1

Reactions of aldehydes and ketone carbonyls

R

O

R'

R' R'

OH

H

R' R'

OH

R"

R' R'

OH

NC

R'R'

OR"

R"O

R R'

R" R"'

R' R'

H H

R

N

R'

R" R

N

R*

R" R"

imine

enamine

cyanohydrin

3• alcohol

!• or 2• alcohol

alkane

Wolff Kisher or Clemmensen

Wittig

O3 or Hot acidic KMnO4

Acidic alcohol-H2O

axcidic water

Benzylic oxidation

Hydride

PCC

RLi or RMgBr

CN-

Base

R'2NHacid

H2O, H+R"NH2acid

H2O, H+

alkene

acetal

2

Chapter 22: Carboxylic Acid Derivatives

R OH

O

R Cl

O

carboxylic acid

acid chloride

R O

O O

R

anhydride

R OH

O

carboxylic acid

R OR'

O

ester

R NR'R"

O

amide

R C N

nitrile

R

OR'

OR'

OR'

ortho ester

3

R

O

OH

R H

OH

H

R C N

RMgX

or

RLi

Ar-Alkyl

Aromatic

R

R

R

O

HCO2

[O]

[O]

[O]

[O]

H2O

[O]

[H]

To date, methods for making carboxylic acids

4

R

O

OH

R R'

OH

R'

R H

OH

H

R CR

O

O-

R

O

OR'

R

O

Cl

R

O

NR'R"

R

O

O

O

R

N

acid chloride

ester

carboxylate

anhydride

3° alcohol1° alcohol

nitriles

amide

5

Anhydrides

O

O

O

Maleic anhydrideO

O

O

Succinic anhydride

O

O

O

Phthalic anhydride

6

Amides

7

Cyclic esters and amides:

Nitriles:

Lactones, Lactams and Nitriles

8

The two most important features of the carbonyl group are:

Structural Features of the Carbonyl Group

9

• Three resonance structures stabilize carboxylic acid derivatives (RCOZ) by delocalizing electron density.

• The more resonance structures 2 and 3 contribute to the resonance hybrid, the more stable RCOZ is.

Resonance of Carboxylic Acid Derivatives

10

• Because the basicity of Z determines the relative stability of the carboxylic acid derivatives, the following stability order results:

• In summary, as the basicity of Z increases, the stability of RCOZ increases because of added resonance stabilization.

Stability of Carboxylic Acid Derivatives

11

• The structure and bonding of nitriles is very different from that of other carboxylic acid derivatives, and resembles the C–C triple bond of alkynes.

• The carbon atom on the CN group is sp hybridized, making it linear with a bond angle of 180°.

• The triple bond consists of one and two bonds.

Structure of Nitriles

12

• For acyclic acid chlorides: change the suffix –ic acid of the parent carboxylic acid to the suffix –yl chloride; or

• When the –COCl group is bonded to a ring: change the suffix –carboxylic acid to –carbonyl chloride.

Nomenclature—Acid Chlorides

13

• Symmetrical anhydrides are named by changing the acid ending of the carboxylic acid to the word anhydride.

• Mixed anhydrides, which are derived from two different carboxylic acids, are named by alphabetizing the names for both acids and replacing the word acid with the word anhydride.

Nomenclature—Anhydrides

14

Composition of Anhydrides

• Anhydride means without water.

• Removing one molecule of water from two molecules of carboxylic acid forms an anhydride.

15

Nomenclature—Esters

16

O

ON

CH3

CH3

CH3

acetyl choline

N

OO

O

O

L-Cocaine

O

O

propyl acetate

(pear)

O

O

benzyl acetate

(peach)

OO

H

isobutyl formate

(raspberry)

OH

O

OMe

Methyl salicylate

(Wintergreen)

OH

O

O

ethyl lactate

(butter)

O

O

ethyl 3-methylbutanoate

(apple)

O

O

propyl isobutyrate

(rum)

O

O

nonyl octanoate

(orange)NH2

O

O

methyl 2-aminobenzoate(Grape, jasmine)

O

O

2-(4-methylcyclohex-3-en-1-yl)propan-2-yl butyrate

(Cherry)

17

• All 1° amides are named by replacing the -ic acid, -oic acid, or -ylic acid ending with the suffix amide.

Nomenclature—Amides

18

N

NH

O

N

H

(6aR,9R)- N,N- diethyl- 7-methyl- 4,6,6a,7,8,9- hexahydroindolo- [4,3-fg] quinoline- 9-carboxamide

Lysergic acid diethylamide (LSD)

HN

H

N

O NH

ON

O

N

HHO O

ergotamine

N

S

OHO

O

NH

O

H

(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Penicillin G

More amides

Nylons, Kevlar are amide based polymers

19

Nomenclature—2° and 3° Amides

20

• In contrast to the carboxylic acid derivatives, nitriles are named as alkane derivatives.

• Find the longest chain that contains the CN and add the word nitrile to the name of parent alkane.

• Number the chain to put CN at C1, but omit this number from the name.

• Common names of nitriles are derived from the names of the carboxylic acid having the same number of carbon atoms by replacing the –ic acid ending of the carboxylic acid with the suffix –onitrile.

• When the CN is named as a substituent it is called a cyano group.

Nomenclature—Nitriles

21

• CH3CH2CN is propanenitrile, not ethanenitrile.

Nomenclature—Nitriles

22

NN

N

NN

N

N

NH

OHO

(S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile

Vildagliptin (anti-diabetic drug)

S

N

5-(methylthio)pentanenitrile

(odor of broccoli)

Nitriles in drugs and foods

23

24

• Nitriles also have dipole-dipole interactions because they

have a polar CN group.

• Because they contain one or two N–H bonds, 1° and 2° amides are capable of intermolecular hydrogen bonding and will have substantially higher melting and boiling points.

Figure 22.1Intermolecular

hydrogenbonding between two

amide molecules

Intermolecular Attractions

25

26

• Like all carbonyl compounds, carboxylic acid derivatives have a strong C=O absorption between 1600 and 1850 cm−1.

• Primary (1°) and 2° amides have two additional absorptions due to N–H bonds:

1. One or two N–H stretching peaks at 3200–3400 cm−1.

2. An N–H bending absorption at ~1640 cm−1.

• As the carbonyl bond becomes more delocalized, the C=O absorption shifts to lower frequency.

• Conjugation shifts a carbonyl absorption to lower frequencies.

• For cyclic carboxylic acid derivatives, decreasing ring size shifts a carbonyl absorption to higher frequencies.

Spectroscopic Properties—IR

27

28

• Protons on the carbon to the carbonyl absorb at 2–2.5 ppm.

• The N–H protons of 1° and 2° amides absorb at 7.5–8.5 ppm.

• In their 13C NMR spectra, carboxylic acid derivatives give a highly deshielded peak at 160–180 ppm due to the carbonyl carbon.

• This is somewhat upfield from the carbonyl absorption of aldehydes and ketones, which occurs at 190–215 ppm.

• Nitriles give a peak at 115–120 ppm in their 13C NMR spectrum due to the sp hybridized carbon.

• This is further downfield than the signal due to the sp hybridized carbon of an alkyne which occurs at 65–100 ppm.

Spectroscopic Properties—NMR

29

• Many low molecular weight esters have pleasant and very characteristic odors.

Interesting Esters and Amides

30

• Several esters have important biological activities.

Biologically Active Esters

31

O

O

SH

Ethyl-3-mercaptopropanoate

Grape flavor

32

Some sweetners

SNH

O

OO

Saccharin

NH

O

O

NH2O

HO

O

CH3

Aspartame

CH3

CH3

O

O

O

OHO

HO

HO HO

O

OH

OH

O

OH

O

HO OH

HO

OH

Steviosid

O

OH

O

HO

NH

HO

NH2

Monatin

O

OH

O

HN

NH

S O NH2

Alitame

33

O O

(R)-6-pentyl-5,6-dihydro-2H-pyran-2-one

Massoia lactone

natural coconut flavouring

6-Pentyl-alpha-pyrone

O O

6-pentyloxan-2-one

O O

delta decalactone

OO

Me

Me

3,6-dimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-one

Wine lactone sweet woody coconut odor

34

Macrocyclic Lactones

35

Proteins are an important group of naturally occurring amides, consisting of polymers of amino acids joined together by amide linkages.

Proteins—Polyamides

36

Useful Drugs Containing Lactams

37

• Nucleophilic acyl substitutions is the characteristic reaction of carboxylic acid derivatives.

• This reaction occurs with both negatively charged nucleophiles and neutral nucleophiles.

Nucleophilic Acyl Substitution

38

• Other nucleophiles that participate in this reaction include:

Mechanism of Nucleophilic Acyl Substitution

39

[1] Find the sp2 hybridized carbon with the leaving group.

[2] Identify the nucleophile.

[3] Substitute the nucleophile for the leaving group. With a neutral nucleophile, the proton must be lost to obtain a neutral substitution product.

Drawing Products of Nucleophilic Acyl Substitution

40

• Based on this order of reactivity, more reactive compounds can be converted into less reactive ones.

• The reverse is not usually true.

Reactivity Related to Leaving Group Ability

41

Comparing Leaving Group and Nucleophile

• Nucleophilic addition to a carbonyl forms a tetrahedral intermediate with two possible leaving groups, Z or Nu.

• Whichever group is a better leaving group will be eliminated.

42

• Since acid chlorides have the best leaving group of acid derivatives, they react readily with a wide range of nucleophiles to form nucleophilic substitution products.

• HCl is usually formed as a by-product.

• A weak base like pyridine is added to the reaction mixture to remove the strong acid (HCl), forming an ammonium salt.

General Reactions of Acid Chlorides

43

• Acid chlorides react with oxygen nucleophiles to form anhydrides, carboxylic acids, and esters.

Reactions of Acid Chlorides and Oxygen Nucleophiles

44

• Acid chlorides also react with ammonia, and 1° and 2° amines to form 1°, 2° and 3° amides, respectively.

• Two equivalents of NH3 or amine are used.

• One equivalent acts as the nucleophile to replace Cl, while the other reacts as a base with the HCl by-product to form an ammonium salt.

Reactions of Acid Chlorides and Amines

45

• As an example, reaction of an acid chloride with diethylamine forms the 3o amide N,N-diethyl-m-toluamide, popularly known as DEET.

• DEET is the active ingredient in the most widely used insect repellents, and is effective against mosquitoes, fleas, and ticks.

Amide Formation

46

Mechanisms of Acid Chloride Substitutions

47

Mechanisms of Acid Chloride Substitutions

O

Cl

HO

H N

O

OH NHCl

pKa 5.25pKa 15.7

HO

H N

pKa 15.7

NH

pKa 5.25

OH 0.14M pyridine in water pH 9

O

Cl

OH

O

Cl

OH

O

O H

pKa 4.76

N O

O

Kb = 1.8 x 10-9 =[pyrH+][OH-]

[pyr][pyrH+] = [OH-] = x

[pyr] = (0.1 M -x)

Kb = 1.8 x 10-9 = x2/(0.1 -x)

If [pyr]0 = 0.1 M

x = 1.3 x 10-5 = [OH]

pOH = 4.87

if x <<<< 0.1M, = x2/(0.1)

pH = 14- pOH = 9.23

Kb = 1.8 x 10-9

48

Just add water to acid chloride: Acid catalyzed

O

Cl

HO

H

O

ClO

H H

O

OH

H

O

Cl

O

O

H

O

Cl

HO

H

O

OH+ HCl

O

Cl

HO

H

O

ClO

H H

O

OH

H

O

Cl

O

O

H

H H H

O

ClO

H

H

-H+

O

O

H

H

H

O

O

H

At first:

49

• Anhydrides are somewhat less reactive than acid chlorides, but still readily react with most nucleophiles.

• Nucleophilic attack occurs at one carbonyl group, while the second carbonyl becomes part of the leaving group.

General Reaction of Anhydrides

50

Reactions of Anhydrides

51

• Besides the usual steps for nucleophilic addition and elimination of the leaving group, the mechanism involves an additional proton transfer.

Mechanism of Anhydride Substitution

52

• Reactions that result in the transfer of an acetyl group are known as acetylations.

Anhydrides Use in Acetylation Reactions

53

• Nucleophiles that are also strong bases react with carboxylic acids by removing a proton first, before any nucleophilic substitution reaction can take place.

General Reactions of Carboxylic Acids

54

Figure 22.2

Acyl Substitution Reactions of Carboxylic Acids

55

• Treatment of a carboxylic acid with thionyl chloride (SOCl2) affords an acid chloride.

• This is possible because thionyl chloride converts the OH group of the acid into a better leaving group, and because it provides the nucleophile (Cl¯) to displace the leaving group.

Formation of Acyl Halides

56

Mech for formation of Acid chlorides (Incorrect in Smith textbook)

O

OH

SOCl

Cl O

OH

SCl

Cl

O

O

OH

SCl

Cl

O

O

OH

S

Cl

O

Cl

O

OH

S

Cl

O

Cl O

Cl

H

OS

O

Cl O

Cl

57

R

O

OH

R

O

OR'

R

O

Cl

R

O

NR'R"

R H

OH

HR

O

R'

R

O

Ar R

OH

R'

R

O

HR'

58

• Although carboxylic acids cannot readily be converted into anhydrides, dicarboxylic acids can be converted to cyclic anhydrides by heating to high temperatures.

• This is a dehydration reaction because a water molecule is lost from the diacid.

Anhydrides through Dehydration of Carboxylic Acids

59

• Treatment of a carboxylic acid with an alcohol in the presence of an acid catalyst forms an ester.

• This reaction is called a Fischer esterification.

• The reaction is an equilibrium, so it is driven to the right by using excess alcohol or by removing water as it is formed.

Fischer Esterification of Carboxylic Acids

60

O

OH

H A

O

OH

H

MeO

H

OH

OHOMe H

MeO

H

OH

OHOMe

HA

OH

OOMe

H

H OOMe

HMe

OH O

OMe

Acid catalyzed esterification mechanism

RCO2H to RCO2R’

61

• Esterification of a carboxylic acid occurs in the presence of acid but not in the presence of base.

• Base removes a proton from the carboxylic acid, forming the carboxylate anion, which does not react with an electron-rich nucleophile.

No Base Catalysis of Fischer Esterification

62

Can use carboxylates as Nucleophiles with primary (and some secondary) alkyl halides (SN2)

R

O

OH

OH

R

O

O

R' Br

R

O

O

R

63

Esters by Steglich reaction (DCC)

R

O

OH R'OH

DCC

DMAPR

O

O R' N NNCN

Dicyclohexylcarbodiimide (DCC)N,N-dimethylpyridin-4-amineDMAP

R

O

OH

N

C

N

N

C

N

H

R

O

O

N

C

N

H

R

OO

HOR'

N

C

N

H

R

OO

OR'H

N

C

N

H

R

OO

OR'

N

C

N

H

R

O

O

OR' N

C

N

H

OH

N

N

N

N

H

64

Mitsunobu Reaction (not required for exam)

N N

O

O

EtO OEt

(E)-diethyl diazene-1,2-dicarboxylate

DEAD

PhPPh

Ph

N N

O

O

EtO OEt

Ph

PPh

Ph

RO

OH

N NH

O

O

EtO OEt

Ph

PPh

Ph

R

O

O

N NH

O

O

EtO OEt

Ph

PPh

Ph R

O

O

R' OH

HN N

H

O

O

EtO OEt

R' O

Ph

PPh

PhR

O

O

Ph

PPh

Ph R'O

RO

O

RO

O

R'

Ph

PPh

Ph O

R

O

OH

Ph3PDEADR

O

O

R' R"

OH

R"

R'

65

• Intramolecular esterification of - and -hydroxy carboxylic acids forms five- and six-membered lactones.

Intramolecular Fischer Esterification

66

• Carboxylic acids cannot be converted into amides by reaction with NH3 or an amine because amines are bases, and undergo an acid–base reaction to form an ammonium salt before nucleophilic substitution occurs.

• However, heating the ammonium salt at high temperature (>100°C) dehydrates the resulting ammonium salt of the carboxylate anion to form an amide, although the yield can be low.

Amide Formation from Carboxylic Acids

67

• The overall conversion of RCOOH to RCONH2 requires two steps:

[1] Acid–base reaction of RCOOH with NH3 to form an ammonium salt.

[2] Dehydration at high temperature (>100°C).

Amide Formation from Carboxylic Acids

68

• A carboxylic acid and an amine readily react to form an amide in the presence of an additional reagent, dicyclohexylcarbodimide (DCC), which is converted to the by-product dicyclohexylurea in the course of the reaction.

DCC in Amide Formation

69

• DCC is a dehydrating agent.

• The dicyclohexylurea by-product is formed by adding the elements of H2O to DCC.

• DCC promotes amide formation by converting the carboxy group OH group into a better leaving group.

DCC in Amide Formation

70

R

O

OH

N

C

N

N

C

N

HR

O

O

N

C

N

H

R

O

O

N

C

N

H

R

OO

H2NR'

N

C

N

H

R

OO

NR'H

H

H2NR'

N

C

N

H

R

OO

NR'

H

N

C

N

H

R

O

O

NR'

H

NR'

HHH

N

C

N

H

OH

DCC amide prep. (Smith is wrong again)

71

• Esters are hydrolyzed with water in the presence of either acid or base to form carboxylic acids or carboxylate anions, respectively.

• Esters react with NH3 and amines to form 1°, 2°, or 3° amides.

Reactions of Esters

72

O

OCH3

H+

H2OO

OH Acid catalyzed hydrolysis of ester

O

OCH3

HB

O

OCH3

H

HO

H

O

OCH3

H

OH H

B

O

OCH3

H

OH H

B

O

OCH3

H

OH

H -MeOH

+MeOH

O

OH

HB

O

OH

ester

acid

73

• Basic hydrolysis of an ester is also called saponification.

• Hydrolysis is base promoted, not base catalyzed, because the base (OH–) is the nucleophile that adds to the ester and forms part of the product.

• It participates in the reaction and is not regenerated later.

Base Hydrolysis of Esters

R

O

O

OH

R

O

OOH

R

O

O OHR

O

O

HO

74

• The carboxylate anion is resonance stabilized, and this drives the equilibrium in its favor.

• Once the reaction is complete and the anion is formed, it can be protonated with strong acid to form the neutral carboxylic acid.

Basic Hydrolysis of Esters

75

Lipid Hydrolysis

76

Figure 22.3

Structure of a Saturated Triacylglycerol

77

• The first step in the metabolism of a triacylglycerol is hydrolysis of the ester bonds to form glycerol and three fatty acids.

• The three bonds of the triacylglycerol drawn in red are cleaved in hydrolysis.

• In cells, this reaction is catalyzed by lipases.

• The fatty acids produced on hydrolysis are then oxidized, ultimately yielding CO2 and H2O, as well as nearly twice as much energy as an equal amount of carbohydrate.

Lipid Hydrolysis

78

• One recent attempt to reduce calories in common snack foods has been to substitute “fake fats” such as olestra for triacylglycerols.

Fat Substitutes

79

• Soap is prepared by the basic hydrolysis or saponification of a triacylglycerol.

• Heating an animal fat or vegetable oil with aqueous base hydrolyzes the three esters to form glycerol and sodium salts of three fatty acids.

Soap Formation

80

• Amides are the least reactive of the carboxylic acid derivatives.

• Amides are hydrolyzed in acid or base to form carboxylic acids or carboxylate anions.

• In acid, the amine by-product is protonated as an ammonium ion, whereas in base, a neutral amine forms.

Reactions of Amides

81

Amide Hydrolysis

R

O

NH2

OH

R

O

NH2HO

R

O

OH

NH2

R

O

O

NH3

HO H

R

O

NH2

OH

R

O

NH2HO

R

O

OH

NH3

R

O

O

NH3

OH

or

82

• Penicillin and related -lactams kill bacteria by a nucleophilic acyl substitution reaction.

• All penicillins have an unreacted side chain and a very reactive amide that is part of a -lactam.

• The -lactam is more reactive than other amides because it is part of a strained, four membered ring that is readily opened with nucleophiles.

-Lactam Antibiotics

83

• Bacterial cell walls are composed of carbohydrates linked together by peptide chains containing amide linkages formed by the enzyme glycopeptide transpeptidase.

• A nucleophilic OH group of the glycopeptide transpeptidase enzyme cleaves the -lactam ring of penicillin by a nucleophilic acyl substitution reaction.

• The reaction causes covalent modification of the enzyme, thus inactivating it and halting cell wall construction killing the bacterium.

The Mechanism of Action of -Lactam Antibiotics

84

85

• Natural fibers are obtained from either plant or animal sources

• Fibers like wool and silk are proteins obtained from animals.

• Cotton and linen are derived from carbohydrates having the general structure of cellulose.

Figure 22.4

Natural Fibers

86

• There are a number of synthetic polyamides (nylons), but the most well known is nylon 6,6.

• Nylon 6,6 can be synthesized from two six-carbon monomers which react together to form new amide bonds.

• Nylon is a condensation polymer because a small molecule (in this case, HCl) is eliminated during its synthesis.

Synthetic Fibers: Nylon—A Polyamide

87

• The most common polyester is polyethylene terephthalate (PET), which is sold under a variety of trade names (Dacron, Terylene, and Mylar), depending on its use.

Synthetic Fibers: Polyesters

88

• One method of synthesizing a polyester is by acid-catalyzed esterification of a diacid with a diol (Fischer esterification).

Synthesis of Polyesters

89

• In cells, acylations occur with the sulfur analogue of an ester (a thioester).

• The most common ester is acetyl coenzyme A (acetyl CoA).

Biological Acylations

90

• An example of a biological acyl transfer reaction is the formation of the neurotransmitter acetylcholine from choline and acetyl CoA.

• Other important acyl transfer reactions include the reaction of thioesters of fatty acids with cholesterol, forming cholesteryl esters.

• These esters are the principal form in which cholesterol is stored and transported in the body.

• It is carried in the blood stream in particles that also contain proteins and phospholipids.

• These particles are classified by their density: low density lipoproteins (LDL) and high density lipoproteins (HDL).

Acyl Transfer Reactions

91

Figure 22.5

Cholesteryl Esters and LDL Particles

92

• Nitriles are prepared by SN2 reactions of unhindered methyl and 1° alkyl halides with ¯CN.

Formation of Nitriles

• Dehydration of primary amides

93

• Nitriles are hydrolyzed with water in the presence of acid or base to yield carboxylic acids or carboxylate anions.

• In this reaction, the three C–N bonds are replaced by three C–O bonds.

Hydrolysis of Nitriles

94

• The mechanism of this reaction involves formation of an amide tautomer.

• Two tautomers can be drawn for any carbonyl compound, and those for a 1° amide are as follows:

Amide Tautomers

95

• The imidic acid and amide tautomers are interconverted by treatment with acid or base, analogous to keto-enol tautomers of other carbonyl compounds.

Keto-Enol Tautomers

96

97

• Treatment of a nitrile with LiAlH4 followed by H2O adds two equivalents of H2 across the triple bond, forming a 1o amine.

• Treatment of a nitrile with a milder reducing agent such as DIBAL-H followed by water forms an aldehyde.

Reduction of Nitriles

98

Nitrile Reduction Mechanisms

• With LiAlH4, two equivalents of hydride are sequentially added to yield a dianion which is then protonated with H2O to form an amine.

99

• With DIBAL-H, nucleophilic addition of one equivalent of hydride forms an anion which is protonated with water to generate an imine.

• The imine is then hydrolyzed in water to form an aldehyde.

Nitrile Reduction Mechanisms

100

• Both Grignard and organolithium reagents react with nitriles to form ketones with a new C–C bond.

Reduction of Nitriles with Organometallics

101

• The reaction occurs by nucleophilic addition of the organometallic reagent to the polarized C–N triple bond to form an anion, which is protonated with water to form an imine.

• Water then hydrolyzes the imine, replacing the C=N with C=O.

• The final product is a ketone with a new C–C bond.

Organometallic Reduction Mechanism

102

R

O

OHR C

R

O

NH2

N

R NH2

R R"

O

RX

CN-R H

NH

R H

O