Chapter 19 Aldehydes and Ketones: Nucleophilic Addition Reactions

1. Chapter 19Aldehydes and Ketones: Nucleophilic Addition Reactions

2. Aldehydes and Ketones • Aldehydes (RCHO) and ketones (R2CO) are characterized by 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. Functional Group Priority • Carboxylic Acids (3 O bonds, 1 OH) • Esters (3 O bonds, 1 OR) • Amides • Nitriles • Aldehydes (2 O bonds, 1H) • Ketones (2 O bonds) • Alcohols (1 O bond, 1 OH) • Amines • Alkenes, Alkynes • Alkanes • Ethers • Halides The parent will be determined based on the highest priority functional group.

5. 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

6. Naming Aldehydes pentanal 5-chloropentanal 2-ethylbutanal m-chloro-benzaldehyde 5-chloro-2-methylbenzaldehyde 3,4-dimethylhexanal 5-methoxy-2-methylbenzaldehyde

7. 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

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

9. Naming Ketones 1-chloro-3-pentanone 2-pentanone 5-chloro-2-pentanone 4-ethylcyclohexanone 2-fluoro-5-methyl-4-octanone

10. Naming Ketones

11. 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 (lower priority functional group)

12. Ketones/Aldehydes as minor FGs, benzaldehydes

13. Solubility of Ketones and Aldehydes • Good solvent for alcohols • Lone pair of electrons on oxygen of carbonyl can accept a hydrogen bond from O—H or N—H. • Acetone and acetaldehyde are miscible in water.

14. 19.2 Preparing Aldehydes and Ketones • Preparing Aldehydes • Oxidize primary alcohols using PCC (in dichloromethane) • Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes • Reduce an ester with diisobutylaluminum hydride (DIBAH) • Like LiAlH4

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

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

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

18. Limitations of FC Acylation • Does not occur on rings with electron-withdrawing substituents or basic amino groups

19. Mechanism of FC Acylation Not subject to rearrangement like FC alkylation.

20. Methyl Ketones by Hydrating Alkynes • Hydration of terminal alkynes in the presence of Hg2+ (catalyst: Section 9.4) • Markovnikov addition • Produces enol that tautomerizes to ketone • Works best with terminal alkyne

21. 19.3 Oxidation of Aldehydes • CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently • Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent)oxidizes aldehydes

22. Oxidation of Ketones • 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

23. 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

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

25. 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

26. 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

27. 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

28. 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

29. Hydration of Aldehydes • Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols • Relatively unreactive under neutral conditions, but can be catalyzed by acid or base.

30. Hydration of Carbonyls Acid catalyzed • Hydration occurs through the nucleophilic addition mechanism, with water (in acid) or hydroxide (in base) serving as the nucleophile. Base catalyzed • The hydroxide ion attacks the carbonyl group. • Protonation of the intermediate gives the hydrate.

31. 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 (unstable alcohol)

32. 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

33. 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+.

34. 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

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

36. 19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation • RNH2 adds to R’2C=O to form imines, R’2C=NR (after loss of HOH) • R2NH yields enamines, R2NCR=CR2 (after loss of HOH) (ene + amine = unsaturated amine)

37. Mechanism of Formation of Imines • Primary amine adds to C=O • Proton is lost from N and adds to O to yield an amino alcohol (carbinolamine) • Protonation of OH converts it 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 • Optimum pH = 4.5

38. 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

39. Enamine Formation • After addition of R2NH and loss of water, proton is lost from adjacent carbon

40. 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 • Can be conducted near room temperature using dimethyl sulfoxide as solvent • Works well with both alkyl and aryl ketones

41. 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

42. Mechanism of Acetal Formation

43. Mechanism of Acetal Formation

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

45. 19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction • The sequence converts C=O 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

46. Mechanism of the Wittig Reaction

47. Product of Wittig Rxn • The Wittig reaction converts the carbonyl group into a new C═C double bond where no bond existed before. • A phosphorus ylide is used as the nucleophile in the reaction. • Ylide usually CH2 or monosubstituted, but not disubstituted. • Unstabilized ylide tends to favor Z-alkene.

48. 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

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

50. 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