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64 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 3-9.Examples of drug molecules that contain aliphatic and alicyclic amines with
their respective pKa values. All drug molecules have been drawn in their ionized form.
group, located three atoms away from the amine, has an electronic withdrawing effect leading to a
pKa value less than that seen with gabapentin. The tertiary amine within the structure of orphenadrine has similar electron donating and withdrawing groups, as seen with albuterol. The three
directly adjacent methyl and methylene carbon atoms donate electrons, while the ether oxygen is
more electronegative and acts as an electron withdrawing group. There is a little more steric hindrance for the tertiary amine of orphenadrine as compared with the secondary amine of albuterol,
which is reflected by the slightly lower pKa value. Finally, the alicyclic tertiary amine seen in the
structure of ticlopidine has a significantly lower pKa value. There are two reasons for this. First, the
alicyclic tertiary nature of this amine causes more steric hindrance, as compared with the amines on
the other three drugs. Second, the chlorine atom is electron withdrawing in character and decreases
the availability of the lone pair of electrons.
Aromatic Amines
Aromatic amines, also known as anilines, are amines directly attached to an aromatic ring and are
much less basic than aliphatic and alicyclic amines. The reason for this decreased basicity lies in the
fact that the aromatic ring, through resonance, serves as an electron withdrawing group and significantly decreases the availability of the nitrogen atom’s lone pair of electrons. The simple insertion
of a methylene group changes the aromatic amine into an aliphatic amine and significantly increases
the basicity of the nitrogen atom since it is no longer directly attached to the aromatic ring.
The typical pKa values for aromatic amines range from 2 to 5. As such, aromatic amines are
appreciably ionized in the stomach and perhaps an acidified urine (based on the specific pKa). In all
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other physiologic environments, aromatic amines are not appreciably ionized and can be treated
as neutral functional groups. Whenever a nitrogen atom is attached to two aromatic rings, it can
donate its electrons into either ring. This results in an additional decrease in basicity with pKa values
that are often less than 1. Examples of aromatic amines are shown in Figure 3-10.
FIGURE 3-10.Examples of drug molecules that contain an aromatic amine.
Imines and Hydrazines
Imines contain an unsaturated bond between the nitrogen atom and an adjacent carbon atom. The
term unsaturated refers to the presence of the double bond and the fact that the nitrogen atom and
the adjacent carbon atom are missing hydrogen atoms (i.e., they are no longer saturated with hydrogen atoms). Imines, also known as Schiff bases, are not commonly seen in drug molecules because
they can be easily hydrolyzed unless they are conjugated with an aromatic ring. One example is seen
in the benzodiazepine class of drug molecules, exemplified by diazepam (Figure 3-11).
In general, imines are much less basic than amines, with pKa values ranging from 3 to 5. This is
due to the fact that the nitrogen atoms of amines have sp3 hybridization, while the nitrogen atoms
of imines have sp2 hybridization. As a result, the lone pair of electrons present on an imine nitrogen
atom is closer to the nucleus of the atom than it is in an amine nitrogen atom. Because the electrons
are closer to the nucleus, they are less available than those in an amine nitrogen atom. Therefore,
FIGURE 3-11.Examples of drug molecules that contain basic imine and hydrazine
functional groups.
66 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
imines are less basic than their respective amines. Additional factors can further influence electron
availability and basicity. In the case of diazepam, the imine double bond is in conjugation with the
aromatic rings, one of which contains an electron withdrawing chlorine atom. This conjugation
causes the imine nitrogen atom of diazepam to have a pKa value of 3.4. This once again emphasizes
that for any given functional group, a variety of factors can influence its overall basicity or acidity.
Hydrazines have the general structure shown below. This functional group is found in only a
few drug molecules, with the antihypertensive agent hydralazine being the most notable example
(Figure 3-11). The pKa values for hydrazines range from 7.5 to 8.5.
Amidines and Guanidines
An amidine group can be viewed as a nitrogen-substituted imine. The presence of the extra nitrogen
atom allows for resonance delocalization of the positive charge and an increase in the basicity.
Similar to a carboxylic acid in which two oxygen atoms share a negative charge, the amidine
functional group allows two nitrogen atoms to share a positive charge.
Examples of drug molecules containing an amidine group include naphazoline and tetrahydrozoline (Figure 3-12), α adrenergic agonists used as nasal and ophthalmic decongestants. The fivemember alicyclic ring containing the amidine is known as an imidazoline ring. Normal pKa values for
amidines range from 10 to 11.
The addition of one more nitrogen atom to the amidine group results in the formation of a
guanidine group. The additional nitrogen atom further enhances the basicity of the functional group
FIGURE 3-12.Examples of drug molecules that contain a basic amidine functional group.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 67
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by allowing the positive charge to be delocalized over all three nitrogen atoms. Due to this additional resonance stabilization, guanidine groups are very strong bases, with pKa values of 12 to 13.
The most basic nitrogen atom of amidine and guanidine groups is the one that is involved in the
unsaturated bond. In reviewing the resonance structures, please note the direction of resonance
delocalization and electron flow. If the initial protonation occurred at either of the nitrogen atoms
not involved in the unsaturated bond, the same resonance delocalization would not be able to occur.
Examples of drug molecules containing a guanidine functional group are shown in Figure 3-13.
FIGURE 3-13.Examples of drug molecules that contain a basic guanidine functional
group.
How Can Resonance Delocalization Both Increase and
Decrease Basicity?
Resonance delocalization can either help or hinder the ionization of a nitrogen atom, depending on the direction of delocalization and if the delocalization occurs prior to or after a proton binds to a lone pair of electrons on a nitrogen atom. When delocalization occurs after a
group has been ionized, as shown in the resonance structures for an amidine or a guanidine
functional group, the sharing of electrons and the positive charge enhances basicity. This is
very similar to the sharing of a negative charge seen with carboxylic acids and other acidic
functional groups. When delocalization occurs prior to ionization, as shown with aromatic
amines (aka anilines) and heterocyclic nitrogen atoms, the lone pair of electrons becomes less
available to bind with a proton because it is pulled away from the nitrogen atom. This results
in a decrease in basicity.
68 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Nitrogen Containing Aromatic Heterocycles
Nitrogen containing aromatic heterocycles vary in their basicity but are generally much less basic
than aliphatic and alicyclic amines. The term heterocycle refers to a ring system that contains atoms
other than carbon. Some examples of heterocyclic rings containing nitrogen atoms are shown below.
The pKa values for most nitrogen containing aromatic heterocycles range from 1 to 6. These pKa
values are dependent on the size of the ring and the presence, absence, and proximity of other heteroatoms and electron donating and withdrawing functional groups. Five-membered rings and ring
systems that contain a single nitrogen atom, such as pyrrole and indole, are not basic because the
lone pair of electrons on the nitrogen atom are involved in the aromaticity or resonance delocalization of the ring. As such, they are unavailable for binding to a proton. The presence of a second nitrogen atom, such as that in an imidazole ring, enhances its basicity due to resonance stabilization of
the negative charge between the two nitrogen atoms similar to that seen with an amidine. The presence of an oxygen atom decreases the basicity of the isoxazole ring due to the inductive electronwithdrawing property of the oxygen atom. Examples of these effects can be seen in Figure 3-14 with
frovatriptan (indole ring), cimetidine (imidazole ring), and sulfamethoxazole (isoxazole ring).
FIGURE 3-14.Examples of drug molecules with five-membered nitrogen containing
aromatic heterocycles. Basic functional groups are highlighted with boxes.
Six-membered rings and ring systems that contain a single nitrogen atom, such as pyridine and
quinoline, are more basic than pyrrole and indole rings. This is because the lone pair of electrons
on the nitrogen atom is not involved in the aromaticity of the ring and is thus available to bind to a
proton. Examples of this are seen in Figure 3-15 with isoniazid and quinidine. The differences in the
pKa values for these two aromatic nitrogen atoms are due to the differences in the functional groups
attached to their respective rings. The hydrazide group para to the pyridine nitrogen atom is electron
withdrawing and decreases the availability of the lone pair of electrons from accepting a proton.
In comparison, the quinoline ring within the structure of quinidine contains an electron donating
methoxy group that increases the availability of the lone pair of electrons to accept a proton.
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FIGURE 3-15.Examples of drug molecules with six-membered nitrogen containing
aromatic heterocycles. Basic functional groups are highlighted with boxes.
The presence of additional nitrogen atoms within a six-membered ring or ring system can either
enhance or detract from the basicity depending on the ability for resonance delocalization of the
positive charge or removal of the lone pair of electrons through resonance or induction. Prazosin and
ceritinib (Figure 3-15) provide examples of this concept. The basic functional group present within
the structure prazosin is very similar to that seen with a guanidine functional group. Because this
functional group is part of an aromatic ring system, the overall basicity is substantially lower than
an alkyl guanidine. This is similar to the decreased basicity seen in aromatic amines. The structure
of ceritinib contains the same basic nitrogen group as prazosin; however, its pKa is more than 2-fold
less. This decreased basicity is due to the electron withdrawing chloro group that is attached to the
same aromatic ring. As a final point, there are a large number of structural variations in nitrogen
containing aromatic heterocycles. The relative basicities of these rings are due to the cumulative
effects of adjacent atoms and functional groups.
Additional Nitrogen Containing Groups
The following functional groups are not basic but are reviewed here to emphasize a key concept. A
common mistake made by students is to assume that all nitrogen containing groups are basic when,
in fact, these groups can be basic, neutral, acidic, or permanently charged quaternary ammonium
salts. When a nitrogen atom is adjacent to a carbonyl group, it is part of an amide group. The lone
pair electrons on the nitrogen atom are involved in keto-enol tautomerization with the carbonyl
group and are not available for binding to a proton. Similar effects are seen with carbamates and
70 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
ureas. The key point here is that amides, carbamates, and ureas are neutral functional groups, not basic
functional groups.
In addition, when a nitrogen atom is adjacent to two carbonyl groups or a sulfonyl group, the
functional group is an imide or a sulfonamide, respectively. As previously discussed, these are acidic
functional groups.
Alkylation of a tertiary amine results in a quaternary ammonium salt (or group). In the example
shown below, please note that the nitrogen atom in this group has four bonds and thus does not
have an available lone pair of electrons or a proton. Since this functional group can neither gain nor
lose a proton, it is neither basic nor acidic; however, similar to acidic and basic functional groups, it
can dissociate into ions in solution and thus can carry an electrical current. As such, drug molecules
that contain this functional group are often classified as electrolytes.
Summary of Key Points Regarding Acidic and Basic
Functional Groups
• For a functional group to be acidic in character, it must meet two criteria.
It must have at least one hydrogen atom that can dissociate from the functional
group.
The remaining atoms must be able to delocalize the resulting negative charge via
resonance.
• Acidic functional groups have general (or normal) pKa ranges due to the presence of
adjacent functional groups.
The presence of adjacent electron withdrawing groups enhances the acidity of the
functional group and results in a lower pKa value.
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The presence of adjacent electron donating groups decreases the acidity of the
functional group and results in a higher pKa value.
• For a functional group to be basic in character, it must have a nitrogen atom with a
lone pair of electrons that can bind to and accept a proton.
• Basic functional groups have general (or normal) pKa ranges due to two reasons: (1) the
presence of adjacent functional groups and (2) the presence or lack of steric hindrance
around the lone pair of electrons.
The presence of adjacent electron donating groups enhances the basicity of the
functional group and results in a higher pKa value.
The presence of adjacent electron withdrawing groups decreases the basicity of the
functional group and results in a lower pKa value.
Steric hindrance around the lone pair of electrons decreases the ability of a proton
to bind, resulting in decreased basicity and a lower pK
value.
a
• Not all nitrogen containing functional groups are basic.
A summary of the typical pKa ranges for all of the acidic and basic functional groups discussed
in this chapter is shown in Table 3-1. Please note that some of the drug molecules that you will
encounter have functional groups with pKa values that are slightly outside of these ranges. This typically occurs whenever adjacent functional groups contribute a significant electronic effect through
either resonance or induction; however, there may be situations in which steric effects can hinder
ionization. Based on the discussions in this chapter and in Chapter 2, you should be able to offer
TABLE 3-1.Approximate pK
Values for Common Acidic and
a
Basic Functional Groups
Functional Group Acidic or Basic pKa Range
Carboxylic acids Acidic 2.5-5
β-Dicarbonyl groups (includes imides) Acidic 4.5-8.5
Sulfonamides Acidic 4.5-11
Sulfonylureas Acidic 5-6
Tetrazoles Acidic 4.5-6
Phenols Acidic 9-10
Thiols Acidic 10-11
Sulfates Acidic 1-2
Phosphates and phosphonates Acidic 1.5-2.5 (first phosphate)
Aliphatic amines and alicyclic amines (aka
saturated heterocycles)
Aromatic amines (aka anilines) Basic 2-5
Imines Basic 3-5
Hydrazines Basic 7.5-8.5
Amidines Basic 10-11
Guanidines Basic 12-13
Nitrogen containing aromatic heterocycles Basic 1-6
Basic 9-11
6.5-7.5 (second phosphate)
72 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
explanations for pKa values that lie outside these ranges as well as those that lie very close to one
end of the range.
Functional Groups Versus Drug Molecules
This chapter has focused primarily on acidic and basic functional groups; however, any given drug
molecule may contain one or more of these functional groups within its structure. Each functional
group is acidic, basic, amphoteric, a permanently charged quaternary ammonium salt, or neutral (i.e.,
not ionizable). Examples of each of the possible combinations are shown in Figure 3-16. A drug molecule such as gemfibroil that contains one or more acidic functional groups and no basic functional
groups within its structure is known as an acidic drug. A drug molecule such as clonidine that contains
one or more basic functional groups and no acidic functional groups within its structure is known
as a basic drug. Drug molecules that contain at least one acidic and one basic functional group are
known as amphoteric molecules. Ciprofloxacin is an example of an amphoteric drug molecule since its
structure contains an acidic carboxylic acid and a secondary amine. Drug molecules that contain only
neutral functional groups, such as eplerenone, are known as nonelectrolytes, whereas drug molecules
that contain a quaternary ammonium salt and no other ionizable functional groups (and therefore
are unable to accept or donate a proton), such as neostigmine bromide, are known as electrolytes.
FIGURE 3-16.Examples of drug molecules that are acidic, basic, amphoteric, a
nonelectrolyte, and an electrolyte.
THE THERAPEUTIC SIGNIFICANCE OF THE ACID/BASE NATURE
OF DRUG MOLECULES
The acid/base nature of a drug molecule influences its chemical, pharmaceutical, and therapeutic
properties. The purpose of this section is to identify these key relationships so you gain a better
appreciation of the applications of acidic and basic drugs and functional groups. Almost all of these
topics are discussed in much more detail in subsequent chapters.
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The most important aspect of an acidic or basic functional group is its ability to be ionized (i.e.,
add a negative or positive charge to the drug). The extent to which a functional group can ionize
depends on its pKa and the environment in which it resides. For example, acids are primarily unionized in an acidic environment, while bases are primarily ionized in an acidic environment. The opposite is true in a basic environment.
Functional group ionization influences the overall water solubility of a drug molecule. An
increase in the ionization of a functional group within a drug molecule provides positive or negative
charges that substantially increase the drug’s water solubility due to enhanced solvation interactions. An increase in water solubility enhances both the rate and extent of dissolution of a drug
molecule within the gastrointestinal (GI) tract. This also allows a drug to be concentrated in a small
volume for use in intravenous (IV) and ophthalmic solutions. The overall oral absorption of a drug
molecule depends first on its ability to dissolve in the GI tract and second on its ability to traverse
the lipid bilayer membrane. Although ionized functional groups aid in the dissolution of a drug molecule, the unionized forms of these same functional groups are much more favorable for the passage
through lipid membranes. Given that ionization is an equilibrium process, the acid or base strength
of a functional group determines the extent to which it is ionized or unionized in any given environment. Thus, the pK
ranges provided for the various functional groups can help determine the overall
a
effect that a given acidic or basic functional group has on absorption. Ionization of a drug molecule
within the urinary tract is also important in terms of passive renal reabsorption. Drug molecules that
are highly ionized are much less likely to be passively reabsorbed than those that are unionized. This
same concept applies to the passage of any drug molecule across any membrane barrier. A more
extensive discussion of pH, pKa, and ionization is provided in Chapter 4.
Ionization of a functional group allows for the formation of ionic interactions between a drug
molecule and its target receptors, transport proteins, enzymes, and/or other endogenous biological
targets. As discussed in Chapter 6, ionic interactions are the strongest noncovalent bonds that can
be formed between a drug molecule and its biological target(s), and they are often responsible for
the initial molecular recognition. Ionic interactions between drug molecules and plasma proteins
can extend the duration of action of these drugs by sequestering them from metabolic and elimination pathways. Human serum albumin (aka albumin) is a major transport protein for a number
of endogenous substances and drug molecules. Albumin contains numerous binding sites and is
somewhat nonspecific in its binding but generally tends to bind acidic drug molecules to a much
greater extent than basic drug molecules. In addition, it tends to bind hydrophobic drug molecules
to a much greater extent than hydrophilic drug molecules. Although the binding of acidic drugs to
albumin is somewhat nonspecific, drug interactions can occur if two different acidic drug molecules
are competing for the same binding site. These drug interactions are known as plasma protein bind-
ing interactions or plasma protein displacement interactions and are clinically relevant for those acidic
drugs that are more than 90% plasma protein bound. Some examples are shown in Figure 3-17.
Basic drugs bind to a different plasma protein, α1-acid glycoprotein and, similar to acidic drugs,
could cause plasma protein displacement interactions with other basic drugs competing for the
same binding site on this plasma protein. Some examples are shown in Figure 3-18. Since acidic and
FIGURE 3-17.Examples of acidic drug molecules that are highly bound to the plasma
protein albumin.
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