Lots of libraries

Quick screening of reaction partners is clearly very important for discovery, and one of the things I’ve been working on a lot lately is automated library synthesis. I think this is one of the major advantages to being able to use a flow protocol; a great many of the things we do as chemists are straightforward, repetitive and time-consuming. Any technology that frees us from the laborious tasks and makes us available to work on complex challenges simply has to be an improvement.

We’re able to use a range of different liquid-handlers, and we recently took delivery of a small handler that fits just nicely in my fume hood. I use it with pretty much everything now, sometimes to load reagents, but often just as a collector, allowing me to schedule a list of reactions in the morning and leave it running through the day while I work on other things. I’ve needed to run various analyses on the library compounds, so have gone up to 5 ml loading loops, which at the concentrations I’ve been using give me plenty of material to isolate and analyse in whatever way is needed.  There have been a few challenges along the way; one photochemical library has been producing cyclobutyl adducts from a range of maleimide and uracil derivatives, added via a [2+2] to ethene. The problem is that ethene gas has variable solubility in the different reagent solutions, sometimes most of it dissolves into the liquid, reducing the flow velocity and increasing residence time, then a different substrate is added by the handler and the ethene now doesn’t dissolve, increases flow velocity and pushes everything out of the reactor faster. A bit of a worry when you’re collecting your product automatically.

The solution was quite straightforward for me, I put a UV detector inline and made my collection window larger than it needed to be – I wasn’t carrying out an optimisation so only collecting the steady state wasn’t as important. A more elegant way to work would have been to use the UV to start the collection when it detected the material, I’ll have to do that next time. Either way, the liquid-handler has liberated me from the fume-hood for most of the day, which has enabled me to be more involved with applications support and product development, all the while keeping the output of the lab the same. Of course, when you find something interesting, you’re always going to want more of it but then that’s the advantage of a flow protocol at the lab scale; just run longer.


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Developing an electrochemical reactor

Recently there has been a significant up-surge in the use of electrochemistry for carrying out a range of different transformations. The advantages are clear; no need to use messy, expensive and often hazardous oxidising or reducing agents, simply pass a current through your solution and let the electrons shuffle around by themselves. Flow chemistry is also ideally suited for electrochemistry; small flow channels mean that the electrode separation is short so very little electrolyte, if any, is needed to allow the current to flow.

Now here’s the thing, electrochemistry was always a technique that slipped a little under my radar. When I was training, it was the preserve of a select few groups, with complicated home-built reactors, electrodes and power supplies and so forth. It always seemed to me to be a short-cut to a fairly hefty zap that left you looking like Doc Brown from Back To The Future! Recently however, Vapourtec have joined forces with Prof. Thomas Wirth from Cardiff University and started to develop our own continuous flow electrochemical reactor. I consider myself very lucky that I work with some truly talented engineers, because even the prototype is better than most commercially available reactors.

I’ve been using it for several weeks now, and after only a few minor modifications it’s an impressive piece of equipment. It’s able to operate at pressure, it takes less than a minute to change electrodes, changing the current and maximum permitted voltage is trivial and our test reactions have shown essentially complete conversions with clean products. All in all, it’s been very exciting; the advantages of electrochemistry are clear and right now, I can’t wait to get hold of the next prototype and start looking at some more complicated syntheses.

Blog 1 – Flow Chemistry Blog and 5-fluorouracil hydration

Dr Ryan Skilton is the research scientist at Vapourtec Ltd

Well, hello and how do you do. My name is Ryan Skilton, and I am the research scientist at a company called Vapourtec. We manufacture equipment for flow chemistry. We really wanted to tell everyone a bit more about what we do and how we do it, so I have started to write this blog. Hopefully you will enjoy it and find out a little more about how we go about things.

First things first, who am I? Well, I did undergraduate and PhD in chemistry at the University of Nottingham, where I specialised in automated optimisation in continuous flow. I joined Vapourtec as research scientist in 2016, and I run the laboratory here, conducting our own research and development experiments in flow as we develop new products, and do our best to support our customers when they need it. I’m also often at conferences, demonstrations to customers and help out our team of service engineers with training new users.

Recently, I’ve been doing quite a bit of work with photochemical reactions and it was while working on our application note 59 (available here) that I serendipitously stumbled on the content of application note 60. App note 59 is a library synthesis of a range of different compounds, mostly derived from either maleimide or uracil. I was carrying out a [2+2] photocycloaddition with ethene, and frankly everything was going along very well. Almost all of the compounds in the library were reacting as expected, and I was getting really good conversions to the cyclobutyl adducts.

Then I saw the analysis of 5-fluorouracil. Oh dear. Missing from the NMR were the characteristic peaks of the cyclobutyl ring, but also missing were the characteristic peaks of 5-fluorouracil… something had taken place, but I had no idea what. Happily, our NMR expert and consultant organic chemist Dr Roger Moses was on hand (metaphorically, he was actually in Cornwall), and after a bit of literature mining, found a reference from 1984 that indicated I was carrying out a photochemical hydration. Once I had finished the library application note, I came back to 5-fluorouracil and this odd reaction taking place instead of the cycloaddition, even with a significant excess of ethene.

So, start at the start, I suppose; repeat the initial experiments from App. note 59 to confirm my results. Happily, I found the same thing happened, so I continued to explore the chemistry a little further by firstly taking away the ethene, then turning the lamp off. As one might expect from a photochemical reaction, turning the lamp off had a fairly disastrous effect on the conversion, so I thought it probably best to turn it back on. Just to be sure, I tried a range of conditions thermally as well, but alas with no success. After a bit of work with our HPLC, I’ve been able to follow the reaction chromatographically; although because of vastly different chromophores I can’t quantify anything, I can at least identify complete and incomplete conversions. This approach, backed up with the occasional NMR has enabled me to find some high throughput conditions quickly, and I am very close to running a gram-scale synthesis, isolating and purifying, then I can publish the note. This project has really been lovely to work on, all I have had to do is dissolve the reagent in water with a drop of acetone, shine the light on it in the UV-150, and the product even crashes out once it has been sat for a few minutes.

Watch this space.