*3 enolates and alkylations aldol - claisen - michael

Click here to load reader

  • date post

    11-May-2015
  • Category

    Technology

  • view

    320
  • download

    4

Embed Size (px)

Transcript of *3 enolates and alkylations aldol - claisen - michael

  • 1.1! 1) Keto-Enol Tautomerism A) acid catalyzed Keto form Enol form (more stable) (less stable) There MUST be a hydrogen on the -carbon (only need a tiny amount)

2. 2! B) base catalyzed Keto form Enol form (more stable) (less stable) 2) Keto-Enol Tautomerism There MUST be a hydrogen on the -carbon (only need a tiny amount) 3. A) INTRAmolecular hydrogen bonding B) Aromaticity 3) What Stabilizes the Enol Tautomer ? (has conjugation) (has aromaticity) 4. Chapter 22! 4! 50% (S) Enantiomer 50% (R) Enantiomer 4) Keto-Enol Tautomerization: Racemization Racemic Mixture 50:50 mix of each enantiomer (S) Enantiomer only 5. 1) An Enol is a weak Nucleophile Carbonyl compounds that have an -hydrogen(s) will form an enol, which will undergo substitution reactions at the -carbon: an -substitution reaction 6. 2A) Enol Reaction: Acid-Catalyzed -Halogenation 2 7. The dipole +/- that forms in the new carbon-halogen bond destabilizes the a-carbon towards tautomerization (forming another enol and reacting further). Mechanism Only ONE halogenation Acetic acid commonly serves as the acid catalyst. (and the solvent) 2B) Enol Reaction: Acid-Catalyzed -Halogenation 8. 4! 3A) Hell-Volhardt-Zelinsky Reaction(HVZ) overall reaction P + Br2 PBr3 How to make PBr3 9. 5! 3B) Hell-Volhardt-Zelinsky Reaction Mechanism 1) 2) 2) 2) 10. -halo carboxylic acid derivatives undergo E2 reactions by heating in the presence of pyridine Enone 4) Follow-On Reaction of -halo carbonyls -halo ketones undergo E2 reactions by heating in the presence of t-butoxide (KO-tBu)) Enone Enone HVZ product HVZ product 11. The -Hydrogen Is Slightly Acidic the anion is stabilized by resonance 12. The partial positive charge on the carbonyl carbon helps stabilize the negative charge forming on the adjacent carbon. So, hydrogens on carbons next to ANY EWG are slightly acidic. Examples 13. Enolate Equilibrium: Example #1 14. Enolate Equilibrium: Example #2 15. Enolate Equilibrium: Example #3 16. Enolates of Unsymmetrical Ketones when treated with base, two enolates are possible. Path [1] occurs faster (Kinetic Control at Low Temp.) because it results in removal of the less hindered 20 H but forms the less stable enolate. Path [2] results in formation of the more stable enolate (under Thermodynamic Control at higher temperature) when equilibrium is established. 17. 2 Very Strong (nonnucleophilic) Base ensures that the easiest to form enolate is produced rapidly. A bulky base like LDA removes the more accessible -proton on the less substituted carbon much faster than an -proton from the more sterically hindered side.. Polar Aprotic solvent: polar to dissolve the polar starting materials and intermediates and aprotic so that it does not protonate the less stable enolate that is formed first. Low temperature (-78C) to prevent the kinetic enolate from equilibrating to the more stable thermodynamic enolate. Kineticic Enolate (from unsymmetrical ketones) is favored by: 18. 3 Thermodynamic Enolate (from unsymmetrical ketones) is favored by: Strong Base that can form all enolates, so that the more stable, more substituted enolate is present in a higher concentration. Common bases are Na+OCH2CH3, and other alkoxides. Protic Solvent (CH3CH2OH and other alcohols). For the reaction to be reversible, enolates need to be protonated to re-form the carbonyl starting material. Heat (25C or higher). Enough energy is needed to establish equilibrium, so the more stable, more substituted enolate is present in a higher concentration. 19. 4 Making (about 100%) Thermodynamic Enolate 20. and silyl halides (R3Si-X) The Carbon site acts like a nucleophile (attacks carbons) An Enolate is a Great Nucleophile/Base The Oxygen site acts like a base (attacks protons) 21. Treatment of propiophenone with Br2 and aqueous hydroxide, OH yields a dibromoketone. 2A) Enolate Reactions: Base-Promoted Halogenation 22. 2B) Enolate Reactions: Base-Promoted Halogenation The mono-halogenated product has a more acidic -hydrogen than the a-hydrogen in the initial reactant. Cannot stop the Halogenation Reaction (in base) after addition of just one halogen atom to the carbon. (not catalytic) 23. 3A) Enolate Reactions: The Haloform Reaction If I2 is used, haloform reaction yields iodoform If Br2 is used, haloform reaction yields bromoform If Cl2 is used, haloform reaction yields chloroform An Iodoform reaction produces carboxylates (then are protonated with acid to carboxylic acids) and iodoform (yellow color) from methyl ketone (reactants). Iodoform Test for methyl ketones 24. 3B) Enolate Reactions: The Haloform Reaction HO - (xs) I2 (xs) 25. Treatment of an enolate with an alkyl halide results in alkylation substitute OUT H (Hydrogen) / substitute IN R (alkyl group) on the carbon atom. 4A) Enolate Reactions: Direct Alkylation (with R-X) 26. 4B) Enolate Reactions: Direct Alkylation (with R-X) This is an SN2 reaction, so extremely fast with methyl halides and fast with primary alkyl halides (tertiary halides (R-X) do NOT work) 27. 1 Enolate Alkylations: The acetoacetic ester synthesis: is a stepwise method to make a methyl ketone (having one or two alkyl groups on the carbon). Uses the reactant ethyl acetoacetate 1) Acetoacetic Ester Synthesis (AES) from double alkylationfrom single alkylation 28. 2 1) Acetoacetic Ester Synthesis (AES) A) Single Alkylation 29. 3! General Decarboxylation Mechanism methyl In AES (using ethyl acetoacetate), the decarboxylation step always forms a methyl ketone. 30. 4 B) Double Alkylation 1) Acetoacetic Ester Synthesis (AES) 31. 5! B) Double Alkylation mechanism Decarboxylation (loss of CO2) 1) Acetoacetic Ester Synthesis (AES) 1) 2) 4)3) 32. 6 Key: Both R-X (alkyl halides) are in the same reagent C) INTRAmolecular AES (Ring Forming) 1) Acetoacetic Ester Synthesis (AES) 33. 7 to determine what starting materials are needed to prepare a given methyl ketone using the acetoacetic ester synthesis (AES). 1) Acetoacetic Ester Synthesis (AES) D) Use Retro-Synthetic Analysis 34. 1 Enolate Alkylations: The malonic ester synthesis: is a stepwise method to make a carboxylic acid (having one or two alkyl groups on the carbon). Uses the reactant diethyl malonate 2) Malonic Ester Synthesis (MES) from double alkylationfrom single alkylation 35. 2) Malonic Ester Synthesis (MES) A) Single Alkylation example 36. 1) The diester with acid, water, heeeet will hydrolyzes both esters to carboxy groups. 2) -Diacids are unstable to heat and will decarboxylate resulting in a carboxylic acid and CO2(gas). General Decarboxylation Mechanism Overall 37. 4 2) Malonic Ester Synthesis (MES) B) Double Alkylation 38. 5 C) INTRAmolecular MES (Ring Forming) 2) Malonic Ester Synthesis (MES) Key: Both R-X (alkyl halides) are in the same reagent 39. 6 D) Use Retro-Synthetic Analysis 2) Malonic Ester Synthesis (MES) to determine what starting materials are needed to prepare a given carboxylic acid using the malonic ester synthesis (MES). 40. The Aldol Reaction A) Self-Condensation Reaction 41. The Aldol Reaction A) Self-Condensation Reaction One molecule of a carbonyl compound acts as a nucleophile and the other carbonyl compound acts as an electrophile 42. The Aldol Addition product is often not isolated. Instead, it loses water (H2O) from the and carbons to form a Aldol Condensation product (an enone). Aldol Addition Product Aldol Condensation Product The Aldol Reaction Heat Acid or Base (dehydration) Enone The Aldol Addition -vs- Condensation Products 43. The Aldol Reaction The Aldol Addition -vs- Condensation Products Examples of Aldol Addition products Draw the Aldol Condensation Products Conjugated Enones 44. The Aldol Reaction B) Mixed/Crossed - Directed (Stepwise) 1) 2) 3) Take Note: How much enolate (what percent) is formed? 45. The Aldol Reaction B) Mixed/Crossed - Directed (Stepwise) Take Note: How much enolate (what percent) is formed? 1) 2) 3) Acid + heat (or Base + Heat) will form the Aldol Condensation Product Draw the structure of the Aldol Condensation product 46. The Aldol Reaction C) Mixed/Crossed Claisen-Schmidt Take Note: The electrophile (aldehyde or ketone) has NO -Hydrogens Take Note: The electrophile is in situ enone 47. The Aldol Reaction C) Mixed/Crossed Claisen-Schmidt Take Note: The electrophile (aldehyde or ketone) has NO -Hydrogens Take Note: The electrophile is in situ SlowerFaster Relative Rates of Enolate Reactions Major Addition Product We will learn the 48. The Aldol Reaction D) Mixed/Crossed - Directed (in situ) Take Note: Electrophile is in situ Take Note: The enolate is very easily formed (compared to the electrophile) 49. The Aldol Reaction D) Mixed/Crossed - Directed (in situ) Take Note: Electrophile is in situ What is the weakest base that you can use and still product 100% enolate? Draw the structure of the Enolate from each Take Note: The enolate is very easily formed (compared to the electrophile) active methylene compounds are more reactive towards base 50. The Aldol Reaction E) INTRAmolecular Take Note: Electrophile is within the same molecule Take Note: only form unstrained 5- or 6-membered rings A mixture of products may form from unsymmetrical reactants 51. The Aldol Reaction E) INTRAmolecular Take Note: Electrophile is within the same molecule Take Note: only form unstrained 5- or 6-membered rings A mixture of products may form from unsymmetrical reactants Draw the structure of the OTHER cyclopentenone that forms? 52. The Aldol Reaction F) RetroSynthetic Analysis 53. The Aldol Reaction F) Retro Synthetic Analysis Draw the reagents structures needed to make each product shown Which Aldol Reaction Type (Self / Directed(stepwise) / Directed(in situ) / Claisen-Schmidt / INTRAmolecular) was needed to make each product shown ? 54. The Claisen Reaction: Any enolate attacking an ester The product will be a 1,3-dicarbonyl compound 1) 2) Must have at least two -hydrogens on the reactant. 55. two molecule