Journal of Flow Chemistry Blog

New addition to the blog resource arena (– Christopher Hone has started a blog discussing articles from the Journal of Flow Chemistry — so you should expect to see a number of different types of synthetic processes on the blog ranging from traditional organic transformations to materials and inorganic chemistry. Excited to see this considering this is the premier continuous flow journal in our area of chemistry. Happy Reading!

Flow: Chemistry Unatainable by Batch and Dangerous Reactions Made Safe

Two back-to-back articles should be at the top of your list of reading if you are new to continuous flow chemistry or looking into how to generate a method for a selected transformation. These can be found in Specialty Chemicals Magazine May 2014, with Mark Bratt and Ollie Tames of IntensiChem  pp. 42-44– and Gyorgy Dorman and Richard Jones of ThalesNano pp. 45-47.

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The first article is on the fundamental thinking that goes along in flow chemistry and how it is different than the traditional batch model. Mark and Ollie take us through a storyline where chemists tend to use batch process in their strategies in developing flow methods. Their discussion leads into batch reactions that simply aren’t very good and for a number of different reasons….as opportunities were continuous flow methods would have better potential as a process. Examples with fixed bed catalysis and hydrogenations pop out as the examples that one would like to see, but several factors on temperature and pressure expands the capability some batch process simply can’t carry without major equipment by comparison. Read through several of the examples indicating opportunities where batch processes don’t measure up.

The next phase of the article is spent on the mindset — optimized batch processes have been used from optimized chemistry and that had worked very well for things done. For flow, this is a possibility for industries and reactions where the chemistry is not so well worked out — and how the flow process development can be much more streamlined and provide data and feasibility in a more efficient manner. Mark and Ollie walk us through the differences — flow requires different solutions for different schemes — with in-line analytical techniques, these development times could be lowered considerably…..again the comparisons are made with batch processes and industries involved, which gives us a clearer view of where some of the challenges exist. —- Thanks for the perspective Mark and Ollie!

The second article sets the tone by laying out some specs that are present in modern day flow instrumentation to go along with the reproducibility, speed and telescoping capability. But quickly switching gears, Gyorgy and Richard paint a picture of why flow should be used in place of some of our older techniques with dangerous reactions and reagents — just think about all of the news today on safety and explosion examples in our field. If for no other reason than this, the investment pays for itself on the first level in academia and industry. Since Gyorgy and Richard categorized a number of examples: high temperature thermal cyclizations, hydrogenations, diazotizations, low-temperature transformations, gas-liquid reactions, etc., I will leave you with the article to read. The importance of the article is that is helps provide a complete picture of using this technology in fields where small molecule heterocyclic chemistry is used, be it specialty chemicals or bench medicinal chemistry. Each category shows important parameters that can be utilized in flow to keep a clean, safe operation of reactions that have special conditions when used in a batch format. Thanks for the perspective Gyorgy and Richard

Enabling technology as a silo? Continuous flow

Following a look into flow photochemistry and electrochemistry and listening to some very strong challenges to how they fit into the bigger picture, I sat down with a few chemists who have always been forward thinkers into what the reality looks like. We discussed everything from combichem to the hardcore natural product total synthesis labs. In that process, I mentioned the article in Nature over the summer: Organic Synthesis: The robo-chemist as part the general collective.

So here is the summary:

1. Enabling technologies such as microwave and flow chemistry are wonderful and to be part of a sustainable future, education and infrastructure need to match the ideal of the technology for the most part. Chemists (and this is not a blanket over all) tend to hold their cards to their chest, rather than playing them, so as a personality it isn’t exactly what you would want as a starting point….but if convinced and educated on the value of the new “gadget” — we will call it that, then we might see a larger user base.

2. What about retrosynthetic analysis? This is an area we have all been trained to use, but what is the percentage of it is involved in our daily process? The group felt that it has become intuitive in the larger scope, but not manifested in all chemists. Not that different than the education and use argument. Let me know your thoughts on this — I am convinced today that in the US, it is not broadly used, whereas in other areas it is practiced a bit more.

3. Photochemistry or electrochemistry as specialties — can these areas find themselves in the day to day strategies as part of the technology tool? I think on the surface the answer is much like our goal across the spectrum — for so many years, the measureable for a year ended with the number of compounds made for the company, rather than the impact — clinical candidate, better route, cost savings. It’s hard to roll the dice against the grain and come up a winner — remember, the house always wins. For these two areas, we need a common system which will ensure a broad education and effective implementation for it to be used. The amount of new chemical space should be stamped on your lambskin degree so that you remember to use it.

4. The robo-chemist: Ah yes, a movement to automate both the hardware and now the software side — maybe it will allow the decision makers to concentrate on decisions. For the software side, it is apparent that they are putting the retrosynthetic portion into the process so that we have a best case scenario of things to do or prioritize….awesome, but it is still counter to the original premise…what is the basic nature of the chemist be it pharma, specialty chemicals, polymer, etc? These card holding players have been accustomed to a lack of sharing their toys without a benefit. Take a read through the article and comment back: there is a section on data collecting through electronic notebooks since we don’t share the things that don’t work. Personally, I am glass half empty here, since I can’t imagine enough traction even if the technology is there.

5. Europe, Asia and the US (apply the rest): In terms of enabling, most of the forward thinking has been in Europe and parts of Asia. The US is now building a framework, but is behind…..just use flow chemistry as an example. With over 2000 mid-level colleges teaching chemistry, a small percent have used microwave chemistry in their curriculum, and even less flow. Under the microscope, a hand few of the major schools in the US have implemented flow as a real bullet point in their teaching — oh sure a couple have, but not like Europe… it is safe to say that it is years away.

Of course we became less critical as the number of beers added up, and the hope was that we see change in the labs opening their budgets to better chemical methods. And the feeling is still that education will impact the process more than the number of units sold (maybe there is strong correlation — lots of press announcements). I praise the academic institutions who are charging forward with the new technologies and empowering their students to increase the footprint and thinking into becoming tomorrow’s synthetic enabling chemist.

Let me know your thoughts here……I know we all have some strong opinions in a number of these categories — and many that I didn’t summarize.

Electrochemistry in Flow: Nazlinine and more

Electrochemistry falls into one of those categories of expansion, where the chemists who perform these reactions are more similar to their specialties — as is the case with photochemistry. These simply don’t fall into the area of study, education or applied retrosynthetic strategies. However, flow chemistry allows us to level the playing field a bit, and asks us to include new reaction space which we would otherwise never draw on the chalkboard.

In a recent example (OL 2014), we are treated with a modification on a throwback Shono oxidation of cyclic amines (protected as a carbamate or amide in the generation of an acyl iminium species with a nucleophilic attack of MeOH). I particularly like this since I have used this reactions in the past, but it requires some care into the appropriate choice of anode and salt bridge — in this case electrolyte in flow).

The scheme to Nazlinine is shown below with a flow oxidation reaction followed by a microwave accelerated Pictet-Spangler to several additional non-natural Nazlinine analogs:

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The table below illustrates the use of a microreactor with choice of anode, electrolyte, flow rate and current (Carbon, 20% Et4NBF4, 43mA, flow,100-120 microliters/min).

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Expanding beyond pyrrolidine expands the utility and the chemical space for libraries around Nazlinine, but also into areas of related systems beyond the scope of the paper:

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Although not the focus of my post, the second reaction, which would otherwise take 15 hours to complete, was shortened to 30 min using microwave irradiation as a final step into Nazlinine and related compounds. You will notice a big effect in the acid choice — they found optimized results with CSA in H2O, but with a deprotection, imiminium formation, and more than one amine, screening additional acids will add additional opportunities here (med chemists — you know that I am talking to you).

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Enjoy the rest of the paper in looking at additional substitutions on the indole and extension of the exo-alkylamine. This should help you think of additional electrochemical reactions that are out there to be used — I can think of a few that I would want to incorporate (please note that references 1-2 in the paper include examples of electrochemical and photochemical reviews as excellent starting points when considering flow approaches). Happy Reading!

Sulfur Extrusion: Eschenmoser Continuous Flow Style

Ah, back to my old thiolactam days, when I would utilize and Rapaport protocol to extend a pyrrolidine or piperidine out. So I thought this has to be a reaction that has been reduced in a continuous flow manner — low and behold, someone has used this sequence in functionalizing pyrimidines (Beilstein JOC 2011)……..are my med chem colleagues in the house?

As a starting point if you haven’t ever performed these reactions, a scheme for the secondary lactam transformation is shown below and the subst version just below that.

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Using this concept, the transformation was applied to some substituted sulfur-pyrimidines.

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As part of the reaction intensification process, this group found the kinetic profile quickly to go along with the concentration for the residence time and made a small library of compounds (see paper for how the kinetic studies were performed). The tables below indicate the materials to start and corresponding final compounds and their yields.

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The coiled capillary reactor design is shown for the control of temperature and flow. Happy Reading!

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The Chemical Playbook: Reactive Substrates on Demand

A post from a former co-worker of mine, David Dickson, on LinkedIn got me thinking about reactive intermediates and complicated transient materials that we often encounter in batch synthetic processes — and how do you harness these in an opportunistic way for medicinal chemists or techniques which can be scaled-out for process development — let’s open up the chemical space again. And although there are a number of these published, Dave pointed out  a nice publication (Chem Sci 2014) out of the Ley group where one might think to generate reactive species On-Demand, pulling back a way for a medicinal chemists let’s say, to make it when you need it strategy (btw, this probably goes without saying but the power within the flow methods allow a creative med chemists a virtual playground of possibilities.

So back to the article: Aryl azide generation and transformations have been covered, but the ability to use hydrazones in a similar capacity:sp2 and sp3 couplings provides a number of new handles (scaffolds) that would otherwise be avoided due to the chemistry — intermediates that can themselves be modified again at a later stage. Below we see the thought process of generating a diazo substrate which is ‘translocated’ to a new chemical environment.

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Examples of continuous flow of stabilized diazo have been shown in the past — and although extremely useful, the addition of several reagents limits the scope and utility — so the mild MnO2 oxidative-decomposition into the reactive and unstable diazo intermediate was set to react with a partner while in flow (several oxidative reactions of this type are well known in the literature). In the example shown below: the simple reaction with an aryl boronic acid in contact with the transient intermediate produces the Ar-coupled alkyl compounds in high yield at RT.

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Examples of the type of library or large amounts of an advanced intermediate is shown below (some nice asymmetrical bis-aryls — nice.

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The Ley group details the reaction thought process and mechanism behind the tranformation and illustrates in these examples that electronics play a role in the kinetics of the reaction sequence, and that now that these transformations are done under less extreme conditions, we are learning what can and can not be done. Enjoy the paper and thanks Dave for pointing it out…..should be a thump on the head for the ability to take reactive intermediates and diverting these to several different partners to harness several different types of chemistry in demand. Happy Reading!