Based on McMurry’s Organic Chemistry, 7th edition

Dr M. Mehrdad University of Guilan, Department of Chemistry,

Rasht, Iran

m-mehrdad@guilan.ac.ir

2شیمی آلی

Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

2

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

coenzyme

involved in

a large

number of

metabolic

reactions

a steroid

hormone

secreted by

the adrenal

glands to

regulate fat,

protein, and

carbohydrate

metabolism

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

5

For cyclic aldehydes in which the -CHO group is directly

attached to a ring, the suffix -carbaldehyde is used.

6

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

7

Ketones with Common Names

IUPAC retains well-used but unsystematic names

for a few ketones

8

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

19.2 Preparation of Aldehydes and Ketones

Preparing Aldehydes

Oxidize primary alcohols using pyridinium chlorochromate

Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes

Reduce an ester with diisobutylaluminum hydride (DIBAH)

10

Preparing Ketones

Oxidize a 2° alcohol

Many reagents possible: choose for the specific

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

11

Ketones from Ozonolysis

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

12

Aryl Ketones by Acylation

Friedel–Crafts acylation of an aromatic ring with an

acid chloride in the presence of AlCl3 catalyst

13

Methyl Ketones by Hydrating

Alkynes

Hydration of terminal alkynes in the presence of Hg2+

14

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 (no acid)

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

16

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

17

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

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

20

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

21

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

22

Reactivity of 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

More stableMore reactive

aliphatic aldehyde

Aromatic aldehyde

23

19.5 Nucleophilic Addition of

H2O: Hydration Aldehydes and ketones react with water to yield 1,1-

diols (geminal (gem) diols)

Hyrdation is reversible: a gem diol can eliminate water

24

Relative Energies

Equilibrium generally favors the carbonyl compound over

hydrate for steric reasons

Acetone in water is 99.9% ketone form

Exception: simple aldehydes

In water, formaldehyde consists is 99.9% hydrate

25

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

26

Acid-Catalyzed Addition of

Water

Protonation of

C=O makes it

more electrophilic

27

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

28

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-

Addition of CN to C=O yields a tetrahedral intermediate, which is then protonated

Equilibrium favors adduct

29

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

30

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 +.

31

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

32

Hydride Addition

Convert C=O to CH-OH

LiAlH4 and NaBH4 react as donors of hydride ion

Protonation after addition yields the alcohol

33

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)

34

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

35

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

R R

RR

36

Enamine

Formation

After addition of

R2NH, proton is lost

from adjacent

carbon

37

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

38

Hydrazone

anion

Carbanion

39

19.10 Nucleophilic Addition of

Alcohols: Acetal Formation

Alcohols are weak nucleophiles but acid

promotes addition forming the conjugate acid

of C=O

40

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

Oxonium ion

Protonated acetal

41

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)

42

19.11 Nucleophilic Addition of

Phosphorus Ylides:

The Wittig Reaction

The sequence converts C=O is to C=C

A phosphorus ylide adds to an aldehyde

or ketone to yield a dipolar intermediate

called a betaine

43

BETAINE

Pronounced bayta-ene, a special class of zwitterions in which the positive

site has no hydrogen atoms attached to it.

YLIDE

A neutral species whose structure may be represented as a 1,2-dipole

with a negatively charged carbon or other atom having a lone pair of

electrons, bonded to a positively charged heteroatom. The term is

usually preceded by the name of the hetero-atom.

(a) The phosphorus ylide

methylenetriphenylphosphorane

(b) the nitrogen ylide

(trimethylammonio)methylide

44

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

45

Mechanism of the Wittig Reaction

A Betaine

a betaine

The betaine

46

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

47

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)

48

19.13 Conjugate Nucleophilic Addition to

-Unsaturated Aldehydes and Ketones

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

49

Conjugate Addition of Amines

Primary and secondary amines add to , -

unsaturated aldehydes and ketones to yield -amino

aldehydes and ketones

50

Conjugate Addition of Alkyl

Groups: Organocopper Reactions 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

51

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

52

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.

53

C=O Peak Position in the IR

Spectrum

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

54

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

55

13C NMR of C=O

C=O signal is at 190 to 215

No other kinds of carbons

absorb in this range

56

Mass Spectrometry –

McLafferty Rearrangement

Aliphatic aldehydes and ketones that have hydrogens

on their gamma () carbon atoms rearrange as shown

57

Mass Spectroscopy:

-Cleavage

Cleavage of the bond between the carbonyl group

and the carbon

Yields a neutral radical and an oxygen-containing

cation