1. Chemistry 125: Lecture 73 April 28, 2010 Benzoin, Claisen, Robinson (Ch. 19) Two Un-Natural Products This For copyright notice see final page of this file

2. The Benzoin Condensation (prob. 19.90) Ph C OH C N CH 3 OH H C N nucleophile like C=O an  -activator leaving group H C Ph O also an  -activator (benzylic) Ph C O C N H H C Ph OH N C base - HCN CN “reverses the polarity” of O=C  + to C - (“umpolung”) need Ph-C O to attack O=CH-Ph H+H+ C N where we’re going: what we have: not basic enough  pK a > 30

3. The Claisen Condensation (sec 19.8)

4. The Claisen Condensation (sec 19.8) Driving Force

5. Nature’s Claisen (sec 19.6) Fatty Acids have even numbers of C atoms! Driving Force

6. Robinson Annulation (sec 19.11)

7. REVIEW 1: The Synthesis of Two Unnatural Products (in order to settle a question in the theory of organic chemistry)

8. Is cyclobutadiene antiaromatic (4n)? Diels- Alder O O O O + O=C=O h h (must be disrotatory) Make it and see. (2  +2  forbidden thermally) very strained (2  +2  forbidden thermally, but it happens anyway) Presumptive Evidence. Spectroscopy?

9. Make one molecule per cage Making & Studying “antiaromatic” Cyclobutadiene (for solubility) O CH CH 2 Ph mouth Cram, Tanner, and Thomas (1991)

10. Preparing Dihydrocinnamaldehyde O CH CH 2 Ph O CH Ph O CH CH 3 O CH Ph

11. (as mixture with tetra- substituted and two disubstituted analogues) Start with Hemisphere O H + H + etc. The electrophilic aromatic substitution is reversible, and ultimately the desired “tetramer” stereoisomer precipitates from the equilibrating mixture in 69% yield based on hydrocinnamaldehyde. O-CH 2 bonds by S N 2 Ar-O - with CH 2 BrCl How to form the C 16 ring? 1) “Br + ” / -H + (3 moles) Br 2) - - BrCH 2 Cl Hydrocinnam- aldehyde (from benzaldehyde see above) Resorcinol Lucky! H+H+ (OH activating o,p-directing) (by chromatography; 5% from tetramer)

12. Joining Hemispheres 1) Br + /-H + (3 moles) Br 3) BuLi 4) B(OR) 3 5) HOO - Li B(OR) 2 OH O-CH 2 bonds by S N 2 Ar-O - with CH 2 BrCl 2) - - ~40% (1% overall) HO O - O-B(OR) 2 HO - - O-O- 6) O-CH 2 bonds by S N 2 Ar-O - with CH 2 BrCl (add “Ar - ” to B ; lose RO - ) (insert O between C and B. Cf. hydroboration/oxidation; (halogen-metal exchange  more stable “Ar - anion”) Note: the purpose of 1,3,4,5 is to “hide” an OH group between the OH groups of resorcinol, and then reveal it. HO - lose most stable ArO - anion)

13. CHCl 3 CH3CNCH3CN CH3CNCH3CN CH3CNCH3CNCH3CNCH3CN HC-N(CH 3 ) 2 held within molecule. O Stereo Pair X-Ray View JACS, 113, 7717 (1991) (easier to see without a viewer if you make it small) CHCl 3 & CH 3 CN are held between molecules in crystal but lost with t 1/2 = 34 hrs at 140°C.

14. ......... as guestBenzene Antiaromatic upfield shift? Most shift comes from other rings, still ~1.5 ppm above benzene Normal Replace DMF by  -Pyranone above center of 8 benzene rings.... O O O O.... O O.... Proton NMR

15. End of Lecture 73 April 28, 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

16. These last six frames are left over from a previous year (and a different textbook). Instead of discarding them, I left them here in case they might be useful as you review.

17. Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis (Cf. p. 1068) ,  -unsaturated carbonyl  Aldol H acetaldehyde H Cinnamaldehyde (prepared by this method in 1884) Ph-CH 2 -CH 2 -CHO H 2 / cat (see frame 13)

18. Ester Enolate (Ch. 22) C nucleophile ** **

19. “Claisen” or “Acetoacetic Ester” Condensation (pp. 1072-1075) substitution at ester Why not use OH - ? Equilibrium position?

20. Biological Claisen X = SR = coA (sec. 22.6, pp. 1081-1083)

21. Biological Claisen X = SR = coA (sec. 22.6, pp. 1081-1083)

22. Acid Derivatives : A/D Substitution at C=O How to go “wrong” way? (e.g. R-CO-OH  R-CO-Cl) S O Cl O-O- O S O-O- O O Cl - O S O Cl O SO 2 Cl Cl - O Cl O-O- Trick with SOCl 2. X = Cl ; Y = Cl + stable SO 2 O-O- X Y Y-Y- X O X-X- Y O ROH O-O- O Equilibrium favors the more stable anion: Cl - > - O-C-R > - OR > NR 2 - O pK a -2.2 4.8 16 35