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 ) 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

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)? 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?

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

Preparing Dihydrocinnamaldehyde O CH CH 2 Ph O CH Ph O CH CH 3 O CH Ph

(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)

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)

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.

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

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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) ,  -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)

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

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

Biological Claisen X = SR = coA (sec. 22.6, pp )

Biological Claisen X = SR = coA (sec. 22.6, pp )

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