Separating drug enantiomers
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Separating drug enantiomers
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[post_date] => 2025-01-14 05:34:46
[post_date_gmt] => 2025-01-14 10:34:46
[post_content] => Practice Passage (Question 1-5)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Citalopram received FDA approval in 1998 and is one of the most commonly prescribed antidepressants. In 2012, the (S)-stereoisomer of citalopram was patented, leading to allegations of "evergreening" - when pharmaceutical companies apply for patents on structurally similar drugs to maximize profitability. The chemical structures for (R)-citalopram and (S)-citalopram are shown below.
In fact, commercially available citalopram is a racemic mixture of 50% (R)-citalopram and 50% (S)-citalopram. Only the (S)-stereoisomer has antidepressant activity. The separation technique known as chiral resolution, first employed by Louis Pasteur, may be utilized in separating the (R)- and (S)- stereoisomers. A generalized schematic of the chiral resolution process is presented below (Figure 1).
Figure 1: Generalized schematic of chiral resolution for enantiomers.
A scientist decides to separate (R)-citalopram (CR) and (S)-citalopram (CS) using the chiral resolution scheme above. (R,R)-tartaric acid was chosen as the resolving agent (BR). The method used to separate the resulting diastereomers CR-BR and CS-BR is described below.
The scientist proceeds to select a solvent. A small amount of solvent is added to the solid diastereomer mixture at room temperature in a test tube and stirred ("room temperature"). Then, the test tube is heated in a hot water bath to a temperature close to the boiling point of the solvent and stirred ("hot water bath"). The results of several trials are presented below:
Table 1: Solubility results for crystallization experiment using different solvents.
Eventually, the scientist successfully separates the diastereomers and the enantiomer.
Excited, the scientist decides to look up the physical properties of citalopram to learn more about how it may behave in the human body as a drug. During his search, he comes across a "log P" value, which predicts the polarity of a given compound. Compounds that dissolve in organic, nonpolar solvents have higher log P values, and compounds that dissolve in aqueous, polar solvents have lower log P values. Intrigued, the scientist decides to search for the log P values of citalopram and several other compounds.
Table 2: Selected log P values for assorted compounds.
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[question] => What is the hybridization and the bond angle of the central carbon in the C-C≡N bond in citalopram?
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[answer] => 4
[description] => Reason for the Correct Answer:
There is a triple bond at the central carbon in the C-C≡N bond.
Carbon’s ground state configuration is 
. In a triple bond, the 2s orbital mixes with one of the p orbitals to get 1s2sp1sp12p12p1.
The central carbon in the C-C≡N bond is sp-hybridized and has a bond angle of 180 degrees (linear configuration).
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[each_answer] => A.sp, 120 degrees
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[each_answer] => B.sp2, 180 degrees
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[each_answer] => C.sp2, 120 degrees
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[each_answer] => D.sp, 180 degrees
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[1] => Array
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[quiz_unique_key] => 3873426850
[question] => What properties would be expected to be identical between (R)-citalopram and (S)-citalopram?
I. Boiling point
II. IR spectrum
III. Rate of reaction with the same achiral reagent
IV. Rate of reaction with the same chiral reagent
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[answer] => 3
[description] => Reason for the Correct Answer:
(R)-citalopram and (S)-citalopram are enantiomers, non-superposable mirror images of each other.
Enantiomers have almost identical chemical and physical properties in a symmetrical environment.
Since enantiomers have different orientations, they would likely not react similarly with another chiral reagent.
Therefore, the following properties would be expected to be identical between (R)-citalopram and (S)-citalopram: boiling point, IR spectrum, and rate of reaction with the same achiral reagent.
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[each_answer] => A.I, III, and IV
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[each_answer] => B.I, II and IV
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[each_answer] => C.I, II, and III
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[each_answer] => D.I, II, III, and IV
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[quiz_unique_key] => 83407773
[question] => Which of the following molecules correctly represents (R,R)-tartaric acid (C4H6O6)?
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[answer] => 3
[description] => Reason for the Correct Answer:
Two of the answer choices are actually identical molecules. For instance, try rotating the wedge-dash diagram so they are all in the same orientation on paper (the central C-C bond all angling to the lower right, for instance).
If you rotated the diagrams, you should see that the answer choices with the -OH wedges on the same side (both -OH groups coming out at you) are the same molecule (mesotartaric acid).
Now use the “steering wheel” method to figure out which compound should have the R configuration at both chiral centers. One of the remaining answer choices is (R,R) – the other one is (S,S). If you’re having trouble, check out the excellent Khan Academy tutorial on the “Cahn-Ingold-Prelog system for naming enantiomers.”
is the (R,R) enantiomer. The chiral center on the left is already set up in the “steering wheel” configuration with H (the lowest priority group) pointing away from you. -OH is the highest priority group, then the -COOH, then finally the -C(COOH)(OH)(H). The groups are arranged in a clockwise configuration, making the chirality center R. You can flip the -OH and -H around at the other chiral center so that -H is pointing away from you – this is an exact replica of the first chiral center, making this compound (R,R).
Using the same reasoning,
can be shown to be the (S,S) enantiomer.
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[each_answer] => A.
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[each_answer] => B.
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[each_answer] => C.
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[each_answer] => D.
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[question] => In Table 1, which is the best solvent for the scientist to use to separate the diastereomers?
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[answer] => 3
[description] => Reason for the Correct Answer:
Crystallization aims to exploit differences in solubility between the compound of interest and impurities that may be contaminating that compound.
It is difficult to continue to experiment if the solute dissolves in room temperature because then the temperature of the solution will need to be lowered to below room temperature. The solvent and solute mixture is usually heated to a high temperature, and then allowed to cool slowly so the crystals of the compound of interest can gradually precipitate out of the solution above room temperature.
The best solvent is C – the solutes do not dissolve at room temperature, but dissolves at a higher temperature so then the compound of interest may precipitate out of solution as the temperature is gradually lowered.
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[each_answer] => A.A
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[each_answer] => B.B
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[question] => Based on the log P values provided in Table 2, what general assumptions can be made about citalopram’s properties as a drug in the human body? (Hint: In pharmacology, volume of distribution is a theoretical measure that tries to estimate how much drug gets absorbed into tissue)
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[answer] => 2
[description] => Reason for the Correct Answer:
Heptane is very non-polar, and hydrochloric acid is very polar.
Lipophilic drugs tend to distribute into fatty tissue in the body, while hydrophilic drugs tend to stay in the circulation.
Citalopram appears to be non-polar (similar to heptane), making it lipophilic. It is acceptable to assume that lipophilic drugs generally have a higher volume of distribution in the body due to the volume of fatty tissue present.
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[each_answer] => A.Lipophobic with high volume of distribution
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[each_answer] => B.Lipophilic with high volume of distribution
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[each_answer] => C.Lipophobic with low volume of distribution
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