Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

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Aldehydes and Ketones Aldehydes (RCHO) and ketones (R2CO) are characterized

by the the carbonyl functional group (C=O) The compounds occur widely in nature as intermediates

in metabolism and biosynthesis

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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

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19.1 Naming Aldehydes: 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

Ethanal

acetaldehyde

Propanal

Propionaldehyde 2-Ethyl-4-methylpentanal

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19.1 Naming Aldehydes and Ketones

(Common)Methanal (IUPAC)

(Common)Propanone (IUPAC)

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Naming Aldehydes

If the CHO group is attached to a ring, use the suffix carbaldehyde.

Cyclohexanecarbaldehyde 2-Naphthalenecarbaldehyde

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Naming Aldehydes:

Common Names end in aldehyde

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Naming Ketones

Replace the terminal -e of the alkane name with –one Parent chain is the longest one that contains the ketone grp

Numbering begins at the end nearer the carbonyl carbon

3-Hexanone(New: Hexan-3-one)

4-Hexen-2-one(New: Hex-4-en-2-one)

2,4-Hexanedione(New: Hexane-2,4-dione)

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Ketones with Common Names

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

Acetone Acetophenone Benzophenone

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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

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

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Learning Check: Name the following:

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Solution: Name the following:

2-methyl-3-pentanone(ethyl isopropyl ketone)

3-phenylpropanal(3-phenylpropionaldehyde)

2,6-octanedione

Trans-2-methylcyclohexanecarbaldehyde

4-hexenal

Cis-2,5-dimethylcyclohexanone

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19.2 Preparation of Aldehydes

Aldehydes Oxidation of 1o alcohols with pyridinium chlorochromate PCC

Oxidative cleavage of Alkenes with a vinylic hydrogen with ozone

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Preparation of Aldehydes

Aldehydes Reduction of an ester with diisobutylaluminum hydride

(DIBAH)

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Preparing Ketones

Oxidation of a 2° alcohol Many reagents possible: Na2Cr2O7, KMnO4, CrO3

choose for the specific situation (scale, cost, and acid/base sensitivity)

Ketones

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Ketones from Ozonolysis

Oxidative cleavage of substituted Alkenes with ozoneKetones

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Aryl Ketones by Acylation

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

Ketones

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Methyl Ketones by Hydrating Alkynes

Hydration of terminal alkynes in the presence of Hg2+ catKetones

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Preparation of Ketones

Gilman reaction of an acid chlorideKetones

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Learning Check:

Carry out the following transformations:

3-Hexyne 3-Hexanone

Benzene m-Bromoacetophenone

Bromobenzene Acetophenone

1-methylcyclohexene 2-methylcyclohexanone

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Solution:

Carry out the following transformations:

3-Hexyne 3-Hexanone

Benzene m-Bromoacetophenone

CH3 CH2 C C CH2 CH3 CH3 CH2 C

O

CH2 CH2 CH3Hg(OAc)2,

H3O+

O

BrCH3 C

O

Cl , AlCl31)

2) Br2, FeBr3

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Solution:

Carry out the following transformations:Bromobenzene Acetophenone

1-methylcyclohexene 2-methylcyclohexanone

Br

O

CH3 C

O

H

1) Mg in ether

2)

3) H3O+

4) PCC

CH3 CH3

O1) BH3

2) H2O2, NaOH

3) PCC

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19.3 Oxidation of Aldehydes & Ketones

CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids (acidic conditions)

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

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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

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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

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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

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Nucleophiles

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Reactions variations

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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

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Aldehyde C=O is more polarized than ketone C=O Ketone has more electron donation alkyl groups,

stabilizing the C=O carbon inductively

Aldehydes are generally more reactive than ketones in nucleophilic addition reactions

Relative Reactivity of Aldehydes and Ketones

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Reactivity of Aromatic Aldehydes 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

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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

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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

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Acid-Catalyzed Addition of Water

Protonation of C=O makes it more electrophilic

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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

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19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation 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-

A cyanohydrin

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Uses of Cyanohydrins The nitrile group (CN) can be reduced with LiAlH4 to yield a

primary amine (RCH2NH2)

Can be hydrolyzed by hot acid to yield a carboxylic acid

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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 +.

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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

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Hydride Addition

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

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19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation

RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)

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

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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 RNH2

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Imine Derivatives:

2,4-dinitrophenylhydrazine readily forms

2,4-dinitrophenylhydrazones

These are usually solids and help in characterizing liquid ketones or aldehydes by melting points

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

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Enamine Formation

After addition of R2NH, proton is lost from adjacent carbon

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Imine / Enamine Examples

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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

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The Wolff–Kishner Reaction: Examples

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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

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Acetal Formation

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Uses of Acetals

Acetals can be protecting groups for aldehydes & ketones Use a diol, to form a cyclic acetal (reaction goes faster)

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19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

The sequence converts C=O 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

An ylide

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Mechanism of the Wittig Reaction

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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

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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)

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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

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Conjugate Addition of Amines Primary and secondary amines add to , b-unsaturated

aldehydes and ketones to yield b-amino aldehydes and ketones

Reversible so more stable product predominates

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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

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Mechanism of Alkyl Conjugate Addition

Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, to an enone

Transfer of an R group and elimination of a neutral organocopper species, RCu

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19.14 Spectroscopy of Aldehydes and Ketones

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.

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C=O Peak Position in the IR Spectrum The precise position of the peak reveals the

exact nature of the carbonyl group

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NMR Spectra of Aldehydes

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

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13C NMR of C=O

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

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Mass Spectrometry – McLafferty Rearrangement Aliphatic aldehydes and ketones that have hydrogens

on their gamma () carbon atoms rearrange as shown

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Mass Spectroscopy: -Cleavage Cleavage of the bond between the carbonyl group

and the carbon Yields a neutral radical and an oxygen-containing

cation