CHAPTER 16

1. CHAPTER 16 Aldehydes and Ketones – Part I Nucleophilic Addition Reactions of the Carbonyl Group

2. Chapter 16 • Section 1— Introduction • Section 2— Nomenclature of Aldehydes and Ketones • Section 3— Phusical Properties • Section 4— Synthesis of Aldehydes • Section 5— Synthesis of Ketones • Section 6— The Addition of Hydrogen Cyanide • Section 7— The Addition of Primary and Secondary Amines

3. Chapter 16 • Section 8— The Addition of Primary and Secondary Amines • Section 9— The Addition of Hydrogen Cyanide • Section 10— The Addition of Ylides: The Wittig Reaction • Section 11— Oxydation of Aldehydes • Section 12— Chemical Analyses for Aldehydes and Ketones • Section 13— Spectroscopic Properties of Aldehydes and Ketones • Section 14— Summary of Aldehyde and Ketone Addition Reactions

4. Aldehydes and Ketones INucleophilic Addition to the Carbonyl Group

5. General Features of the Carbonyl Group The contributing resonance structures are: The carbon and oxygen atoms are both sp2 hybridized. The polarization of the double bond of the carbonyl group arises from the difference in electronegativities between C (2.5) and O (3.5). The C=O bond polarization is clearly evident in this map of electrostatic potential for the simplest ketone, acetone (CH3COCH3).

6. Nomenclature of Aldeydes • Common names are derived from those of the corresponding carboxylic acids by dropping the “(o)ic acid” and adding “aldehyde.” • IUPAC (systematic) names are based on the following rules when the aldehyde function has priority and is named by use of a suffix. • Select the longest continuous chain containing the –CHO and use as the parent the name of the alkane of that chain length. • Replace “e” in the alkane name with “al.” • Number from the end where the carbonyl group is located and follow all the other rules for locating substituent groups. EXAMPLES:

7. Nomenclature of Ketones • Common names are widely used for many of the simpler ketones. • Common names of aryl ketones, where a benzene ring (phenyl group) is attached to the carbonyl, have a “phenone” ending. The prefix is derived from the carboxylic acid source of the acyl group.

8. IUPAC systematic names for ketones are based on these rules: • The name of the longest alkane chain present that contains the carbonyl group is used as the parent. • Replace the “e” in the alkane name with the suffix “one” and indicate the carbonyl position by a number. Number from the end that gives the lower number to the ketone position. • Designate the substituents and their positions in the usual way.

9. Physical Properties of Aldehydes and Ketones • Because of the polar carbonyl group (μ~2.3-2.8 D), aldehydes and ketones have higher boiling points than hydrocarbons of comparable size. However, they have lower boiling points than alcohols of comparable size because only the latter have intermolecular hydrogen bonds. • Aldehydes and ketones form hydrogen bonds to water molecules and consequently the lower MW ones are soluble in water up to about C6. The smallest ones (formaldehyde and acetone) are miscible with water.

10. Synthetic Methods for Aldehydes • Because aldehydes are between 10 alcohols and carboxylic acids in the oxidation-reduction sequence, they can be synthesized by either selective oxidation of 10 alcohols or by selective reduction of carboxylic acid derivatives. • It is a unique Cr+6 oxidant. Other oxidants carry oxidation on to the carboxylic acid stage because aldehydes are more easily oxidized than alcohols.

11. Selective Reductions by Metal Hydrides • Aldehydes can be prepared b controlled reduction of carboxylic acids. Acids can be reduced with lithium aluminum hydride (LAH), a powerful reducing agent, but the process goes all the way to 10 alcohols. Lithium aluminum hydride (lithium tetrahydridoaluminate) and other metal hydride reducing agents, transfer hydride ion (H:-) to the electropositive carbon of the carbonyl group.

12. Selective Reductions by Metal Hydrides • Selective reduction of a carboxylic acid to an aldehyde can be achieved by first converting the acid to an acyl chloride (RCOCl) and then using a less powerful reducing agent. • Two selective reducing agents are: • These reducing agents succeed in the controlled reduction:

13. Hydride Transfer Mechanism

14. Reduction of Esters with DIBAL-H • Esters are selectively reduced to aldehydes with DIBAL-H when one equivalent of the reducing agent is used at low temperature. • A Proposed Mechanism • DIBAL-H is a trivalent aluminum species and is coordinatively unsaturated (i.e., a Lewis acid). The aluminum complexes with a nonbonding electron pair of the carbonyl oxygen:

15. Hydride Transfer: Nucleophilic Addition to the Carbonyl At higher temperature and with excess reagent, the aldehyde products are reduced to primary alcohols.

16. Ester and Nitrile Reductions by DIBAL-H SUMMARY: General Synthetic Schemes for Reductive Synthesis of Aldehydes

17. Ketone Syntheses

18. Ketones from Nitriles • Reaction of a nitrile with either a Grignard or organolithium reagent, followed by hydrolysis, yields a ketone. • The nitrile is a polar function similar to a carbonyl. The carbanionic center of an organometallic reagent adds to the electropositive carbon of the nitrile producing the salt of an imine. • During aqueous workup, the imine is hydrolyzed to a ketone.

19. Examples

20. Ketones by Hydration of Alkynes Alkynes, like alkenes, add water in the presence of electrophilic catalysts such as H+ or Hg2+. Hydration of alkynes is conducted in aqueous solution of sulfuric acid with mercuric sulfate as catalyst. It follows Markovnikov’s rule, with the hydrogen attaching to the carbon with the greater number of hydrogens. The “enol” rapidly rearranges to the ketone. The enol and ketone constitutional isomers actually are connected by an equilibrium which usually lies heavily on the side of the ketone. This process called tautomerization is catalyzed by acid.

21. Designing a Multistep Synthesis by Retrosynthetic Analysis • Design a synthesis of 1-phenyl-2-butanone.

22. The Synthesis of 1-Phenyl-2-butanone

23. Nucleophilic Addition to the Carbon-Oxygen Double Bond Because of the permanent dipole, nucleophiles add to the electropositive carbon and electrophiles add to the electronegative oxygen. These are the most characteristic reactions of aldehydes and ketones. Two General Mechanisms for Nucleophilic Addition (1)When the reagent is a strong nucleophile (Nu:-) such as an organometallic or metal hydride reagent, addition usually occurs first to the carbon center, forming an alkoxide ion. Electrophilic addition then occurs to the oxide. (2)A second general mechanism is acid-catalyzed nucleophilic addition. This involves a weaker nucleophile adding to the carbonyl group in the presence of catalytic amounts of acid, which protonates the carbonyl oxygen.

24. First General Mechanism In these additions, E+ is often a proton or metal ion.

25. Second General Mechanism

26. Relative Reactivity: Aldehydes versus Ketones Generally, aldehydes are more reactive than ketones because of both steric and electronic factors. Steric Factors When a nucleophile adds to the carbonyl group, the reaction center changes from trigonal planar (sp2) to tetrahedral (sp3): there is a closing of the angle between R and R’(H) groups from~120° to ~109°. With ketones, where R and R’ are alkyl or aryl groups, there is more buildup of steric strain as the groups move closer together than there is with aldehydes, where at least one of the groups being squeezed together is the very small hydrogen atom.

27. Electronic Factors A ketone carbonyl is stabilized relative to that of an aldehyde by the presence of two electron-releasingalkyl groups. This diminishing of C=O carbon charge in ketones contributes to their lower reactivity compared with that of aldehydes. Alkyl ketones are generally more reactive than aryl ketones because of greater electronic stabilization of the starting state of the latter by π- electron delocalization. SUMMARY: Any reduction in the partial positive charge on the C=O carbon decreases its reactivity in nucleophilic addition. Any increase, e.g., by the presence of a strongly electron withdrawing group like -CF3, increases reactivity.

28. Addition Reactions of Aldehydes and Ketones Addition of Water and Alcohols: Hydrates and Acetals The position of equilibrium depends on the size and electronic effects of the R groups. For most ketones, K’=K[H2O]=<<1. Most ketones exist essentially 100% in the carbonyl form. Aldehydes hydrate somewhat more extensively. Bulky and/or electron-donating R groups stabilize the carbonyl compound in the above equilibrium. Electron-withdrawing groups destabilize the carbonyl compound and promote formation of the hydrate. These factors are illustrated in the table that follows. Hydrates: gem-Diols

30. Mechanism for Hydrate Formation • The rate of hydration is much faster under basic (higher pH) or acidic (lower pH) conditions than at pH 7.

31. Additions of Alcohols: Hemiacetals and Acetals Alcohols (R-OH) add to carbonyl compounds like water does. One important difference is that, overall, two molecules of ROH can react with one of an aldehyde or ketone. Alcohols (R-OH) add to carbonyl compounds like water does. One important difference is that, overall, two molecules of ROH can react with one of an aldehyde or ketone. A hemiacetal is formed from the addition of one molecule of ROH. An acetal results from the addition of two molecules of ROH. If the carbonyl compound is a ketone, the terms hemiketal and ketal are often but not always used in place of hemiacetal and acetal.

32. Typical Reaction Conditions for Acetal Formation The rate of the addition of alcohol is accelerated by acid and, like the hydration reaction, there is an equilibrium between the carbonyl compound and the tetrahedral product. To promote hemiacetal and acetal formation, the reaction is run by allowing the aldehyde to stand with a large excess of the alcohol with a small amount of anhydrous acid. The water produced can be removed as an azeotrope with benzene to drive the reaction to completion. A Mechanism for Acetal Formation

33. Acetal formation Overview

34. Hemiacetals

35. Hydrolysis of Acetals • All the steps in acetal formation are reversible. In an aqueous acid solution, acetals hydrolyze back to aldehydes.

36. Mechanism Continued • Further acid-catalyzed hydrolysis of the hemiacetal

37. The equilibrium is catalyzed by acid, but the position of the equilibrium is determined by the concentrations of the reactants. Acetal formation occurs when the aldehyde is reacted in the presence of a large excess of ROH. Hydrolysis of an acetal occurs when there is a large excess of H2O.

38. Ketals: Acetals of Ketones • Acetal (ketal) formation with ketones is generally not a favorable process: • Cyclic ketals, formed from 1,2-or 1,3-diols, are an exception: • Cyclic acetals or ketals hydrolyze easily in aqueous acid solution:

39. Acetals as Protecting Groups • While acetals readily hydrolyze back to the carbonyl compound in the presence of acid as a catalyst, they are stable to bases, even strong bases. • Acetals often are used to protect aldehyde and ketone functions from undesired reactions in the presence of strong bases during syntheses. The acetal function, a geminal (1,1) diether, is not reactive towards nucleopiles, and its hydrogens are very non-acidic.

40. An Example: The Selective Reduction of an Esterin the Presence of a Ketone

41. Protection of the Alcohol Function: Tetrahydropyranyl (THP) Acetals • Alcohols, ROH, are relatively acidic functions that rapidly react with very basic reagents such as organometallics and metal hydrides. • They may be “protected” by forming a THP acetal by reaction with 2,3-dihydro-4H-pyran(DHP) in the presence of a catalytic amount of acid.

42. Thioacetals and Their Desulfurization • Raney-nickel reduction of thioacetals (see synthetic sequence below) isan alternative to the Clemmensen reduction. • While the Clemmensen reduction (see below) is carried out under strongly acidic conditions, the above reduction is run under mildly basic (almost neutral) conditions. The sensitivity of the compound to strong acid or base may determine which method to use.

43. Imines: Addition of 10 Amines • Note: All steps are reversible, so imines hydrolyze to carbonyl compounds in aqueous acid solution.

44. Imine formation • proceeds fastest within a pH range where there are optimal concentrations of the species involved in the nucleophilic addition step. This key step involves the free base attacking the more reactive protonated carbonyl compound.

45. Imine-Type Carbonyl Derivatives

46. Enamines: Addition of 20 Amines

47. Addition of Hydrogen Cyanide: Cyanohydrins • Hydrogen cyanide (HCN) adds to aldehydes and unhindered ketones to produce cyanohydrins. • In the reaction, a mineral acid is added to a mixture of the carbonyl compound and sodium cyanide. Too much acid slows the reaction by tying up the nucleophilic cyanide ion as HCN. The following sequence describes the mechanism of cyanohydrin formation.

48. Synthetic Uses of Cyanohydrins

49. The Addition of Ylides: The Witting Reaction One of the most useful and general synthetic reactions in organic chemistry is the conversion of aldehydes and ketones into alkenes by the Witting reaction, discovered by Georg Wittig in 1954 (co-recipient of the Nobel Prize in Chemistry in 1979). The classic reaction involves addition of a phosphorus ylide to the carbonyl compound. An ylide is a neutral compound with an anionic carbon bonded to a cationic heteroatom such as P or S.

50. Synthesis of Ylides The ylides required for the Wittig reaction may usually be made by a two-step synthesis beginning with triphenylphosphine. Step 1. Triphenylphosphine reacts with sterically unhindered alkyl halides by an SN2 mechanism yielding alkyltriphenylphosphonium halides, which are analogous to quaternary ammonium halide salts, R4N+X-.