Page 184 - Medicinal Chemistry Self Assessment

Section 4 Whole Molecule Drug Evaluation

Answers

2.16 Haloperidol

Shown below is the structure of haloperidol. Six of its functional groups have been identified.

E
C D

A

F
B

1. Using the table below, identify the six boxed functional groups. For each of the functional groups you
1. Using the se.
identified, indicate if it is hydrophilic or hydrophobic in character. Also provide a brief explanation for
2. Based on their electronic induction.
your response.
3. Using the in pH environments of 1.7, 5.5, 6.0, 7.4, and 8.5.
Answer
Answer
Functional Group Name Hydrophilic or Hydrophobic
Halogen; fluorine
Effects can vary; fluorine can act as a hydrogen bond acceptor; however, studies have
A The structure of haloperidol contains only one basic functional group and no acidic functional groups.
shown that the substitution of a hydrogen atom with a fluorine atom tends to slightly
enhance lipid solubility.
Tertiary amine
B Ketone Hydrophilic due to its ability to act as a hydrogen bond acceptor.
OH
C Alkyl group; alkyl chain; aliphatic chain Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
N
groups enhance lipid solubility.
D Tertiary amine Hydrophilic due to its ability to ionize (form an ion–dipole interaction with water) and to
F participate in hydrogen bonding (acceptor) in its unionized form.
Cl
O
E Tertiary hydroxyl group; tertiary alcohol Hydrophilic due to its ability to form hydrogen bonds as either a donor or an acceptor.

F Phenyl ring; aromatic ring; aromatic Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
hydrocarbon groups enhance lipid solubility.

4. Shown below is a structural analog can enhance the duration of haloperidol.
2. Based on their electronic properties AND their relative positions in the molecule, identify if functional

groups A, C, and E are electron withdrawing or electron donating. Additionally, identify if this effect is
due to resonance or induction.
Answer
• Functional Group A is a halogen. Because all halogens are more electronegative than an adjacent
aromatic ring, the fluorine atom acts as an electron withdrawing group through induction.

• Functional Group C is an alkyl group and has a lower electronegativity than the oxygen atom of the
ketone or the nitrogen atom of the tertiary amine; therefore, it acts as an electron donating group
through induction.

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5. Using the table below ionizable functional groups.

C
B
D
A