Question

When oxaloacetic acid and acetyl-coenzyme A (acetyl-CoA) labeled with radioactive carbon-14 in position 2 are incubated with citrate synthase, an enzyme of the tricarboxylic acid cycle, only the following enantiomer of [2-14C]citric acid is formed stereoselectively. Note that citric acid containing only \({ }^{12} \mathrm{C}\) is achiral. Assign an \(R\) or \(\$$ configuration to this enantiomer of \)[2-14\( C]citric acid. (Note: Carbon-14 has a higher priority than carbon-12.) O=C(O)CC(O)(CC(=O)O)C(=O)O Oxaloacetic acid Acetyl-CoA \)\left[2^{-14} \mathrm{C}\right]$ Citric acid

Short answer

Answer: The enantiomer of [2-14C]citric acid has an \(S\) configuration.

Step-by-step solution

Recall the Cahn-Ingold-Prelog rules

To determine the \(R\) or \(S\) configuration of a chiral carbon, we should follow the Cahn-Ingold-Prelog (CIP) rules. The CIP rules involve the following steps: 1. Assign priority to each of the four atoms or groups directly attached to the chiral center, with the highest atomic number having the highest priority, and the lowest atomic number having the lowest priority. 2. Arrange the molecule in such a way that the atom or group with the lowest priority is pointing away from you. 3. Observe the direction of the remaining three atoms/groups in order of decreasing priority (from highest to lowest). If the direction is clockwise, the absolute configuration is \(R\). If the direction is counterclockwise, the absolute configuration is \(S\).

Analyze the [2-14C]citric acid structure

Observe the structure of the [2-14C]citric acid and identify the chiral center with carbon-14. Visualize the molecule in a way that the group with the lowest priority is pointing away from you.

Assign priority to atoms/groups

Now, we need to identify the highest to lowest priority groups attached to the chiral center (Carbon-14). The priority is as follows: 1. Oxygen (higher atomic number) 2. Carbon-14 (higher priority than Carbon-12) 3. Carbon-12 4. Hydrogen (lowest atomic number)

Determine the \(R\) or \(S\) configuration

With the group of lowest priority (Hydrogen) pointing away from you, follow the order of decreasing priority. In this case, Oxygen (1) -> Carbon-14 (2) -> Carbon-12 (3). Since the direction is counterclockwise, the configuration for the [2-14C]citric acid's enantiomer is \(S\). The enantiomer of [2-14C]citric acid has an \(S\) configuration.

Key concepts

Cahn-Ingold-Prelog rules

The Cahn-Ingold-Prelog (CIP) rules are an essential part of stereochemistry, a branch of organic chemistry that deals with the three-dimensional arrangement of atoms within molecules. The task of the CIP rules is to provide a consistent method for assigning a unique descriptor to the configuration of stereocenters—typically chiral centers—within a molecule.

To apply the CIP rules, you first need to assign priority to the atoms or groups attached to the chiral center. The higher the atomic number, the higher the priority. In the case of isotopes, the heavier isotope gets higher priority. Next, orient the molecule so that the group with the lowest priority is pointing away from you, and observe the direction the other groups decrease in priority. If it's clockwise, the center is assigned an 'R' (from the Latin 'rectus', meaning 'right') configuration; counterclockwise is assigned an 'S' (from 'sinister', meaning 'left').

Utilizing these rules helps chemists describe the layout of molecules accurately, which is incredibly important for understanding how molecules interact with biological systems since the function of molecules in biochemistry is often highly dependent on their stereochemistry.

Chiral centers

Chiral centers are specific types of atoms within a molecule that have four different atoms or groups attached to them—leading to non-superimposable mirror images, known as enantiomers. These centers are a point of asymmetry in the molecule and are the reason why certain molecules can exist in two forms that are mirror images of each other.

Identifying chiral centers is crucial in organic chemistry because each enantiomer of a molecule can have different physical and chemical properties, and oftentimes, completely different biological activities. For example, one enantiomer of a drug might be therapeutically beneficial, while its mirror image could be inert or even harmful. In an educational setting, recognizing and manipulating these centers in chemical structures enables students to predict how these molecules will behave in a biological context, such as in the tricarboxylic acid cycle.

Tricarboxylic acid cycle

The tricarboxylic acid cycle, also known as the citric acid cycle or Krebs cycle, is a crucial metabolic pathway that generates energy in aerobic organisms. In this cycle, acetyl coenzyme A (acetyl-CoA) combines with oxaloacetic acid to form citric acid, which then undergoes a series of transformations to produce energy in the form of adenosine triphosphate (ATP), electron carriers, and carbon dioxide.

The cycle is not only significant for its role in energy production but also for its involvement with other metabolic processes such as amino acid synthesis and fatty acid catabolism. Moreover, the intermediates and enzymes of the tricarboxylic acid cycle are chiral, and their stereochemistry is vital. For instance, the enzyme citrate synthase mentioned in the textbook exercise ensures that the reaction between oxaloacetic acid and acetyl-CoA produces only one stereoisomer of citric acid. This specificity is a direct result of the enzyme's ability to recognize and catalyze reactions in a stereochemically precise manner.

Enantiomer identification

Enantiomers are pairs of molecules that are non-superimposable mirror images of each other, which typically occur due to the presence of chiral centers. Identifying enantiomers is important because the two forms can have dramatically different effects in biological systems. For example, the scent of oranges vs. lemons, the flavor of spearmint vs. caraway, and the efficacy of pharmaceuticals can all differ between enantiomers.

In the context of the textbook exercise, identifying the [2-14C]citric acid enantiomer involves recognizing the stereocenter with carbon-14 and applying the CIP rules to determine the molecule's absolute configuration. The process includes visualizing the molecule's 3D structure and deciding the configuration ('R' or 'S') based on the arrangement of groups around the chiral center. Accurate enantiomer identification is key to the study of not just organic chemistry, but also pharmacology and medicinal chemistry, as it determines the biological activity and potential uses of chiral compounds.