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# Separating enantiomers in a prescription drug

## Problem

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, percent (R)-citalopram and 50, percent (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:
SolventRoom temperatureHot water bath
ANo solute visibleNo solute visible
BNo solute visibleSolute visible
CSolute visibleNo solute visible
DSolute visibleSolute visible
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.
Compoundlog P
Heptane4, point, 40
Ethyl acetate0, point, 71
Methanolminus, 0, point, 76
Hydrochloric acidminus, 1, point, 32
Citalopram3, point, 58
Table 2: Selected log P values for assorted compounds.
What is the hybridization and the bond angle of the central carbon in the C-C≡N bond in citalopram?
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