Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 1 of 17.
Date: October 5, 2012
Chapter 15: Carboxylic Acids and Their Derivatives and 21.3 B, C/21.5 A
“Acyl-Transfer Reactions”
I. Introduction
Examples: note: R could be "H"
R
Z
R
O H
R
carboxylic acid
O
O
R'
ester
O
O
an acyl group bonded to
an electronegative atom (Z)
R
X
R
acid halide*
R
O
R
R'
O
O
R
Cl
O
O
Z
O
Br
R
amide
R"
acid anhydride
I
O
acid fluoride acid chloride
R
R'
N
one of or both of R' and R"
could be "H"
R
F
thioester
O
* acid halides
R
R'
O
O X = halogen
R, R', R": alkyl, alkenyl, alkynyl,
or aryl group
S
O
acid bromide
acid iodide
sp2 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
O
Z
R
Z
R
C
O
δ
R
Z
Z
C
C
O
δ
O
hybrid
structure
The basicity and size of Z determine
how much this resonance structure
contributes to the hybrid.
* The more basic Z is, the more it donates its electron pair,
and the more resonance structure * contributes to the hybrid.
similar basicity
Cl
R'
O
OH
OR'
NR'R"
O
Trends in basicity:
weakest
base
increasing basiciy
strongest
base
Check the pKa values of the conjugate acids of these bases.
Chem 215 F12 Notes Notes –Dr. Masato Koreeda - Page 2 of 17.
Date: October 5, 2012
Relative stabilities of carboxylic acid derivatives against nucleophiles
As the basicity of Z increases, the stability of
added resonance stabilization.
less stable
(i.e., more reactive)
toward
nucleophiles
R
Cl
R
O
Z
increases because of
O
R'
O
O
acid halide
R
O
R
acid
anhydride
OR'
R
O
O
ester
OH
R
carboxylic
acid
NR'R"
R
O
O
O
amide
carboxylate
Relative stabilities of
R
Z
O
most stable
(i.e., least reactive)
toward
nucleophiles
's against nucleophiles
A few naming issues
R
• The group obtained from a carboxylic acid
an acyl group, i.e.,
by the removal of the OH is called
H3C
e.g.,
acetyl group;
often abbreviated as Ac
O
O
C6H5
benzoyl group;
often abbreviated as Bz
O
• Names of the C2 C=O derivatives [IUPAC names in parentheses]
H 3C
OH
H 3C
acetic acid
(ethanoic acid)
O
O
H 3C
Cl
O
acetamide
(ethanamide)
H3C
sodium acetate
(sodium ethanoate)
O
NH2
H 3C
O Na
acetyl chloride
(ethanoyl chloride)
O
O
CH3
C
H2
ethyl acetate
(ethyl ethanoate)
H3C
O
O
CH3
O
acetic anhydride
(ethanoic anhydride)
[abbreviated as Ac2O]
•
C
N
H 3C C N
cyano group: considered to be an acid derivative as it can be hydrolyzed to form
an amide and carboxylic acid
acetonitrile [IUPAC name: ethanenitrile]
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.
For example,
5 4
3
2
1
H3C-CH2-CH2-CH2-C N
pentanenitrile
[IUPAC name]
C N
benzonitrile
[IUPAC name]
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 3 of 17.
Date: October 5, 2012
II. Acyl-transfer Reactions – Acylation Reactions
"acylating" agent
O
R C
Z
R C
Nucleophilic attack
Z
Nu
Nu
Overall,
For this reaction to occur, Z must
be a better leaving group than Nu.
O
O
R C Nu
Two possible leaving groups
"The acyl group, R-C(=O)-, has been transferred from Z to Nu."
Leaving group ability and pKa values of the conjugate acids of leaving groups
The better the leaving group, the more reactive R C Z is in nucleophilic acyl substitution.
O
Cl
>
O C R'
>>
OR, OH
O
>>
NH2
better leaving group
Compare pKa values of the conjugate acids of these leaving groups:
H-Cl (pKa -6); H-O(O=C)-R' (pKa ~ 4.7);
H-OH (pKa 15.7)H-OR (pKa 16-19); H-NH2 (pKa 35)
Acyl-transfer reactions of carboxylic acid derivatives
Most reactive!
O
O
HO
O
SOCl2
O
or
Cl
Na
O
O
O
O
SCH2CH3
O
NaSCH2CH3
or HSCH2CH3
O
OH
OCH2CH3
H3O+
Represents an acylation
reaction of H2O.
CH3CH2OH/base
or CH3CH2ONa
CH3NH2
(2 or more mol.
equiv.*)
*2nd mol equiv needed to do
O
CH3NH2
(1 mol. equiv.)
O
N
H
N
H3C
N
O
O
H
H
CH3
[can be prepated from any of the above
by treatment with OH]
H
CH3
H
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 4 of 17.
Date: October 5, 2012
III. Synthesis of Carboxylic Acids
(1) With the same number of carbon atoms as the starting material:
H H
a.
R
H
oxidation
OH
R
e.g., pyridinium chlorochromate (PCC)
or Swern method
1°-alcohol
OH
oxidation
R
O
aldehyde
O
carboxylic acid
e.g., Jones' reagent
[CrO3, H2SO4, H2O, acetone]
*A potential byproduct in the Jones oxidation of a
primary alcohol:
O CH2-R
R
Ag2O, NaOH, H2O
(Tollens reagent)
H
b.
R
R
O
aldehyde
H3O+
(to pH ~2)
Na
O
R
R
H
OH
R
O
OH
H
OH
O
Ag O Ag
O
carboxylic acid
Ag0
(silver mirror)
H
(ester)
OH
O
sodium
carboxylate
Selective for aldehyde!
O
R
OH
O
Ag
An example of the selective oxidation of an aldehyde group:
H
H O
Ag2O, NaOH, H2O
(Tollens reagent)
H
H
H-O
H
H3 O+
(to pH ~2)
H O
O-H
H
H-O
H
H
(2) Fewer carbon atoms than the starting material:
OH
1. O3
O
2. oxidative work-up
(e.g., Ag2O, HOthen H3O+)
OH
+
O
(3) One more carbon atom than the starting material:
a. Use of
organometallic reagents
Br
Mg
O MgBr
δ
MgBr
C
δ
O
C
O
O
O-H
H3O+
(to pH ~2)
C
O
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 5 of 17.
Date: October 5, 2012
III Synthesis of carboxylic acid (continued)
(3) b. By an SN2 reaction with C N , followed by hydrolysis
Cl
C
Na
C
N
ethanol
phenylacetonitrile
N
or directly with
H2O, H2SO4, 100 °C
benzyl chloride
H2O, HCl
NH2
OH
O
(NH4)2SO4
+
O
H2O, H2SO4, 100 °C
phenylacetic acid
phenylacetamide
Mechanism for the acid-catalyzed hydrolysis of nitriles:
H
H O
H
δ
R C
δ
N
H
O
H
R
pKa ~ -10
R C
nitrile
H
N H
C
O
N
H
H
H
O
H
H
R
C
O
NH2
H
O
H
amide
R
H
C
H
N
O
C
R
H
O
C
H
N
H
H
R
H O
H
From an amide:
H
H O
R
H
H
N
H
H O
N
H
H
H
H
H
C
O
O
O
H
O
R C NH2
H
H
O
H
O
R C N H
H
H O
H O
R C
R C
carboxylic
acid
NH3
H O
O H
amide
H
O H
R C
O
O
H
H
O H
Note:
Nitriles can be hydrolyzed to the corresponding carboxylates under strongly basic conditions (e.g., NaOH,
-
H2O, Δ). Mechanism? Avoid the formation of a RR’N species.
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 6 of 17.
Date: October 5, 2012
III Synthesis of Carboxylic Acids (cont’d)
Hydrolysis of nitriles under basic conditions: Under milder basic conditions, an amide is obtained.
Mechanism for the base-catalyzed hydrolysis of nitriles:
H O
R C
H
N
*H
H O
O
H
C N
R
nitrile
H O
O
H
H
H
H O
O
H
H
O
R
O
O
C N
H
N
C
R
O
R
H
C N
O
*
R C
N
H
R C N
Alternatively,
H O
H
H
O
H
H
O
H
H
R
H
O
H O
C
O
H
H
**
R
O
C
R
NH2
O
amide
H
C
carboxylate
* This is to avoid the generation of highly unfavorable R-NH species. The pKa of R-NH2 is at ~35.
**
This N is stabilized by resonance with C=O, thus allowable! The pKa of an amide H is at ~12.
IV. Synthesis of Acid Chlorides and Acid Anhydrides
(1) Acid Chlorides: highly electrophilic C=O carbons; react with even weak nucleophiles such as
ROH; need to be prepared under anhydrous conditions. Prepared from carboxylic acids.
O
O
a.With SOCl2:
Δ
+ SOCl
+ SO
+ HCl
(more common)
H3C
2
OH
mechanism:
R
O
O
S
O
H3C
Cl
OH
Cl
OH Cl
R
b. With PCl3:
O
3
H3C
OH
R
Cl
Δ
+ PCl3
S
O
Cl
O
Cl
R
OH
2
Cl
O
S
O
(gas)
O
S
Cl
OH
(gas)
-SO2
-Cl
O
R
Cl
3
H3C
O
+
H
Cl -HCl
Cl
O
R
Cl
H3PO3
Cl
(2) Acid Anhydrides
O
2
H3C
O
Δ
OH
H3C
O
OH
+
O
CH3
H2O
bp higher than H2O
O
2 H3C (H2C)10
O
+
high
temperatures
(800 °C)
H3C
O
O
Δ
CH3
O
removed by
heating at ~100 °C
O
H3C (H2C)10
O
H3C (H2C)10
O
mp 42 °C
An "acyl transfer reaction" at C=O carbons via intermediate
(decanoic
anhydride)
O
H3C
R-COOH becomes highly acidic upon
O
heating at hight emperatures, thus
H3C (H2C)10
(mixed anhydride)
catalyzes anhydride formation by
O
protonating the C=Os.
O
2
H3C
OH
bp 118 °C
(can be selectively distilled
off from the mixture)
+
O
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 7 of 17.
Date: October 5, 2012
V. Esterification
(1) Esterification reactions
O
H3C
OH
H3C-CH2-O-H
+
O
H+
H3C
Δ
ethanol
acetic acid
O
CH2CH3
+
H2O
ethyl acetate
The experimental equilibrium constant for the reaction above is:
Keq =
[ethyl acetate] x [H2O]
[acetic acid] x [ethanol]
= 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
O
H3C
OH
H3C-CH2-O-H
+
O
H+
H3C
Δ
O
CH2CH3
+
H2O
____________________________________________________________________________________________________________________
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
0.993
_____________________________________________________________________________
Taken from “ Introduction to Organic Chemistry”; 4th 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].
O
H3C
OH +
H3C-CH2-18O-H
O
H+
H 3C
Δ
not cleaved in this reaction.
Suggesting H3C- CH2 ---18OH
Also,
this bond
not cleaved
O
H 3C
OH
+
CH2CH3 + H2O
18O
O
HO H
CH3
H+
H3C
this bond
not cleaved
O H
CH3
optically active
Δ
optically active
+
H2O
i) Overall, the Fischer esterification consitutes an acyl transfer from
an OH to an OR' group.
O
H3C
O
H - OR
OH
H+
H3C
O R
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.
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 8 of 17.
Date: October 5, 2012
V. Esterification (cont’d)
Mechanism for the acid-catalyzed esterification
O
H3C
+
OH
O
H+
H3C-CH2-O-H
H3C
Δ
ethanol
acetic acid
CH2CH3
O
+
ethyl acetate
resonance stabilized
alcohol
H B
O
H3C
O
C2H5OH
O H
H3C
H2SO4
(acid catalyst)
acid [acetic acid]
note:
O
H3C
O
O H
H3C
H
O H
H3C
H
H
O
O
pKa -9
O S O
H
O
H
C2H5-OH
Use H-B for the Brφnsted acid.
H
H2O
O
H3C C O H
O
H5C2
O
H3C C O H
O
H5C2
H
O C2H5
ester [ethyl acetate]
B
B
O
H
C2H5-O-H pKa - 2.4
H3C
H
O
O C2H5
+ H2O
H B
ester hydrate
H pKa -6
O H
tetrahedral, sp3
intermediate
lone pairassisted
H ionization!
H3C C
O
H5C2
H
O H
---------------------------------------------------------------------------------------------------------------------------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).
O
H3C
H
O
O
H
H3C
H
O H
"more
basic"
H B
O
O
H3C
The charge stabilized by the two
identical resonance contributors.
O
H
H B
iii) Direct SN2-like substitution not possible at an sp2 center
O
C2H5-OH
H3C
O H
H
H δ+
O
C2H5-O
H3C
δ+O H
H
X
H3C
O H
H
no resonance stabilization of the charge
Not feasible
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 9 of 17.
Date: October 5, 2012
VI. Ester Hydrolysis
As is mentioned on page 7 of this handout, the ester formation from carboxylic acid is reversible. As such,
treatment of an ester with water and a catalytic amount of an (strong) acid leads to the formation of the
corresponding acid and alcohol. This process is called hydrolysis.
1) Acid-catalyzed Hydrolysis of an Ester: usually requires stronger conditions (i.e., high temp.)
O
O
H3O+, Δ
CH2CH3
O
H
+
HO
CH2CH3
Mechanism for the hydrolysis of an ester under acidic conditions is virtually identical with that for the
esterification from an acid, but to the reverse direction.
H B
O
O
H
H
O
CH2CH3
CH2CH3
O
Use H-B for the Brφnsted acid.
B
H
HO
H
O
O
O
H
O
H
CH2CH3
H
O
H B
tetrahedral
intermediate
CH2CH3
good old
lone pair-assisted
ionization!
CH2CH3
H
B
H
H
O
H
H
O
O
CH2CH3
H
O
H
2) Base-catalyzed Hydrolysis of an Ester: under much milder conditions (i.e., usually at room temp).
Requires acidification of the reaction mixture (pH ~1-2) in order to isolate free carboxylic acid. Namely, a
step to protonate the carboxylate species is needed. Overall, the reaction is irreversible.
O
O
CH2CH3
1.NaOH, H2O
OH
2.H3O+ (pH ~1-2)
+
HO
CH2CH3
Mechanism:
O
O
CH2CH3
tetrahedral
intermediate
CH2CH3
O
CH2CH3
O H
or
O
OH
H
O
O
O
H
H
acidification to pH ~1-2
O
H
O
H
OH
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 10 of 17.
Date: October 5, 2012
Chapter 15: Carboxylic Acids and Their Derivatives.
VI. Ester Formation: Some of Other Commonly Used Methods
(1) From carboxylic acids
a. With diazomethane
(diazomethane)
H2C N N
O
O H
O
O CH3
HOCH3
(solvent)
benzoic acid
H2C N N
N N
(gas)
SN2!
O
H3C
O
ester [methyl benzoate]
N N
b. With base and reactive alkyl iodide [usually CH3I or CH3CH2I] or sulfate [usually
(CH3)2SO4 (dimethyl sulfate) or CH3CH2SO4 (diethyl sulfate)]
O
O H
H
HO
HO
H
CH3I
H
H
H
NaHCO3
(weak base)
DMA* (solvent)
H
H
O
O
O
I
O CH3
SN2!
H
Na
H
H
HO
HO
OH
*
H3C
O
HO
HO
OH
H
H
OH
91%
+ NaI
N,N-dimethylacetamide: polar aprotic solvent that can dissolve NaHCO3
N(CH3)2
-------------------------------------------------------------------------------------------------O
O
O
O S O
(diethyl sulfate)
O
Na2CO3 (weak base)
DMF* (solvent)
H
O
N
O
O
*
H
N(CH3)2
O
O
CH2CH3
O
N
O
88%
N,N-dimethylformamide: polar aprotic solvent that can dissolve Na2CO3
(2) With Acid Anhydrides and Acid Chlorides from Alcohols
O
H3CO
OH
H3C
O
O
[acetic anhydride]
[Ac2O]
H3CO
CH3
O
O
CH3
H3CO
[pyridine: solvent]
OAc
or
99%
N
The reaction mechanism involves
the initial formation of
Ac=acetyl
O
N
CH3
O
CH3
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 11 of 17.
Date: October 5, 2012
VII. Lactone Formation
Lactone: A cyclic ester; usually formed from a carboxylic acid and hydroxyl groups in the
same molecule, by an intramolecular reaction.
H
H
O
+
O
OH
27%
H2O
73%
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.
p-TsOH (catalytic)
H
+
benzene
(reflux)
O
H2O
(continuously
removed by using
a Dean Stark
apparatus)
O
95%
OH
9-hydroxynonanoic
acid lactone
9-hydroxynonanoic acid
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.
O
R
O
O
R"OH, acid or base catalyst
R'
R'OH, acid or base catalyst
R
O
R"
acid-catalyzed:
H
O
CH3
O
base-catalyzed:
(CH2)16CH3
O
(CH2)16CH3
O (CH ) CH
2 16
3
O
tristearin (a fat)
+
p-TsOH (catalytic)
Δ
NaOCH3
(catalytic)*
HOCH3
(excess)
HO-CH3
O
H
H
+
3 H3C
O
(CH2)16CH3
O
H
glycerol
*Speculate as to why only a catalytic amount of NaOCH3 is needed here.
The mechanism for the transesterification process involves steps almost identical to those given acidcatalyzed and base-catalyzed ester hydrolysis. However, the major difference is not using water in the
transesterification reaction.
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 12 of 17.
Date: October 5, 2012
VIII. Acylation of ammonia and Amines: Synthesis of Amides
Amides:
O
O
R
cf. 1715 cm-1
N
R'
R
N
CH3
R'
IR: νC=O ~1670 cm-1
R"
R"
An extremely significant
resonance contributor to
the structure of amides.
C
N
CH3
CH3
All atoms except for
the methyl hydrogens
are on the same plane.
O
H
ketone
O
1H
NMR: δ 2.98 ppm (singlet)
CH3
2.89 ppm (singlet)
This C-N bond almost like a double bond. does not
undergo free rotation at room temperature.
The planar nature of amide bonds is the basis of the conformational/helical structure of
proteins (more on this later in the term).
(1) Acylation of 1°- and 2°-amines
a. With acid anhydride
O
O
H3C
+
NH2
H3C
O
O
O
H3C
CH3
+
CH3
N
H
CH3
HO
acyl group transferred
from OC(=O)CH3 to ArNH
Mechanism:
O
O
H3C
H3C
O
O
CH3
H3C
NH2
H3C
O
O
O
CH3
*
N H
H
H
tetrahedral
intermediate
H3C
2
H3C
Not an SN2!!
O
H3C
O
O
CH3
H
O
*
*These two steps could be reversed in order.
X
NH
CH3
N
H3C
O
N
H
O
CH3 +
HO
CH3
or H-B
O
CH3
or
B
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 13 of 17.
Date: October 5, 2012
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
O
NH2
H3C
2
O
O
(acetic anhydride)
H
N
CH3
CH3
NH3
OH
OH
O
+
O
O
OH
CH3
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 NH2 and OH get acetylated.
O
2
NH2
H3C
O
O
H
N
(acetic anhydride)
CH3
CH3
O
O
OH
N
(pyridine)
O
+
2
N
H
CH3
O
CH3
O
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).
O
O
Cl
+
CH3
N
+
CH3
2 HN(CH3)2
H2N(CH3)2
Cl
Mechanism:
O
O
O
HN(CH3)2
O
Cl
Cl
N H
H3C CH3
N H
H3C CH3
HN(CH3)2
CH3
N
+
CH3
H2N(CH3)2
Cl
extremely acidic!
Cl
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.
O
O
Cl
+
HN(CH3)2
N(CH2CH3)3
CH3
N
+
CH3
HN(CH2CH3)3
Cl
O
N(CH2CH3)3
Cl
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.
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 14 of 17.
Date: October 5, 2012
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 (NH3) is used.
O
O
OCH2CH3
+
NH2CH3
N
H
CH3
+
HOCH2CH3
Mehanism:
O
O
O
OCH2CH3
OCH2CH3
H
NH2CH3
O
N
N H
H
CH3
N
H
H
CH3
+
CH3
OCH2CH3
HOCH2CH3
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:
(1)
O
Cl
OCH2CH3
+
NH3
O
H2O
Cl
-10 °C, 1 hr
+
NH2
HOCH2CH3
In the example shown above, the low reaction temperature as well as short reaction time are necessary in
order to avoid the SN2 reaction at the C-Cl site.
(2)
O
O
O
Br
O
Br
N
NH3
0 °C
(CH3)3COH/THF
(solvent)
O
O
O
OH
O
N
O
One of the key steps used in the synthesis of
Tamiflu.
NH
2
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.
O
+
Ph
OH
H2NPh
O
225 °C!
Ph
O
225 °C!
O H NPh
3
+
Ph
NHPh
H2O
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 15 of 17.
Date: October 5, 2012
IX. Reactions of Carboxylic Acid Derivatives [Chapter 21.3 B, C and 21.5 A]
(1) Reduction with hydride reagents
NaBH4: typically in a protic solvent that serves as a proton source (e.g., CH3OH, and
CH3CH2OH) reduces: aldehydes, ketones, imines, acid halides (to RCH2OH),
acid anhydrides [RC(=O)]2O [to RCH2OH and RC(=O)O-]
But, does not reduce esters, acids, or amides.
LiAlH4: reacts with a protic solvent (i.e., R-O-H); use a non-polar solvent such as diethyl
ether and THF; requires acidic workup.
highly reactive; reduces virtually all C=X bonds and cyano group.
(i) esters, carboxylic acid, and lactones
R
OR'
O R' ≠ H
ester
R
1. LiAlH4
R-CH2OH + HO-R'
2. H3O+
workup
1. LiAlH4
2.
lactone
H
H Al H
H
Li
ester
R
O
OH
H3O+
diol
workup
mechanism:
O
R-CH2OH
2. H3O+
workup
OH
O
OR'
1. LiAlH4
O
carboxylic acid
O
R
OH
Far more electrophilic
than the ester C=O carbon.
OR'
H
R
H Al H
H
Li
H
H
H Al
H
Li
+
O
H
H Al Y
H
Li
Thus, the aldehyde gets reduced
faster than the starting ester does.
OR'
H
R
O
H H
[Y = H or OR']
Al Y
H
Li
H3O+
workup
R
OH
H H
The aldehyde intermediate above can't be isolated as this gets quickly reduced..
+ R'OH + 2 H2
+ Al(OH)3 + LiOH
carboxylic acid
R
O
O
H
H
H
H Al H
H
Li
R
H
H Al Y
H
Li
O
O
H
Al H
R
O
Al H
H
O
H
H
+ H2
[Y = H or O(C=O)R]
Li
Li
H Al Y
H Li
R
H
O
+
aldehyde
H
H3O+ workup
R-CH2OH
Y
Al
Li
H
H
O
Al H
H
Li
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 16 of 17.
Date: October 5, 2012
IX. Reactions of Carboxylic Acid Derivatives
(1) Reduction with hydride reagents: (ii) LiAlH4 reduction of amides
R'
N
R
2. aqueous
workup
O
R'
N
R
1. LiAlH4
R"
H H
R"
amine!
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.
mechanism:
NR'R"
H
O
H Al H
amide
H
Li
R
R
O
NR'R"
R'
H
R
H Al H
H
Li
N
H
H
R"
H
+ H Al
H
Li
H Al Y
H
Li
O Li
R
H2O
workup
NR'R"
R
NR'R"
+ Al(OH)3 + LiOH
H H
H H
+ 2 H2
(2) Reactions with Organometallic Reagents: Grignard Reagents
(i) esters
Ph
OCH3
+ 2 CH3MgBr
O
Ph
OCH3
+ CH3MgBr
O
THF
(solvent)
THF
(solvent)
aqueus workup
Ph
OH
(usually with saturated
aqueous NH4Cl)
H3C
CH3
aqueus workup
Ph
OH
(usually with saturated
aqueous NH4Cl)
H3C
CH3
+ HOCH3 + 2Mg(OH)2
+ 2Br
+
Ph
OCH3
O
ca. 1 : 1
virtually no Ph
+ HOCH3
+ Mg(OH)2
+ Br
CH3
(acetophenone) O
obtainable.
Mechanistic interpretation:
δ
H3C
Ph
MgBr
δ
OCH3
O
slow
H3CO MgBr
Ph
H3C
H3C MgBr
OCH3
O MgBr
*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.
fast
Ph
O
Ph
fast
H3C
H3C
CH3
O MgBr
ketone C=O carbon:
far more electrophilic
than ester C=O carbon
aqueous
work-up
Ph
OH
H3C
CH3
Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 17 of 17.
Date: October 5, 2012
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.
Ph
O
O
Ph
H
MgBr
O
+
H3C MgBr
x
CH4
O
H3C MgBr
δ
δ
C=O C too non-electrophilic to reaction with an additional equivalent of a
Grignard reagent
In contrast, more nucleophilic organolithium reagents can add to the intially produced lithium salt.
Ph
O
H +
O
carboxylic
acid
OLi
Ph
2 H3C-Li
+
OLi
Ph
CH4
acidic workup
(pH 1 - 2)
CH3
O
+ H2O + 2 LiOH
CH3
ketone
H
mechanism:
Ph
O
O
+
O Li
Ph
H
CH4
OLi
Ph
H3 O+
O
H3C Li
δ
δ
Ph
H
OH
H3C
OH
CH3
H3C Li
δ
δ
Ph
OH
OLi
O
CH3
reaction
end-product
Ph
O
Ph
CH3
O H
CH3
OH2
(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.
CH3
N
CH3
O
Ph
CH3
N
CH3
O
Ph
H3C MgBr
H3C
O
O
Ph
acidic workup
(pH 1 - 2)
Mg
Br
N-methoxy-N-methylamide
O
CH3
H N O CH3
H
+
CH3
5-membered, stable chelate;
does not fragment to a C=O species
mechanism for the hydrolysis:
Ph
H3C
CH3
N
CH3
O
O
O H
H
H3C
Mg
Br
H
Ph
CH3
N
CH3
O
OH
H
Ph
H3C
H
O H
H
Ph
CH3
N
OH
O
O H
CH3
+
CH3
H
O H
H
H
Ph
OH2
CH3
N
CH3
O
O
CH3
CH3
H N O CH3
H
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).