Carboxyl Derivatives
Classes shown, formally, via dehydration.
O
RCCl
A n acid
chloride
-H2 O
O
RC-OH H-Cl
O O
RCOCR'
An acid
anhydride
-H2 O
O
O
RC-OH H-OCR'
O
RCOR'
An ester
-H2 O
O
RC-OH H-OR'
O
RCNH2
An amide
-H2 O
O
RC-OH H-NH2
RC N
A nitrile
-H2 O
HO H
RC=N
Th e enol of
an amide
18-1
Structure: Acid Chlorides
 The
functional group of an acid halide is an acyl
group bonded to a halogen.
• The most common are the acid chlorides.
• To name, change the suffix -oic acid to -oyl halide.
O
O
RCAn acyl
group
O
CH3 CCl
O
Cl
Ethan oyl ch loride Benzoyl chloride
(Acetyl ch loride)
Cl
Cl
O
Hexan edioyl ch loride
(Adip oyl chloride)
18-2
Related: Sulfonyl Chlorides
• Replacement of -OH in a sulfonic acid by -Cl gives a
sulfonyl chloride.
O
CH3 SOH
O
Methanes ulfon ic
acid
O
CH3 SCl
O
Methanes ulfonyl ch loride
(Mesyl ch loride, MsCl)
O
H3 C
SOH
O
p-Toluen esulfon ic
acid
O
H3 C
SCl
O
p-Toluen esulfon yl chloride
(Tosyl chlorid e, TsCl)
18-3
Structure: Acid Anhydrides
 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
O O
CH3 COCCH3
COC
Acetic anhydride
Benzoic anhydride
18-4
Acid Anhydrides
 Cyclic
anhydrides are named from the
dicarboxylic acids from which they are derived.
O
O
O
S u cci n ic
an h ydride
O
O
O
Male i c
an h ydride
O
O
O
Ph th al ic
an h ydride
18-5
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
O
O
O
Ethyl ethan oate
(Ethyl acetate)
Is op ropyl
ben zoate
EtO
OEt
O
D iethyl butaned ioate
(D ieth yl s uccin ate)
18-7
Esters; Lactones
 Lactone:
A cyclic ester.
• name the parent carboxylic acid, drop the suffix -ic
acid and add -olactone.

2
3
H3 C
O
O
1
O
3-Bu tanolactone
-Butyrolactone)

1
2
O
3 4
 
4-Bu tanolactone
-Bu tyrolacton e)



3
4
2
O
1
O
5 6


6-Hexan olacton e
-Cap rolactone)
18-8
Amides
 The
functional group of an amide is an acyl
group bonded to a nitrogen atom.
• drop -oic acid from the name of the parent acid and
add -amide. (For the common acid name, drop -ic of
the acid name and add -amide.)
• an alkyl or aryl group bonded to the N: name the group
and show its location on nitrogen by N-.
O
CH3 CNH2
A cetamide
(a 1° amide)
ethanamide
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)
18-10
Amides: resonance
18-11
Amides; Characteristics
18-12
Amides; Lactams
 Lactams:
A cyclic amides are called lactams.
• Name the parent carboxylic acid, drop the suffix -ic
acid and add -lactam.

2
3
H3 C
O
1
NH
3-Bu tanol actam
 -Butyrol actam)



3
4
O
2
1
NH
5


6-He xan olactam
 -C aprolactam)
6
Indicates where the N is located.
18-13
Imides
 The
functional group of an imide is two acyl
groups bonded to nitrogen.
• Both succinimide and phthalimide are cyclic imides.
O
NH
O
Succinimide
O
NH
O
Phthalimide
18-14
Related: Nitriles
 The
functional group of a nitrile is a cyano group
• IUPAC names: name as an alkanenitrile.
• common names: drop the -ic acid and add -onitrile.
CH3 C N
Ethanen itrile
(A cetonitrile)
C N
Benzon itrile
CH2 C N
Phenylethan enitrile
(Phenylacetonitrile)
18-15
Acidity of N-H bonds
 Amides
are comparable in acidity to alcohols.
• Water-insoluble amides do not react with NaOH or
other alkali metal hydroxides to form water-soluble
salts.
 Sulfonamides
and imides are more acidic than
amides.
O
CH3 CNH2
Acetamide
pKa 15-17
O
SNH2
O
NH
O
NH
O
O
O
Ben zenesu lfonamide Succinimide Phth alimide
pK a 10
p Ka 9.7
p Ka 8.3
18-16
Acidity of N-H bonds
 Effect
of neighboring carbonyl groups.
1.0
18-17
Acidity of N-H
• Imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts.
O
NH +
O
pK a 8.3
(stron ge r
aci d)
O
N aOH
-
N Na
+
+
H2 O
O
(stron ge r
base )
(weak e r
base )
pK a 15.7
(weak e r
aci d)
18-18
Acidity of N-H bonds
 Imides
are more acidic than amides because
1. the electron-withdrawing inductive of the two adjacent
C=O groups weakens the N-H bond, and
2. More resonance delocalization of the negative charge.
O
N
O
O
N
O
A resonance-stabilized an ion
O
N
O
18-19
Lab related: Sulfonamides (Hinsberg)
Experimental test to distinguish primary, secondary and
tertiary amines.
1
soluble
insoluble
2
insoluble
3
soluble
In base
In acid
Reaction replaces one H with the sulfonyl group. In
18-20
an H remains it is soluble in base.
Characteristic Reactions: Ketones & Aldehydes
 Nucleophilic
acyl Addition:
Protonation makes carbonyl better electrophile. Ok with
poor nucleophile.
Carbonyl weaker electrophile.
Need good nucleophile.
18-21
Characteristic Reactions: Derivatives
 Nucleophilic
acyl substitution: An additionelimination sequence resulting in substitution of
one nucleophile for another.
O
O
R
C
+
Y
:Nu
R
O
C
Nu
R
C
+
Nu
:Y
Y
Te trah edral carbon yl S u bstitu tion
addi tion i n te rme diate
produ ct
Dominant for derivatives due to good leaving group (Y),
uncommon for ketones or aldehydes.
18-22
Characteristic Reactions
Poor bases make good leaving groups.
O
R2 N-
RO-
RCO-
X-
Increasing leaving ability
Increasing basicity
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.
18-23
Water and 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
Acetyl chlorid e
O
CH3 COH + HCl
18-24
Water and Anhydrides
• Low-molecular-weight anhydrides react readily with
water to give two molecules of carboxylic acid.
• Higher-molecular-weight anhydrides also react with
water, but less readily.
O O
CH3 COCCH3 + H2 O
Acetic an hydrid e
O
O
CH3 COH + HOCCH3
18-25
Mechanism- Anhydrides
• Step 1: Addition of H2O to give a TCAI. (Addition)
H +
O
CH3 -C- O-C- CH 3
O-H
H
H
O
O
CH3 -C- O-C- CH 3
+
O H
H
O-H
H
H
O
O
+
CH3 -C- O-C- CH 3 + H- O-H
O
H
H
Te trah edral carbon yl
addi tion i n te rme diate
Acid makes carbonyl better electrophile.
18-26
Mechanism- Anhydrides
• Step 2: Protonation and collapse of the TCAI. (Elimination)
H
H
+O
H
H
H
O
H
O
O
O
CH3 -C-O-C-CH3
O
H
H
H
+O
H
+ H
O
CH3 C O C CH3
H
H
H
O
CH3
O
O
C + O C
O
CH3
H
Acid sets up better leaving group.
18-27
Water and Esters
 Esters
are hydrolyzed only slowly, even in
boiling water.
• Hydrolysis becomes more rapid if they are heated with
either aqueous acid or base.
 Hydrolysis
in aqueous acid is the reverse of
Fischer esterification.
• acid catalyst protonates the carbonyl oxygen and
increases its electrophilic character toward attack by
water (a weak nucleophile) to form a tetrahedral
carbonyl addition intermediate.
• Collapse of this intermediate gives the carboxylic acid
and alcohol.
18-28
Mechanism: Acid/H2O - Esters (1o and 2o alkoxy)
 Acid-catalyzed
R
O
C
ester hydrolysis.
OH
C
+
+
OCH3
Acid makes
carbonyl
Better
electrophile.
H2 O
H
R
H
+
OH
R
O
C
+
OH
CH3 OH
OCH3
Tetrahed ral carbonyl
ad dition intermed iate
Acid sets up
leaving group.
18-29
Mechanism: Reaction with Acid/H2O – Esters (3o alkoxy)
But wait!!!!!!!
water
alcohol
18-30
Reaction with Base/H2O - Esters
 Saponification:
The hydrolysis of an esters in
aqueous base.
• 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
18-31
Mechanism of Reaction with Base/H2O – Esters
• Step 1: Attack of hydroxide ion (a nucleophile) on the
carbonyl carbon (an electrophile). (Addition)
• Step 2: Collapse of the TCAI. (Elimination)
• Step 3: Proton transfer to the alkoxide ion; this step is
irreversible and drives saponification to completion.
O
O
O
(1)
(2)
R- C +
R- C-OCH3+ OH
R- C OCH3
O
OH
H
O
OCH3 (3) R- C + HOCH3
O
18-32
Acidic Reaction with H2O - Amides
 Hydrolysis
of an amide in aqueous acid requires
one mole of acid per mole of amide.
• Reaction is driven to completion by the acid-base
reaction between the amine or ammonia and the acid.
O
O
N H2 + H2 O + HCl
Ph
2-Ph e n ylbu tan am ide
H2 O
heat
OH + N H4
+
Cl
-
Ph
2-Ph e n ylbu tan oi c aci d
18-33
Basic Reaction with H2O - Amides
 Hydrolysis
of an amide in aqueous base requires
one mole of base per mole of amide.
• Reaction is driven to completion by the irreversible
formation of the carboxylate salt.
O
CH3 CNH
N-Phen yleth anamide
(N-Phen ylacetamid e,
Acetan ilide)
+ NaOH
H2 O
heat
O
CH3 CO- Na+ + H2 N
Sodiu m
acetate
A niline
18-34
Mechanism: Acidic H2O - Amides
• Step1: Protonation of the carbonyl oxygen gives a
resonance-stabilized cation intermediate.
O
+
R C NH2 + H O H
H
+H
O
R C NH2
H
H
O
R C
+
O
NH2
R C
+
NH2
+ H2 O
Reso nance-stabil ized catio n i ntermed iate
18-35
Acidic H2O - Amides
• Step 2: Addition of water (a nucleophile) to the carbonyl carbon
(an electrophile) followed by proton transfer gives a TCAI.
OH
+
R C NH2 +
OH
O H
H
R C NH2
O+
H
H
proton
transfe r from
O to N
OH
R C NH3 +
H
O
• Step 3: Collapse of the TCAI and proton transfer. (Elimination)
H
R C NH3 +
OH
H
+
O
R
O
C
+
NH3
R
O
C
+
OH + NH4
OH
18-36
Mechanism: Reaction with Basic H2O - Amides
Amide
hydroxide ion
Dianion!
18-37
Acidic H2O and Nitriles
 The
cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion.
Ph CH2 C N + 2 H2 O + H2 SO4
Phenylacetonitrile
H2 O
heat
O
+
Ph CH2 COH + NH4 HSO4
Ph enylacetic
Ammoniu m
acid
hydrogen s ulfate
• Protonation of the cyano nitrogen gives a cation that
reacts with water to give an imidic acid.
• Keto-enol tautomerism gives the amide.
Acid
OH
O
+
+
H
+
H
O
R-C N
R-C NH
R-C-NH 2
2
Ammonium
A n imidic acid
An amide
ion
(en ol of an amide)
18-38
Basic H2O and Nitriles
• Hydrolysis of a cyano group in aqueous base gives a
carboxylic anion and ammonia; acidification converts
the carboxylic anion to the carboxylic acid.
CH3 ( CH2 ) 9 C N
Un decan enitrile
NaOH, H2 O
h eat
O
+
CH3 ( CH2 ) 9 CO Na + NH3
S od ium und ecanoate
HCl H2 O
O
CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl
Und ecanoic acid
18-39
Synthesis: Reaction with H2O - Nitriles
• Hydrolysis of nitriles is a valuable route to carboxylic
acids.
CH 3 ( CH2 ) 8 CH2 Cl KCN
ethanol,
1-C hlorode cane
water
CH3 ( CH2 ) 9 C N
Unde cane nitril e
OH
H2 SO4 , H2 O
heat
O
CH3 ( CH2 ) 9 COH
Unde canoic aci d
OH
CHO HCN , KCN
CN H2 SO 4 , H2 O
COOH
e th an ol,
heat
wate r
Be n z al de hyde
Be n z al de h yde cyan oh ydrin 2-H ydroxyph e n ylacetic aci d
(Man de l on itri le )
(Man de l ic acid)
(racemic)
(racemic)
18-40
Synthesis: Grignards + Nitriles ->ketone 1
NMgX
RC
N
R'MgX
RCR'
NH
H2O
RCR'
diethyl
ether
 Grignard
reagents add to carbon-nitrogen triple
bonds in the same way that they add to carbonoxygen double bonds.
 The product of the reaction is an imine.
18-41
Synthesis: Grignards + Nitriles ->ketone 2
NMgX
RC
N
R'MgX
RCR'
NH
H2O
RCR'
diethyl
ether
H3O+
Imines hydrolyzed to ketones.
O
RCR'
18-42
Reaction of Alcohols and Acid Halides
 Acid
halides react with alcohols to give esters.
• Acid halides are so reactive toward even weak
nucleophiles such as alcohols that no catalyst is
necessary.
• Where the alcohol or resulting ester is sensitive to HCl,
reaction is carried out in the presence of a 3° amine to
neutralize the acid.
O
O
Cl + HO
Butanoyl
chloride
Cyclohexan ol
O
+ HCl
Cyclohexyl butan oate
18-43
Reaction with Alcohols, Sulfonic Esters
• Sulfonic acid esters are prepared by the reaction of an
alkane- or arenesulfonyl chloride with an alcohol or
phenol.
• The key point here is that OH- (a poor leaving group) is
transformed into a sulfonic ester (a good leaving
group) with retention of configuration at the chiral
center.
OT s
OH
+
(R)-2-Octanol
T sCl
pyridine
p-Toluenesulfonyl
chloride
(Tosyl chloride)
(R)-2-Octyl p-t oluenesulfonate
[(R)-2-Octyl tosylate]
18-44
Reaction of Alcohols and Acid Anhydrides
 Acid
anhydrides react with alcohols to give one
mole of ester and one mole of a carboxylic acid.
O O
CH3 COCCH3 + HOCH2 CH 3
Ace ti c an h ydride Eth an ol
O
O
CH3 COCH2 CH3 + CH3 COH
Ace ti c aci d
Eth yl ace tate
• Cyclic anhydrides react with alcohols to give one ester
group and one carboxyl group.
O
O
O
O
Phth alic
anh yd rid e
+
O
OH
HO
O
2-Butan ol
(sec-Butyl alcohol)
(s ec-Bu tyl h yd rogen
phth alate
18-45
Reaction of Alcohols and Esters
 Esters
react with alcohols in the presence of an
acid catalyst in an equilibrium reaction called
transesterification.
O
+
OCH3
Me th yl prope n oate
(Me th yl acrylate)
(bp 81°C )
HO
1-Bu tan ol
(bp 117°C )
HCl
O
O
+ CH3 OH
Bu tyl prope n oate
Me th an ol
(Bu tyl acrylate)
(bp 65°C )
(bp 147°C )
18-46
Reaction of Ammonia, etc. and Acid Halides
 Acid
halides react with ammonia, 1° amines, and
2° amines to form amides.
• Two moles of the amine are required per mole of acid
chloride.
O
O
Cl + 2 NH3
Hexanoyl
chloride
Ammon ia
+
-
NH2 + NH4 Cl
Hexan amid e
Ammon ium
chloride
18-47
Reaction of Ammonia, etc. and Anhydrides.
 Acid
anhydrides react with ammonia, and 1° and
2° amines to form amides.
• Two moles of ammonia or amine are required.
O O
CH3 COCCH3 + 2 NH3
Acetic
Ammon ia
anh yd rid e
O
O
+
+
CH
CO
NH
CH3 CNH2
3
4
Acetamid e Ammon ium
acetate
18-48
Ammonia, etc. and Esters
 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
OEt + NH3
Ethyl p henylacetate
Ph
NH2 +
Phenylacetamide
Et OH
Ethanol
 Amides
do not react with ammonia or with 1° or
2° amines.
18-49
Acid Chlorides with Salts
 Acid
chlorides react with salts of carboxylic
acids to give anhydrides.
• Most commonly used are sodium or potassium salts.
O
O
+
CH3 CCl + N a - OC
Ace tyl
ch loride
S odiu m
be n zoate
O O
CH3 COC
+
N a+ Cl
-
Ace ti c be n z oic
an h ydride
18-50
Interconversions of Acid Derivatives
18-51
Grignard and an Ester.
Look for two kinds of reactions.
O
OMgX
O
O
R-Mg-X
R-Mg-X
R'
R'
Any
alcohol
will do
here.
OEt
OEt
R'
R
R'
R
R
R
Substitution
EtOH
R'COCl
But where does an ester
come from?
OH
Acid
chloride
R'
SOCl2
R'CO2H
R
R
Perhaps this carboxylic
acid comes from the
oxidation of a primary
alcohol or reaction of a
Grignard with CO2.
Addition
18-52
Grignard Reagents and Formic Esters
• Treating a formic ester with two moles of Grignard
reagent followed by hydrolysis in aqueous acid gives a
2° alcohol.
O
HCOCH3 + 2RMgX
An ester of
formic acid
OH
magnesium H O, HCl
2
alkoxide
HC-R + CH3 OH
salt
R
A 2° alcohol
18-53
Reactions with RLi
 Organolithium
compounds are even more
powerful nucleophiles than Grignard reagents.
O
RCOCH3
1 . 2 R' Li
2 . H2 O, HCl
OH
R- C-R' + CH3 OH
R'
18-54
Gilman Reagents
 Acid
chlorides at -78°C react with Gilman
reagents to give ketones.
O
O
1 . ( CH3 ) 2 CuLi, eth er, -78°C
Cl 2 . H O
2
Pe n tan oyl ch l ori de
2-H exan on e
Gilman Reagents do not react with acid
anhydrides, esters, amides or nitriles under these
conditions. Selective reaction.
18-55
Synthesis: Reduction - Esters by LiAlH4
 Most
reductions of carbonyl compounds use
hydride reducing agents.
• Esters are reduced by LiAlH4 to two alcohols.
• The alcohol derived from the carbonyl group is
primary.
O
Ph
OCH3
Me th yl 2-ph en yl propan oate
(race mic)
1 . LiA lH4 , e t he r
2 . H2 O, HCl
Ph
OH + CH3 OH
2-Ph e n yl-1propan ol
(race mic)
Me th an ol
18-56
Mechanism: Reduction - Esters by LiAlH4
 Reduction
occurs in three steps plus workup:
• Steps 1 and 2 reduce the ester to an aldehyde.
O
R C OR' +
H
(1)
O
R C OR'
(2)
O
R C
H
+
OR'
H
A tetrahedral carbonyl
addition intermediate
• Step 3: Work-up gives a 1° alcohol derived from the
carbonyl group.
O
R C
H
+ H
(3)
O
R C H
H
OH
(4)
R C H
H
A 1° alcohol
18-57
Synthesis: Selective Reduction by NaBH4
 NaBH4
reduces aldehydes and ketones. It does
not normally reduce esters. LiAlH4 reduces all.
 Selective reduction is often possible by the
proper choice of reducing agents and
experimental conditions.
O
O
OEt
NaBH4
OH O
EtOH
OEt
(racemic)
18-58
Synthesis: Reduction - Esters by DIBAlH -> Aldehyde
 Diisobutylaluminum
hydride (DIBAlH) at -78°C
selectively reduces an ester to an aldehyde.
• At -78°C, the TCAI does not collapse and it is not until
hydrolysis in aqueous acid that the carbonyl group of
the aldehyde is liberated.
O
1 . DIBALH , toluen e, -78°C
OCH3
2 . H2 O, HCl
Me th yl h e xan oate
O
H + CH3 OH
He xan al
18-59
Synthesis: Reduction - Amides by LiAlH4
 LiAlH4
reduction of an amide gives a 1°, 2°, or 3°
amine, depending on the degree of substitution
of the amide.
O
1 . LiAlH4
NH2 2 . H O
2
Octanamide
NH2
1-Octanamine
O
NMe2 1 . LiAlH4
2 . H2 O
N,N -D imethylben zamide
NMe2
N ,N-D imeth ylb enzylamine
18-60
Synthesis: Reduction - Nitriles by LiAlH4
 The
cyano group of a nitrile is reduced by LiAlH4
to a 1° amine.
1 . LiA lH4
CH3 CH= CH( CH 2 ) 4 C N
2 . H2 O
6-O cte n en i tri le
CH3 CH= CH ( CH2 ) 4 CH2 N H2
6-O cte n -1-am in e
Can use catalytic hydrogenation also.
18-61
Interconversions
Problem: Show reagents and experimental conditions to
bring about each reaction.
O
Ph
Cl
(a)
(b )
O
Ph
OH
Ph enylacetic
acid
O
O
(d )
Ph
(c)
(e)
Ph
OMe
(g)
(f)
Ph
OH
NH2
(h )
Ph
NH2
18-62