1. Chapter 19 Aldehydes 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. 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

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. Exercise 1

9. 19.2 Preparing Aldehydes and Ketones
1.) Oxidize primary alcohols using pyridinium chlorochromate (PCC) or Dess-Martin Periodinane (DMP) reagent in DCM
2.) Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes
3.) Reduce an ester with diisobutylaluminum hydride (DIBAH)

10. Exercise 2 Preparing Aldehydes
1.) Oxidize primary alcohols using pyridinium chlorochromate (PCC) or Dess-Martin Periodinane (DMP) reagent in DCM
2.) Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes
3.) Reduce an ester with diisobutylaluminum hydride (DIBAH)

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

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

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

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

15. 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

16. Hydration of Aldehydes
Aldehyde oxidations occur through 1,1-diols (“hydrates”)
Formed by reversible nucleophilic addition of water to the carbonyl group
Aldehyde hydrate reacts like typical alcohol and is oxidized to a carboxylic acid by usual reagents

17. 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

18. Exercise 3

19. 19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones
Nu- approaches 75° to the plane of C=O and adds to the electrophilic C=O carbon atom
A tetrahedral alkoxide ion intermediate is produced
Protonation of the alkoxide by addition of acid gives the alcohol product

20. Nucleophiles
Nucleophiles can be negatively charged ( :Nu) or neutral ( :Nu) at the reaction site
If Neutral however, it carries a H atom that can be subsequently eliminated

21. Nucleophilic Addition
Nucleophilic additions aldehydes and ketones generally have two variations.
1st pathway – protonated by water or acid to yield alcohol
2nd pathway – carbonyl oxygen is protonated and then eliminated as OH- or water to yield C=Nu double bond

22. 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

23. 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

24. Reactivity of Aromatic Aldehydes
Aromatic aldehydes are less reactive in nucleophilic addition reactions than aliphatic aldehydes
Due to electron-donating resonance effect of aromatic ring makes C=O less reactive electrophile than the carbonyl group of an aliphatic aldehyde

25. 19.5 Nucleophilic Addition of H2O: Hydration
Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols)
Hydration is reversible: a gem diol can eliminate water
Position of eq. depends on the structure of carbonyl compound

26. 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

27. Acid-Catalyzed Addition of Water
Under acidic conditions, carbonyl oxygen is protonated first, thus making the C=O group more electrophilic

28. Addition of H–Y to C=O
Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”)
Rxn mechanism is similar to addition of water to C=O
Formation is readily reversible, but generally favours carbonyl reactant

29. 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

30. 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

31. 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+.

32. 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

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

34. 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)

35. 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

36. 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

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

38. 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

39. 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+ to which a second alcohol adds to form the acetal
Acetal formation mech. Similar to the hydration rxn discussed earlier

40. Mechanism

41. Mechanism

42. 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)

43. Uses of Acetals
Acetal and hemi-acetals are common in carbohydrate chemistry
E.g. glucose is a polyhydroxy aldehyde that undergoes internal nucleophilic addition rxn and exist as a cyclic hemi-acetal

44. Exercise 4
Show the structure of the acetal you would obtain by acid-catalysed rxn of 2-pentanone with 1,3-propanediol

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. 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

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. 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

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

51. 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

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

53. 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.

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

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

56. 13C NMR of C=O C=O signal is at  190 to  215
No other kinds of carbons absorb in this range