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Chapter 20 Carbonyl compounds

Chapter 20 Carbonyl compounds. Introduction to carbonyls Reductions and oxidations Addition of organometallics (Rli, RMgX, R2CuLi) to carbonyls. Compounds Containing Carbonyl Groups. Polarity of Carbonyl Groups. General Reactions of Carbonyl Compounds. Reactivity to Nucleophilic Addition.

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Chapter 20 Carbonyl compounds

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  1. Chapter 20 Carbonyl compounds Introduction to carbonyls Reductions and oxidations Addition of organometallics (Rli, RMgX, R2CuLi) to carbonyls

  2. Compounds Containing Carbonyl Groups

  3. Polarity of Carbonyl Groups

  4. General Reactions of Carbonyl Compounds

  5. Reactivity to Nucleophilic Addition

  6. Reactivity to Nucleophilic Substitution How does pKa change with Z?

  7. Preview of Oxidation and Reduction Higher energy content

  8. Oxidation and Reduction of Carbonyl Compounds • The three most useful oxidation and reduction reactions of carbonyl starting materials can be summarized as follows:

  9. Metal hydrides are an alternative

  10. Alternative Reducing Agents

  11. Reduction of Aldehydes and Ketones with hydride reagents

  12. Lithium Aluminum Hydride No unactivated alkenes Strong reducing agent. Not very selective

  13. LiAlH4 Reduction Mechanism for esters and acid chlorides

  14. Aldehyde intermediate is more reactive than carboxylic acid and is immediately reduced to alcohol

  15. LiAlH4 Reduction of Amides -NR2 is poor leaving group

  16. Mechanism for reduction of amides with LiAlH4 Imine is rapidly reduced

  17. Sodium Borohydride Reductions in Synthesis Less reactive; More selective Than LiAlH4 Won’t reduce esters, amides, halides, epoxides, carboxylic acids

  18. Sodium Borohydride Reductions in Synthesis Less reactive; More selective Than LiAlH4 Won’t reduce esters, amides, halides, epoxides, carboxylic acids

  19. Sodium Borohydride Reductions with CeCl3 Luche reduction Only reduces ketones, not aldehydes

  20. Stereochemistry of Carbonyl Reduction • Hydride converts a planar sp2 hybridized carbonyl carbon to a tetrahedral sp3 hybridized carbon.

  21. Hydroboration Chemistry Better regio control with hindered boranes:

  22. reductions with BH3 fast slow slow slow Allows carboxylic acids to be reduced in the presence of aldehydes or ketones

  23. Enantioselective Carbonyl Reductions • Selective formation of one enantiomer over another can occur if a chiral reducing agent is used. • A reduction that forms one enantiomer predominantly or exclusively is an enantioselective or asymmetric reduction. • An example of chiral reducing agents are the enantiomeric CBS reagents.

  24. CBS Reducing Agents • CBS refers to Corey, Bakshi, and Shibata, the chemists who developed these versatile reagents. • One B–H bond serves as the source of hydride in this reduction. • The (S)-CBS reagent delivers (H:−) from the front side of the C=O. This generally affords the R alcohol as the major product. • The (R)-CBS reagent delivers (H:−) from the back side of the C=O. This generally affords the S alcohol as the major product.

  25. Enantioselectivity of CBS Reagents • These reagents are highly enantioselective. • For example, treatment of propiophenone with the (S)-CBS reagent forms the R alcohol in 97% enantiomeric excess (ee).

  26. Enantioselective Reductions in Synthesis • Enantioselective reductions are key steps in the synthesis of several widely used drugs, including salmeterol, a long-acting bronchodilator. Figure 20.3

  27. Biological Reductions • Biological reductions that occur in cells always proceed with complete selectivity, forming a single enantiomer. • In cells, the reducing agent is NADH. • NADH is a coenzyme—an organic molecule that can function only in the presence of the enzyme.

  28. Mechanism of NADH Reductions • The active site of the enzyme binds both the carbonyl substrate and NADH, keeping them in close proximity. • NADH then donates H:− in much the same way as a hydride reducing agent.

  29. Enantioselectivity of NADH Reduction • The reaction is completely enantioselective. • For example, reduction of pyruvic acid with NADH catalyzed by lactate dehydrogenase affords a single enantiomer with the S configuration. • NADH reduces a variety of different carbonyl compounds in biological systems. • The configuration of the product (R or S) depends on the enzyme used to catalyze the process.

  30. NAD+ —Biological Oxidizing Agent • NAD+, the oxidized form of NADH, is a biological oxidizing agent capable of oxidizing alcohols to carbonyl compounds (it forms NADH in the process). • NAD+ is synthesized from the vitamin niacin.

  31. Other Metal Hydride Reducing Agents: Use only 1 equiv. DiBAL-H to avoid over reduction LiAlH4 reduces all the way to alcohols.

  32. DIBAL-H Reduction of acid chloride to aldehyde

  33. Reductions with DiBAL-H

  34. Reduction of Esters • In the reduction of an acid chloride, Cl− comes off as the leaving group. • In the reduction of the ester, CH3O− comes off as the leaving group, which is then protonated by H2O to form CH3OH.

  35. DIBAL-H Reduction of an Ester Figure 20.4 The DIBAL-H reduction of an ester to an aldehyde in the synthesis of the marine neurotoxin ciguatoxin CTX3C

  36. Other Metal Hydride Reducing Agents:

  37. Oxidation of Aldehydes • A variety of oxidizing agents can be used, including CrO3, Na2Cr2O7, K2Cr2O7, and KMnO4. • Aldehydes can also be oxidized selectively in the presence of other functional groups using silver(I) oxide in aqueous ammonium hydroxide (Tollen’s reagent). • Since ketones have no H on the carbonyl carbon, they do not undergo this oxidation reaction.

  38. Organometallic Reagents • Li, Mg, and Cu are the most common organometallic metals. • Other metals found in organometallic reagents are Sn, Si, Tl, Al, Ti, and Hg. • General structures of common organometallic reagents are shown:

  39. Reactivity of Common Organometallic Compounds • Since both Li and Mg are very electropositive metals, organolithium (RLi) and organomagnesium (RMgX) reagents contain very polar carbon-metal bonds and are therefore very reactive reagents. • Organomagnesium reagents are called Grignard reagents. • Organocopper reagents (R2CuLi), also called organocuprates, have a less polar carbon–metal bond and are therefore less reactive. • Although they contain two R groups bonded to Cu, only one R group is utilized in the reaction. • In organometallic reagents, carbon bears a − charge.

  40. Preparation of Organolithium Compounds • Crystalline solids, pyrophoric. Sold and used as solution in pentanes. Most reactive of common carbanionic reagents. • Low temperature prevents beta elimination (E2) to afford alkenes instead of metal halogen exchange • primary butyl lithiums can react readily as nucleophiles • t-BuLi never reacts as nucleophile. Only as hindered base or metal halogen exchange • At room temperature BuLi will attack THF

  41. organolithiums in SN2 reacctions

  42. Organolithiums and carbonyyls

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