New Year, New Chem

Welcome back for my first entry of 2017 and a happy new year to all. I spent much of my time off trying not to think about work too much and instead focus on relaxing and refreshing. It’s hard in research to switch off I find as thoughts about work constantly linger in the background.
I enjoyed my break in all honesty but I must admit I missed talking science. You get so used to talking science and discussing concepts, theories and data every day that to sit at home and have someone moan about the weather seems somewhat alien. Trying to watch TV was damn near impossible. To stayed engaged in the trash aired these days for any length of time is impossible. It’s just crap. I did manage to catch Jaws one evening but that was probably about all I managed.
I was also fortunate enough to get out to Rome for a week and had a wonderful time out there. Beautiful people, beautiful food, beautiful weather. I only regret sleeping a little too much on some days. I got the chance to visit many beautiful historic sites and marveled at the work of Caravaggio and Michelangelo.
During my time I also visited a chemistry museum in the instito di chemico, Sapienza Università di Roma.

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Here there were a tonne of interesting artifacts from the chemistry labs of yesteryear. I was particularly intrigued by the old analytical balances. It was only the day prior to my visit I read in Primo Levi’s book “The Periodic Table” about his undergraduate lab assessments and weighing out zinc on an analytical balance. It got me thinking about what they would have looked like back in the 1920’s and a quick google search gave me an idea. But here there were plenty in the museum for me to see. Up close and personal I was able to get a more complete picture, more useful than any google image search could deliver.  Beautiful ornate wooden frames, brass framework and a brass set of balances leading down to a flat brass bed on which to weigh out material. Analytical balances were really a thing of beauty, crafted with care and as much a piece of artwork as a piece of lab equipment. Looking at them they all had their own history, the scratches in the wooden frames like fingerprints illustrating the unique stories of their lives. No two the same.  Nothing like their soulless digital counterparts today.

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In researched based news, remember how I claimed the penny had dropped last week and my research bug was back? Well I ran a total of 25 reactions in my week before the xmas break and low and behold I got a hit. One hit. One mass spec revealing trace (And I really do mean sodding trace) amounts of modified peptide.
Now I intend to repeat the experiment, run a few controls, some blanks and play around with this particular system and see if I can sort out my yields in any way and turn trace hits into dollar tonnes!
If I am honest I am most scared of the experiment simply not working ever again. I’ve had it happen once previously during my placement year where I was successful with a certain reaction only once in my trial run. Then when I repeated the experiment on my actual material believed to be enantiomerically pure, it just did not work and eventually a new route was derived.
Essentially this week I have a load to be getting on with as per usual and a few lab distractions along the way, including a conference at Sheffield. For me this conference is a special one. It was the first real conference I ever attended back in January 2015. The main event was Christina White who presented some phenomenal C(sp3) H bond activation with her patented White catalyst. It was the first time I was truly inspired by a piece of work and I began to think seriously about if I wanted a PhD and a piece of that research life. After many a conversation with Jim Wilkinson on the matter I decided to go for it.
Also this week we have a visitor coming to York which has me getting more excited than a child at Christmas.
Clayden is coming for a talk.
Normally when we have visiting academics coming for an hour or so seminar I either go grudgingly to fill the seats so our guest doesn’t have to orate to an empty room or I make my excuses to not attend. Do I really want to be dragged away from my beloved fume hood to listen to a guy telling me about supramolecular chemistry, gels that can be turned upside down like well whipped cream? No.
But Clayden is an awesome chemist. I emailed him last year about a PhD and he was even kind enough to reply. Funny how Joey Nobodies are far too busy to reply to my emails yet Prof Clayden can…
It’s an ideal time for the conference followed by Clayden’s visit as I am currently occupying that purgatory plane of existence that is waiting for chemicals to arrive. Hopefully something will be delivered next week and I can start planning some further reactions and smashing some work out.
This week’s #ReactionRecap is the Vilsmeier reaction, named after (you guessed it) German chemist Anton Vilsmeier.
The Vilsmeier reaction is an organic reaction used for the conversion of an electron rich aromatic ring to an aryl aldehyde utilising DMF and an acid chloride, typically POCl3. This is followed by an aqueous work-up. The mechanism starts with the reaction of DMF with the acid chloride to form an iminium salt known as the “Vilsmeier reagent”. The electron rich aromatic ring then attacks the iminium ion with loss of aromaticity. A deprotonation step restores aromaticity, which is followed by the release of a chloride ion to form another iminium intermediate. Aqueous work-up then leads to the aryl aldehyde final product shown below.1
In the first step, the amide reacts with POCl3 which removes the amide oxygen atom and substitutes it with a molecule of chlorine. This process would be very unfavorable without the formation of the strong P–O bond.

2

The product formed during the initial stage is an iminium cation which can then react with the pyrrole to generate a more stable iminium salt. The extra stability of the iminium salt is as a direct consequence from the conjugation between the pyrrole nitrogen and the iminium group.

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The work-up with aqueous Na2CO3 hydrolyses the imine salt and removes any acid formed. This method is particularly useful because it works well with Me2NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conventional Friedel–Crafts reaction. This a controlled way of delivering monosubstituted products with high yields in compounds more reactive then an aromatic ring. It is used in industry for the large scale production of the anti-inflammatory compounds Tolmetin and Clopirac.

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That’s me out for this week and the first blog of 2017 done! Hopefully next week I will be able report all my reactions worked with incredible yields and I’m starting on the manuscript (in my fantasies at least). I will definitely give an overview of the Sheffield stereochem conference as well as an overview of Clayden’s talk which I am most excited about.
Hit me up @LewisMGooch all over the Twitter sphere.
And finally for all those wondering, the most read research paper from December in ACS Central Science was of course the two-phase synthesis of Thapsigargin by Phil Baran that I raved heavily about in one of my blogs. It received over 3000 views and can be found here.

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