Organic chemical compounds contain a vast number of isomers, molecules with the same molecular formula but different atomic arrangement, of which there are three types: structural, geometric and optical. The most closely-linked of isomers are optical isomers, which differ only by the three-dimensional placement of the molecule’s attachments, which renders its mirror images to be non-superimposable. The presence of optical isomerism within a molecule is determined by the existence of a chiral centre—a carbon atom with four different groups (see Appendix, figure 1).
Pure optical isomers have identical physical properties such as melting point, boiling point and density, as well as identical chemical properties; thus there are only two ways that they can be distinguished: their interaction with other chiral substances and their interaction with plane polarized light. An enantiomer (one out of a pair of optical isomers) rotates plane polarized light in the opposite direction of which the other enantiomer rotates the plane polarized light, of equal magnitude (see Appendix A, figure 2). An enantiomer that shifts plane polarized light to the left is given the prefix “L” (levorotatory) or “S”, while an enantiomer that shifts plane polarized light to the right is given the prefix “D” (dextrorotatory) or “R”.
Despite their physical and chemical similarities, optical isomers are known to have substantially different behaviours within the human body. This is due to the fact that enzymes and receptors in the body are stereospecific, meaning that they can interact with one enantiomer of certain molecules and not the other. For instance, the human body can only break down D-glucose (dextrose) for energy but not L-glucose, and can only utilize L-amino acids rather than D-amino acids. While one form of a stereoisomer may be beneficial, the other may be ineffective or even harmful, in some cases.
Thus, it is crucial that optical isomerism is taken into account during medicinal drug development and usage. For example, the sedative thalidomide was available in Europe in the 1960s for purposes of alleviating morning sickness in pregnant women. However, the drug was sold as a racemic mixture, which contains equal portions of both enantiomers (this would not shift plane polarized light as the two enantiomers shift in different directions), and while R-thalidomide (see Appendix A, figure 3) works effectively as a sedative; S-thalidomide can cause genetic damage leading to mutation of the fetus. Consequently, 12 000 infants were born worldwide with malformation of the limbs.
To further illustrate the importance of optical isomers in drug action, the drug ibuprofen can be explored. Ibuprofen is a drug used for anti-inflammatory purposes such as pain relief, fever and swelling reduction, and is classified as a nonsteroidal anti-inflammatory drug (NSAID). Derived from propanoic acid in the 1960s by a pharmacy chain called Boot’s UK Limited, ibuprofen was initially launched as a treatment for rheumatoid arthritis, and was awarded the Queen’s Award for Technical Achievement in 1987. It is currently available under a variety of trademarks such as Advil, Motrin, Nurofen, and Brufen, among others.
Ibuprofen works by inhibiting the enzymatic action of cyclooxygenase (COX1 and COX2) within the body, which catalyzes the conversion of a compound called arachidonic acid into prostaglandins. Prostaglandins are locally-acting hormones that cause swelling, heat, loss of function, fever and pain, collectively known as inflammation, at a site of injury through the accumulation of white blood cells. Through inhibiting this reaction, painful symptoms can be reduced or eliminated.
The IUPAC name for ibuprofen is 2-(4-(2-methylpropyl) phenyl) propanoic acid. It is a carboxylic acid which also contains a phenyl group (see Appendix A, figure 5). Due to its chirality, ibuprofen has two enantiomers (see Appendix A, figure 6): S-ibuprofen, which rotates plane polarized light to the left and is pharmacologically active, and R-ibuprofen, which rotates plane polarized light to the right and has no anti-inflammatory effect (and is thus inactive as a drug, since . However, ibuprofen is sold on the market as a racemic mixture. Thus, a dose of ibuprofen contains only 50% of the active enantiomer, S-ibuprofen. Nevertheless, R-ibuprofen undergoes species-specific chiral inversion within the body, in which approximately 60% of R-ibuprofen is converted into S-ibuprofen. The mechanism of the inversion is through an enzyme, alpha-methylacyl-CoA racemase (AMACR) that is present in the liver, the kidney and gastrointestinal tract. A substitution nucleophilic bimolecular (SN2) reaction must take place (see Appendix B, figure 1), which results in the complete conversion of every molecule of one enantiomer to the other. In this case, only R-ibuprofen is converted into S-ibuprofen (see Appendix B, figure 2).
The benefits associated with ibuprofen use include its efficiency as a NSAID in decreasing inflammation, in addition to be non-addictive and affordable. However, ibuprofen often causes stomach irritation, and can impede concentration and cause drowsiness. It may also result in a variety of adverse side effects (see Appendix C, figure 1). An alternative to ibuprofen is the drug acetaminophen, also known as paracetamol. Acetaminophen, (see Appendix A, figure 7), is commercially available under brand names such as Tylenol and Anacin (see Appendix A, figure 8). It works by inhibiting the synthesis of prostaglandins. It does not, however, have any anti-inflammatory action and thus only targets tissue of the nervous system—easing pain without being directed towards the root of the problem. Acetaminophen is known to cause fewer side effects than ibuprofen; however for a list of side effects, see Appendix C, figure 2.
Acetaminophen does not have a chiral centre, and therefore does not have any optical isomers. Both drugs are used to relieve headache pains and fever; however their varying properties impact their function and effectiveness in treating specific symptoms.
The solubility of ibuprofen in water is 0.0002M. Although its carboxyl functional group is highly polar, the large non-polar component greatly decreases its overall polarity. As “like dissolves like”, ibuprofen does not dissolve well in water, which is polar. To solve this problem, ibuprofen is reacted with the amino acid lysine (see Appendix A, figure 9), which together forms the salt ibuprofen lysinate. Ibuprofen is then released into the bloodstream in which the reaction can reverse. On the other hand, acetaminophen is highly soluble in water; with a solubility of 0.091M. Because it contains an amide and an alcohol, there is a substantial degree of hydrogen bonding resulting in high polarity (see Appendix A, figure 10). This allows the drug to be absorbed into the bloodstream effectively.
Ibuprofen has a pKa (acid dissociation constant) of approximately 4.43, while the pKa of acetaminophen is 9.51 and 25°C, making ibuprofen more acidic. Because neutral substances pass through bodily membranes more easily, acetaminophen is more easily absorbed. Acetaminophen also has more acid stability. Administered orally, an ibuprofen capsule has an enteric coating, which prevents stomach acid from breaking down the drug before it reaches the small intestine, where it is absorbed. A film coating is used on a tablet of acetaminophen, which protects the tongue from the contents, as well as protecting the contents from moisture and light. Within the body, the film can be broken down by saliva or stomach acid, and the way in which the drug is absorbed is not affected.
Appendix A: Images
Figure 1: Molecule with a chiral centreFigure 2: Plane polarized light beamed through a filter. The two enantiomers shift light in opposite directions.
Figure 1: Type of isomer vs. molecule melting and boiling point Type of Isomers
Melting Point and Boiling Point
MP: -140°C BP: -1° C
MP: -159.6°C BP: -11.7 °C
MP: -138.9 °C BP: 3.7 ºC
MP: -105.5 °C BP: 0.9 °C
MP: -115 °C BP: 98-100 °C
MP: -115 °C BP: 98-100 °C
Figure 3: The two optical isomers of thalidomide. R-thalidomide works effectively as a sedative, while S-thalidomide can damage the fetus.
Figure 5: Skeletal diagram of ibuprofen, with the functional group labeled
Appendix A (cont’d): Images
Figure 6: Optical isomers of ibuprofen; S-ibuprofen is on the left and R-ibuprofen is on the right
Figure 7: Skeletal diagram of acetaminophen,
with the functional groups labeled
Figure 9: Skeletal diagram of the amino acid lysine, which is reacted with ibuprofen in order to allow it to ultimately dissolve into the bloodstream
Figure 10: Polarity of ibuprofen vs. acetaminophen
Appendix B: Reactions
Figure 1: The process of a substitution nucleophilic bimolecular (SN2) reaction
Figure 2: “The mechanism of the enzymatic [chiral] inversion of R-ibuprofen (42) into S-ibuprofen. At first, the carboxylic acid is converted into an intermediate thioester (43a) by acyl-CoA ligase… [This] is then converted to the opposite configuration by an epimerase, and the resultant thioester (43b) is hydrolyzed by a hydrolase, releasing S-ibuprofen.”
Appendix C: Tables
Figure 1: Side effects of ibuprofen
Mild side effects include:
upset stomach, mild heartburn, diarrhea, constipation;
dizziness, headache, nervousness;
skin itching or rash;
Serious side effects include:
chest pain, weakness, shortness of breath, slurred speech, problems with vision or balance; black, bloody, or tarry stools, coughing up blood or vomit that looks like coffee grounds; swelling or rapid weight gain;
urinating less than usual or not at all;
nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; bruising, severe tingling, numbness, pain, muscle weakness; or severe headache, neck stiffness, chills, increased sensitivity to light, and/or seizure (convulsions).
Figure 2: Side effects of acetaminophen
Mild side effects include:
Serious side effects include:
low fever with nausea, stomach pain, and loss of appetite;
dark urine, clay-colored stools; or
jaundice (yellowing of the skin or eyes)
liver failure (with overdose)
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