O-Chem in Real Life: An Anti-Aromatic Drug

This is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, more commonly known as olanzapine. It is apparently a pretty effective antipsychotic agent.

The "core" of this molecule is the central ring. Seven-membered rings containing two nitrogens are know as diazepines. The fused benzene ring (on the left) makes this a benzodiazepine. The fused sulfur heterocyclic ring makes this a theienobenzodiazepine (the 5-membered sulfur ring is called thiophene). The substituent ring at the back with the two nitrogens in a 1,4 arrangement is called a piperidine ring, in this case, it also has a methyl on the 4-position.

The diazepine structure is commonly associated with pharmacological activity. In this particular diazepine, the two fused rings impart a special form of activity. Look carefully at the central ring. Specifically, count the number of electrons in the pi-system in the ring. Eight, right? The Huckel rule tells us that (4n + 2) electrons in a conjugated cyclic system are more stable than they would be in a corresponding linear conjugated system (aromatic is stable). Conversely, 4n electrons in a cyclic conjugated system are less stable than they would be in a corresponding linear conjugated system (anti-aromatic is unstable). The central ring in olanzapine is anti-aromatic, when flat!

So, just like cycloctatetraene, it avoids anti-aromaticity by bending into a boat-like conformation. The steric energy cost of this conformation change is offset by the energy gain of avoiding anti-aromaticity. This bending points the benzene and the thiophene ring upwards, so that the molecule overall adopts a "butterfly" shape, shown below.

This is apparently critical to its function. The butterfly shape enables the drug to fit into the critical receptor site. Anti-aromaticity has a use!