Question

The chiral catalyst \((R)\)-BINAP-Ru is used to hydrogenate alkenes to give alkanes (Section \(6.7 \mathrm{C}\) ). The products are produced with high enantiomeric excess. An example is the formation of \((S)\)-naproxen, a pain reliever. (a) What kind of isomers are the enantiomers of BINAP? (b) How can one enantiomer of naproxen be formed in such high yield?

Short answer

Answer: The enantiomers of BINAP are stereoisomers. The chiral catalyst (R)-BINAP-Ru selectively promotes the formation of one enantiomer, (S)-naproxen, due to its interaction with the substrate, which favors the formation of (S)-naproxen while suppressing the formation of its mirror image. Consequently, (S)-naproxen is formed with high yield and enantiomeric excess.

Step-by-step solution

Understand Isomers and Enantiomers

Isomers are chemical compounds with the same molecular formula but different structural arrangements. There are two main classes of isomers: constitutional isomers and stereoisomers. Stereoisomers are further classified into enantiomers and diastereomers. Enantiomers are non-superimposable mirror images of each other, and their three-dimensional arrangement plays a crucial role in their properties.

Identify the type of isomers that enantiomers of BINAP are

Since enantiomers are a type of stereoisomer and have different spatial arrangements, the enantiomers of BINAP are classified as stereoisomers.

Understand Chiral Catalysts

Chiral catalysts are chemical compounds that can enable the formation of one enantiomer of a product over the other, leading to enantioselectivity. This can be achieved by selectively interacting with one enantiomer of the substrate in the reaction, which further translates into different reaction rates for the enantiomers.

Explain how one enantiomer of naproxen can be formed with high yield

In the given hydrogenation process, the chiral catalyst (R)-BINAP-Ru selectively promotes the formation of one enantiomer of the product - in this case, (S)-naproxen. This is due to the interaction between the chiral catalyst and the substrate, which favors the formation of (S)-naproxen while suppressing the formation of its mirror image. As a result, one enantiomer of naproxen, the desired (S)-naproxen, is formed with high yield and enantiomeric excess.

Key concepts

Enantiomers

Enantiomers are one of the two major categories of stereoisomers, molecules that have the same molecular formula and sequence of bonded atoms (constitution), but which differ in the three-dimensional orientations of their atoms in space. Unlike diastereomers, which are stereoisomers that are not mirror images, enantiomers are non-superimposable mirror images of each other—like left and right hands.

This seemingly minor difference can have a major impact on the biological activity of the molecules, as their interactions with other chiral molecules (including many biomolecules) can differ markedly. For instance, the two enantiomers of a drug can have vastly different therapeutic effects or side effects. To give an example closer to the one from the exercise, (R)-naproxen and (S)-naproxen are enantiomers where one of them, usually the (S)-isomer, is therapeutically active as a pain reliever, while the other may be less active or have different biological effects.

The distinct interactions of enantiomers with polarized light are also characteristic, with one enantiomer rotating the plane of polarized light to the left (levorotatory) and the other to the right (dextrorotatory). These optical activities are one way to identify and distinguish between enantiomers in the laboratory.

Stereoisomers

Stereoisomers are molecules that share the same molecular formula and connectivities but differ in the spatial arrangement of their atoms. While enantiomers represent mirror-image isomers, another form of stereoisomers—diastereomers—are not mirror images of each other and can differ in physical properties like melting point and boiling point.

Types of Stereoisomers

Stereoisomers can fall into several subcategories:

• Enantiomers – Mirror-image isomers that are non-superimposable.
• Diastereomers – Non-mirror-image isomers; these include cis-trans isomers in alkenes and compounds with multiple stereocenters that aren't mirror images.
• Conformational isomers – Isomers that can be interconverted solely by rotations about formally single bonds.

Understanding the nature of these different types of isomers is essential for predicting the behavior of molecules in various environments, including biological systems and chemical reactions. Because their differences lie in the 3D structure, the physical properties and reactivities of stereoisomers can be very distinct, leading to significant implications in fields such as pharmaceuticals, where the right isomeric form of a compound can mean the difference between a cure and a treatment with no effect or undesired side effects.

Enantioselective Synthesis

Enantioselective synthesis, also known as asymmetric synthesis, is a method in organic chemistry that aims to preferentially produce one enantiomer over the other in a chemical reaction. This preference is incredibly significant in the creation of compounds for pharmaceuticals, as the desired biological activity is often associated with only one enantiomer.

Role of Chiral Catalysts

Chiral catalysts play an integral role in enantioselective synthesis. In these reactions, a chiral catalyst, such as (R)-BINAP-Ru used in the textbook example, can accelerate the rate of reaction for one enantiomer over the other. This chiral environment provided by the catalyst leads to the majority formation of one specific enantiomer, often resulting in high enantiomeric excess (ee), which is the percentage difference between the two enantiomers produced.

The advantage of using such catalysts is that they are not consumed in the reaction, can be used in small quantities, and can often be recovered and reused. Their use in synthesis is an elegant solution to the problem of producing large quantities of a single enantiomer, making the process more economical and environmentally friendly. The enantioselective synthesis of (S)-naproxen is a brilliant example of how chiral catalysts can be used in industrial-scale reactions to produce a high yield of a desired enantiomer with significant therapeutic value.