Carboxylic Acid Derivatives

1
Chapter 20

• Carboxylic Acid Derivatives
• Nucleophilic Acyl Substitution

2
Acyl Halides

• name the acyl group and add the word chloride,
  fluoride, bromide, or iodide as appropriate
• acyl chlorides are, by far, the most frequently
  encountered of the acyl halides

3
Acyl Halides
acetyl chloride
3-butenoyl chloride
p-fluorobenzoyl bromide
4
Acyl Halides
acetyl chloride
3-butenoyl chloride
p-fluorobenzoyl bromide
5
Acid Anhydrides
acetic anhydride
benzoic anhydride
benzoic heptanoic anhydride
6
Esters

• name as alkyl alkanoates
• cite the alkyl group attached to oxygen first
  (R')
• name the acyl group second substitute the
  suffix-ate for the -ic ending of the
  corresponding acid

7
Esters
ethyl acetate
methyl propanoate
2-chloroethyl benzoate
8
Amides having an NH2 group

• identify the corresponding carboxylic acid
• replace the -ic acid or -oic acid ending by -amide

9
Amides having an NH2 group
acetamide
3-methylbutanamide
benzamide
10
Amides having substituents on N
and

• name the amide as before
• precede the name of the amide with the name of
  the appropriate group or groups
• precede the names of the groups by the letter N-
  (standing for nitrogen and used as a locant)

11
Amides having substituents on N
N-methylacetamide
N,N-diethylbenzamide
N-isopropyl-N-methylbutanamide
12
Nitriles
ethanenitrileor acetonitrileor methyl
cyanide
benzonitrile
2-methylpropanenitrileor isopropyl cyanide
13
Figure 20.1(page 833)
The key to managing the information inthis
chapter is the same as alwaysstructure
determines properties. The key structural
feature is how well thecarbonyl group is
stabilized. The key property is reactivity in
nucleophilicacyl substitution.
14
(No Transcript)
15
Electron Delocalization and the Carbonyl Group

• The main structural feature that distinguishes
  acyl chlorides, anhydrides, thioesters, esters,
  and amides is the interaction of the substituent
  with the carbonyl group. It can be represented
  in resonance terms as

16
Electron Delocalization and the Carbonyl Group

• The main structural feature that distinguishes
  acyl chlorides, anhydrides, thioesters, esters,
  and amides is the interaction of the substituent
  with the carbonyl group. It can be represented
  in resonance terms as

17
Electron Delocalization and the Carbonyl Group

• The extent to which the lone pair on X can be
  delocalized into CO depends on
• 1) the electronegativity of X
• 2) how well the lone pair orbital of X
  interacts with the ? orbital of CO

18
Reactivity is related to structure
Stabilization
very small

• The more stabilized the carbonyl group, the less
  reactive it is.

small
moderate
large
19
Nucleophilic Acyl Substitution
In general
HY
HX

• Reaction is feasible when a less stabilized
  carbonyl is converted to a more stabilized one
  (more reactive to less reactive).

20
most reactive
a carboxylic acid derivative can be converted by
nucleophilic acyl substitution to any other type
that lies below it in this table
least reactive
21
Nucleophilic Acyl Substitution
HNu
HX

• Reaction is feasible when a less stabilized
  carbonyl is converted to a more stabilized one
  (more reactive to less reactive).

22
Mechanism for Nucleophilic Acyl Substitution

• This mechanism involves the formation of a
  tetrahedral intermediate.

23
Esters are very common natural products
3-methylbutyl acetate

• also called "isopentyl acetate" and "isoamyl
  acetate"
• contributes to characteristic odor of bananas

24
Esters of Glycerol

• R, R', and R" can be the same or different
• called "triacylglycerols," "glyceryl triesters,"
  or "triglycerides"
• fats and oils are mixtures of glyceryl triesters

25
Cyclic Esters (Lactones)
(Z)-5-Tetradecen-4-olide(sex pheromone of female
Japanese beetle)
26
Preparation of Esters

• Fischer esterification (Sections 15.8 and 19.14)
• from acyl chlorides (Sections 15.8 and 20.4)
• from carboxylic acid anhydrides (Sections
  15.8and 20.6)
• Baeyer-Villiger oxidation of ketones (Section
  17.16)

27
Boiling Points

• Esters have higher boiling points than alkanes
  because they are more polar.
• Esters cannot form hydrogen bonds to other ester
  molecules, so have lower boiling points than
  alcohols.

boilingpoint
28C
O
57C
CH3COCH3
99C
28
Solubility in Water

• Esters can form hydrogen bonds to water, so low
  molecular weight esters have significant
  solubility in water.
• Solubility decreases with increasing number of
  carbons.

Solubility(g/100 g)
0
O
33
12.5
29
Reactions of Esters

• with Grignard reagents (Section 14.10)
• reduction with LiAlH4 (Section 15.3)
• with ammonia and amines (Sections 20.12)
• hydrolysis (Sections 20.10 and 20.11)

30
Acid-Catalyzed Ester Hydrolysis
is the reverse of Fischer esterification

R'OH

• maximize conversion to ester by removing water
• maximize ester hydrolysis by having large excess
  of water
• equilibrium is closely balanced because carbonyl
  group ofester and of carboxylic acid are
  comparably stabilized

31
Example
(80-82)
32
Mechanism of Acid-CatalyzedEster Hydrolysis

• Is the reverse of the mechanism for
  acid-catalyzed esterification.
• Like the mechanism of esterification, it involves
  two stages
• 1) formation of tetrahedral intermediate (3
  steps)
• 2) dissociation of tetrahedral intermediate
  (3 steps)

33
Key Features of Mechanism

• Activation of carbonyl group by protonation of
  carbonyl oxygen
• Nucleophilic addition of water to carbonyl
  groupforms tetrahedral intermediate
• Elimination of alcohol from tetrahedral
  intermediate restores carbonyl group

34
18O Labeling Studies

H2O

• Ethyl benzoate, labeled with 18O at the carbonyl
  oxygen, was subjected to acid-catalyzed
  hydrolysis.
• Ethyl benzoate, recovered before the reaction had
  gone to completion, had lost its 18O label.
• This observation is consistent with a tetrahedral
  intermediate.

H

H2O
35
Ester Hydrolysis in Aqueous Base

R'OH

• is called saponification
• is irreversible, because of strong stabilization
  of carboxylateion
• if carboxylic acid is desired product,
  saponification is followedby a separate
  acidification step (simply a pH adjustment)

36
Example

NaOH
water-methanol, heat

(95-97)
37
Soap-Making

• Basic hydrolysis of the glyceryl triesters (from
  fats and oils) gives salts of long-chain
  carboxylic acids.
• These salts are soaps.

K2CO3, H2O, heat
CH3(CH2)xCOK
CH3(CH2)yCOK
CH3(CH2)zCOK
38
Mechanism of Ester Hydrolysisin Base

• Oxygen Labeling Studies Conclude
• Mechanism Involves two stages
• 1) formation of tetrahedral intermediate 2) diss
  ociation of tetrahedral intermediate

39
Reactions of Esters
Esters react with ammonia and aminesto give
amides


R'2NH
R'OH
40
Example
heat
(61)
41
Thioesters
Thioesters are compounds of the type

• Thioesters are intermediate in reactivity between
  anhydrides and esters.
• Thioester carbonyl group is less stabilized than
  oxygen analog because CS bond is longer than CO
  bond which reduces overlap of lone pair orbital
  and CO ? orbital

42
Thioesters
Many biological nucleophilic acyl
substitutionsinvolve thioesters.


R'S
H
43
Preparation of Amides
Amides are prepared from amines by acylationwith

• acyl chlorides (Table 20.1)
• anhydrides (Table 20.2)
• esters (Table 20.5)

44
Preparation of Amides
Amines do not react with carboxylic acids to
giveamides. The reaction that occurs is
proton-transfer(acid-base).




R'NH3
R'NH2
heat

H2O
45
Example


225C

H2O
(80-84)
46
Lactams
Lactams are cyclic amides. Some are
industrialchemicals, others occur naturally.
47
Lactams
Lactams are cyclic amides. Some are
industrialchemicals, others occur naturally.
48
Imides
Imides have 2 acyl groups attached to
thenitrogen.
49
Imides
The most common examples are cyclic imides.
O
NH
O
Phthalimide
Succinimide
50
Preparation of Imides
Cyclic imides are prepared by heating the
ammonium salts of dicarboxylic acids.
NH3
51
Hydrolysis of Amides
Hydrolysis of amides is irreversible. In acid
solution the amine product is protonated to
give an ammonium salt.



R'NH3


H2O
H
52
Hydrolysis of Amides
In basic solution the carboxylic acid product is
deprotonated to give a carboxylate ion.



R'NH2

HO
53
Example Acid Hydrolysis
H2O

H2SO4heat
(88-90)
54
Example Basic Hydrolysis
KOH

H2Oheat
(95)
55
Mechanism of Acid-CatalyzedAmide Hydrolysis

• Acid-catalyzed amide hydrolysis proceeds viathe
  customary two stages
• 1) formation of tetrahedral intermediate 2) diss
  ociation of tetrahedral intermediate

56
Mechanism of Amide Hydrolysisin Base

• Involves two stages
• 1) formation of tetrahedral intermediate 2) diss
  ociation of tetrahedral intermediate

57
Preparation of Nitriles
Nitriles are prepared by

• nucleophilic substitution by cyanide onalkyl
  halides (Sections 8.1 and 8.13)
• cyanohydrin formation (Section 17.7)
• dehydration of amides

58
Example
KCN
CH3(CH2)8CH2Cl
ethanol-water
(95)

• SN2

59
Preparation of Nitriles
By dehydration of amides

• uses the reagent P4O10 (often written as P2O5)

(69-86)
60
Hydrolysis of Nitriles
Hydrolysis of nitriles resembles the
hydrolysisof amides. The reaction is
irreversible. Ammonia is produced and is
protonated to ammonium ion in acid solution.
61
Hydrolysis of Nitriles
In basic solution the carboxylic acid product is
deprotonated to give a carboxylate ion.
62
Mechanism of Hydrolysis of Nitriles
H2O
H2O

• Hydrolysis of nitriles proceeds via
  thecorresponding amide.
• We already know the mechanism of
  amidehydrolysis.
• Therefore, all we need to do is to see how
  amides are formed from nitriles under the
  conditions of hydrolysis.

63
Mechanism of Hydrolysis of Nitriles
OH
H2O
RC
NH

• The mechanism of amide formation is analogousto
  that of conversion of alkynes to ketones.
• It begins with the addition of water across
  thecarbon-nitrogen triple bond.
• The product of this addition is the nitrogen
  analog of an enol. It is transformed to an
  amideunder the reaction conditions.

64
Addition of Grignard Reagents to Nitriles
R'MgX
H2O
diethylether

• Grignard reagents add to carbon-nitrogen
  triplebonds in the same way that they add to
  carbon-oxygen double bonds.
• The product of the reaction is an imine.

65
Addition of Grignard Reagents to Nitriles
R'MgX
H2O
diethylether
H3O
Imines are readily hydrolyzed to
ketones.Therefore, the reaction of Grignard
reagents with nitriles can be used as a synthesis
of ketones.
66
Example
CH3MgI
1. diethyl ether
2. H3O, heat
(79)
67
Infrared Spectroscopy
CO stretching frequency depends on whether
thecompound is an acyl chloride, anhydride,
ester, oramide.
68
Infrared Spectroscopy
Anhydrides have two peaks due to CO stretching.
One results from symmetrical stretching of the
COunit, the other from an antisymmetrical
stretch.
CO stretching frequency ?
1748 and 1815 cm-1
69
Infrared Spectroscopy
Nitriles are readily identified by absorption due
to carbon-nitrogen triple bond stretching in the
2210-2260 cm-1 region.
70
1H NMR
1H NMR readily distinguishes between
isomericesters of the type
and
71
1H NMR
For example
CH3CH2COCH3
and
Both have a triplet-quartet pattern for an
ethylgroup and a methyl singlet. They can
beidentified, however, on the basis of
chemicalshifts.
72
Figure 20.9
Chemical shift (?, ppm)
73
13C NMR
Carbonyl carbon is at low field (? 160-180 ppm),
but not as deshielded as the carbonyl carbon of
an aldehyde or ketone (? 190-215 ppm). The
carbon of a CN group appears near ? 120ppm.
74
UV-VIS
n?? absorption ?max
235 nm
225 nm
207 nm
214 nm
75
Mass Spectrometry
Most carboxylic acid derivatives give a
prominentpeak for an acylium ion derived by
thefragmentation shown.

76
Mass Spectrometry
Amides, however, cleave in the direction that
givesa nitrogen-stabilized cation.