Atropisomer

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.