Condensations (J&F Ch. 19) Fischer’s Glucose Proof - Introduction Chemistry 125: Lecture 73 April 25, 2011 -H Reactivity (J&F Ch. 19) Condensations (J&F Ch. 19) Fischer’s Glucose Proof - Introduction This For copyright notice see final page of this file

-Alkylation Ketones / Aldehydes (e.g. J&F Sec.19.5a) ? CH3-I

Electrostatic Potential p attack HOMO favors C -143 -170 s attack Electrostatic Potential favors O

-Alkylation Ketones / Aldehydes (e.g. J&F Sec.19.5a) (CH3)3Si-Cl Si(CH3)3 t-Bu negligible 85% CH3 negligible major CH3-I

-Alkylation Ketones / Aldehydes (e.g. J&F Sec.19.5a) pKa 32 pKa ~20 Ph3C- K+ CH3OC2H4OCH3 + 22% CH3I (2 eq) added to enolate solution House and Kramar, JOC, 38, 3368 (1963) Org. Syn. Coll vol 76, p. 239, 1999 41% 9% 21% 6%

-Alkylation Ketones / Aldehydes (e.g. J&F Sec.19.5a) i-Pr2N- Li+ -78°C “LDA” MnCl2 • 2LiCl -78°C PhCH2Br (1.3 eq) room temp House and Kramar, JOC, 38, 3368 (1963) Org. Syn. Coll vol 76, p. 239, 1999 88% distilled “Org. Syn. Prep.”

-Alkylation Carboxylic Acids (e.g. J&F Sec. 19.5b) i-Pr2N- Li+ “LDA” LDA R-Br R

-Alkylation -Dicarbonyls (e.g. J&F Sec.19.5c) HO- EtO- R-L (not HO-) b-ketoester EtO- HO- R-L malonic ester HO- EtO- R-L or cyanoacetic ester

-Alkylation Decarboxylation (e.g. J&F Sec. 19.5d) “Acetoacetic Ester Synthesis” of Ketone “Malonic Ester Synthesis” of Acid H+ D Arndt-Eistert, C N, Grignard/CO2 add one C to chain; these syntheses & add two.

The Aldol “Condensation” (e.g. J&F Sec 19.6) b-Hydroxyaldehyde “aldol” HOH HO- acetaldehyde favorable equilibrium -H2O H+ catalysis also works for both steps a,b-Unsaturated Aldehyde

The Aldol “Condensation” (e.g. J&F Sec 19.6) Boil Condense b-Hydroxyketone HO- HOH ketone unfavorable equilibrium Make tea by pouring hot water through tea bag in funnel? Better to use Soxhelet extractor containing solid base, Ba(OH)2

The Crossed Aldol “Condensation” (e.g. J&F Sec 19.6) can’t form enolate! favorable equilibrium unfavorable equilibrium b-Hydroxyketone HO- HOH a,b-Unsaturated Ketone -H2O

Conjugate Addition (e.g. J&F Sec 19.6c)

Robinson Annulation - 1935 (e.g. J&F Sec 19.11) Robert Robinson R. B. Woodward by permission J. D. Roberts pinacol rearr. aldol pinacol reduction conjugate addition to Methyl Vinyl Ketone

The Claisen “Condensation” (e.g. J&F Sec 19.8) starts like aldol but has a leaving group b-Ketoester -RO- RO- ester RO- Drives the Equilibrium “eats the lye”

Nature’s Claisen “Condensation” (e.g. J&F Sec 19.10) Malonyl-coA CO2- 2 Acetyl-coA unfavorable equilibrium HScoA = -CO2 Drives the Equilibrium 1) Reduce 2) Dehydrate H 3) Reduce Natural fatty acids have even numbers of C atoms.

Carbohydrate (C•HOH)n CHOH CHOH CHOH H OH CHOH CHOH CHOH Couper 1858

Carbohydrate (C•HOH)n CHOH C=O H CHOH C=O H C=O CHOH H CHOH

Heinrich Kiliani 1855-1945

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