Atropisomerism

In 1933, German scientist Richard Kuhn invented the term atropisomer as a theoretical idea for Karl Freudenberg’s pioneering Stereochemie book. George Christie and James Kenner discovered atropisomerism in a tetrasubstituted biphenyl, a diacid, in 1922. Michinori ki refined the definition of atropisomers to account for the temperature dependence of conformer interconversion, clarifying that atropisomers interconvert with a half-life of at least 1000 secs at a specific temperature, correlating to an energy barrier of 93 kJ mol-1 (22 kcal mol -1) at 300 K (27 °C).

Atropisomers are isomers that may be isolated by preventing or restricting rotation around a single bond, often between 2 planar moieties. Atropisomerism is derived from the Greek terms: “a” which means “not,” and tropos, which means “turn.” Suppose there is a bulky group in the ortho position of biphenyl or a strained ring structural characteristic. Bulky substitutions or strained rings may increase the barrier to rotations between two dissimilar conformations to the point that atropisomers may be seen. Atropisomerism is also known as axial chirality, and the chirality is an axis rather than a centre or a plane. Because axial chirality is based on rotational stability around a single bond, the key prerequisites for this stability must be examined. Because the C-C bond allows for easy rotation and is symmetric, simple biphenyl is achiral. The C-C sigma bond is referred to as a crucial bond.

Atropisomerism in axial chirality

Individual atropisomers’ stability is provided by repulsive interactions that prevent rotation. The electrostatic bulk and, in theory, the length and stiffness of the link joining the two subunits both have a role. Because atropisomerism is a kind of fluxionality, it is often examined using dynamical nuclear magnetic resonance spectroscopy. Inferences from theory, as well as the outcomes and yields of reactions, play a role.

Atropisomers are axially chiral (planar chirality). When the barriers to racemisation are large, as shown by the BINAP ligands, the phenomenon has practical applications in asymmetric synthesis. Methaqualone, a hypnotic-sedative and anxiolytic, is a famous example of a pharmacological molecule that shows atropisomerism.

There are two prerequisites for an atropisomerism to exist:

1. A rotational axis but stable in nature.

2. Both sides of the axis must possess different substituents.

Three variables primarily influence the conformational stability of axially chiral biaryl compounds:

i. The merged steric request of the methyl group in the vicinity of the axis.

ii. The presence, length, and stiffness of bridges.

iii. Atropisomerisation method other than a simple physical rotation around the axis, such as a photochemically or chemically triggered process.

Newman projections along the axis of impeded rotation may be used to determine the axial chiral molecules of biaryl atropisomers. The ortho and, in certain situations, meta substituents are given precedence first, according to the Cahn–Ingold–Prelog priority criteria. One naming approach is based on imagining the helicity specified by these groupings. The shape is allocated P or for clockwise and M or counterclockwise, starting with the highest priority substituent in the nearest ring and progressing along the shortest route to the highest priority substituent in the opposite ring. Alternatively, all four groups may be prioritised using Cahn–Ingold–Prelog priority criteria, with the groupings on the “front” atoms of the Newman projection receiving overall priority. In similarity to the classic R/S for a typical tetrahedral stereocenter, the configurations are Ra and Sa.

Atropisomerism in non-bridged biphenyls

Biphenyl is a chemical formula (C6H5)2 aromatic hydrocarbon. It is significant as a precursor to manufacturing polychlorinated biphenyls (PCBs), which were previously extensively employed as dielectric fluids and heat exchange agents. Biphenyl is also used as a precursor in synthesising organic molecules such as emulsifiers, optical brighteners, agricultural implements, and polymers. Water is insoluble in biphenyl; however, it is soluble in most organic solvents. The biphenyl molecule is made up of two linked phenyl rings. Because the ortho positions of biphenyl are replaced with two separate bulky groups, it is chiral and resolvable owing to limited rotation through the pivotal bond.

Stereochemistry in Biphenyls

Biphenyl exhibits conformational isomerism rather than geometrical isomerism; rotation around a single bond is feasible in biphenyls, and notably, their ortho-substituted counterparts are sterically restricted. As a result, certain substituted biphenyls exhibit atropisomerism, which means that the separate C2-symmetric-isomers are visually stable. Some derivatives and related compounds, such as BINAP, are used as ligands in synthetic chemistry. The equilibrium torsional angle of unsubstituted biphenyl is 44.4°, and the torsional barriers are fairly tiny, 6.0 kJ/mol at 0° and 6.5 kJ/mol at 90°. The barrier is substantially increased by adding ortho substituents: in the 2, 2′-dimethyl derivatives instance, the resistance is 17.4 kcal/mol (72.8 kJ/mol).

Conclusion

Many atropisomers are found in nature, but some have the potential for drug creation. Mastigophorene A, a natural substance, has been discovered to help with nerve development. Vancomycin, derived from such an Actinobacterium, and knipholone, discovered in the stems of Kniphofia foliosa of the Asphodelaceae family, are two further instances of naturally occurring atropisomers. Vancomycin’s structural complexity is notable because of the intricacy of its stereochemistry, which contains numerous stereocenters and two chiral orientations in its stereogenic biaryl axis. Knipholone, which exhibits axial chirality, is found in the environment and has been proven to have antimalarial and anticancer properties, notably in the M form.

The use of atropisomeric medications allows pharmaceuticals to have stereochemical differences and precision in design. (–)-N-acetyl allocolchinol, for example, is a medication that was identified to help in chemotherapeutic cancer treatment.