1

1

Organic Chemistry, Third Edition

Janice Gorzynski SmithUniversity of Hawai’i

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Chapter 21Aldehydes and Ketones—Nucleophilic Addition

Prepared by Rabi Ann MusahState University of New York at Albany

2

Aldehydes and ketones contain a carbonyl group. An aldehyde contains atleast one H atom bonded to the carbonyl carbon, whereas the ketone has twoalkyl or aryl groups bonded to it.

21.1 Introduction

Two structural features determine the chemistry and properties of aldehydesand ketones.

2

3

• Aldehydes and ketones react with nucleophiles.• As the number of R groups around the carbonyl carbon increases, the

reactivity of the carbonyl compound decreases, resulting in the followingorder of reactivity:

4

• If the CHO is bonded to a chain of carbons, find the longest chaincontaining the CHO group, and change the –e ending of the parent alkaneto the suffix –al. If the CHO group is bonded to a ring, name the ring andadd the suffix –carbaldehyde.

• Number the chain or ring to put the CHO group at C1, but omit thisnumber from the name. Apply all the other usual rules of nomenclature.

21.2 Nomenclature of Aldehydes

Figure 21.1Three examples of

Aldehyde nomenclature

3

5

• Like carboxylic acids, many simple aldehydes have common names thatare widely used.

• A common name for an aldehyde is formed by taking the common parentname and adding the suffix -aldehyde.

• Greek letters are used to designate the location of substituents incommon names.

6

• In the IUPAC system, all ketones are identified by the suffix “one”.• Find the longest continuous chain containing the carbonyl group,

and change the –e ending of the parent alkane to the suffix -one.• Number the carbon chain to give the carbonyl carbon the lowest

number. Apply all of the usual rules of nomenclature.• With cyclic ketones, numbering always begins at the carbonyl

carbon, but the “1” is usually omitted from the name. The ring isthen numbered clockwise or counterclockwise to give the firstsubstituent the lower number.

Nomenclature of Ketones

4

7

• Most common names for ketones are formed by naming both alkyl groupson the carbonyl carbon, arranging them alphabetically, and adding theword “ketone”.

• Three widely used common names for some simple ketones do not followthis convention:

8

• Sometimes, acyl groups must be named as substituents. The three mostcommon acyl groups are shown below:

Figure 21.2Two examples of

ketone nomenclature

5

9

21.3 Physical Properties

10

• Aldehydes and ketones exhibit a strong peak at ~1700 cm-1 due to the C=O.• The sp2 hybridized C—H bond of an aldehyde shows one or two peaks at

~2700 –2830 cm-1.

21.4 Spectroscopic Properties—IR Spectra

Figure 21.3The IR spectrum of

propanal, CH3CH2CHO

6

11

• Most aldehydes have a carbonyl peak around 1730 cm-1, whereas forketones, it is typically around 1715 cm-1.

• Ring size affects the carbonyl absorption in a predictable manner.

Spectroscopic Properties—IR Spectra

12

• Conjugation also affects the carbonyl absorption in a predictable manner.

Figure 21.4 The effect of conjugation on the carbonyl absorption in an IR spectrum

7

13

Aldehydes and ketones exhibit the following 1H and 13C NMRabsorptions.

Spectroscopic Properties—NMR Spectra

• The sp2 hybridized C—H proton of an aldehyde is highly deshieldedand absorbs far downfield at 9-10 ppm. Splitting occurs with protonson the carbon, but the coupling constant is often very small (J = 1-3 Hz).

• Protons on the carbon to the carbonyl group absorb at 2-2.5 ppm.Methyl ketones, for example, give a characteristic singlet at ~2.1ppm.

• In a 13C NMR spectrum, the carbonyl carbon is highly deshielded,appearing in the 190-215 ppm region.

14

Figure 21.5The 1H and 13C NMR spectra

of propanal, CH3CH2CHO

8

15

Spectroscopic Properties—NMR Spectra

16

21.5 Interesting Aldehydes and Ketones

Billions of pounds of formaldehyde are producedannually for the oxidation of methanol. It is sold as a37% solution called formalin which is used as adisinfectant, antiseptic, and preservative forbiological specimens. It is a product of incompletecombustion of coal, and is partly responsible for theirritation caused by smoggy air.

Acetone is an industrial solvent. It is also produced invivo during breakdown of fatty acids. Diabetics oftenhave unusually high levels of acetone in their bloodstreams. Thus, its characteristic odor can be detectedon the breath of diabetic patients when the disease ispoorly controlled.

9

17

Many aldehydes and ketones with characteristic odors occur in nature.

Figure 21.6 Some naturally occurring aldehydes and ketones with strong odors

18

• Many steroid hormones contain a carbonyl along with other functionalgroups.

• Cortisone and prednisone are two anti-inflammatory steroids with closelyrelated structures.

• Cortisone is secreted by the body’s adrenal gland, whereas prednisone isthe synthetic analogue and is used as an anti-inflammatory for asthma andarthritis.

10

19

Common methods to synthesize aldehydes:

21.6 Preparation of Aldehydes and Ketones

20

Common methods to synthesize ketones:

11

21

Aldehydes and ketones are also both obtained as products of theoxidative cleavage of alkenes.

22

[1] Reaction at the carbonyl carbon—the elements of H and Nu are added tothe carbonyl group.

21.7 Reactions of Aldehydes and Ketones—GeneralConsiderations

[2] Reaction at the carbon.

12

23

• With negatively charged nucleophiles, nucleophilic addition followsa two-step process—nucleophilic attack followed by protonation, asshown below.

• This process occurs with strong, neutral or negatively chargednucleophiles.

24

• With some neutral nucleophiles, nucleophilic addition only occurs ifan acid is present—In this mechanism, protonation precedesnucleophilic attack as shown below.

13

25

It is important to know what nucleophiles will add to carbonyl groups.

• Cl¯, Br¯ and I¯ are good nucleophiles in substitution reactions at sp3hybridized carbons, but they are ineffective nucleophiles in addition.

• When these nucleophiles add to a carbonyl, they cleave the C—O bond,forming an alkoxide. Since X¯ is a much weaker base than the alkoxideformed, equilibrium favors the starting materials, not the addition product.

26

Figure 21.7Specific examples ofnucleophilic addition

14

27

Treatment of an aldehyde or ketone with either NaBH4 or LiAlH4 followed byprotonation forms a 1° or 2° alcohol. The nucleophile in these reactions is H:¯.

21.8 Nucleophilic Addition of H¯ and R¯—A Review

Hydride reduction occurs via a two-step mechanism.

28

Treatment of an aldehyde or ketone with either an organolithium (R”Li) orGrignard reagent (R”MgX) followed by water forms a 1°, 2°, or 3° alcoholcontaining a new C—C bond. In these reactions, R”¯ is the nucleophile.

Nucleophilic addition occurs via a two-step mechanism.

15

29

• Treatment of an aldehyde or ketone with NaCN and a strong acid such asHCl adds the elements of HCN across the C—O bond, forming acyanohydrin.

• The mechanism involves the usual two steps of nucleophilic addition—nucleophilic attack followed by protonation.

21.9 Nucleophilic Addition of ¯CN

30

• Cyanohydrins can be reconverted to carbonyl compounds by treatmentwith base. This process is just the reverse of the addition of HCN:deprotonation followed by elimination of ¯CN.

• The cyano group of a cyanohydrin is readily hydrolyzed to a carboxy groupby heating with aqueous acid or base.

16

31

• Linamarin and Amygdalin are two naturally occurring cyanohydrinderivatives.

• Both compounds are toxic because they are metabolized to cyanohydrins,which are hydrolyzed to carbonyl compounds and HCN gas.

32cassava

17

33

• The Wittig reaction uses a carbon nucleophile (the Wittig reagent) to formalkenes—the carbonyl group is converted to a C=C.

21.10 The Wittig Reaction

34

• The Wittig reagent is an organophosphorus reagent.• A typical Wittig reagent has a phosphorus atom bonded to three phenyl

groups, plus another alkyl group that bears a negative charge.

• A Wittig reagent is an ylide, a species that contains two oppositely chargedatoms bonded to each other, with both atoms having octets.

• Phosphorus ylides are also called phosphoranes.

18

35

• Since phosphorus is a second-row element, it can be surroundedby more than eight electrons.

• Thus, a second resonance structure can be drawn that places adouble bond between carbon and phosphorus.

• Regardless of which resonance structure is drawn, a Wittig reagenthas no net charge.

• However, note that in one resonance structure, the carbon bears anet negative charge, making it nucleophilic.

36

Wittig reagents are synthesized by a two-step procedure.

19

37

To synthesize the Wittig reagent Ph3P=CH2, use the following twosteps:

Step [1] Form the phosphonium salt by SN2 reaction of Ph3P: andCH3Br.

Step [2] Form the ylide by removal of a proton using BuLi as a strongbase.

38

The currently accepted mechanism of the Wittig reaction involves twosteps.

20

39

One limitation of the Wittig reaction is that a mixture of stereoisomerssometimes forms.

The Wittig reaction has been used to synthesize many natural products.Figure 21.8 A Wittig reaction used to synthesize β-carotene

40

The Wittig Reaction

21

41

42

• An advantage of the Wittig reaction over elimination methods used tosynthesize alkenes is that you always know the location of the doublebond—the Wittig reaction always gives a single constitutional isomer.

• Consider the two methods that can be used to convert cyclohexanone intocycloalkene B.

22

43

• Amines are classified as 1°, 2°, or 3° by the number of alkyl groups bondedto the nitrogen atom.

21.11 Addition of 10 Amines—Formation of Imines

• Treatment of an aldehyde or a ketone with a 1° amine affords an imine (alsocalled a Schiff base).

44

• Because the N atom of an imine is surrounded by three groups (twoatoms and a lone pair), it is sp2 hybridized, making the C—N—Rbond angle 120°, (not 180°). Imine formation is fastest when thereaction medium is weakly acidic (pH 4-5).

23

45

46

• In imine formation, mild acid is needed for protonation of thehydroxy group in step 3 to form a good leaving group.

• Under strongly acidic conditions, the reaction rate decreasesbecause the amine nucleophile is protonated—with no free electronpair, it is no longer a nucleophile, and so nucleophilic additioncannot occur.

24

47

• Many imines play vital roles in biological systems.• A key molecule in the chemistry of vision is the highly conjugated imine

rhodopsin, which is synthesized by the rod cells of the eye from 11-cis-retinal and a 1° amine in the protein opsin.

48

25

49

Figure 21.9The key reaction in the

chemistry of vision

50

• A 2° amine reacts with an aldehyde or ketone to give an enamine. Enamineshave a nitrogen atom bonded to a C—C double bond.

21.12 Addition of 2° Amines—Formation of Enamines

26

51

52

Figure 21.10 Theformation of imines and

enamines compared

27

53

• Because imines and enamines are formed by a reversible set ofreactions, both can be converted back to carbonyl compounds byhydrolysis with mild acid.

• The mechanism of hydrolysis is the exact reverse of the mechanismwritten for formation of imines and enamines.

Imine and Enamine Hydrolysis

54

• Treatment of a carbonyl compound with H2O in the presence of an acid orbase catalyst adds the elements of H and OH across the C—O bond,forming a gem-diol or hydrate.

21.13 Addition of H2O—Hydration

• Gem-diol product yields are good only when unhindered aldehydes oraldehydes with nearby electron withdrawing groups are used.

28

55

• Increasing the number of alkyl groups on the carbonyl carbon decreasesthe amount of hydrate at equilibrium. This can be illustrated by comparingthe amount of hydrate formed from formaldehyde, acetaldehyde andacetone.

56

Other electronic factors come into play as well.

This explains why chloral forms a large amount of hydrate at equilibrium.Three electron-withdrawing Cl atoms result in a partial positive charge on the carbon of the carbonyl, destabilizing the carbonyl group, and thereforeincreasing the amount of hydrate at equilibrium.

29

57

Both acid and base catalyze the addition of H2O to the carbonyl group.

• With base, the nucleophile is ¯OH, and the mechanism follows theusual two steps: nucleophilic attack followed by protonation.

• The reaction rate increases in the presence of base because thebase converts H2O into ¯OH, a stronger nucleophile.

58

• The reaction rate increases in the presence of acid because the acidprotonates the carbonyl group, making it more electrophilic andthus more susceptible to nucleophilic attack.

30

59

21.14 Addition of Alcohols—Acetal Formation

• Aldehydes and ketones react with two equivalents of alcohol to formacetals.

• Acetal formation is catalyzed by acids, such as TsOH.• Note that acetals are not ethers.

60

• When a diol such as ethylene glycol is used in place of twoequivalents of ROH, a cyclic acetal is formed.

• Like gem-diol formation, the synthesis of acetals is reversible, andoften, the equilibrium favors the reactants.

• In acetal synthesis, since water is formed as a by-product, theequilibrium can be driven to the right by removing H2O as it isformed using distillation or other techniques. Driving an equilibriumto the right by removing one of the products is an application of LeChâtelier’s principle.

31

61

62

• The mechanism for acetal formation can be divided into two parts,the first of which is addition of one equivalent of alcohol to form thehemiacetal.

32

63

• The second part of the mechanism involves conversion of thehemiacetal into the acetal.

64

• Because conversion of an aldehyde or ketone to an acetal is areversible reaction, an acetal can be hydrolyzed to an aldehyde orketone by treatment with aqueous acid.

• Since the reaction is also an equilibrium process, it is driven to theright by using a large excess of water for hydrolysis.

33

65

21.15 Acetals as Protecting Groups

• Acetals are valuable protecting groups for aldehydes and ketones.• Suppose we wish to selectively reduce the ester to an alcohol in

compound A, leaving the ketone untouched.• Because ketones are more readily reduced, methyl-5-

hydroxyhexanoate is formed instead.

66

To solve this problem, we can use a protecting group to block themore reactive ketone carbonyl. The overall process requires threesteps.

[1] Protect the interfering functional group—the ketone carbonyl.[2] Carry out the desired reaction.[3] Remove the protecting group.

34

67

21.16 Cyclic Hemiacetals

Cyclic hemiacetals containing five- and six-membered rings are stablecompounds that are readily isolated.

68

Cyclic hemiacetals are formed by intramolecular cyclization ofhydroxy aldehydes.

Such intramolecular reactions to form five- and six-membered ringsare faster than the corresponding intermolecular reactions. The tworeacting functional groups (OH and C=O), are held in close proximity,increasing the probability of reaction.

35

69

Hemiacetal formation is catalyzed by both acid and base.

70

Intramolecular cyclization of a hydroxy aldehyde forms a hemiacetalwith a new stereogenic center, so that an equal amount of twoenantiomers results.

Cyclic hemiacetals can be converted to acetals by treatment with analcohol and acid.

36

71

Cyclic Hemiacetals

72

Cyclic Hemiacetals

• In the conversion of hemiacetals to acetals, the overall result is thereplacement of the hemiacetal OH group by an OCH3 group.

• This reaction occurs readily because the carbocation formed in step 2 isstabilized by resonance. This fact makes the hemiacetal OH group differentfrom the hydroxy group in other alcohols.

• Thus, when a compound with both an alcohol OH and a hemiacetal OH istreated with an alcohol and acid, only the hemiacetal OH reacts to form theacetal.

37

73

21.17 Introduction to Carbohydrates

• Carbohydrates, commonly referred to as sugars and starches, arepolyhydroxy aldehydes and ketones, or compounds that can be hydrolyzedto them.

• Many carbohydrates contain cyclic acetals or hemiacetals. Examplesinclude glucose and lactose.

74

• Hemiacetals in sugars are formed by cyclization of hydroxy aldehydes.• The hemiacetal in glucose is formed by cyclization of an acyclic

polyhydroxy aldehyde (A), as shown.

• When the OH group on C5 is the nucleophile, cyclization yields a six-membered ring, and this ring size is preferred.

• Cyclization forms a new stereogenic center—the new OH group of thehemiacetal can occupy the equatorial or axial position.