Transcript ch15[1].

William H. Brown
Thomas Poon
www.wiley.com/college/brown
Chapter Fifteen
Functional Derivatives of Carboxylic
Acids
Carboxyl Derivatives
• In this chapter, we study four classes of organic
compounds.
• Under the general formula of each is a drawing to help
you see how it is related to the carboxyl group.
O
RCCl
An acid chlorid e
-H2 O
O
RC-OH H-Cl
O O
RCOCR'
An acid an hydride
-H2 O
O
O
RC-OH H-OCR'
O
RCOR'
An ester
-H2 O
O
RC-OH H-OR'
O
RCNH2
An amid e
-H2 O
O
RC-OH H-NH2
15-2
Acid Chlorides
• The functional group of an acid halide is an acyl group
bonded to a halogen.
• The most widely used are the acid chlorides.
• To name, change the suffix -ic acid to -yl chloride.
O
CH3 CCl
Eth anoyl chlorid e
(Acetyl chlorid e)
O
CCl
Ben zoyl ch loride
15-3
Acid Anhydrides
• The functional group of an acid anhydride is two acyl
groups bonded to an oxygen atom.
• The anhydride may be symmetrical (two identical acyl
groups) or mixed (two different acyl groups).
• To name, replace acid of the parent acid by anhydride.
O O
CH3 COCCH3
Acetic anhydride
O O
O O
COC
CH3 COC
Benzoic anhydride
Acetic benzoic
anhydride
15-4
Acid Anhydrides
• A phosphoric acid anhydride contains two phosphoryl
groups bonded to an oxygen atom.
• Shown here are two phosphoric anhydrides.
• Each is shown on the right as it would be ionized at pH
7.4, the pH of blood.
O O
HO-P-O-P-OH
OH OH
D iph os phoric acid
(Pyrop hosph oric acid )
O O
O-P-O-P-O
O O
D iphosp hate ion
(Pyroph os phate ion)
O O O
HO-P-O-P-O-P-OH
OH OH OH
Triph os phoric acid
O O O
O-P-O-P-O-P-O
O- O- OTriphosph ate ion
15-5
Esters
• The functional group of an ester is an acyl group bonded
to -OR or -OAr.
• Name the alkyl or aryl group bonded to oxygen followed
by the name of the acid.
• Change the suffix -ic acid to -ate.
O
O
CH3 COCH2 CH3
Ethyl Ethan oate
(Eth yl acetate)
O
O
O
D iethyl bu tanedioate
(D iethyl succinate)
15-6
Lactones
• Lactone: a cyclic ester
• IUPAC: name the parent carboxylic acid, drop the suffix
-ic acid, and add -olactone.
• The location of the oxygen atom on the carbon chain is
commonly indicated by a Greek letter.
O
4-Butanolactone 
(A -lacton e)
1
O
2
3 4


15-7
Phosphoric esters
• Phosphoric acid forms mono-, di-, and triesters.
• Name by giving the name of the alkyl or aryl group(s)
bonded to oxygen(s) followed by the word phosphate.
• In more complex phosphate esters, it is common to name
the organic molecule followed by phosphate.
O
CH3 O-P-OH
OCH3
D imethyl
phosp hate
CHO
H OH
HO H
H OH
H OH O
CH2 -O-P-OOD -Glucose
6-ph os phate
CHO
HO
H3 C
O
-
CH2 O-P-O
ON
Pyrid oxal p hosph ate
15-8
Amides
• The functional group of an amide is an acyl group
bonded to a trivalent nitrogen.
• IUPAC: drop -ic acid from the name of the parent acid
and add -amide.
• If the amide nitrogen is bonded to an alkyl or aryl group,
name the group and show its location on nitrogen by N-.
O
CH3 CNH2
A cetamide
(a 1° amide)
O H
CH3 C-N
CH3
O CH3
H-C-N
CH3
N-Methylacetamide N ,N-D imethyl(a 2° amid e)
formamid e (DMF)
(a 3° amide)
15-9
Lactam
• Lactam: a cyclic amide.
• Name the parent carboxylic acid, drop the suffix -ic acid
and add -lactam.
• The location of the nitrogen atom in the ring is commonly
indicated by a Greek letter, , , etc.
O

2 1
3
NH
H3 C
3-Bu tanolactam
A-lactam)



3
4

O
2
5
1
6

NH
6-Hexanolactam
An -lactone)
• 6-hexanolactam is an intermediate in the synthesis of
nylon 6 (Section 17.5A).
15-10
The Penicillins
• The penicillins are a family of -lactam antibiotics
• one of the first discovered was penicillin G.
the penicillins differ
in the group bonded
to the acyl carbon
H
CH2 C
O
Penicillin G
N
O
H H
S CH3
N
CH3
COOH
15-11
The Penicillins
• Amoxicillin, a -lactam antibiotic.
HO
O
H
H
S
HN
NH2
N
O
COOH
15-12
Cephalosporins
• The cephalosporins are also -lactam antibiotics.
O
The cep halosporins
differ in th e grou p
bonded to th e carbonyl
carbon...
N
H
NH2
O
H H
N
S
...and th e group b on ded
to th is carbon of the
six-memb ered rin g
CH3
COOH
Keflex
(a -lactam antibiotic)
15-13
Characteristic Reactions
• Nucleophilic acyl substitution: an addition-elimination
sequence resulting in substitution of one nucleophile for
another.
• The reaction depends on having a suitable leaving group
bonded to the acyl carbon, here indicated Lv.
-
O
+
C
R
Lv
-
Nu
R
O
O
C
C
Nu
Lv
Tetrah edral carbonyl
addition in termediate
R
+
Lv
-
Nu
Su bstitu tion
product
15-14
Characteristic Reactions
• In the general reaction, we showed the nucleophile as an
anion; this need not be the case.
• Neutral molecules such as water, alcohols, ammonia, and
amines can also serve as nucleophiles.
• In the general reaction, we showed the leaving group as
an anion to illustrate an important point about them: the
weaker the base, the better the leaving group.
15-15
Characteristic Reactions
• Halide ion is the weakest base and the best leaving
group; acid halides are the most reactive toward
nucleophilic acyl substitution.
• Amide ion is the strongest base and the poorest leaving
group; amides are the least reactive toward nucleophilic
acyl substitution.
15-16
Hydrolysis - Acid Chlorides
• Low-molecular-weight acid chlorides react rapidly with
water.
• Higher molecular-weight acid chlorides are less soluble in
water and react less readily.
O
CH3 CCl + H2 O
O
CH3 COH + HCl
15-17
Hydrolysis - Acid Anhydrides
• Low-molecular-weight acid anhydrides react readily with
water to give two molecules of carboxylic acid.
• Higher-molecular-weight acid anhydrides also react with
water, but less readily.
O O
CH3 COCCH3 + H2 O
O
O
CH3 COH + HOCCH3
15-18
Hydrolysis - Esters
• Esters are hydrolyzed only slowly, even in boiling water.
• Hydrolysis becomes more rapid if they are heated with
either aqueous acid or aqueous base.
• Hydrolysis in aqueous acid is the reverse of Fischer
esterification.
O
R
C
OH
+
OCH3
+ H2 O
H
R
O
+
H
C
OH
R
C
OH
+ CH3 OH
H3 CO
Tetrah edral carbonyl
addition in termediate
15-19
Hydrolysis - Esters
• Hydrolysis of an ester in aqueous base is often called
saponification.
• Each mole of ester hydrolyzed requires 1 mole of base;
for this reason, ester hydrolysis in aqueous base is said to
be base promoted.
O
RCOCH3 + NaOH
H2 O
O
-
RCO Na
+
+
CH3 OH
• Base-promoted ester hydrolysis involves formation of a
tetrahedral carbonyl addition intermediate followed by its
collapse.
15-20
Hydrolysis - Esters
Step 1: Addition of hydroxide ion to the carbonyl carbon.
O
R-C-OCH3
+
O
R-C OCH3
OH
OH
• Step 2: Collapse of the addition intermediate.
O
O
R-C OCH3
R-C OH
+
OCH3
OH
• Step 3: Proton transfer completes the reaction.
O
R-C O H
+
OCH3
O
R-C O
+
H-OCH3
15-21
Hydrolysis - Esters
• There are two major differences between acid-catalyzed
and base-promoted ester hydrolysis.
1. For acid-catalyzed hydrolysis, acid is required in only
catalytic amounts; for base-promoted hydrolysis, base is
required in equimolar amounts.
2. Hydrolysis of an ester in aqueous acid is reversible;
base-promoted hydrolysis is irreversible.
15-22
Hydrolysis - Amides
• Hydrolysis of an amide requires much more vigorous
conditions than hydrolysis of an ester.
• Hydrolysis in aqueous acid requires 1 mole of acid for
each mole of amide.
• The products are a carboxylic acid and an ammonium or
an amine salt.
O
O
NH2 +
Ph
2-Phenylbutan amide
H2 O + HCl
H2 O
heat
+
-
OH + NH4 Cl
Ph
2-Phen ylb utanoic acid
15-23
Hydrolysis - Amides
• Hydrolysis of an amide in aqueous base requires 1 mole
of base per mole of amide.
• The products are a carboxylate salt and an amine.
O
CH3 CNH
+
N-Phenylethanamide
(N-Phenylacetamide,
Acetanilide)
NaOH
H2 O
heat
O
+
CH3 CO Na + H2 N
Sodiu m acetate
Aniline
15-24
Hydrolysis
• Summary of reactions with water (hydrolysis)
15-25
Reaction with Alcohols
• Acid chlorides react with alcohols to give an ester and
HCl.
O
Cl + HO
Butanoyl
chloride
Cyclohexanol
O
O
+
HCl
Cyclohexyl butanoate
15-26
Reaction with Alcohols
• Acid anhydrides react with alcohols to give 1 mole of
ester and 1 mole of carboxylic acid.
O O
O
CH3 COCCH3 + HOCH2 CH3
Acetic anhydride
Ethan ol
O
CH3 COCH2 CH3 + CH3 COH
Ethyl acetate
Acetic acid
• Aspirin is prepared by the following reaction:
COOH
OH
O O
+ CH3 COCCH3
2-Hydroxyben zoic Acetic
acid
anh yd rid e
(Salicylic acid)
COOH
O
O
Acetylsalicylic
acid
(Asp irin )
+ CH3 COOH
Acetic
acid
15-27
Reaction with Alcohols
• Esters undergo an exchange reaction called
transesterification.
• The exchange is acid catalyzed.
• The original -OR group is exchanged for a new -OR
group.
O
Ph
HO
OCH3 +
O
H2 SO4
OH
Ph
O
Ph + 2 CH OH
3
O
O
Meth yl
benzoate
1,2-Ethan ediol
(Ethylene glycol)
A dies ter of
eth ylen e glycol)
15-28
Reaction with Alcohols
• Amides to not react with alcohols under any conditions.
• Summary of reactions with alcohols.
O
R-C-Cl + HOR"
O
R-C-OR" + HCl
O O
R-C-O-C-R + R"OH
O
O
R-C-OR" + HO-C-R
O
H2 SO4
R-C-OR' + R"OH
O
R-C-OR" + R'OH
O
R-C-NH2 + R"OH
N o Reaction
15-29
Reaction with NH 3 and Amines
• Acid halides react with ammonia, 1° amines, and 2°
amines to form amides.
• 2 moles of the amine are required per mole of acid
chloride; one to form the amide and one to neutralize the
HCl formed.
O
O
Cl + 2 NH3
Hexan oyl
ch loride
Ammonia
+
-
NH2 + NH4 Cl
Hexan amid e
Ammonium
chloride
15-30
Reaction with NH 3 and Amines
• Acid anhydrides react with ammonia, and with 1° and
2° amines to form amides.
• 2 moles of ammonia or amine are required; one to form
the amide and one to neutralize the carboxylic acid
byproduct.
• Here the reaction is broken into two steps.
O O
CH3 COCCH3 + NH3
O
CH3 COH + NH3
O O
CH3 COCCH3
+ 2 NH3
O
O
CH3 CNH2 + CH3 COH
O
CH3 CO- NH4 +
O
O
CH3 CNH2 + CH3 CO- NH4 +
15-31
Reaction with NH 3 and Amines
• Esters react with ammonia, and with 1° and 2° amines
to form amides.
• Esters are less reactive than either acid halides or acid
anhydrides.
O
Ph
O
O
Ethyl phenylacetate
+
N H3
Ph
N H2 + HO
Phenyl acetamide
Ethanol
• Amides do not react with ammonia, or with 1° or 2°
amines.
15-32
Reaction with NH 3 & Amines
• Summary of reaction with ammonia and amines.
O
R-C-Cl + 2 NH3
O O
R-C-O-C-R + 2 NH3
O
R-C-OR' + NH3
O
R-C-NH2 + NH4 + ClO
O
R-C-NH2 + R-C-O-NH4 +
O
R-C-NH2 + R'OH
O
R-C-NH2 N o reaction w ith ammonia or amines
15-33
Interconversion
• FIGURE 15.1 Interconversion of functional groups.
15-34
Esters with Grignard Reagents
• A formic ester with 2 moles of Grignard reagent followed
by hydrolysis gives a 2° alcohol.
O
HCOCH3 + 2 RMgX
An es ter of
formic acid
OH
magnes ium H O, HCl
2
alkoxide
salt
HC-R + CH3 OH
R
A 2° alcohol
• Reaction of an ester other than a formate gives a 3°
alcohol.
O
CH3 COCH3 + 2 RMgX
An es ter of any acid
oth er th an formic acid
magnes ium H O, HCl
2
alkoxide
salt
OH
CH3 C-R + CH3 OH
R
A 3° alcohol
15-35
Esters with Grignard Reagents
• Steps 1 and 2
1
O
2
CH3 -C-OCH3 + R MgX
1
O [ MgX]
+
O
CH3 -C OCH3
R 2
CH3 -C
4
3
3 O
CH3 -C + R MgX
O [MgX]
CH3 -C-R
R
A ketone
R
Magn esium salt
-
+
-
CH3 O [ MgX]
R
A magnes ium s alt
• Steps 3 and 4
+
A ketone
4
H O H, HCl
OH
CH3 -C-R
R
A 3° alcohol
15-36
+
Reduction
• Esters are reduced by LiAlH4 to two alcohols.
• The alcohol derived from the carbonyl group is primary.
O
Ph
OCH3
1 . LiA lH4 , e t he r
2 . H2 O, HCl
Methyl 2-phenylpropanoate
Ph
OH + CH3 OH
2-Phenyl-1propanol
Methanol
• NaBH4 does not normally reduce esters, but it does
reduce aldehydes and ketones
O
O
NaBH4
OEt
Et OH
OH O
OEt
15-37
Reduction
• LiAlH4 reduction of an amide gives a 1°, 2°, or 3°
amine, depending on the degree of substitution of the
amide.
O
NH2
Octanamide
1 . LiAlH4
2 . H2 O
NH2
1-Octanamine
O
NMe2
1 . LiAlH4
2 . H2 O
N,N -D imethylben zamide
NMe2
N ,N-D imeth ylb enzylamine
15-38
Some Interconversions
• from Example 15.7
O
Ph
SOCl2
CH3 OH, H2 SO4
OH
Fischer
Phenylacetic esterification
acid
1 . LiAlH4
2 . H2 O
NH3 ( 2 eq)
CH3 OH
O
Ph
Cl
O
O
Ph
NH3
Ph
OCH3
(a)
1 . LiAlH4
2 . H2 O
Ph
OH
(d )
NH2
(b )
1 . LiAlH4
2 . H2 O
Ph
NH2
(c)
15-39
Functional
Derivatives of
Carboxylic Acids
End Chapter 15
15-40