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54 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
The resulting anion is stabilized by the two carbonyl oxygen atoms via resonance delocalization.
Similar to carboxylic acids, the ability to share and stabilize the negative charge among multiple
atoms favors ionization of this functional group.
The structures of six drug molecules that contain a β-carbonyl group are shown in Figure 3-2. A
few key points need to be made as they relate to these structures. When the “X” of a β-dicarbonyl
group is a carbon atom, the β-dicarbonyl may exist in either its keto or enol tautomeric form.
These tautomeric forms are different from the resonance structures shown above and involve
the movement of a proton as well as a shift in the bonding electrons. Please note that when this
occurs, the acidic hydrogen moves from the carbon atom to an oxygen atom or vice versa. Keto
and enol tautomers can also be classified as structural isomers, molecules with the same molecular
formula and with a different arrangement of atoms and functional groups. Tautomers, or tautomeric isomers, are distinct from the stereochemical isomers discussed in Chapter 7 and unique from
other structural isomers in that they can spontaneously be interconverted. Most drug molecules
that contain this type of β-dicarbonyl group normally exist in their enol forms. This is exemplified
in Figure 3-2 by warfarin and piroxicam. One drug molecule that primarily exists in its keto form is
oxyphenbutazone; however, due to the development of safer agents within this drug class, it is no
longer prescribed in the United States.
As previously mentioned, when the “X” of a β-dicarbonyl group is a nitrogen atom, the functional group is more commonly known as an imide. Shown in Figure 3-2 are three drug molecules
that contain an imide functional group; however, only phenobarbital and phenytoin are acidic.
Trimethadione also contains a β-dicarbonyl group that could stabilize a negative charge; however,
because the nitrogen atom has been methylated, this functional group does not contain an acidic
hydrogen atom. Trimethadione serves as an example to reinforce a key concept: for a functional
group to be acidic, it must contain a hydrogen atom that can dissociate.
In comparing β-dicarbonyl groups, it should be noted that, in general, imides are much less
acidic than their carbon analogs. The primary reason for this is the differences in the relative electronegatives of the atoms involved (see Table 2-2 in Chapter 2). Oxygen is much more electronega-
tive than carbon and readily accepts the negative charge from the carbon atom once the proton has
left. In contrast, while oxygen is also more electronegative than nitrogen, the comparative difference is less, resulting in a decreased electron flow from the nitrogen atom to the oxygen atoms and a
decrease in acidity. This fact is exemplified by the drug molecules shown in Figure 3-2. Phenobarbital
and phenytoin are imides (“X” = N) and have pKa values of 7.41 and 8.33, respectively. These pKa
values are two to three log units higher than those for warfarin (pKa = 5.05), piroxicam (pKa = 5.10),
and oxyphenbutazone (pKa = 4.70), drugs that have a carbon atom (“X” = C) between the carbonyl
groups. The general pKa range for β-dicarbonyl groups is 4.5 to 8.5, with imides generally having a
higher pKa than when “X” of a β-dicarbonyl group is a carbon atom.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 55
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FIGURE 3-2.Examples of drug molecules that contain a a-dicarbonyl group. The
functional groups and acidic hydrogen atoms have been highlighted with boxes.
Sulfonamides and Sulfonylureas
Sulfonamides are similar to β-dicarbonyl groups in that the initial negative charge can be shared by
two adjacent oxygen atoms. The only difference here is that both oxygen atoms are attached to a
single sulfur atom.
56 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 3-3.Examples of drug molecules that contain a sulfonamide and how an
adjacent functional group can affect the pKa.
Examples of drug molecules that contain a sulfonamide are shown in Figure 3-3. As indicated
by these examples, the acidic nature of sulfonamides can vary widely (typical pKa range is 4.5 to 11)
and is strongly influenced by the electronic effects of adjacent groups or resonance-linked groups.
Sulfanilamide was one of the first sulfonamide drugs used to treat bacterial infections. The unsubstituted, aromatic sulfonamide present within its structure is weakly acidic. This trend can also be
seen with celecoxib, which has a similar functional group. The addition of adjacent electron withdrawing groups such as the aromatic heterocycle present in sulfisoxazole and the carbonyl present in
sulfacetamide and zafirlukast increases delocalization of the resulting negative charge and increases
the acidity of the proton. For sulfacetamide and zafirlukast, the electron withdrawing ability is due
to a direct resonance delocalization of the negative charge into the adjacent carbonyl group. For
sulfisoxazole, the heterocyclic ring can withdraw electrons through either resonance or an inductive
effect. A key point to remember is that electron withdrawing groups increase the acidity of adjacent
functional groups or resonance-linked functional groups. The exact opposite is true of electron donating groups. The aliphatic sulfonamide groups seen in tirofiban and sumatriptan emphasize this last
point. These sulfonamide groups are adjacent to electron donating alkyl chains. As a result, these
functional groups are much less acidic, as indicated by their pKa values.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 57
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Application Question
How does the acidity of the following drug molecule compare with those in Figure 3-3?
Answer: Similar to what was discussed with drug molecules containing a β-dicarbonyl group,
the sulfonamide functional group must contain an ionizable hydrogen atom (proton; H+). In
this case, the nitrogen atom within the sulfonamide functional group has been acetylated.
Thus, it no longer contains an acidic proton and therefore is not acidic. It is still a sulfonamide
(i.e., it is a “sulfur-containing” amide), but since the nitrogen is substituted, the functional
group is neutral. Sulfisoxazole acetyl is actually a prodrug. As discussed in much more detail
in Chapters 5 and 8, a prodrug is a drug molecule that has been covalently modified to either
an inactive or weakly active analog for the purposes of achieving a specific therapeutic benefit. Once the prodrug is administered, it undergoes metabolic activation to release the active
drug molecule. In this case, sulfisoxazole acetyl must be converted in vivo to sulfisoxazole for
it to exert its activity.
Sulfonylureas are very closely related to sulfonamides. The resonance delocalization of an ionized sulfonylurea can occur across all three adjacent sulfonyl and carbonyl bonds and is similar to the
ionizations previously discussed with sulfacetamide and zafirlukast. The pKa values of sulfonylureas
generally range from 5 to 6.
58 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Tetrazoles
Tetrazole rings are isosteres of carboxylic acids. As discussed in more detail in Chapter 9, isosteres
are functional groups with a similar distribution and location of electron density and a similar size
and shape. The lone hydrogen atom in this ring system is acidic.
The resulting negative charge can be equally shared among all five atoms of the tetrazole ring
by resonance, thus allowing the charge to be distributed over a larger area than that seen for a carboxylic acid.
In comparison with a carboxylic acid, a tetrazole ring is less acidic (typical pKa range is 4.5 to 6)
and more lipophilic. Not many drugs or drug classes contain a tetrazole; however, angiotensin II
receptor blockers almost exclusively include this functional group instead of a carboxylic acid
(Figure 3-4). Advantages gained by using the tetrazole ring instead of a carboxylic acid for this class
of drug molecules include better oral bioavailability and enhanced metabolic stability.
FIGURE 3-4.Examples of drug molecules that contain an acidic tetrazole ring.
Phenols
Phenols (i.e., hydroxyl groups attached to an aromatic ring) are weakly acidic functional groups.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 59
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Similar to previously discussed functional groups, the negative charge can be delocalized. In this
case, the negative charge can be shared with the carbon atoms in the aromatic ring.
Although the aromatic ring allows resonance delocalization, it must be noted that carbon
atoms are less electronegative than oxygen atoms and thus are less likely to want to share the negative charge. The end result of this effect is that phenols are much weaker acids than those functional
groups previously discussed. The pKa values of phenols normally range from 9 to 10. At any physiologically relevant pH, most phenols are not appreciably ionized. A good example of this guideline
is illustrated by estradiol (Figure 3-5). Estradiol can be technically and correctly classified as a very
weak acid; however, because the phenol is not appreciably ionized at physiologic pH, estradiol is
commonly classified as a nonelectrolyte.
Definitions
An electrolyte is a molecule that can dissociate into ions in solution and thus can carry an
electrical current. Drug molecules that contain one or more of the acidic and/or basic functional groups discussed in this chapter are therefore electrolytes. In contrast, a nonelectro-
lyte is a molecule that does not dissociate into ions in solution and thus does not carry an
electric current. Drug molecules that lack acidic or basic functional groups, or only possess
weakly acidic or weakly basic functional groups that are not appreciably ionized, are termed
nonelectrolytes.
Electron withdrawing groups, such as the iodine atoms seen in liothyronine and levothyroxine
in Figure 3-5, increase the acidity of phenols. While estradiol is only 0.1% ionized at a physiologically relevant pH, liothyronine is approximately 10% ionized at a pH of 7.4. Appreciable ionization
can occur with very strong electron withdrawing groups or with the presence of multiple electron
withdrawing groups. The latter is seen in levothyroxine. The two adjacent iodine atoms increase the
acidity almost four log units as compared with estradiol. As a result, levothyroxine is approximately
FIGURE 3-5.Examples of drug molecules that contain a phenol (highlighted with a box)
and an aliphatic hydroxyl group.
60 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
83% ionized at a pH of 7.4. It should be noted that the number of drug molecules with appreciably
ionized phenols is extremely small and should be treated as the exception rather than the rule.
What About Aliphatic Hydroxyl Groups?
Aliphatic hydroxyl groups, such as the secondary hydroxyl group seen in estradiol (Figure 3-5)
and the one seen below in isosorbide mononitrate, are not acidic within physiological environments. The reason for this is the absence of any resonance stabilization of the resulting
charge. Unlike the functional groups previously discussed, an aliphatic hydroxyl group is not
directly adjacent to a functional group that could share or stabilize a negative charge (e.g., a
carbonyl group, a sulfonyl group, or an aromatic ring). As a result, the proton is not ionizable
in any physiological environment and the functional group is not acidic.
Thiols
Thiols (aka sulfhydryl groups) are approximately 4 to 5 log units more acidic than hydroxyl groups.
Aliphatic thiols have pKa values that range from 10 to 11, as illustrated with captopril and penicillamine (Figure 3-6). Similar to the phenol in estradiol, aliphatic thiols can be technically and correctly classified as very weak acids; however, since these thiols are not appreciably ionized at any
physiologic pH, they are most commonly classified as nonelectrolytes. Aromatic thiols, due to the
availability of resonance stabilization, are much more acidic than aliphatic thiols and generally have
a pKa value near 6. Because aromatic thiols are highly nucleophilic and highly reactive, they are not
present in drug molecules. In general, the key chemical property of a thiol is its nucleophilicity, not
its acidity.
FIGURE 3-6.Examples of drug molecules that contain a thiol (aka sulfhydryl group).
Sulfates, Phosphates, and Phosphonates
Sulfates, phosphates, and phosphonates are similar to β-dicarbonyls, sulfonamides, and sulfonylureas in that the initial negative charge can be shared with adjacent double-bonded oxygen atoms.
Sulfates have one acidic hydrogen atom with a pKa value that ranges from 1 to 2, while phosphates
and phosphonates have two acidic hydrogen atoms. The pKa value for the ionization of the first
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hydrogen atom is approximately 1.5 to 2.5, while the pKa value for the ionization of the second
hydrogen atom is higher, ranging from 6.5 to 7.5.
These acidic functional groups are seen occasionally; however, they are not as prevalent as carboxylic acids and β-dicarbonyl groups. In many cases they are used to create a more water-soluble
prodrug to enhance dissolution. Further discussion of this concept is discussed in Chapter 5. As seen
in the examples in Figure 3-7, drug molecules that contain these functional groups are often marketed as their respective salts.
FIGURE 3-7.Examples of drug molecules that contain a phosphate, sulfate, or
phosphonate salt.
62 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
BASIC FUNCTIONAL GROUPS
Opposite of acids, basic functional groups are those that can accept (or gain) a proton. In a very
simplistic view, a base can be represented in the following way:
The key structural feature of a basic functional group is the presence of an atom with a lone
pair of electrons (e.g., nitrogen atom) that can bind to and accept a proton. The availability of these
electrons to perform this function determines the basicity of the functional group. Adjacent electron withdrawing groups that increase the acidity of acidic functional groups decrease the basicity
of basic functional groups. By the same reasoning, adjacent electron donating groups increase the
basicity of the functional group.
Similar to acidic functional groups, pKa values are used to measure the relative basicity of functional groups. Opposite of acidic functional groups, a higher pKa value indicates a stronger base. As
an example, a basic functional group with a pKa of 9.8 is more basic than one with a pKa of 6.7.
Because pKa values are based on acid equilibrium equations, it is important that you understand
why these values can also be used for bases and what the values actually indicate. The pKa value is
based on the dissociation equilibrium of an acid. This can be seen in Equilibrium 1, shown below. To
use pKa values for bases, an analogous equilibrium, Equilibrium 2, must be considered.
In this case, the pKa of the base in Equilibrium 2 is based on the dissociation of B:H+, its conjugate
acid. An important point applicable to both of these equilibrium equations is that a low pKa value indicates that the equilibrium lies to the right (i.e., favors the loss of a proton and the ionization of HA)
and that a high pKa value indicates that the equilibrium lies to the left (i.e., favors the acceptance
of a proton and the ionization of B:). Thus, a low pKa value is seen with both strong acids and weak
bases, whereas a high pKa value is seen with both strong bases and weak acids.
Back to General Chemistry
Once an acidic functional group loses its proton and becomes ionized (or deprotonated), it
becomes what is known as a conjugate base. This is because, like a base, it is now able to
accept protons. Thus, A− in Equilibrium 1 is the conjugate base of the acid HA. Likewise, once
a basic functional group, such as B: in Equilibrium 2, accepts a proton and becomes ionized (or
protonated), it becomes a conjugate acid because it is now able to lose the proton.
Aliphatic and Alicyclic Amines
Shown in Figure 3-8 are four drug molecules, each of which has an aliphatic or alicyclic amine as
part of its structure. These amines have been highlighted and drawn in their unionized form. The
lone pairs of electrons available to accept protons are also shown here and in the general structures
shown below; however, caution is warranted here. Most drug structures that you will encounter do
not show these lone pair of electrons. Thus, it is important that you recognize and understand that
these electrons are present and available to accept a proton even if they are not actually shown.
As illustrated in Figure 3-8, aliphatic amines are designated as primary, secondary, or tertiary
depending upon the number of alkyl groups attached to the nitrogen atom. Alicyclic amines, or
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 63
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FIGURE 3-8.Examples of drug molecules that contain aliphatic and alicyclic amines.
All drug molecules have been drawn in their unionized form.
saturated heterocycles, can be either secondary or tertiary since two carbon atoms are required to
form the ring.
The term aliphatic denotes that the amine is part of a saturated chain or a nonaromatic ring.
The highlighted amine in ticlopidine can also be classified as an alicyclic amine or a saturated heterocycle. Either one of these terms can be used to describe an amine that is part of a nonaromatic
ring. Aliphatic amines are the most common basic functional groups present on drug molecules. The
ionized forms of each of these drug molecules along with the pKa values for their respective amines
are shown in Figure 3-9.
In comparing the relative basicity of primary, secondary, and tertiary amines, two factors must
be considered: the presence or absence of adjacent functional groups that are either electron donating or electron withdrawing in character and steric hindrance. Because alkyl groups such as methyl
groups, ethyl groups, and methylene carbons are electron donating, secondary and tertiary amines
are often more basic than primary amines. Steric effects must also be considered as they can hinder
the access of protons to the lone pair of electrons on the nitrogen atom. This issue is more prevalent with tertiary amines; thus, secondary amines are often more basic than tertiary amines. The
presence of adjacent electron withdrawing groups decreases the availability of the electrons on the
nitrogen atom and decreases basicity and the pKa. While exceptions arise, the pKa range generally
listed for aliphatic and alicyclic amines is 9 to 11.
The drugs in Figure 3-9 were specifically chosen to illustrate the variations in this range and
the concepts listed above. The structure of gabapentin contains a primary amine that is adjacent to
an aliphatic chain connected to an alicyclic ring. The lack of steric hindrance, the electron donating
effects of the aliphatic chain, and the absence of any electron withdrawing functional group allow
the lone pair of electrons to be readily available. Thus, gabapentin contains the strongest basic
functional group among these four drugs. Albuterol contains a secondary amine. The t-butyl group
donates electrons to the basic nitrogen, as does the adjacent carbon atom; however, the hydroxyl
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