1 / 69

Organic Chemistry II Alpha Substitution Reactions

Organic Chemistry II Alpha Substitution Reactions. Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University. The  Position. The carbon next to the carbonyl group is designated as being in the  position. Objectives. Keto-enol tautomerism

moira
Download Presentation

Organic Chemistry II Alpha Substitution Reactions

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Organic Chemistry IIAlpha Substitution Reactions Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

  2. The  Position • The carbon next to the carbonyl group is designated as being in the  position

  3. Objectives • Keto-enol tautomerism • Enols –  substitution • Enol acidity – the enolate • Alkylation of the enolate • Carbonyl Condensation Reactions • Aldol • Claisen • Michael Reaction • Stork Enamine • Robinson Annulation

  4. Enolization • conditions permit the enolization of ketones • Substitution can occur at the alpha position through either an enol or enolate ion

  5. Equilibrium of Tautomerism • Enol formation is equilibrium process • Keto form is predominant species • Enol is present in sufficient concentration to be involved in any reaction

  6. Tautomers • Tautomers are structural isomers • Tautomers are not resonance forms • Resonance forms are representations of contributors to a single structure • Tautomers interconvert rapidly while ordinary isomers do not

  7. Enols • The enol tautomer is usually present to a very small extent and cannot be isolated • However, since it is formed rapidly, it can serve as a reaction intermediate

  8. Acid Catalysis of Enolization • Brønsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the  protons

  9. Base Catalysis of Enolization • Brønsted bases catalyze keto-enoltautomerization • The hydrogens on the  carbon are weakly acidic and transfer to water is slow • In the reverse direction there is also a barrier to the addition of the proton from water to enolate carbon

  10. Reactivity of Enols • Enols have very e- rich double bonds • Very Nucleophilic • React with variety of electrophiles

  11. Generalized Reaction • When an enol reacts with an electrophile the intermediate cation immediately loses the OH proton to give a substituted carbonyl compound

  12. Halogenation • Aldehydes and ketones can be halogenated at their  positions by reaction with Cl2, Br2, or I2 in acidic solution

  13. Kinetics • Rate is independent of identity of X2 • Cl2, Br2, I2 react at same rate • Rate is independent of [X2] • Rate determining step occurs before X2 • Rate determining step is enolization step • Rate = k[ketone][H+]

  14. Ramification of Enolization • Optically active ketones can lose optical activity

  15. Elimination Reactions of-Bromoketones • -Bromo ketones can be dehydrobrominated by base treatment to yield ,b-unsaturated ketones

  16. Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii Reaction • Carboxylic acids do not react with Br2 (Unlike aldehydes and ketones) • They are brominated by a mixture of Br2 and PBr3 (Hell–Volhard–Zelinskii reaction)

  17. Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation • Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60) • The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen

  18. Enolate Formation - Bases • Ketones are weaker acids than the OH of alcohols so a a more powerful base than an alkoxide is needed to form the enolate • NaOH and NaOCH3) are too weak • Sodium hydride (NaH), sodamide (NaNH2), or lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form the enolate

  19. Lithium Diisopropylamide (LDA) • LDA is made from butyllithium (BuLi) and diisopropylamine (pKa 40) • Soluble in organic solvents and effective at low temperature with many compounds (see Table 22.1) • Not nucleophilic

  20. Similar Bases • Lithium tetramethylpiperdide • Lithium dicyclohexylamide

  21. Acidity of the alpha Hydrogen

  22. Acidity of -Dicarbonyls • When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced • Negative charge of enolate delocalizes over both carbonyl groups

  23. Acidities of Organic Compounds

  24. Reactivity of Enolate Ions • The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive)

  25. Enolate Reactions • Enolate has two resonance forms • Reacts at both sites with E+ depending upon conditions

  26. Two Reactions Sites on Enolates • Reaction on oxygen yields an enol derivative • Reaction on carbon yields an a-substituted carbonyl compound

  27. Enol Ether Formation • Enolates react with trimethylsilyl chloride to form the enol ether

  28. Alkylation • Alkylation occurs at C

  29. Revisit Halogenation of the Enolate The Haloform Reaction • Base-promoted reaction occurs through an enolate ion intermediate

  30. Further Reaction: Cleavage • Monohalogenated products are themselves rapidly turned into enolate ions and further halogenated until the trihalo compound is formed from a methyl ketone • The product is cleaved by hydroxide with -CX3 as the leaving group, stabilized anion

  31. Halogenation: Summary • Base catalyzed process • Can’t be stopped at one halogen • Cleaves methyl ketones to give HCX3 • Acid catalyzed process • Second halogenation is very slow • Useful reaction for monohalo ketones

  32. Alpha Selenylation • Used to make unsaturated ketones

  33. Alkylation of Enolate Ions • Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide or tosylate and displaces the leaving group

  34. Constraints on Enolate Alkylation • SN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate • R should be primary, methyl, allylic or benzylic • Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination

  35. Alkylation of Ketones • Base must be weaker acid than ketone • Complete proton abstraction • Base cannot be nucleophilic • Adds to carbonyl • LDA meets both criteria • Consider:

  36. Deprotonation by LDA

  37. Analysis • Least hindered product predominates • Steric size of base • Approach to more substituted side restricted • Increase in the size of the base increases the predominance of the less substituted side product

  38. The Malonic Ester Synthesis • For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms

  39. Formation of Enolate and Alkylation • Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol • The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an a-substituted malonic ester

  40. Dialkylation • The product has an acidic -hydrogen, allowing the alkylation process to be repeated

  41. Hydrolysis and Decarboxylation • The malonic ester derivative hydrolyzes in acid and loses CO2 (“decarboxylation”) to yield a substituted monoacid

  42. Malonic Acid Syntheses • Very useful reaction, • For example • All can be decarboxylated to the mono acids

  43. Decarboxylation of b-Ketoacids • Decarboxylation requires a carbonyl group two atoms away from the CO2H • The second carbonyl permit delocalization of the resulting enol • The reaction can be rationalized by an internal acid-base reaction

  44. Decarboxylation • Beta-dicarboxylic acids readily lose CO2 • Other beta carboxy carbonyls should also • Look at Ethyl acetoacetate (pKa = 11)

  45. Acetoacetate Synthesis

  46. Reminder of Overall Conversion • The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms

  47. Decarboxylation of Acetoacetic Acid • b-Ketoacid from hydrolysis of ester undergoes decarboxylation to yield a ketone via the enol

  48. Generalization: b-Keto Esters • The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to b-keto esters in general • Cyclic b-keto esters give 2-substituted cyclohexanones

  49. Carbonyl Condensation Reactions • Carbonyls behave • Electrophile or Nucleophile • Electrophilic Behavior • Nu: add to C=O • Nucleophilic Behavior • Enols or enolates react with E+ • Condensation Reactions • Combine both reactions • Uses two carbonyl compounds • One is the Nu: through an enolate • Second is the E+

  50. The Aldol Reaction • Equilibrium reaction • Products favored for aldehydes • Reactants favored for ketones

More Related