John E. McMurry

www.cengage.com/chemistry/mcmurry

Paul D. Adams • University of Arkansas

Chapter 19Aldehydes and Ketones:

Nucleophilic Addition Reactions

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

Aldehydes and Ketones

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

Why this Chapter?

1. Carboxylic Acids (3 O bonds, 1 OH)

2. Esters (3 O bonds, 1 OR)

3. Amides

4. Nitriles

5. Aldehydes (2 O bonds, 1H)

6. Ketones (2 O bonds)

7. Alcohols (1 O bond, 1 OH)

8. Amines

9. Alkenes, Alkynes

10. Alkanes

11. Ethers

12. Halides

The parent will be determined based on the highest priority functional group.

O OH

OH

2-ethyl-4-hydroxybutanoic acid

Functional Group Priority

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

Naming Aldehydes

O

HCH3

pentanal

Cl

O

H

5-chloropentanalH O

CH3CH3

2-ethylbutanal

CH3

O

H

CH3

CH3

3,4-dimethylhexanal

Cl

CH3 O

H

5-chloro-2-methylbenzaldehyde

Cl

O

H

m-chloro-benzaldehyde

CH3

O

CH3 O

H

5-methoxy-2-methylbenzaldehyde

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

Naming Ketones

IUPAC retains well-used but unsystematic names for a few ketones

Ketones with Common Names

Naming Ketones

2-pentanone 5-chloro-2-pentanone 1-chloro-3-pentanone

4-ethylcyclohexanone 2-fluoro-5-methyl-4-octanone

O

CH3 CH3

ClO

CH3

O

Cl

CH3

O

CH3CH3

F O

CH3

CH3

Naming Ketones

O

butan-2-one

O

Cl

O

O

but-3-en-2-one

OHO

4-hydroxybutan-2-one

O

O

octane-2,7-dione

O

3-methylcyclopentanone

O

cyclohex-2-en-1-one

Cl

O

Br

7-bromo-3-chloro-4-methylcyclooctanone

3-chloro-5-ethylheptan-4-one3,5-dimethylheptan-4-one

Cl

O

3-chloro-5-ethyloct-7-en-1-yn-4-one

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)

Ketones and Aldehydes as Substituents

O O

H

3-oxopentanal

O O

OH

O

3,4-dioxopentanoic acid

O O

H

O

3,4-dioxopentanal

O

H

O

OH

2-formylbenzoic acid

H

O

benzaldehyde

ClH

O

3-chlorobenzaldehyde

O O

HO

methyl 3-oxopropanoate

O O

O

methyl 3-oxobutanoate

O O

HH

O

3-oxopropanoic acid

Ketones/Aldehydes as minor FGs, benzaldehydes

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.

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

19.2 Preparing Aldehydes and Ketones

Oxidize a 2° alcohol (See chapter on alcohols) Many reagents possible: choose for the specific

situation (scale, cost, and acid/base sensitivity)

Preparing Ketones

Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted

Ketones from Ozonolysis

Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst

Aryl Ketones by Acylation

+

O

Cl

OAlCl3Heat

Limitations of FC Acylation

Does not occur on rings with electron-withdrawing substituents or basic amino groups

+

O

ClAlCl3Heat No Rxn

NH2

Mechanism of FC Acylation

Not subject to rearrangement like FC alkylation.

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

Methyl Ketones by Hydrating Alkynes

CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently

Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes

19.3 Oxidation of Aldehydes

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

Oxidation of Ketones

Nu- approaches 75° to the plane of C=O and adds to C

A tetrahedral alkoxide ion intermediate is produced

19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones

Nucleophiles can be negatively charged ( :Nu) or neutral ( :Nu) at the reaction site

The overall charge on the nucleophilic species is not considered

Nucleophiles

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

Relative Reactivity 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

Electrophilicity of Aldehydes and Ketones

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

Reactivity of Aromatic Aldehydes

Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols)

Hyrdation is reversible: a gem diol can eliminate water

19.5 Nucleophilic Addition of H2O: Hydration

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.

Hydration of Aldehydes

Hydration occurs through the nucleophilic addition mechanism, with water (in acid) or hydroxide (in base) serving as the nucleophile.

Acid catalyzed

Base catalyzed

• The hydroxide ion attacks the carbonyl group. • Protonation of the intermediate gives the hydrate.

Hydration of Carbonyls

Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”)

Formation is readily reversible (unstable alcohol)

Addition of H–Y to C=O

Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN

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

19.6 Nucleophilic Addition of HCN: Cyanohydrin 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+.

19.7 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation

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

Mechanism of Addition of Grignard Reagents

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

Hydride Addition

RNH2 adds to R’2C=O to form imines, R’2C=NR (after loss of HOH)

R2NH yields enamines, R2NCR=CR2 (after loss of HOH) (ene + amine = unsaturated amine)

19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation

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

Mechanism of Formation of Imines

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

Imine Derivatives

After addition of R2NH and loss of water, proton is lost from adjacent carbon

Enamine Formation

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

19.9 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction

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

19.10 Nucleophilic Addition of Alcohols: Acetal Formation

Mechanism of Acetal Formation

Mechanism of Acetal Formation

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)

Uses of Acetals

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

19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

Mechanism of the Wittig Reaction

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.

+(Ph)3P

+-CHCH3

THF(Ph)3P=OO

H

Z-alkene

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

19.13 Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones

Primary and secondary amines add to , -unsaturated aldehydes and ketones to yield -amino aldehydes and ketones

Conjugate Addition of Amines

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

Conjugate Addition of Alkyl Groups: 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

Mechanism of Alkyl Conjugate Addition: Organocopper Reactions

Infrared Spectroscopy Aldehydes and ketones show a strong C=O peak 1660 to

1770 cm1

aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.

19.14 Spectroscopy of Aldehydes and Ketones

The precise position of the peak reveals the exact nature of the carbonyl group

C=O Peak Position in the IR Spectrum

Aldehyde proton signals are near 10 in 1H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J 3 Hz

NMR Spectra of Aldehydes

C=O signal is at 190 to 215 No other kinds of carbons absorb in this range

13C NMR of C=O

Aliphatic aldehydes and ketones that have hydrogens on their gamma () carbon atoms rearrange as shown

Mass Spectrometry – McLafferty Rearrangement

Cleavage of the bond between the carbonyl group and the carbon

Yields a neutral radical and an oxygen-containing cation

Mass Spectroscopy: -Cleavage