Making Amends

A quiet week this week with not much to report. Only that my bench is sorted, my fume hood is prepped and now waiting for some reagents to arrive so I can get cracking. I’m not sure how many first year PhDs just see a synthesis involving 35ml of DIBAL and go yeah fuck it no problem.
Testament to my organolithium air sensitive training I guess. Despite being highly reactive and fairly dangerous I still feel more comfortable working with it than I do peptides in water. Not sure why? Probably my reflex knee jerk reaction to anything that’s remotely bio bollocks. Although as I keep being reassured I’ll have learnt to embrace it by the time I finish up. Seems like forever away from now but no doubt when the time comes round I will think “where the hell did that time go!? I still have so much to do”. Such is the nature of research.
With this week being so quiet I figured I would pick a paper at random (from my beloved feed demon) and break it down and give my thoughts. Great practice for me to paper review plus fills up some blog space. I would love to pick some massive total synthesis but fear my knowledge isn’t up to scratch on that so feel something simpler will have to do. Organolithium work it is.
Now after slagging off massively important and far more successful people than I last week (here), I suppose I’d also better make amends. And as luck would have it Feringa (last week’s nobel prize winner 2016 chem) has published this week in Angew chemie communications. And it’s something I get. And it involves lithiations. Perfect.
Direct and Versatile Synthesis of Red-Shifted Azobenzenes.
Essentially in this work they are focussing on the synthesis of compounds that are photo switchable. Meaning that they have one conformation or structural design which then changes (e.g. Cis-Trans) when blasted with specific frequencies of light. Such as UV or infra-red. This work is very much applicable in the real world and I’ll elaborate on that later.

The paper starts by introducing the topic and then goes on quickly to slag off work by A. Woolley. I suppose when you win a nobel prize you can slag off whom you like. At least he read Woolley’s work though, major boost for him. I doubt Feringa’s next paper will start by slagging my work off anytime soon.
This is where it goes into efficiency vs applicability. Feringa reports synthesis of azobenzenes in a much more direct manner than Woolley utilising organolithium approaches. Very smartly, they also used a boronic acid substituted aryldiazonium salt to produce a boronic acid containing azobenzene. This is ace as it sets up a Suzuki coupling directly after. He does admit that purification was a bitch for this (“purification of the product proved challenging”) which one would speculate meant no one fancied performing anaconda sized chromatography and that it wouldn’t crystallise from petrol. This work relies heavily on methoxy directing groups for the lithiation. Ideal as it is effective and produces the ideal conditions for lithiation to occur, directing that lithium to the now acidic proton on the ortho C-H bond. In all it’s a nice 2 step, one pot way of churning out some smart compounds.
My criticisms?
Methoxy is not the only directing group in the world, it would have been nice to see other groups attempted here.
He describes it as a 3 step 1 pot reaction. This I have trouble with as it means he is counting his organolithium intermediate as a separate step. It is not. Lithiate and add electrophile.
Lithiation strategies are also regioselective. For truly diverse results an approach that offers a broader spectrum could be investigated.
There is sadly no mention if TMEDA or sec-BuLi were trialled for efficient Lithiation.
There is a lovely table showing the various substrates attempted highlighting the diversity of the reaction. This is ok but again apart from only methoxy directing groups, they are all homocyclic rings. Whack a heterocycle in there and see what happens. Doesn’t work? So what, at least it looks more rounded. Often heterocycles don’t follow the rules and I think some people don’t put them in on purpose as their results don’t fit their narrative for the publication. I am not referring to the scaffold itself here as it would no longer be azobenzene work, just the R groups.
But most of all, remember how Woolleys approach was dismissed as long and cumbersome (this is where I back track on bio bollocks to fit my narrative- my blog my rules). Woolley’s approach is longer but it is mostly scalable. This means it can be quickly turned from a reaction undergone on lab benches and milligrams to large scale multi tonne production without much fuss. With organolithium chemistry this simply cannot be done. You can’t drop hundreds of litres of solvent (that somehow you have to dry first) to -78oC. Followed by a ridiculous addition of lithium. When I critique my work from research 2014-15 I make similar observations.
This isn’t the main gripe though.
Woolley’s compounds have lovely amide handles incorporated into his compounds. But it did mean a longer synthesis. Remember that efficiency vs applicability thing I mentioned earlier? Well Woolley used these amide handles to attach his photo switchable molecules directly onto peptides. It gets better. Because they were now incorporated onto peptides they were able to inject them directly into mammalian cells for real life in vivo testing. Super smart stuff here. And why is this more useful than molecular motors? Simple really. Control. Instead of flooding the body with toxic chemotherapy compounds resulting in horrendous side effects, you can swamp the body with inert compounds that then become active only when exposed to a light source at the correct frequency.

(Woolley et al., 2013)

Overall I really like this paper and this field. I even have a friend working on a similar project investigating photo switchable molecules for use as anti-cancer reagents. Feringa demonstrates some nice science that can be used in the real world for a worthy cause. My review may lead some to think the work is unworthy of Angew chemie and that if Joey Nobody submitted it, they’d be rejected. Not true really. It has not been accepted only on name value as the paper does go on to analyse the photochromic compounds in depth and has plenty of spectra to boot.
And there you have it. Being somewhat nice about a guy whom I wasn’t nice about last time who doesn’t even know I exist.
Please continue the bizarre tweets at bizarre times, I love it all @LewisMGooch



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