Mixing organic and aqueous phases in flow – moving forward fast

Enjoying the efforts of of Christopher Hone and his jflowchemistry blog. His latest article on catalyst, organic and liquid phase models for flow reaction chemistry was intriguing to say the least. There is a lot of interest in the ability to mix organic and aqueous phases – and then add reactive gas into the mix as it were. His description of Yap and co-workers at the National University of Singapore indicates that feasibility studies are ongoing to have a cleaner picture of what is controlling this sort of reaction (mass flow, heat transfer). What I enjoyed most is the subtleties of moving from a fixed bed or homogeneous catalysis into a design with the catalyst immobilized in the aqueous phase and work out the parameters — mixing, organic phase wetting, and finally introduction of gas. With the improvement and advancement of catalyst design — nanocatalyst — we may well see a number of new things being applied to flow design in the near future.

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Nice job Chris — keep em coming! Happy reading to the audience!

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Labeling under flow conditions: Understanding added applications

Stepping outside traditional synthetic labs into specialty applications is not always something we are looking for in the literature, but it is an excellent way to see different techniques which might be utilized in your own labs. Neil Vasdev’s group at the Harvard Medical School specializes in labeling compounds for more advanced analysis – imaging techniques as tracers for the study of advanced disease states. His group has been using flow chemistry and flow hydrogenation for some time so I thought it be interesting for everyone to see the work.

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Two recent publications illustrate their research. In the first publication Chem Commun 2013, 49, 8755  the group uses three examples where they incorporate a label for study into an advanced intermediate C11 or F18 through a microfluidic reaction, followed by a strategic deprotection of a benzyl  group or CBz under flow hydrogenation. Without going into significant detail, the group absolutely needed an optimized profile for these sorts of reactions due to the nature of the labeling and ran a number of studies with variations of solvent, temperature and pressure. It is worth the read to understand the significance of finding a fast, reliable method for multiple processes for their strategies. Labeling and incorporation of more substituents are being explored using these technologies then the literature provides — and the number of uses for flow hydrogenation can’t be undervalued with all of the transformations within.

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The second paper, which I found to be even more interesting because it shows the application of the strategy — the imaging of the compounds made. I would be remiss if I didn’t mention Steven Liang from MGH as a critical part of both papers…..but the paper describes a specific compound made under microfluidic flow conditions for the labeling and subsequent study. Mol Imaging. 2014 Sep 1;13:1-5 is where you can find the citation but if you are exceptional at google (hehe) then you can find a pdf of the article.

Enjoy the articles but keep an eye toward uses of these flow techniques in your own discovery efforts — several new applications show up every week. Happy Reading!

 

New Publications to keep your eye on — flow synthesis and enabling tech

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Organic Synthesis: March of the MachinesAngewandte Chemie Int DOI: 10.1002/anie.201410744 Early Addition on-line prior to print — Review focusing on the implications of workflow in a modern organic chemistry lab.

External Trapping of Halomethyllithium Enabled by Flow  Adv. Synth. Catal. 2015, 357, No. 01, 21-27  Trapping and reactions of thermally reactive and unstable intermediates in flow reactors.

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Expanding the toolbox of asymmetric organocatalysis by continuous-flow process Chem. Commun., 2015, Advance Article DOI: 10.1039/C4CC08748H. Recent advances on the asymmetric side

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What do you do when flow requires long residence times?

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There is a lot of talk about how to traverse moving from batch to flow, and how to make the process of finding a good method quicker under flow conditions. There are some factors keeping us from crossing the goal line: I’ve done it this way for so long and it works – why change (cryogenic or several mainstay transformations)?; the reaction takes too much time in a flow set up; and product survivability. I cringe when I hear these things – largely because the mantra for the last 50 years has been if it is going to 50% at 100C, then just heat it up! — Well you can call me a bit of a dummy and you would be right, but flow chemistry can offer efficiencies that a traditional batch reaction can’t — we know that — mass transfer, time spent at specific temperature can be minimized, and I could go on. Listen this isn’t a blanket that I get to throw over all chemistry, but having come from a microwave background, I think the space available for chemical transformations is untapped — we just haven’t gone there often enough……I just can’t simply buy into chemists simply doing the same reaction over and over for 20 years without finding themselves in a new reaction transformation — there is a lot of it out there and we need to untap this potential.

Let’s just improvise here and generate some discussion — -78C for an anion generation — doesn’t need to be that way for flow: the residence time doesn’t equate with 20-30 mins, then quench with an electrophile. Because the the flow in a microreactor allows kinetic conversion, the reaction can be almost immediate followed by diverting the reactive intermediate in several directions — although I have done this following cooling and anion generation in batch nearly 10000 times — and reverse added this to several other flasks….it just isn’t the best way to do it.

Reactions take longer at lower temperature — I guess you can call that a blanket. There are expanding examples of reactions and transformations that moving from batch to flow that simply do not decrease the time spent — that is without raising the temperature — or even temp/pressure if you have the opportunity. In a sense I am talking about reactions that go from 100C to 150-200C, but also reactions we don’t normally think of at temps of 350C. How many of these can you point to from experience? Well many of the products out there survive at these high temps and survive them for short and long reaction times….pharma, Ag, petro, etc. But the nice thing is that it is generally held that many transformations at these high temps can be done in a short time, and with limited “reaction time” at these high temperatures……get used to it; expansing methods are being developed.

So give you chemistry a bit more thought and challenge some of the traditional techniques used. That text book in the corner is starting to collect some dust: find some examples that would serve as a good model outside a batch process.