Download esters and related carboxylic acid derivatives

Principles of Drug Action 1, Spring 2005, Esters
ESTERS AND RELATED CARBOXYLIC ACID DERIVATIVES
Jack DeRuiter
I. Structure and Preparation
Esters are derivatives of carboxylic acids that arise via replacement of the hydroxyl (OH) portion of
the acid COOH function with an "ether" moiety (-OR):
O
C
O
O
H
C
O
C
Acid
Ester
Note that replacement of the acid OH group with an "ether" moiety removes the acidic function
from the parent structure (acid) resulting in the formation of non-acidic (neutral, but somewhat
polar) compounds (esters). Esters can be sub-classified based on their general structure as aliphatic,
aromatic or cyclic (called "lactones") as illustrated by the examples below:
O
O
CH2CH3
CH2CH3
O
CH3
O
O
O
Aliphatic Ester
Cyclic Ester (Lactone)
Aromatic Ester
A variety of methods have been developed for the preparation of esters. Most of these methods
involve reaction of an alcohol with an "activated carboxylic acid" compound (i.e. acid chloride):
O
O
H
C
X
O C
C
-
"Activated" acid (X=Cl)
(Electrophile)
Alcohol
(Nucleophile)
X
O
C
Ester
The ester functionality does not introduce a center of asymmetry and thus optical and geometric
isomerism does not result from the presence of this functional group. The ester functionality (the
carbonyl and ether oxygen) is composed of an sp2 hybridized carbon so it cannot be chiral, and
since there is free rotation about the ether bond geometric isomerism also is not possible at the sp2
center.
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Principles of Drug Action 1, Spring 2005, Esters
II. Solubility of Esters
Esters contain carbonyl (C=O) and ether (O-C) dipoles arising from covalent bonding between
electronegative oxygen atoms and electronically neutral carbon atoms. Because of the π-bonding
arrangement of the carbonyl (C=O), this is the stronger of the two dipoles. The presence of these
dipoles allows esters to act as hydrogen-bond acceptors. Thus esters can participate in hydrogen
bonding with water and other protic solvents; the oxygen atoms can accept hydrogen bonds from
water. As a result the water solubility of esters is greater than that of corresponding hydrocarbons
as illustrated below:
H O H
H O H
H O H
H H
O
C
..
O
..
C
H
O H
C
C
H H
H
Ester: Hydrogen bonding and solubility
O H
Hydrocarbon: Hydrogen bonding not possible!
While hydrogen bonding may enhance the water solubility of esters relative to hydrocarbons
(alkanes, alkenes, alkynes and aromatic compounds), esters typically are regarded as compounds
with relatively low water solubility. They are significantly less water soluble than comparable acids
or alcohols due to: 1). Their non-ionic character, 2). the inability to both donate and accept
hydrogen bonds from water (they can only be H-bond acceptors) and, 3). the presence of non-polar
hydrocarbon functionality. Consider the comparisons above. Alcohols have an OH group that can
both accept and donate H-bonds with water. An ester can only accept H-bonds from water.
Carboxylic acids can both donate and accept hydrogen bonds, AND can ionize at pHs above their
pKas to further enhance solubility:
H O
H O
O H
H
O H
H
H
H
O
C O
H
O H
O C
C
H
Alcohol H-bonding
H O
Ester H-bonding
H O
H O
O H
H
O
C
O H
H
H
O H
H
H O
H
Acids: H-bonding
H
O
Ionization
O H
H
C
O H
O
-
H
H O
H
2
Ionized Acid: H-bonding
Principles of Drug Action 1, Spring 2005, Esters
III. Reactivity of Esters
B. Hydrolysis and Nucleophilic Attack at Carbonyl
The presence of a carbonyl (C=O) and ether (O-C) dipole renders the "central" carbonyl carbon of
an ester electron deficient; it is an electrophilic carbon atom. This can be illustrated by the
resonance structures for an ester drawn below:
Ester
Carbonyl
Resonance structure
.. (-)
O
O
CH3
Ether
..
..O
..
..
CH3 (+) O CH2CH3
CH2CH3
Electrophilic carbon
Thus the esters carbonyl carbon is susceptible to "attack" by electron rich atoms (nucleophiles)
including the oxygen of water and the nucleophilic residues at the active sites of esterase enzymes.
When in the presence of a nucleophile, an ester may undergo reaction leading to cleavage of the
carbonyl carbon-ether bond as shown below. Initial nucleophilic attack at the electrophilic carbonyl
of an ester results in the formation of a tetrahedral intermediate. This reaction is reversible and may
simply revert back to the original reactants, or go forward resulting in ether bond cleavage
(hydrolysis) yielding an acid and alcohol product if the nucleophile is water (or an esterase
enzyme). The "forward" reaction resulting in hydrolysis is determined by the ability of the "ether"
bond (-O-C) to be cleaved and the stability of the alcohol product.
Electrophilic carbonyl
O
CH3
O
+
N(CH3) 3
O
CH3
O
H O H Nucleophile
H
-
O
+
N(CH3) 3
O
+
H
CH3
Acid
O
-
+
+
N(CH3) 3
HO
Alcohol
Tetrahedral intermediate
Simple hydrolysis of an ester (with water) may be catalyzed (rate of the reaction increased) by
acids, bases or enzymes as illustrated in the examples below:
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Principles of Drug Action 1, Spring 2005, Esters
•
Acids enhance the reaction by protonation of the carbonyl oxygen as shown below and thereby
increasing the electrophilicity of the carbonyl carbon and thus its susceptibility to nucleophilic
attack:
H
H+
O
..
O
..
R
(+) O
R'
..
O
..
R
O
H
R
H
R'
O
..
..
etc
O R'
H
O
H
•
Basic conditions enhance the rate of ester hydrolysis by increasing the concentration of
attacking nucleophile at the reaction site as shown below:
..
O
..
..
R
•
O
O
O
R'
R
..
O
..
R
R'
-
O
O H
(-)
..
..
etc
O R'
H
Enzymes (esterases) catalyze hydrolysis by a variety of mechanisms including entropic
factors (binding and locating the ester on the catalytic site of the enzyme) as well as being
able to accomplish simultaneous acid and base catalysis with acidic and basic moieties on
the surface of the enzyme as shown below:
O H
..
..
O H
O
O
..
O
..
R
H O
O
H
R
R'
O H
R'
OH
O
Esterase
Esterase
..
..
R
O
O H
OH
H
Esterase
Nucleophiles other than water, such as amines, thiols, etc. can react with esters and form cleavage
products. Consider the example below where a primary amine (nucleophile) reacts with the ester to
form and amide and alcohol product:
O
O
..
..
O CH3
N
H2N
+
HO-CH3
H
Ester
Amine
Amide
Alcohol
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Principles of Drug Action 1, Spring 2005, Esters
In addition to the electrophilic nature of the ester carbonyl, the electronic nature of the "ether" group
(O-C) may influence hydrolysis reactions. For example, esters in which the "ether oxygen" is
linked to a strong electron withdrawing group (by resonance or induction) undergo hydrolysis more
readily. This is due to stabilization of the developing negative charge in the "ether" (actually
"alkoxide") leaving group by the electron withdrawing functionality as illustrated below:
O
O
+
H /H2 O
O CH3
O-
-
O-CH3
+
(Slower Rxn)
No stabilization of
negative charge
Electron donating
ether leaving group
O
O
O
O
O
+
H /H2 O
N O
O-
-
+
(Faster Rxn)
O
N O
Stabilization of negative
charge by resonance
Electron withdrawing
ether leaving group
In addition to the electrophilic nature of the ester carbonyl, steric factors also may influence ester
hydrolysis reactions. Large or sterically bulky near the reaction site may hinder attack of the
nucleophile (i.e. HO-) at the ester carbonyl and thereby slow down the rate of hydrolysis. Usually
the larger the group and the closer it is to the reaction site, the greater "steric inhibition" of
hydrolysis. In the example below the effect of increasing steric bulk on the alpha-carbon on
hydrolysis is illustrated:
O
CH3
CH3
O CH3
CH2
CH3O
O
O
CH3
O CH3
CH
CH3
O CH3
C
O CH3
CH3
CH3
Fastest Hydrolysis
Slowest Hydrolysis
Bulk on the "ether" carbon atoms may also slow the rate of hydrolysis by a similar mechanism.
Again, the larger the group and the closer it is to the reaction site, the greater "steric inhibition" of
hydrolysis:
O
CH3
O
O
O
H
H
H
Relatively Fast Hydrolysis
CH3
CH3
H
O
H
CH3
CH3
O
CH3
CH
CH3
CH3
Relatively Slow Hydrolysis
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Principles of Drug Action 1, Spring 2005, Esters
B. Acidity: Ester carbonyl's effect on adjacent C-H bonds
In the introduction of this section it was noted that esters are derivatives of carboxylic acids which
arise via replacement of the -OH portion of the acid COOH function with an "ether" moiety (-OR)
and that this replacement removes the acidic function from the parent structure (acid) resulting in
the formation of nonacidic (neutral) compounds (esters). It should be noted, however, that the
electron-withdrawing carbonyl (by resonance) of the ester functionality has an effect on adjacent
(so-called "α-carbons”) C-H bonds and increases the acidity of these protons relative to
hydrocarbons lacking a carbonyl functionality. This effect is identical to that seen in aldehydes,
ketones and even carboxylic acids and is due to both induction and resonance stabilization of the
resulting anion.
Weakly acidic
α−protons
(all equal)
H
..
..O
H
H
O-
O
O
CH2CH3
H
(-)
H
O CH2CH3
O CH2CH3
H
H
Non-acidic protons
Resonance stabilization
by the carbonyl
Ionization
While protons present on carbons α- to a carbonyl are somewhat acidic, they are much less acidic
(pKas>9) than carboxylic acid protons (pKas 3-5). Thus these protons (and esters in general)
typically do not display a significant degree of ionization under physiological conditions:
O
O R
R CH2
pH>10
(-)
R CH
O
O R
Ester
O
O
pH>6
O H
CH3
CH3
O-
Acid
IV. Prodrugs and Esters Formed from Metabolism
The ester functionality is commonly used in the design of “prodrugs” (also called latentiated drug or
bioreversible derivative). A prodrug is a derivative of a drug that lacks pharmacological activity, but is
converted to an active agent upon interaction with the biological system. The activation process may
involve enzymatic or non-enzymatic (chemical) mechanisms. Prodrugs are often employed to
overcome a pharmaceutical, pharmacokinetic or pharmacological disadvantage of an existing parent
drug. For example, a number of drugs (penicillins, cephalosporins, macrolides nucleosides, etc.) are
too polar or unstable to be efficiently absorbed from the GI tract. This problem has been resolved to a
significant degree with these compounds by development of ester prodrugs. For example, bacampici-
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Principles of Drug Action 1, Spring 2005, Esters
llin the ester prodrug of the amino acid drug ampicillin, is absorbed far more readily from the GI tract.
Once absorbed, it is cleaved by esterases to the parent, active drug:
H H
CHCONH
NH2
S
CH3
H H
CHCONH
CH3
N
O
1. Admnistration
2. Absorption
3. Hydrolysis
NH2
CH3
N
O
COOCH(CH3)OCOCH2CH3
CH3
S
COOH
Ampicillin
Bacampicillin
In the introductory portion of this chapter, a general synthetic approach is described for the
preparation of esters. Ester derivatives of certain drugs also can be formed as part of normal human
metabolic reactions as illustrated for the cephalosporin and dihydropyridine drugs below. Note in
these cases that oxidation of a benzylic-type carbon occurs first to yield a nucleophilic hydroxyl
group in proximity to an acid functionality or derivative. These two groups can then react to form a
cyclic ester or lactone:
H
R
N
O
H
H
H
R
S
N
O
O
N
O
CH3
R
S
N
O
OH
N
O
O
COOH
H
S
N
O
O
COOH
O
Desacetyl Intermediate
Cephalosporin
X
ROOC
H
Lactone
X
X
ROOC
COOR
O
ROOC
COOR
O
N
CH3
CH3
CH3
N
CH3
CH2OH
H
H
Dihydropyridine
Oxidation Intermediate
N
H
Lactone Metabolite
V. Other "Ester-like" Functional Groups
There are a number of other functional groups that are derivatives of traditional esters or "esterlike" including amides and amide derivatives (carbamates, ureas, etc.), carbonates, anhydrides and
phosphate esters. The amide and amide derivatives are discussed in a separate chapter:
O
R
O
R'
N
R O
O
O
R"
Amides
Carbonates
R
R
O
O
O
Anhydrides
R
R O
P O
R
X
Phosphate Esters
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Principles of Drug Action 1, Spring 2005, Esters
Generally, amides and carbonates are less susceptible than esters to hydrolysis or nucleophilic
reactions based on the increased electron donation by resonance by the atoms linked to the central
carbonyl group. Anhydrides are more susceptible than esters to hydrolysis or nucleophilic reactions
because the second carbonyl creates an electron withdrawing moiety by resonance. Phosphate
esters may be more or less reactive than traditional esters, depending on their overall structure.
Phosphate esters are essential components of human biochemistry. They provide the linkage
between nucleosides in RNA and DNA (the 3'-5' phosphodiester bond), and the "high energy
bonds" of biochemical messengers such as cyclic AMP and intermediates of metabolism such as
glucose-6-phosphate:
O
NA
X
5'
O
O
Etc
P O
O-
3'
O
P O
O O 5'
NH2
N
N
O
O
O
O
P
OHO
O
P
OH
O
-
O
O
NA
3'
Etc
O
OH
OH
HO
OH
O
X
Glucose-6-Phosphate
Cyclic AMP
RNA (X=OH) and DNA (X=H)
These biochemical substrates undergo hydrolysis reactions in vivo catalyzed by kinases and other
related enzymes as illustrated for glucose-6-phosphate below:
O
O
P
OH
O
-
OH
O
Kinases
OH
OH
HO
OH
Glucose-6-Phosphate
O
O
+
OH
OH
HO
OH
P
HO
OH
O
-
Phosphate
Glucose
The phosphate ester group also is an essential component of a number of drugs including the
organophosphate acetylcholinesterase inhibitors (OP-AChEIs). It also is a common structural
component of nerve gases and insecticides, and can be used as a prodrug functionality. The OPAChEIs consist of a phosphate ester moiety with a good leaving group (X). This structure is
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Principles of Drug Action 1, Spring 2005, Esters
capable of being recognized by the enzyme AChE and chemically reacting with a nucleophile (OH)
present on the enzyme as shown below. More details regarding the structure, reactivity and
pharmacologic activity of the OP-AChEIs is presented in the Acetylcholine Inhibitor Chapter:
O
O
R O
P
O
R O
X
R
HO
O
P
X
O
R
R O
P
O R
O
Phosphate Ester
Acetylcholinesterase
Acetylcholinesterase
The use of phosphate esters in prodrug design is illustrated by clindamycin phosphate. The parent
drug clindamycin is a relatively lipophilic, water insoluble drug. The phosphate prodrug is water
soluble and thus can be dissolved in aqueous solutions for parenteral administration. Once
administered, the phosphate moiety is rapidly hydrolyzed to yield the parent, active drug in the
circulation as shown below:
CH3CH2 CH2
CH3CH2 CH2
CH3
H
N
H
H
H
H
CH3
H
H
H
1. Adminstration
2. Hydrolysis
Cl
H
CONH
HO
H
OH
H
H
H
SCH3
O
H
O
P O-
Cl
CONH
H
O
HO
H
OH
H
H
Clindamycin Phosphate
H
CH3
H
H
H
O
CH3
N
H
Clindamycin
H
H
H
SCH3
H
OH
OH
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Principles of Drug Action 1, Spring 2005, Esters
VI. Problems
1. Answer the questions below (a-c) for the follow series of compounds:
a.
b.
c.
d.
e.
f.
g.
SO2NH2
CO2CH3
COOH
OH
CONH2
CH3
CH3
CH3
CH3
A
CH3
B
C
D
E
Which compound above is MOST acidic?
Which compound above is LEAST acidic?
Which compound above is MOST susceptible to hydrolysis?
Which compound would be MOST likely to undergo electrophilic substitution?
Which compound(s) above would be predominately ionized at physiologic pH?
Which compound(s) above would yield a salt upon treatment with NaHCO3?
Which compound would be MOST water soluble at pH 7?
2. The palmitate ester of chloramphenicol is used as a prodrug to mask the unpleasant taste of the
chloramphenicol in oral dosage forms. Esterfication occurs selectively at the primary alcohol
group of chloramphenicol. Show the structure of this ester prodrug and explain why
esterification occurs preferentially at the primary alcohol group.
OH
H
Cl
N
CH3(CH2)14COOH
Cl
O 2N
OH
O
Chloramphenicol
3. A new compound known as Coca ethylene is often found in the plasma and brain tissue of
cocaine abusers who also abuse alcohol (CH3CH2OH). This new substance has all the same
pharmacological properties as cocaine, suggest a structure for this new compound.
CH3
N
COOCH3
H
OOCC6H5
H
Cocaine
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Principles of Drug Action 1, Spring 2005, Esters
4. The cyclic ester (lactone) below is rapidly hydrolyzed under physiologic conditions to yield the
hydroxy-acid product, gamma-hyroxybutyric acid (GHB). Show the structure of GHB:
O
O
Hydrolysis
Lactone
5. Aspartame (Nutrasweet) is a low calorie sugar substitue used in many food and beverage
products. There are some claims (but minimal scientific evidence) that high levels of aspartame
use exposes individuals to low but sustained levels of methanol. By what chemical or metabolic
process could metahnol be formed from aspartame?
HOOC
H
N
H2N
O
O
CH3
O
Aspartame
6. Some drug molecules contain multiple ester groups. In the di-ester heroin shown below,
relative chemical reactivity allows for the hydrolysis of one ester group at a faster rate to yield
one major mono-ester product. Show the product from the hydrolysis of the more labile ester
group for heroin.
CH3
O
O
O
O
CH3
H
NCH3
O
Heroin
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Principles of Drug Action 1, Spring 2005, Esters
7. Show the structure of the ester hydrolysis products for the following compound, noscapine
and the exact structure of this hydrolysis product at pH 7.4.
O
N
O
H3CO
CH3
Ester hydrolysis
pH 7.4
O
OCH3
O
OCH3
8. Show the structure of the ester hydrolysis products for the following drug. Also, show the
product of oxidation of the secondary alcohol group of the hydrolysis product.
CH2OOCCH2CH2COOH
CHOH
Ester hydrolysis
CH2O
Oxidation of
Secondary
Alcohol
HO
9. The major process in the inactivation of the neurotransmitter acetylcholine (ACh) is hydrolysis
by the enzyme acetylcholinesterase (AChE). The mechanism of this reaction involves an ester
exchange (transesterification) reaction between the primary hydroxyl group of a serine residue
present on the active site of AChE and the substrate ACh. Show the product of this ester
exchange reaction.
O
CH3
O
O
N(CH3)3
Acetylcholine (ACh)
H
+
N
H
O
H
N
N
O
OH
H
N
O
Acetylcholinesterase (AChE)
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Principles of Drug Action 1, Spring 2005, Esters
10. Show all the products that form from carbamate hydrolysis of the following molecule.
O
O
O
N
C
CH3
H3CO
C O
NHCH2CH3
11. Carbenicillin is an acid unstable penicillin and thus cannot be administered orally. The initial
acid-catalyzed decomposition reaction this compound undergoes in the stomach is
decarboxylation in the 6-acylamino side chain. Why does this decarboxylation reaction occur?
Also, propose a prodrug derivative of carbenicillin to overcome (or minimize) this problem.
O
HO
H
N
O
S
N
CH3
CH3
O
COOH
Carbenicillin
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