Microwave scale-up and scale-out: Feasible?

A number of commercial vendors and engineering groups have developed large scale batch reactors — so it always gets me thinking about the challenges with microwave technology in general: 1) penetration depth limits its’ usage 2) how to build a continuous flow microwave reactor and 3) transfer of technology. I value the field a great deal – it has offered a sustainable way to speed up and make a number of transformations doable. For small scale research and discovery, the ability to make large libraries quickly will always make this a preferred technology, and let’s face it, it has been around for awhile now.

Challenges: The penetration depth issue has been overcome in a couple of different ways (and I am sure there are more solutions out there that I don’t know about. 915 MHz can be used in batch and flow process, enabling the capability of having much larger reactor volumes. Sairem offers batch reactors up to 500L with a proprietary INTLI microwave transmission technology with both 900 MHz and 2.45 GHz frequencies for microwave synthesis — not sure what the specs are, but to be effective, the size isn’t the only factor which needs addressed — temperature and pressure also need to be high enough to cover the scope of the majority of the chemistry. Sairem isn’t the only game in town: Upscale microwave, out of Pennsylvania, has a couple of large batch reactor microwaves in the 20-50L range and is operating at a custom manufacturer (I have have posted feasibility studies on them before, see example below).

Kilo scale reactors are also available from Milestone and Anton Paar, which would make an excellent addition into CROs and kilo process groups in pharma and biotech chemistry research groups. As I mentioned, the value on the research side still lies in the small-scale approach, but the need to be able to produce kilos of material quickly is often stumbling block for traditional chemistry.

Continuous flow: One way to overcome microwave batch technology is to look into continuous flow. Easier said than done — the engineering, materials for the reactor design, temperature and pressure capabilities present some obstacles. For homogeneous organic synthesis, the have been a number of small scale approaches with glass, quartz or pyrex tubes inside a multimode cavity and even some reinforced Teflon reactors inside as well. I can think of 2 examples where proof-of-concept studies resulted in a viable, working microwave reactor that can be used in full scale production. The first example comes from the Cambrex Corporation and their reactor developed for in-house custom synthesis and manufacturing — you can read an announcement from early 2010 in Manufacturing Chemist. The capability of the instrument is a little on the low side for some chemistries but I am sure they put this to good use — and if you read through their material the big thing that stands out is the capability of running heterogenous metal-catalyzed reactions in full scale capacity. A separate intriguing design was published in Green Processing and Synthesis 2012, and involved a number of companies along with Oliver Kappe and his technology research team, coming together with the design, construction and implementation of a safe, high-capability flow reactor – again pictures are below — and the key features include an Al2O3 microwave reactor tube (310C/60 bar) and the ability to transfer microwave power efficiently through the tube. To illustrate some of the chemistry is shown below:

Clariant Produkte Deutschland GmbH, Innoturn GmbH, Püschner GmbH and Christian Doppler Laboratory for Microwave Chemistry (CDLMC) – University of Graz

Cambrex Continuous Flow CaMWave

UpScale Microwave – Floor large mw batch reactor

Pilot scale continuous flow mw reactor

Technology Transfer: The ‘scale-out’ from small scale to multi kg/day has been published and be a topic for another day. But it does mean that we can reflect on the need to continue to use small scale single mode and parallel and added-capability multimode instrumentation, because we can take the method and information and apply it to larger batch and mw flow without the problems of the past – and although, I shouldn’t mention it here I have to — there are a number of examples where a microwave method has been transferred back to conventional heating on a production scale level.

An upcoming post will include several microwave methods which have been easily tranferred to flow reactors – there will be some comparisons and thoughts on what we do with the studies with both technologies doing so well today. Happy Reading!

Microwave synthesis of Medicinally Relevant Indoles

At first glance this may seem like an extension to the installments (there are 5) on microwave methods toward the construction of indoles — but it has a bit more of a story than that. I found a minireview out of Northeastern University by Graham Jones and Nadeesha Ranasinghe that I posted on my flow chemistry resource blog — mainly because the journal article emphasis both continuous flow, microwave and the combination thereof. So some of the introduction and historical perspective can be found there. For this I will stick closer to the theme: microwave methods and show a few more examples that one can dig into off-line.

Although it would be the place to start – the Fisher Indole synthesis is one of the most published methods around and there are some examples using microwave to speed up the reaction — I think this is one that can be done in a large microwave batch reactor easily. But the emphasis here is on indoles, and their rightful place in the top 2-3 of the heterocyles researched in drug discovery.

The first example shows a movement away from solvent into a solvent-free approach using p-TSA and several enolizable ketones from Horaguchi in J Het Chem 2011.

In keeping with a similar theme, Barluenga reported (Chem Eur J 2010) a heterogeneous Pd-sequential coupling of arenes to a number of imine starting materials in aqueous media to reduce reaction times from 24-48 hours to 30-60 min in high yield (no organic solvents and sequential steps).

Moving over to drug targets, Thirupathi Reddy reported (Bioorg Med Chem 2010) an approach to marine natural product mimics of aplysinopsin, with the preparation of indole-2-imidazoline-2,4-diones under microwave heating and a comparison to conventional heating.

 

A multi-step combinatorial approach to a library of compounds was reported with indole-2-carboxylic acid, ethyl pyruvate with amines and isocyanides as a four component, 2-step Ugi and subsequent cyclization in TL 2009.

An approach to antitubercular activity was reported in a library of compounds made in a modified Fisher indole synthesis to 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles using microwave heating for 3-6 min at 90C (Biorg Med Chem Lett 2009).

And we can end on an approach I mentioned in my 4th installment of microwave indole construction, Peter Wipf’s usage of an intramolecular diels alder with a pendant amino furan (IMDAF) as a tandem diels-alder rearrangement sequence to provide an array of substituted indoles under microwave heating (JOC 2013).

And for those us who enjoy the arrows, you can see the release of H2O in the cycloadduct to form the indole.

Several examples have been shown where microwave technology has been a key step in the formation of indoles as targets in basic research and in the formation of medicinally important compounds, either in the form of analog libraries or mimics to compounds hitting targets of interest. This certainly indicates to me that we have a number of current approaches to indole targets and microwave synthesis can be used as a tool to rapidly provide compounds for testing or quickly decide the relevance of a target class. I end by pointing back to the minireview as a source of information and inspiration. Happy Reading!

Expanding the scope of enabling technologies: Flow Chemistry

I have decided to cast a wider net on enabling technologies for organic and materials synthesis to the area of flow chemistry. Both microwave and flow methodologies go hand in hand as current and emerging areas of research and development. My hope is that with the success of the microwave forum, the flow chemistry site will provide a good resource of information and discussion for our fields of interest. Take a look at synthflow.wordpress.com and let me know what you think and areas where it can be improved to provide a rich resource of information.

Microwave Labs: University of Turin – Giancarlo Cravotto

Having the pleasure of working directly with Professor Cravotto leaves me a little biased on the microwave front. But his interests in enabling technologies on many fronts makes his efforts increasingly more impactful than simply microwave methods and instrumentation development. He is largely the single source of single-reaction chamber (SRC) microwave synthesis around today – and he has coupled ultrasound techniques with microwaves for a long time. Check out his publication pages on his website to get an idea of how he is pushing these technologies forward for practical benefits….it includes a long lists of reviews and books surrounding microwave and additional research.

Microwave Labs: Florida State University – Gregory Dudley

Professor Dudley’s recent work in microwave chemistry has certainly heated up the place. His group is trying to dive into more complex studies surrounding microwave acceleration above the normal predicted amount. I have enjoyed the pursuit of his work over the last couple of years and we should see continued efforts coming out soon. Take a look at some of his recent contributions at Florida State — seems the university has a number of efforts in microwave methodologies to keep track.

Microwave Heating as a Tool for Sustainable Chemistry

This book is an easy one to post about — Nicholas Leadbeater is such a proficient writer and editor that although I have only had the opportunity to read a small portion I enjoy the combination of education that it provides the newcomer with the practical nature of keeping us informed of making good decisions of bringing in the technology into the lab — outlining what’s out there is important to review to match up your research with commercial vending choices.

 

Dipolar cycloadditions with microwave heating

The field of cycloadditions under microwave control is vast and has been represented in a fair number of books and review articles. What is noteworthy is the array of important advanced intermediates that can be used as handles or core heterocycles and complex carbocyles for future chemistry. Without a lecture I will highlight a few examples from a review article from Erik Van der Eycken (a well known microwave strategists) in Chem Soc Reviews 2010 (can be found as a pdf with a quick google search).

The review is broken down into the types of cycloadditions starting with the familiar [3+2] triazole forming reactions (click, click) then proceeds to other [3+2], [4+2] and ends with [2+2] reactions. At the risk of labeling these tranformations as percyclic reactions, we will hand wave and and end that some are very quick step transformations (and often concerted) and their selectivity patterns are well documented. I certainly have a fondness for these reactions with my background in isoxazole, diels-alder and isomunchnone cascade studies — so I have to like these, right? Well below, I have used a couple of examples from the review to give you a flavor, but left the triazole chemistry for you:

[3+2] Polycyclic pyrrolidines 1,3-dipolar process

Condensation of diaminoarene to form an N-allylhydrobendimidazole intermediate provided the requisite backbone to react with a variety of amino esters. The s-ylide could be then be react with the 1,3-dipole under microwave heating in toluene at 130C for 20-30 minutes to provide the fused system in high yields – much faster, cleaner and higher yields when compared with conventional heating.

 

Isoxazole formation via nitrile oxide intermediate

This was a rather slick method when you can use it. The group started with an aldoxime — generated the corresponding nitrile oxide alumina-NCS under microwave heating at 110-150C with a 3 min pulse of microwave power and the advanced acetylene was added for a 2 step-one pot solid phase formation of a library of isoxazoles — sure beats the classical ways of the formation of nitrile oxides and when you can get a terminal alkyne — take it. It is mentioned that the yields were much higher and less time consuming than the traditional solution phase heating of up to 5 hours.

[4+2] Pendant furan cycloaddition-rearrangement a plus cascade reaction to Strychnine

Al Padwa seemed to always have an elegant approach to complex structures – I was lucky enough to have a number of interactions with him and a number of his students who had passed through Emory University (of course I got the smelly Pummerer reactions, LOL!). Rather than looking into his volumes of straight-up DA reactions we will go to a COOL example. The example highlighted involved the use of a pendant amido-furan under a Mg-I2 catalysed [4+2] cycloaddition reaction followed by rearrangement to form an advanced tetracycle on the way to Strychnine (this is a great example for anyone drawing the arrows to push the formation of the intermediate cycloadduct then rearrangement — I think I still have it on a napkin someplace).

And lastly because the formation of 4,5,6 and 7 positions of an indole can be difficult to build substitution patterns the use of cycloaddition strategies can prove highly useful. The [4+2] cycloaddition of a representative set of 2H-pyran-2-ones and a suitable alkyne to form the requisite amido-arene with the double bond positioned for ring closure to the indole system, which was also performed under microwave heating. Although this group used a two-step 2-pot approach, it is likely that conditions could be used to add reagents for this transformation to be done in one-pot — I know the process chemists would find a way. Great example of the use of this strategy.

Many more examples are available to read — and too many for a single post so enjoy the article.

UCLM – Microwave and Sustainable Organic Chemistry

Should have posted this research facility a long time ago — so enough of the excuses. The UCLM group has a department dedicated to microwave methodologies for organic and nano-organic and nano-inorganic areas. This group has pushed the field forward and continue to evolve their work into flow chemistry as the newest enabling organic technology available to us now. If you are interested in the current thinking utilizing microwave approaches – dive into the deep end and roam around, you won’t be disappointed. There is even some work at additional frequencies to provide the added penetration depth of the microwaves and opening up larger scale reactions.

Idaho State University – Professor Joshua Pak

Looking at the growth of materials research, I wanted to begin providing examples of inorganic or metal-based microwave laboratory efforts going on here in my own backyard at Idaho State University – Joshua Pak’s lab. I met Professor Pak moons ago as we discussed using microwaves for some of materials research interest. For folks who don’t know — materials researches like to find methods and instrumentation that go beyond basic research and into the applied application arena. His group looks for opportunities to make catalysts and materials that will be tested and used — and eventually find a way into the mainstream. Kudos to that!

Take a look at some of the research going on in his group — maybe get a flavor for something outside of your daily research endeavors.

Undergraduate microwave teaching

The organic chemistry undergraduate curriculum has evolved over the last 20 years into half name reaction and theory with a fair amount of instrument introduction for what students will see if they enter the workforce or go to graduate school in this area. I remember microscale chemistry was a push in my time simply to reduce the internal costs of solvents and reagents per student if you will — and we spent time on the NMR, TLC and IR analysis. Today much of this has changed. Having helped a number of universities incorporate microwave synthesis into their core teaching strategies has been a fun process, but it has also enabled teachers to spend their time aligning the material with technologies that a real once they move forward — but it doesn’t have to start from zero. There are a number of resources to build 4-5 lab days into microwave technology with the information at hand. Whether the university or mid-level teaching college using a small microwave footprint or a larger multimode system to cover up to 32-40 students in a single lab – it is out there. One of the newest and quickest resources I have come across is a Laboratory Experiments using Microwave Heating (Nicholas Leadbeater @ University of Connecticut and Cynthia McGowan @ Merrimack College): a step-by-step guide to understanding microwaves and a load of defined experiments — a real plug and play way for any institution to grab hold of new technology and provide a great positive growth to our organic chemistry community. Take a look into the book for a low price point as an avenue into microwave chemistry.