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

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

3. 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. 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. 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. 6 Ketones with Common Names IUPAC retains well-used but unsystematic names for a few ketones

7. 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 CH 3 CO: acetyl; CHO: formyl; C 6 H 5 CO: 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. 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. 9 Preparing Ketones Oxidize a 2° alcohol Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity)

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

11. 11 Aryl Ketones by Acylation Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl 3 catalyst

12. 12 Methyl Ketones by Hydrating Alkynes Hydration of terminal alkynes in the presence of Hg 2+ (catalyst: Section 8.4)

13. 13 19.3 Oxidation of Aldehydes and Ketones CrO 3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently Silver oxide, Ag 2 O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes (no acid)

14. 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. 15 Ketones Oxidize with Difficulty Undergo slow cleavage with hot, alkaline KMnO 4 C–C bond next to C=O is broken to give carboxylic acids Reaction is practical for cleaving symmetrical ketones

16. 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. 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. 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. 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. 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. 21 19.5 Nucleophilic Addition of H 2 O: 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. 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. 23 Acid-Catalyzed Addition of Water Protonation of C=O makes it more electrophilic

24. 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. 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. 26 Uses of Cyanohydrins The nitrile group (  C  N) can be reduced with LiAlH 4 to yield a primary amine (RCH 2 NH 2 ) Can be hydrolyzed by hot acid to yield a carboxylic acid

27. 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. 28 Mechanism of Addition of Grignard Reagents Complexation of C=O by Mg 2+, 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. 29 Hydride Addition Convert C=O to CH-OH LiAlH 4 and NaBH 4 react as donors of hydride ion Protonation after addition yields the alcohol

30. 30 19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation RNH 2 adds to C=O to form imines, R 2 C=NR (after loss of HOH) R 2 NH yields enamines, R 2 N  CR=CR 2 (after loss of HOH) (ene + amine = unsaturated amine) “Thompson Now” (Section 19.8)

31. 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 RNH 2

32. 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. 33 Enamine Formation After addition of R 2 NH, proton is lost from adjacent carbon

34. 34 19.9 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction Treatment of an aldehyde or ketone with hydrazine, H 2 NNH 2 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. 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, R 2 C=OR + to which a second alcohol adds to form the acetal

36. 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. 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) 3 P=O Formation of the ylide is shown below

38. 38 Mechanism of the Wittig Reaction

39. 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 CH 3 MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes

40. 40 19.12 The Cannizaro Reaction The adduct of an aldehyde and OH  can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)

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

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

43. 43 Conjugate Addition of Alkyl Groups: Organocopper Reactions Reaction of an ,  -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. 44 Mechanism of Alkyl Conjugate Addition Conjugate nucleophilic addition of a diorganocopper anion, R 2 Cu , to an enone Transfer of an R group and elimination of a neutral organocopper species, RCu

45. 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. 46 C=O Peak Position in the IR Spectrum The precise position of the peak reveals the exact nature of the carbonyl group

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

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

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

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