation Problems NO 2 Cl NO 2 Cl 2 FeCl 3 NO 2 Cl Cl 2 FeCl 3 (Cl + FeCl 4 - ) NH 2 Cl HNO 3 H 2 SO 4 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!

8. Yale ‘98S

9. 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

10. 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 2D 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!

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

12. Benzylic Reactivity - Anion - pK a (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

13. Triphenylmethyl Free Radical 110 years old

14. Transcript 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)

15. 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)

16. 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

17. 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...

18. 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

19. 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)

20. O 2 N- - 3 C - + EtOH O 2 N- - 3 C-H EtO - Back in Ann Arbor (1898-9) Confirmed Mol. Wt. 0.285° 318 (320 calc.) “Unlike the trinitrotriphenylmethane… it does not dissolve in sodium ethylate, nor does it give any coloration…” How about O 2 N- - 3 C-C - -NO 2 3 ? Prepared O 2 N- - 4 C (99.5% yield)

21. Prepared "Hexaphenylethane" C+H = 93.97, 94.20, 94.00, 94.57% from first 4 methods. Reported more than 17 methods. Prepared authentic peroxide from Na 2 O 2. Prepared hydrocarbon in CO 2 atmosphere using special apparatus with ground glass joints. Ph 3 C-Cl Zn Ph 3 C-CPh 3 Ph 3 CO-OCPh 3 O2O2 ( C+H = 93.82 )

22. Free Radical! (1900) Highly “Unsaturated” (O 2, Cl 2, Br 2, I 2 !) Launched an American Century of Chemistry

23. October, 1900

24. End of Lecture 63 March 31, 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