1. Chapter 9 Aldehydes and Ketones: Nucleophilic Addition Reactions
Suggested Problems: 24-5,29-34,37-9,41-43,45-6,53

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. 9.1 The Nature of Carbonyl Compounds
Two general categories based on the kinds of chemistry they undergo although both contain C=O
Aldehydes and ketones: leaving groups H and R resulting from attack at carbonyl do not stabilize negative charge and can’t act as leaving groups
Carboxylic acids and their derivatives: leaving groups X on O=C-X can stabilize negative charge and can act as leaving groups

4. 9.1 The Nature of Carbonyl Compounds

5. Electronic Structure of the Carbonyl Group
C=O, the carbon atom (Lewis acidic) is positively polarized relative to the oxygen atom (Lewis basic)

6. 9.2 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

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. 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

10. 9.3 Synthesis of Aldehydes and Ketones
Preparing Aldehydes
Oxidize primary alcohols using pyridininium chlorochromate (PCC) or Dess-Martin periodinane reagent in dichloromethane solvent

11. 9.3 Synthesis of Aldehydes and Ketones
Preparing Aldehydes
Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes
Reduce an ester with diisobutylaluminum hydride (DIBAH)

12. 9.3 Synthesis of Aldehydes and Ketones
Secondary alcohols yield ketones with chromic acid derivatives, (CrO3 or Na2Cr2O7 or PCC) or periodinane

13. 9.3 Synthesis of Aldehydes and Ketones
Ketones can also be produced by
The hydration of a terminal alkyne
Friedal-Crafts acylation of an aromatic ring

14. 9.4 Oxidation of Aldehydes
CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently (only PCC stops at the aldehyde stage)

15. 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
Note the hydrogen on the carbonyl group!

16. 9.5 Nucleophilic Addition Reactions
Most common reaction of aldehydes and ketones is the nucleophilic addition reaction
Nu– adds to the C of the C=O
A tetrahedral alkoxide ion intermediate is produced
Can occur under acidic or basic conditions.

17. 9.5 Nucleophilic Addition Reactions

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

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

20. 9.6 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation
Aldehydes are reduced to primary alcohols and ketones to secondary alcohols by hydride
Convert C=O to CH-OH
LiAlH4 and NaBH4 react as donors of hydride ion
Protonation after addition yields the alcohol

21. 9.6 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+.

22. 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 good leaving group

23. Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation
Grignard reagents also react with esters to give alcohols
The intermediate is an aldehyde which reacts with a second equivalent of Grignard to give a tertiary alcohol
The reaction cannot be stopped at the aldehyde stage.

24. Limitations of the Grignard Reaction
Grignard reagents cannot be prepared from compounds that contain the following functional groups.

25. 9.7 Nucleophilic Addition of H2O: Hydrate Formation
Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols)
Hydration is reversible: a gem diol can eliminate water

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
Protonation of C=O makes it more electrophilic

28. 9.8 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 to produce an acetal, (R2CO(OR′)2
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

29. Mechanism Converting a Hemiacetal to an Acetal

30. Acetals in Carbohydrate Chemistry

31. Acetal Protecting Groups
We can use an acetal to selectively protect an aldehyde or ketone from reacting in the presence of other electrophiles
Fill in necessary reagents or intermediates

32. 9.9 Nucleophilic Addition of Amines: Imine Formation
Ammonia and primary amines, RNH2, add to aldehydes and ketones to form imines, R2C=NR′
Occurs by nucleophilic addition of the amine to the carbonyl group followed by loss of water

33. Imines as Intermediates in Biological Reactions

34. 9.10 Conjugate Nucleophilic Addition Reactions
A nucleophile can add to the C=O double bond of an aldehyde or a ketone (direct addition, or 1,2 addition)

35. 9.10 Conjugate Nucleophilic Addition Reactions
A nucleophile can also add to the C=C double bond of an ,b-unsaturated aldehyde or a ketone (conjugate addition, or 1,4 addition)
The initial product is a resonance-stabilized enolate ion, which is then protonated

36. 1,4 or Conjugate Addition
Conjugate addition occurs due to the effect of the electronegative oxygen atom on the b carbon
Common with softer amine nucleophiles and water
Occurs in many biological pathways