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

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

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

9.1 The Nature of Carbonyl Compounds

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

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

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

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

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

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

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)

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

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

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

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!

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.

9.5 Nucleophilic Addition Reactions

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

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

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

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+.

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

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.

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

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

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

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

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

Mechanism Converting a Hemiacetal to an Acetal

Acetals in Carbohydrate Chemistry

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

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

Imines as Intermediates in Biological Reactions

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)

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

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