Atropisomer

Some tiny things cannot turn.

They stay stuck in one shape. This happens because they are too bulky. The big parts bump into each other. This stops the parts from spinning.

These shapes can be found in nature. They can even help make new medicines. Some help treat cancer. This is a neat trick of nature. Can you imagine being stuck like that?

Some tiny molecules have a special trait. They cannot spin easily. This trait is called atropisomerism.

Most molecules can spin around a single bond. But some molecules have big parts. These parts bump into each other. This bumping makes it hard to turn.

Because they cannot spin, they stay in one shape. These shapes are called atropisomers. They can be found in nature. Some are used to make new medicines. For example, a drug called vancomycin has a very complex shape.

Scientists also use these shapes in labs. They use them to help make other chemicals. This is called asymmetric catalysis. It helps make the right shapes for new tools. One drug used for cancer is an atropisomer. Some atropisomers even help with nerve growth. It is important to study them well. This is because different shapes might act differently in the body.

Some molecules have a very special way of being shaped. Most tiny molecules can spin easily around their center bonds. However, some molecules have large parts that get in the way. These large parts bump into each other and stop the spinning. This trait is called atropisomerism, which comes from a word meaning "not to be turned."

Because they cannot spin freely, these molecules stay in fixed shapes. These different shapes are known as atropisomers. They are important because their specific shape changes how they work in nature.

How does this stopping happen? It works because of something called steric strain. This happens when bulky parts of the molecule try to occupy the same space.

This creates a barrier that prevents the molecule from rotating. The bond connecting the two parts might also be very rigid. To stay separate, the molecules must have a high energy barrier. A rule from scientist Michinori Ōki says they must stay in shape for at least 1000 seconds. This allows scientists to study each shape one at a time.

People have been studying these shapes for a long time. In 1922, George Christie and James Kenner first found them. They saw this in a specific type of molecule called a diacid. Later, in 1933, a German biochemist named Richard Kuhn used the term atropisomer. He created the name for a book by Karl Freudenberg.

Since then, scientists have learned much more about how these shapes change with temperature. They use special tools like magnetic resonance to watch them move.

There are many different kinds of these molecules in the world. Many examples are biaryls, which are made of two rings joined together.

Some special versions, like BINAP and BINOL, are used in labs. Scientists use them for asymmetric catalysis, which helps build new chemical shapes. Other examples include things like vancomycin or the plant chemical knipholone. Knipholone is found in the roots of a plant called Kniphofia foliosa. It can help fight malaria and even tumors.

Atropisomers are very important for making new medicines. For instance, the drug methaqualone is an example of this phenomenon. Another drug, telenzepine, has two different shapes that act differently. One shape is 500 times more active than the other in certain tests.

Some atropisomers, like mastigophorene A, even help with nerve growth. Because different shapes act differently in the body, doctors must study them carefully. This ensures that the medicine works the right way for patients.

Atropisomers are a specific type of stereoisomer. They arise because of hindered rotation around a single bond. In most molecules, parts can spin freely around their central bonds. However, in atropisomers, bulky groups create a barrier to this movement. This barrier is created by steric strain, which occurs when parts of the molecule bump into each other.

Because they cannot rotate easily, these molecules stay in fixed shapes. These shapes are called rotamers. This phenomenon is vital for understanding how molecules interact in biological systems and in chemical design.

The mechanism of atropisomerism depends on energy barriers. The stability of an individual atropisomer is provided by repulsive interactions. These interactions prevent the subunits from spinning past one another. Both the steric bulk of the groups and the rigidity of the central bond contribute to this effect.

To be considered a true atropisomer, the molecules must stay in their specific shapes for a certain amount of time. Scientist Michinori Ōki refined this definition. He specified that atropisomers must interconvert with a half-life of at least 1000 seconds at a specific temperature. This corresponds to an energy barrier of 93 kJ·mol⁻¹ at 300 K. Scientists often study these moving parts using dynamic nuclear magnetic resonance spectroscopy.

Atropisomers are categorized based on their chemical structure and symmetry. When the substituents on the molecule are achiral, the conformers are called enantiomers. These are specifically known as atropoenantiomers and exhibit axial chirality. If the substituents are not achiral, the molecules are called diastereomers, or atropodiastereomers.

Most studied examples are derivatives of biphenyl, which consist of two joined rings. Other systems include acyclic structures like amides and thioamides. In these cases, the C-N bonds have partial double bond character. Some aliphatic ring systems, like cyclohexanes, can also show this behavior if they have bulky substituents.

The history of this discovery began in the early 20th century. In 1922, George Christie and James Kenner first experimentally detected atropisomerism. They observed it in a tetra-substituted biphenyl diacid. Later, in 1933, the German biochemist Richard Kuhn coined the term "atropisomer." He used the name for a theoretical concept in Karl Freudenberg's volume, *Stereochemie*. The name comes from the Greek meaning "not to be turned."

Since then, researchers have moved from observing these shapes to using them in complex chemical reactions.

Scientists use several methods to create and separate these molecules. Axially chiral biaryl compounds can be prepared through coupling reactions. These include the Ullmann coupling, the Suzuki–Miyaura reaction, or palladium-catalyzed arylation.

Once a racemic mixture is made, it can be resolved into individual shapes. One way to do this is through seed-directed crystallization. For example, 1,1'-binaphthyl can crystallize from a melt as individual enantiomers. Scientists can also use chiral bridges or chiral auxiliaries to achieve diastereoselective coupling. Enantioselective coupling may involve using a chiral leaving group or specific oxidative conditions.

Atropisomers play a massive role in modern medicine and chemistry. Certain biaryl compounds, such as BINAP, QUINAP, and BINOL, are used as chiral ligands.

These ligands are essential for asymmetric catalysis, which helps create specific molecular shapes. They are used in metal-catalyzed reactions like hydrogenation, epoxidation, and allylic alkylation. In nature, atropisomers are also common. The natural product mastigophorene A helps with nerve growth. The molecule vancomycin is highly complex and includes two chiral planes in its biaryl axis. Another example is knipholone, found in the roots of *Kniphofia foliosa*. The M form of knipholone shows antimalarial and antitumor activities.

Understanding these shapes is critical for drug design. The drug methaqualone is a classical example of a molecule exhibiting atropisomerism. Another example is telenzepine, which has a central thienobenzodiazepine ring. The (+)-isomer of telenzepine is about 500-fold more active than the (–)-isomer at certain receptors.

However, designing drugs with atropisomers can be difficult. If the isomers interconvert faster than expected, the drug's effect might change. Because different shapes interact with the body differently, scientists must test them carefully. This ensures that the specific shape reaches the right target in the patient.