Axial chirality is cool


I like axial chirality and I like phosphines. And since I’ve been occupied the last couple of weeks taking tiny amounts of ridiculously expensive substituted BINOL derivatives and trying to convert them into the corresponding phosphines (BINAP), it’s my choice for my first chemdoodle.

This is what it looks like when it’s not crappily drawn by me.

With a dihedral angle of about 90° and the limited rotation around the carbon-carbon bond that connects the two napthyl rings it is the archetype of axial chirality.

In 1922 three brilliant chemists figured out that 6,6′-dinitrodiphenic acid, despite not having a chiral centre, must have two enantiomers. They went on straight ahead and did a chiral resolution with brucine (closely related to strychnine but not quite as toxic) that gave them beautiful crystals of the diastereomeric salts and the proof of a new form of chirality.

Chiral resolution with brucine
Chiral resolution with brucine

Chemists had been making axial chiral compounds before – I found descriptions on how to make BINOL from the early 1880s – but they just might have never attempted to resolve the enantiomers. I can’t quite pin down when BINOL was first made in an enantiopure fashion but what I can say is that I do love Brussee’s and Jansen’s 1983 synthesis: 2-naphthol, some copper and a sprinkle of enantiopure amphetamine and voilá – enantiopure BINOL. I always wondered if the writers of Breaking Bad could be convinced to alter their story: Let the protagonists make ampthetamine, use it to synthesise enantiopure BINOLs and illegally sell them way below market price to desperate, broke chemists. Instead of being chased by the police, they’d be chased by the sales reps of Sigma Aldrich. That’d make a way better story in my opinion!

BINOL is the chiral ligand in Shibasaki catalysts: These heterobimetallic systems with a central lanthanide atom and three alkali metal atoms arranged around them are good for all kinds of enantioselective reactions (aldol reactions, conjugate additions, Diels-Alder reactions). They also have really pretty crystal structures which I just had to show!

Crystal structure of an early Shibasaki catalyst.
Crystal structure of an early Shibasaki catalyst.

The really neat thing is, that BINOL can be converted into BINAP in just two easy steps (find out how on buzzfeed Organic Syntheses)! This axial chiral phosphine, where the OH-groups of the BINOL are replaced by PPh2 groups, is a great ligand for late transition metals like rhodium or palladium. Sadly, Noyori and Takaya missed the chance to give their new phosphine a fancy name when they presented it in 1980; but that is to be excused, given the fact that it works really amazingly for a bunch of enantioselective reactions, particularly asymmetric hydrogenations (also, Noyori got a Nobel Prize in 2001, which is probably even better than to name your own phosphine).

90° dihedral angle between the two naphthyl groups in BINAP
X – the 90° dihedral angle between the two naphthyl groups in BINAP.

BINAP is one of the few industrially important chiral ligands; particularly for the synthesis of (−)-menthol. Menthol is cool, literally, as it binds to receptors in human skin that usually responds to cold temperatures, causing the brain to think that it is experiencing cold.

Menthol in Mojito
One of the best ways to experience menthol.

From “cooling” cosmetics and cocktail additive to decongestants and cough medicine: we use way more menthol than can be reasonably extracted from natural source. This is where the synthesis developed by Noyori comes in handy. Five steps, including the famed asymmetric hydrogenation with a ruthenium-BINAP catalyst, from the easily available terpene Myrcene gives menthol. Good thing this process is enantioselective; the other enantiomer of menthol is just not as “refreshing” as the natural one.

BINAP also inspired a whole new class of axial chiral phosphines with interesting modifications, like TunaPhos (or TunePhos), which not only looks like a fish but whose dihedral angle can be tuned to one’s liking, depending on the number of carbons in the diether chain connecting the two phenyl rings. …I’m talking about phosphines again, aren’t I? ….

C3-TunaPhos (or TunePhos) in its natural habitat.

3 Comments Add yours

  1. Hi, I’m including you in a blog post on female scientists I recommend people should follow on twitter. Would you mind if I used your twitter profile image to go next to your name? Or if you’d like to send me any doodles that I can attribute to you, that would be great! Best regards, Amy

    1. Hi Amy,
      I’ve not been active on the blog for a little while but I’m thinking of taking it up again. Please go ahead and use images if you like, it’d be great if you could attribute them and link to my blog though.

      1. Hi Grumpy Chemist
        Just to let you know, the post is now live – feel free to take a look:
        Happy International Women’s Day for yesterday!
        Best regards

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