Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

1. Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions Based on McMurry’s Organic Chemistry, 7th edition

2. Aldehydes and Ketones • Aldehydes (RCHO) and ketones (R2CO) are characterized by the the carbonyl functional group (C=O) • The compounds occur widely in nature as intermediates in metabolism and biosynthesis

3. Why this Chapter? • Much of organic chemistry involves the chemistry of carbonyl compounds • Aldehydes/ketones are intermediates in synthesis of pharmaceutical agents, biological pathways, numerous industrial processes • An understanding of their properties is essential

4. 19.1 Naming Aldehydes and Ketones • Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al • The parent chain must contain the CHO group • The CHO carbon is numbered as C1 • If the CHO group is attached to a ring, use the suffix carbaldehyde. • See Table 19.1 for common names

5. Naming Ketones • Replace the terminal -e of the alkane name with –one • Parent chain is the longest one that contains the ketone group • Numbering begins at the end nearer the carbonyl carbon

6. Ketones with Common Names • IUPAC retains well-used but unsystematic names for a few ketones

7. Ketones and Aldehydes as Substituents • The R–C=O as a substituent is an acyl group, used with the suffix -yl from the root of the carboxylic acid • CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl • The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain

8. 19.2 Preparation of Aldehydes and Ketones • Preparing Aldehydes • Oxidize primary alcohols using pyridinium chlorochromate • Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes • Reduce an ester with diisobutylaluminum hydride (DIBAH)

9. Preparing Ketones • Oxidize a 2° alcohol • Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity)

10. Ketones from Ozonolysis • Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted

11. Aryl Ketones by Acylation • Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst

12. Methyl Ketones by Hydrating Alkynes • Hydration of terminal alkynes in the presence of Hg2+ (catalyst: Section 8.4)

13. 19.3 Oxidation of Aldehydes and Ketones • CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently • Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent)oxidizes aldehydes (no acid)

14. Hydration of Aldehydes • Aldehyde oxidations occur through 1,1-diols (“hydrates”) • Reversible addition of water to the carbonyl group • Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols

15. Ketones Oxidize with Difficulty • Undergo slow cleavage with hot, alkaline KMnO4 • C–C bond next to C=O is broken to give carboxylic acids • Reaction is practical for cleaving symmetrical ketones

16. 19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones • Nu- approaches 75° to the plane of C=O and adds to C • A tetrahedral alkoxide ion intermediate is produced

17. Nucleophiles • Nucleophiles can be negatively charged ( : Nu) or neutral ( : Nu) at the reaction site • The overall charge on the nucleophilic species is not considered

18. Relative Reactivity of Aldehydes and Ketones • Aldehydes are generally more reactive than ketones in nucleophilic addition reactions • The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b) • Aldehydes have one large substituent bonded to the C=O: ketones have two

19. Electrophilicity of Aldehydes and Ketones • Aldehyde C=O is more polarized than ketone C=O • As in carbocations, more alkyl groups stabilize + character • Ketone has more alkyl groups, stabilizing the C=O carbon inductively

20. Reactivity of Aromatic Aldehydes • Less reactive in nucleophilic addition reactions than aliphatic aldehydes • Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophile than the carbonyl group of an aliphatic aldehyde

21. 19.5 Nucleophilic Addition of H2O: Hydration • Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols) • Hyrdation is reversible: a gem diol can eliminate water

22. Base-Catalyzed Addition of Water • Addition of water is catalyzed by both acid and base • The base-catalyzed hydration nucleophile is the hydroxide ion, which is a much stronger nucleophile than water

23. Acid-Catalyzed Addition of Water • Protonation of C=O makes it more electrophilic

24. Addition of H-Y to C=O • Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”) • Formation is readily reversible

25. 19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation • Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN • Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN- • Addition of CN to C=O yields a tetrahedral intermediate, which is then protonated • Equilibrium favors adduct

26. Uses of Cyanohydrins • The nitrile group (CN) can be reduced with LiAlH4 to yield a primary amine (RCH2NH2) • Can be hydrolyzed by hot acid to yield a carboxylic acid

27. 19.7 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation • Treatment of aldehydes or ketones with Grignard reagents yields an alcohol • Nucleophilic addition of the equivalent of a carbon anion, or carbanion. A carbon–magnesium bond is strongly polarized, so a Grignard reagent reacts for all practical purposes as R :MgX +.

28. Mechanism of Addition of Grignard Reagents • Complexation of C=O by Mg2+, Nucleophilic addition of R :,protonation by dilute acid yields the neutral alcohol • Grignard additions are irreversible because a carbanion is not a leaving group

29. Hydride Addition • Convert C=O to CH-OH • LiAlH4 and NaBH4 react as donors of hydride ion • Protonation after addition yields the alcohol

30. 19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH) R2NH yields enamines, R2NCR=CR2 (after loss of HOH) (ene + amine = unsaturated amine) “Thompson Now” (Section 19.8)

31. Mechanism of Formation of Imines • Primary amine adds to C=O • Proton is lost from N and adds to O to yield a neutral amino alcohol (carbinolamine) • Protonation of OH converts into water as the leaving group • Result is iminium ion, which loses proton • Acid is required for loss of OH – too much acid blocks RNH2

32. Imine Derivatives • Addition of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines • For example, hydroxylamine forms oximes and 2,4-dinitrophenylhydrazine readily forms 2,4-dinitrophenylhydrazones • These are usually solids and help in characterizing liquid ketones or aldehydes by melting points

33. Enamine Formation • After addition of R2NH, proton is lost from adjacent carbon

34. 19.9 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction • Treatment of an aldehyde or ketone with hydrazine, H2NNH2 and KOH converts the compound to an alkane • Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature

35. 19.10 Nucleophilic Addition of Alcohols: Acetal Formation • Alcohols are weak nucleophiles but acid promotes addition forming the conjugate acid of C=O • Addition yields a hydroxy ether, called a hemiacetal (reversible); further reaction can occur • Protonation of the OH and loss of water leads to an oxonium ion, R2C=OR+ towhich a second alcohol adds to form the acetal

36. Uses of Acetals • Acetals can serve as protecting groups for aldehydes and ketones • It is convenient to use a diol, to form a cyclic acetal (the reaction goes even more readily)

37. 19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction • The sequence converts C=O is to C=C • A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine • The intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O • Formation of the ylide is shown below

38. Mechanism of the Wittig Reaction

39. Uses of the Wittig Reaction • Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure • For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes

40. 19.12 The Cannizaro Reaction • The adduct of an aldehyde and OH cantransfer hydride ionto another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)

41. 19.13 Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones • A nucleophile can add to the C=C double bond of an ,b-unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition) • The initial product is a resonance-stabilized enolate ion, which is then protonated

42. Conjugate Addition of Amines • Primary and secondary amines add to , b-unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones

43. Conjugate Addition of Alkyl Groups: Organocopper Reactions • Reaction of an , b-unsaturated ketone with a lithium diorganocopper reagent • Diorganocopper (Gilman) reagents form by reaction of 1 equivalent of cuprous iodide and 2 equivalents of organolithium • 1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups

44. Mechanism of Alkyl Conjugate Addition • Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, to an enone • Transfer of an R group and elimination of a neutral organocopper species, RCu

45. 19.14 Spectroscopy of Aldehydes and Ketones • Infrared Spectroscopy • Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm1 • aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.

46. C=O Peak Position in the IR Spectrum • The precise position of the peak reveals the exact nature of the carbonyl group

47. NMR Spectra of Aldehydes • Aldehyde proton signals are at  10 in 1H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J 3 Hz

48. 13C NMR of C=O • C=O signal is at  190 to  215 • No other kinds of carbons absorb in this range

49. Mass Spectrometry – McLafferty Rearrangement • Aliphatic aldehydes and ketones that have hydrogens on their gamma () carbon atoms rearrange as shown

50. Mass Spectroscopy: -Cleavage • Cleavage of the bond between the carbonyl group and the  carbon • Yields a neutral radical and an oxygen-containing cation