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Chapter 15: Carboxylic Acids and Their Derivatives and 21.3 B, C/21.5 A
“Acyl-Transfer Reactions”
I. Introduction
R
Z
O
an acyl group bonded to
an electronegative atom (Z)
R O
O
R, R', R": alkyl, alkenyl, alkynyl,
or aryl group
H
Examples:
R X
O
X = halogen
R O
O
R S
O
R N
O
R O
O
R F
O
R Cl
O
R Br
O
R I
O
carboxylic acid
R'
R'
R"
R'
R'
O
acid halide*
acid anhydride
ester
thioester
amide
note: R could be "H"
one of or both of R' and R"
could be "H"
* acid halides
acid fluoride acid chloride acid bromide
acid iodide
R
Z
O
sp
2
hybridized; trigonal planar making it relatively " uncrowded "
The electronegative O atom polarizes the C=O group, making the C=O carbon
" electrophilic ."
Resonance contribution by Z
R
C
Z
O
R
C
Z
O
R
C
Z
O
The basicity and size of Z determine
how much this resonance structure
contributes to the hybrid.
R
C
Z
O
δ
δ
hybrid
structure
* The more basic Z is, the more it donates its electron pair,
and the more resonance structure * contributes to the hybrid.
Trends in basicity:
Cl
O
O R'
OH OR' NR'R"
similar basicity
weakest
base
strongest
base
increasing basiciy
Check the pKa values of the conjugate acids of these bases.
O
R
H
3
C OH
O
H
3
C
O
H
3
C O
O
H
3
C O
O
H
3
C NH
2
O
CH
3
O
H
3
C Cl
O
- The group obtained from a carboxylic acid
by the removal of the OH is called an acyl group, i.e.,
acetyl group;
often abbreviated as Ac
2
C=O derivatives [IUPAC names in parentheses]
H
3
C O Na
O
C
H
2
CH
3
ethyl acetate
(ethyl ethanoate)
acetic acid
(ethanoic acid)
sodium acetate
(sodium ethanoate)
acetamide
(ethanamide)
acetyl chloride
(ethanoyl chloride)
acetic anhydride
(ethanoic anhydride)
C
N
cyano group: considered to be an acid derivative as it can be hydrolyzed to form
an amide and carboxylic acid
H
3
C C N
The suffix - nitrile is added to the name of the hydrocarbon containing the same number
of carbon atoms, including the carbon atom of the CN group.
acetonitrile [IUPAC name: ethanenitrile]
C N
H
3
C-CH
2
- CH
2
- CH
2
- C
5 4 3
2 1
benzonitrile
[IUPAC name]
pentanenitrile
[IUPAC name]
For example,
e.g.,
N
Relative stabilities of carboxylic acid derivatives against nucleophiles
O
R Z
As the basicity of Z increases, the stability of increases because of
added resonance stabilization.
O
R
Z
R
Cl
O
R
OR'
O
R
OH
O
R
NR'R"
O
R
O
O
R O
O
R'
O
acid halide
acid
anhydride
ester carboxylic
acid
amide
carboxylate
less stable
(i.e., more reactive)
toward
nucleophiles
Relative stabilities of
's against nucleophiles
A few naming issues
C
6
H
5
O
benzoyl group;
often abbreviated as Bz
[abbreviated as Ac
2
O]
most stable
(i.e., least reactive)
toward
nucleophiles
III. Synthesis of Carboxylic Acids
(1) With the same number of carbon atoms as the starting material:
R
OH
H H
a.
1 °-alcohol
R
H
O
R
OH
O
aldehyde carboxylic acid
oxidation
oxidation
e.g., pyridinium chloro-
chromate (PCC)
or Swern method
e.g., Jones' reagent
[CrO
3
, H
2
SO
4
, H
2
O, acetone]
*A potential byproduct in the Jones oxidation of a
primary alcohol:
R
O
O
CH
2
- R
(ester)
R
H
O
R
O
O
sodium
carboxylate
aldehyde
b.
Ag
2
O, NaOH, H
2
O
(Tollens reagent)
R
OH
O
carboxylic acid
Na
H
3
O
(to pH ~ 2 )
Selective for aldehyde!
R
H
O
OH
R
H
O
OH
Ag O Ag
R
H
O
OH
Ag
OH
Ag
0
(silver mirror)
H
O
H H
H
H-O
H
Ag
2
O, NaOH, H
2
O
(Tollens reagent)
H
3
O
(to pH ~ 2 )
O-H
O
H H
H
H-O
H
An example of the selective oxidation of an aldehyde group:
(2) Fewer carbon atoms than the starting material:
1. O
3
- oxidative work-up
(e.g., Ag
2
O, HO
then H
3
O
O
OH
O
OH
(3) One more carbon atom than the starting material:
a. Use of organometallic reagents
Br
MgBr
δ
δ
Mg
C
O
O
O
C
MgBr
O
O
C
O-H
H
3
O
(to pH ~ 2 )
III Synthesis of carboxylic acid (continued)
( 3 ) b. By an S
N
2 reaction with C N, followed by hydrolysis
Cl
benzyl chloride
C
N
phenylacetonitrile
Na C N
ethanol
NH
2
O
phenylacetamide
H
2
O, HCl
OH
O
H
2
O, H
2
SO
4
, 100 °C
(NH
4
2
SO
4
phenylacetic acid
or directly with
H
2
O, H
2
SO
4
, 100 °C
C N
Mechanism for the acid-catalyzed hydrolysis of nitriles:
R
δ δ
H
O
H
H
R C N H
H
O
H
H O
H
pKa ~ - 10
R
C
N
H
O
H H
H
O
H
R
C
N
H
O
H
H
O
H
H
R
C
N
H
H O
H
R
C
N
H
O
H
H
R
C
NH
2
O
amide
nitrile
R
C
N
H
O
H
H
H O
H
O
R C NH
2
O
H
H
H
O
R C N
O
H
H
O
R C NH
3
O
H
H
From an amide:
H O
H
H
H
H
O
H
H
R C
O
O H
H
R C
O
O H
H
O
H
amide
carboxylic
acid
Note:
Nitriles can be hydrolyzed to the corresponding carboxylates under strongly basic conditions (e.g., NaOH,
H
2
O, Δ). Mechanism? Avoid the formation of a RR’N
species.
V. Esterification
(1) Esterification reactions
H
3
C OH
O
acetic acid
H
3
C-CH
2
- O-H
ethanol
H
H
3
C O
CH
2
CH
3
O
H
2
O
ethyl acetate
The experimental equilibrium constant for the reaction above is:
[ethyl acetate] x [H
O]
[acetic acid] x [ethanol]
K
eq
= = 3. 38
As in any equilibrium processes, the reaction may be driven in one direction by adjusting the
concentration of one of the either the reactants or products (Le Châtelier’s principle).
Equilibrium compositions
H
3
C OH
O
H
3
C-CH
2
- O-H
H
H
3
C O
CH
2
CH
3
O
H
2
O
i) at start: 1.0 1.0 0 0
at equilibrium 0.35 0.35 0.65 0.65_
ii) at start 1.0 10.0 0 0
at equilibrium 0.03 9.03 0.97 0.97_
iii) at start 1.0 100.0 0 0
at equilibrium 0.007 99.007 0.993 0.
_____________________________________________________________________________
Taken from “ Introduction to Organic Chemistry”; 4
th
Ed.; Streitweiser, A. et al.; Macmillan Publ.: New York, 1992.
(2) The mechanism for the acid-catalyzed esterification [Commonly referred to as the Fischer
esterification: see pp 623-624 of the textbook].
H
3
C
O
H
3
C-CH
2
18
O-H
H
H
3
C
18
O
CH
2
CH
3
O
H
2
O
Suggesting H
3
C- CH
2
18
OH
not cleaved in this reaction.
H
3
C
O
CH
3
HO
H
optically active
CH
3
O
H
optically active
H
H
3
C
O
H
2
O
this bond
not cleaved this bond
not cleaved
Also,
OH
OH
i) Overall, the Fischer esterification consitutes an acyl transfer from
an OH to an OR' group.
H
3
C
OH
O
H
3
C
O R
O
H
H - OR
ii) Esterification of a carboxylic acid can't take place in the presence of base.
Base deprotonates the carboxylic acid, forming a carboxylate anion, thus preventing
a nucleophile (i.e., ROH) from attacking the carbonyl carbon.
V. Esterification (cont’d)
Mechanism for the acid-catalyzed esterification
H
3
C O
O
H
H B
H
3
C O
O
H
S
O
O
O O
H
H
H
H
3
C O
O
H
H
resonance stabilized
C
2
H
5
- OH
H C
3
C O
O
O
H
H
5
C
2
H
H C
3
C O
O
O
H
H
5
C
2
H
tetrahedral, sp
3
intermediate
H
ester hydrate
H C
3
C O
O
O
H
H
5
C
2
H
H
H
3
C O
O
C
2
H
5
+ H
2
O
H
3
C O
O
C
2
H
5
ester [ethyl acetate]
acid [acetic acid]
H
alcohol
H
2
SO
4
C
2
H
5
OH
(acid catalyst)
pK
a
C
2
H
5
- O- H
H
pK
a
H
3
C O
O
H
H
pK
a
note:
H
3
C OH
O
acetic acid
H
3
C-CH
2
- O-H
ethanol
H
H
3
C O
CH
2
CH
3
O
H
2
O
ethyl acetate
Use H-B for the Brφnsted acid.
B
H B
B
lone pair-
assisted
ionization!
Notes: i) The acid-catalyzed esterification reaction is reversible. The reverse reaction from an ester with
an acid and water is the acid-catalyzed hydrolsis of an ester to form the corresponding acid and alcohol.
ii) The C=O lone pairs are more “basic” than those of the ether oxygen of an ester (i.e., - OR).
H
3
C O
O
H
H
3
C O
O
H
H
3
C O
O
H
H
H
3
C O
O
H
H H
H B
H B
no resonance stabi-
lization of the charge
"more
basic"
The charge stabilized by the two
identical resonance contributors.
X
H
3
C O
O
H
H
C
2
H
5
- OH
H
3
C
O
O
H
H
C
2
H
5
- O
H
δ+
δ+
iii) Direct S
N
2 - like substitution not possible at an sp
2
center
Not feasible
Chapter 15: Carboxylic Acids and Their Derivatives.
VI. Ester Formation: Some of Other Commonly Used Methods
(1) From carboxylic acids
a. With diazomethane
O H
O
benzoic acid
H
2
C N N
HOCH
3
(solvent)
O CH
3
O
H
2
C N N
O
O
H
3
C N N
N N
(gas)
ester [methyl benzoate]
(diazomethane)
S
N
b. With base and reactive alkyl iodide [usually CH
3
I or CH
3
CH
2
I] or sulfate [usually
(CH
3
)
2
SO
4
(dimethyl sulfate) or CH
3
CH
2
SO
4
(diethyl sulfate)]
OH
HO
HO
O
O
H
H
H
H H
OH
HO
HO
O
O
H
H
H H
OH
HO
HO
O
O
CH
3
H
H
H H
CH
3
I
NaHCO
3
(weak base)
DMA* (solvent)
N , N - dimethylacetamide: polar aprotic solvent that can dissolve NaHCO
3
Na
H
3
C I
NaI
S
N
N(CH
3
2
O
O
H
O
N
O
O
O S O
O
O
(diethyl sulfate)
N , N - dimethylformamide: polar aprotic solvent that can dissolve Na
2
CO
3
Na
2
CO
3
(weak base)
DMF* (solvent)
O
CH
2
CH
3
O
N
O
O
H N(CH
3
2
O
(2) With Acid Anhydrides and Acid Chlorides from Alcohols
OH
H
3
CO
O
H
3
CO
CH
3
O
H
3
C O CH
3
O O
[Ac
2
O]
[acetic anhydride]
N
[pyridine: solvent]
OAc
H
3
CO
or
Ac=acetyl
CH
3
O
The reaction mechanism involves
the initial formation of
N
CH
3
O
VII. Lactone Formation
Lactone : A cyclic ester; usually formed from a carboxylic acid and hydroxyl groups in the
same molecule, by an intramolecular reaction.
O
OH
O
H
H
2
O
H
Five- and six-membered lactones are often more stable than their corresponding open-chain hydroxy acids.
Lactones that are not energetically favored may be synthesized from hydroxy acids by
driving the equilibrium toward the products by continuous removal of the resulting water.
OH
O
O
H
2
O
9 - hydroxynonanoic acid
9 - hydroxynonanoic
acid lactone
p - TsOH (catalytic)
benzene
(reflux)
(continuously
removed by using
a Dean Stark
apparatus)
H
The mechanism for the formation of lactones from their hydroxy acid precursors follows
exactly the same pathway as in the (intermolecular) esterification reaction.
VIII. Transesterification
Transfer of an acyl group from one alcohol to another. A convenient method for the
synthesis of complex esters starting from simple esters.
R
O
R'
R
O
R"
O O
R"OH, acid or base catalyst
R'OH, acid or base catalyst
acid-catalyzed:
O
CH
3
O
O
HO-CH
3
p - TsOH (catalytic)
H
base-catalyzed:
(CH
2
16
CH
3
(CH
2
16
CH
3
(CH
2
16
CH
3
O
O
O
H
3
C
O (CH
2
16
CH
3
O
NaOCH
3
(catalytic)*
HOCH
3
(excess)
tristearin (a fat)
H
H
H
glycerol
*Speculate as to why only a catalytic amount of NaOCH
3
is needed here.
The mechanism for the transesterification process involves steps almost identical to those given acid-
catalyzed and base-catalyzed ester hydrolysis. However, the major difference is not using water in the
transesterification reaction.
VIII. Acylation of ammonia and Amines: Synthesis of Amides
Acylation of amines: a. With acid anhydrides (cont’d)
- Selective reaction on an amino group over a hydroxyl group
OH
NH
2
H
3
C O CH
3
O O
OH
H
N
CH
3
O
O CH
3
O
(acetic anhydride)
OH
NH
3
Note stoichiometry between an amine and acid anhydride (explanation on this in section VIII b below).
Also, even if excess acetic anhydride is used, only the amide product can be obtained selectively.
Acetylation of a hydroxyl group with an acid anhydride is quite slow at room temperature. However,
when the reaction is carried out in the presence of pyridine, both NH
2
and OH get acetylated.
OH
NH
2
H
3
C O CH
3
O O
O
H
N
CH
3
O
O CH
3
O
(acetic anhydride)
N
(pyridine)
CH
3
O
N
H
b. With acid chlorides: highly reactive with amines: Treatment of a 1°- or 2°-amine with
an acid halide results in the rapid formation of its amide derivative. However, because of
the extreme acidity of the N
- H in the initially produced amide-like product, at least two
mol. equivalents of an amine are required (see the mechanism shown below).
Cl
O
HN(CH
3
2
N
O
H
2
N(CH
3
2
CH
3
CH
3
Cl
Mechanism:
Cl
O
HN(CH
3
2
Cl
O
N
H
3
C CH
3
H
O
N
H
3
C CH
3
H
HN(CH
3
2
N
O
H
2
N(CH
3
2
CH
3
CH
3
Cl
Cl
extremely acidic!
Alternatively, with the use of an appropriate base (usually a tertiary amine), an amide can
be prepared in high yield with only one mol. equivalent of a 1°- or 2°-amine.
Cl
O
HN(CH
3
2
N
O
HN(CH
2
CH
3
3
CH
3
CH
3
Cl
N(CH
2
CH
3
3
N(CH
2
CH
3
3
O
Note: Even if a tertiary amine reacts with an acid halide,
the resulting quaternary amine product undergoes reaction
with a halide anion to recover the original acid halide.
Cl
VIII. Acylation of ammonia and Amines: Synthesis of Amides (cont’d)
c. With esters and lactones
Esters and lactones easily react with 1° or 2°-amines to form amides and alcohols, often
referred to as aminolysis; ammonolysis when ammonia (NH
3
) is used.
OCH
2
CH
3
O
NH
2
CH
3
N
H
CH
3
O
HOCH
2
CH
3
OCH
2
CH
3
O
NH
2
CH
3
OCH
2
CH
3
O
N
H
H
CH
3
OCH
2
CH
3
N
CH
3
O
H
H
N
H
CH
3
O
HOCH
2
CH
3
Mehanism:
Unlike the reaction of an acid chloride and an amine that requires two equivalents of amine, the aminolysis
of an ester or lactone requires only one equivalent of amine. This is because the more basic alcoxide
generated picks up the H+ generated in the reaction intermediate (see above).
More examples:
Cl
OCH
2
CH
3
O
Cl
NH
2
O
HOCH
2
CH
3
NH
3
H
2
O
In the example shown above, the low reaction temperature as well as short reaction time are necessary in
order to avoid the S
N
2 reaction at the C-Cl site.
N
O
O
O
Br
O
O
NH
3
(CH
3
3
COH/THF
(solvent)
0 °C
N
O
O
O
Br
OH
O
NH
2
One of the key steps used in the synthesis of
Tamiflu.
d. With carboxylic acids
An amide can also be prepared directly from a carboxylic acid and a 1°- or 2°-amine. However, the
reaction mixture needs to be heated at high temperatures in order to form an amide bond from the initially
formed ammonium carboxylate salt.
Ph OH
O
H
2
NPh
Ph O
O
H
3
NPh
Ph NHPh
O
H
2
O
225 °C!
225 °C!
IX. Reactions of Carboxylic Acid Derivatives
(1) Reduction with hydride reagents: (ii) LiAlH
4
reduction of amides
mechanism :
R NR'R"
O
amide
Li
Al
H
H
H
H
R NR'R"
O
H
H Al
H
H
Li
R N
H
Li
Al
H
H
H
O
Li
Al
H
H
H
Y
R NR'R"
H H
R NR'R"
H H
H
2
O
workup
+ 2 H
2
3
R
N
R"
O
R'
R
N
R"
H
R'
H
- LiAlH
4
- aqueous
workup
amine!
R'
R"
Li
Unlike an OR group, the N of an NR'R" group is basic and nucleophilic.
Thus, it donates its lone-pair electrons to kick out Al-O- species.
(2) Reactions with Organometallic Reagents: Grignard Reagents
Ph OCH
3
O
+ 2 CH
3
MgBr
THF
(solvent)
(usually with saturated
aqueous NH
4
Cl)
aqueus workup
Ph OH
H
3
C
CH
3
HOCH
3
2 Mg(OH)
2
2 Br
Ph OCH
3
O
+ CH
3
MgBr
THF
(solvent)
(usually with saturated
aqueous NH
4
Cl)
aqueus workup
Ph OH
H
3
C
CH
3
HOCH
3
Mg(OH)
2
Br
(i) esters
Ph OCH
3
O
ca. 1 : 1
virtually no
Ph CH
3
O
(acetophenone)
obtainable.
Ph OCH
3
O
Ph OCH
3
H
3
C
MgBr
δ
δ
H
3
C
O MgBr
Ph
H
3
C
O
H
3
C MgBr
Mechanistic interpretation:
Ph OH
H
3
C
CH
3
Ph
CH
3
H
3
C
O MgBr
slow fast fast
aqueous
work-up
ketone C=O carbon :
far more electrophilic
than ester C=O carbon
*As soon as a small amount of an ester
reacts with the Grignard reagent, the adduct
immediately produces a ketone, which
reacts quite rapidly with the Grignard reagent
in solution, thus not accumulating the ketone
product.
H
3
CO MgBr
IX. Reactions of Carboxylic Acid Derivatives : (2) Reactions with Organometallic Reagents
(ii) Reaction with carboxylic acids: Grignard reagents react to form carboxylate salts and
the resulting salts do not undergo a further reaction with the Grignard reagents at room
temperature.
δ δ
Ph O
H
O
H
3
C MgBr
Ph O
O
MgBr
CH
4
C=O C too non-electrophilic to reaction with an additional equivalent of a
Grignard reagent
H
3
C MgBr
x
In contrast, more nucleophilic organolithium reagents can add to the intially produced lithium salt.
δ δ
Ph O
H
O
H
3
C Li
Ph O
O
Li
CH
4
Ph O
H
O
2 H
3
C-Li
Ph
OLi
OLi
CH
3
CH
4
acidic workup
(pH 1 - 2 )
Ph O
CH
3
H
2
O 2 LiOH
mechanism :
δ δ
H
3
C Li
Ph
OLi
OLi
CH
3
Ph
OH
OH
CH
3
Ph O
CH
3
reaction
end-product
H
3
O
Ph
OH
O
H
3
C
H
H
Ph O
CH
3
H
OH
2
ketone
carboxylic
acid
(iii) Reactions with amides: In general, amides are not quite reactive with most
organometallic reagents (RM), but under forcing conditions, they react similarly as esters.
N - Methoxy- N - methylamides (Weinreb amides) : special class of amides that react with most
RMs and the initially formed addition products exist as stable chelate, thus affording ketones upon acid
hydrolysis.
Ph N
O
CH
3
O
CH
3
N - methoxy- N - methylamide
H
3
C MgBr
Ph N
O
CH
3
O
CH
3
H
3
C
Mg
Br
5 - membered, stable chelate;
does not fragment to a C=O species
acidic workup
(pH 1 - 2 )
Ph O
CH
3
N
O
CH
3
CH
3
H
H
Ph N
O
CH
3
O
CH
3
H
3
C
Mg
Br
Ph N
O
CH
3
OH
CH
3
H
3
C
O H
H
H
Ph N
O
CH
3
OH
CH
3
H
3
C
H
O H
H
H
N
O
CH
3
CH
3
H
Ph O
CH
3
H
OH
2
O H
H
H
Ph O
CH
3
N
O
CH
3
CH
3
H
H
mechanism for the hydrolysis :
Note: Even if excess RM reagents are used, the chelated adduct does not react further with the reagent.
This is an extremely convenient method for the synthesis of ketones from carboxylic acids (via Weinreb
amides).
