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 The Benzoin Condensation (prob. 19.90) CN “reverses the polarity” of O=C+ to C- (“umpolung”) also an -activator (benzylic) OH like C=O an what we have: Ph C C N -activator leaving N C H O H C H Ph group C N base Ph C C N not basic enough O C N nucleophile C N pKa > 30 H C Ph OH where we’re going: O need Ph-C to attack O=CH-Ph H+ The Claisen Condensation (sec 19.8) The Claisen Condensation (sec 19.8) Driving Force Nature’s Claisen (sec 19.6) Fatty Acids have even numbers of C atoms! Driving Force Robinson Annulation (sec 19.11) REVIEW 1: The Synthesis of Two Unnatural Products (in order to settle a question in the theory of organic chemistry) Is cyclobutadiene antiaromatic (4n)? O O h O (must be disrotatory) O h Make it and see. Presumptive Evidence. Spectroscopy? (2 +2 forbidden thermally) DielsAlder (2 +2 forbidden thermally, but it happens anyway) + O=C=O very strained Make one molecule per cage Making & Studying “antiaromatic” Cyclobutadiene mouth O CH CH2 CH2 (for solubility) Ph Cram, Tanner, and Thomas (1991) Preparing Dihydrocinnamaldehyde O O O CH CH CH2 CH CH2 CH O Ph Ph CH CH CH3 Ph 1) “Br+” / -H+ (3 moles) by SN2 2 bonds mixture with tetra2)(asO-CH - Ar-O withand CH2two BrCl substituted disubstituted analogues) - Cl BrCH2 - Br Br Start with Hemisphere Br How to form the C16 ring? (by chromatography; 5% from tetramer) Resorcinol Hydrocinnamaldehyde (from benzaldehyde see above) H+ OH H+ + (OH activating etc. etc. o,p-directing) The electrophilic aromatic substitution is reversible, and ultimately the desired “tetramer” stereoisomer precipitates from the equilibrating mixture in 69% yield based on hydrocinnamaldehyde. Lucky! 1) Br+/-H+ (3 moles) 2) O-CH- 2 bonds by SN2 Ar-O with CH2BrCl 3) Joining Hemispheres exchange BuLi (halogen-metal more stable “Ar- anion”) - - Li Br OH B(OR)2 Br Li OH B(OR)2 ~40% HO - -overall) HO(1% HO O O-B(OR) 2 O-Li Br OH B(OR) 2 4) B(OR)3 (add “Ar- ” to B ; lose RO-) 5) HOO- (insert O between C and B. Cf. hydroboration/oxidation; lose most stable ArO- 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. 6) O-CH- 2 bonds by SN2 Ar-O with CH2BrCl CHCl3 CHCl3 Stereo Pair X-Ray View JACS, 113, 7717 (1991) (easier to see without a viewer if you make it small) CH3CN CH3CN CH3CN CH3CN CHCl3 CHCl3 & CH3CN are held between molecules in crystal O HC-N(CH3)2 held within molecule. but lost with t1/2 = 34 hrs at 140°C. CHCl3 Replace DMF by -Pyranone O O . . O . .O . . . . O O . . . . Most shift comes from Antiaromatic other rings, still ~1.5 upfield ppm above shift? benzene . Proton NMR Normal Benzene as guest above center of 8 benzene rings . . .. . . .. 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). 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 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. Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis (Cf. p. 1068) Ph-CH2-CH2-CHO H2 / cat (see frame 13) H H acetaldehyde Cinnamaldehyde (prepared by this method in 1884) ,-unsaturated carbonyl Aldol * Ester Enolate (Ch. 22) C nucleophile * “Claisen” or “Acetoacetic Ester” Condensation (pp. 1072-1075) Why not use OH-? substitution at ester Equilibrium position? Biological Claisen X = SR = coA (sec. 22.6, pp. 1081-1083) Biological Claisen X = SR = coA (sec. 22.6, pp. 1081-1083) Acid Derivatives : A/D Substitution at C=O O- O Y X- X O O Y X YEquilibrium favors the more stable anion: O OROH Cl- > -O-C-R > -OR > NR2pKa -2.2 4.8 16 35 How to go “wrong” way? (e.g. R-CO-OH R-CO-Cl) Trick with SOCl2. O O O O O O SO2 O O O O S ClCl S S Cl Cl Cl Cl Cl Cl ClX = Cl ; Y = Cl + stable SO2