Another Equilibrium: Reaction At The α-position

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1 Another Equilibrium: Reaction At The α-position D 3 + D 3 C CD 3 2 C 2 the keto form the enol form chanism: + C 2 C 2 C 2 D D 2 D 2 repeat 5 times D 3 C CD 3

2 alogenation At The α-position Br 2, 2 C 2 Br I 2, 2 C 2 I Cl 2, 2 C 2 Cl Arthur Lapworth, in 1904, discovered that the above reactions have exactly the same rates and are 1st order in acetone but zero order in halide!

3 alogenation At The α-position Br 2, 2 C 2 Br Arthur Lapworth, in 1904, discovered that the above reactions have exactly the same rates and are 1st order in acetone but zero order in halide! slow C 2 fast C 2 Br + Br Br Br Rate dietermining step Acid, which is produced in the reaction, is also a catalyst in the reaction. This process is therefore autocatalytic. This step is after the rate determining step and does not enter into the rate equation.

4 Carbonyls: Weak Acids At The α-position C 2 C 3 pk a = pk a = 44 pk a = 60+ C 2 C 3 localized anion Reminder alcohols have a pk a range!

5 Carbonyls: Weak Acids At The α-position β γ α D, D 2 D 3 C CD 3 chanism: C 2 C 2 C 2 C 2 an enolate D D D D repeat 6 times D 3 C CD 3

6 The aloform Reaction Excess Br 2, chanism: enolate repeat 2 times C 2 formation C 2 Br Br C 2 Br CBr 3 α-bromo ketone is now more acidic CBr 3 + CBr 3

7 The Aldol Reaction C 2 enol a β-hydroxy carbonyl

8 Mixed Aldol Reactions: Non-Enolizable Aldehydes Acidic: 3 + C 2 a β-hydroxy carbonyl Basic: 2 C 2 2 a β-hydroxy carbonyl

9 Mixed Aldol Reactions: Enolizable Aldehydes C 2 C 2 Mixture of Aldol Addition Products

10 Aldol Reactions With Unsymmetrical Ketones + C 2 + Less stable, less hindered More stable, more hindered Mixture of Aldol Addition Products

11 The Aldol Condensation 3 + E2 Acidic: R R a β-hydroxy carbonyl an α,β-unsaturated carbonyl 2 E2 Basic: R R an α,β-unsaturated carbonyl

12 ow can we make this compound from a linear precursor?

13 ow can we make this compound from a linear precursor? comes from an aldol condensation comes from an aldol addition Linear Precursor (what is this compound called?) + "irreversible" step 2 2

14 Irreversible Enolate Formation: A "Better" Base LDA pk a = only enolate formed N BuLi Li N diisopropyl amine pk a = 35 Lithium Diisopropyl Amide (LDA) LDA is very hindered it will not add to carbonyl groups as a nucleophile Enolate formation is kinetically controlled and irreversible.

15 Reactions of Enolates LDA Li I C 2 C 2 D 2 Br 2 R C 2 D C 2 Br R

16 Enol and Enolate Formation: Stereoelectronic Restrictions An anion can only be resonance stabilized if the orbitals are aligned: base σ C π * C C LP π * C base All 4 α-hydrogens are equivalent (pk a = 19) C LP π * C pk a > 60, no overlap between C LP and π * C

17 Enol Equilibria of Carbonyl Compounds 2 C 2 K eq = 6 X 10-9 the keto form the enol form 2 K eq = 4.0 the keto form the enol form Does this compound exist? Why or why not?

18 Enol and Enolate Formation: Stereoelectronic Restrictions Et base What enolate is formed?

19 Enol and Enolate Formation: Stereoelectronic Restrictions Et base Et no overlap with π * C ring ring b t-bu Et good overlap with π * C a a ring t-bu group "anchors" this chair conformation ring b Et

20 Aldol-Type Reactions with Conjugated Acceptors: The Michael Reaction MgCl 2 CuLi?

21 Aldol-Type Reactions with Conjugated Acceptors: The Michael Reaction The 1,2-addition product Thermodynamically Favored bserved Product The 1,4-addition product

22 Tandem Aldol and Michael Reactions: The Robinson Annulation 3 +

23 Basic Disproportionation of Non-Enolizable Aldehydes: The Cannizaro Reaction K 2 Aldol reaction products K % 50%

24 The Aldol Reaction X base X M R X * * R Forms a Carbon-Carbon bond, generates a β-hydroxy carbonyl compound Creates 2 stereocenters

25 Retro-biosynthesis Et Erythromycin A The Aldol Reaction in Biology N 2 Et Et Erythromycin Seco Acid Polypropionate Biosynthesis: The Elementary Steps R Acylation Reduction R SR SR C 2 R SR Acylation C 2 R Reduction SR R SR Erythromycin Seco Acid 7 Propionate Subunits