Chem 215 F12 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 –Dr. Masato Koreeda - Page 2 of 17.
Date: October 5, 2012
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 3 of 17.
II. Acyl-transfer Reactions – Acylation Reactions
Date: October 5, 2012
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 4 of 17.
III. Synthesis of Carboxylic Acids
(1) With the same number of carbon atoms as the starting material:
(2) Fewer carbon atoms than the starting material:
(3) One more carbon atom than the starting material:
Date: October 5, 2012
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 5 of 17.
Date: October 5, 2012
III Synthesis of carboxylic acid (continued)
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 – 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.
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.
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 7 of 17.
Date: October 5, 2012
V. Esterification
(1) Esterification reactions
The experimental equilibrium constant for the reaction above is:
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
____________________________________________________________________________________________________________________
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].
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 8 of 17.
Date: October 5, 2012
V. Esterification (cont’d)
Mechanism for the acid-catalyzed esterification
---------------------------------------------------------------------------------------------------------------------------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).
Chem 215 F12 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.)
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.
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.
Chem 215 F12 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
b. With base and reactive alkyl iodide [usually CH3I or CH3CH2I] or sulfate [usually
(CH3)2SO4 (dimethyl sulfate) or CH3CH2SO4 (diethyl sulfate)]
--------------------------------------------------------------------------------------------------
(2) With Acid Anhydrides and Acid Chlorides from Alcohols
Chem 215 F12 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.
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.
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.
acid-catalyzed:
base-catalyzed:
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 – Dr. Masato Koreeda - Page 12 of 17.
Date: October 5, 2012
VIII. Acylation of ammonia and Amines: Synthesis of Amides
Amides:
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
Mechanism:
Chem 215 F12 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
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.
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).
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.
Chem 215 F12 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.
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)
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)
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.
Chem 215 F12 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.
Chem 215 F12 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
(2) Reactions with Organometallic Reagents: Grignard Reagents
Chem 215 F12 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.
(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.
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).