Archive for October, 2014


With so many labs utilizing microwave chemistry for their drug discovery processes, the effective ability to monitor the temperature of a reaction (solvent) is critical. Since each commercial microwave vessel will have its’ own set of specifications will have limitations to the temperature that can be reached without generating a significant amount of pressure, and perhaps even more critical cause an unsafe reaction and damage equipment.

Examples of commonly used solvents and their temperature and vapor pressure set at 25 bar:

Hexane: 226C

CH2Cl2 172C

Toluene 281C

EtOH 191C

Dioxane 256C

Acetonitile 218C

I set the pressure at 25 bar to illustrate that depending on the solvent, very different conditions would be used in a chemical synthesis and while may here are above the temperature normally set, often the amount of pressure held within a microwave vessel is lower. I have often found these temperatures have been used and resulted in complications to a microwave and the chemistry.

While there have been a number of reports using IR or FO temperature monitoring, it depends on the reaction being used, how much agitation, and the type of vessel material — that’s a lot to keep track of in addition to the chemistry itself. Fortunately, there are set-ups which take into account each of these key features for our benefit. I am going to outline a portion of Oliver Kappe’s presentation at EUCHEM 2012, where he spoke on each of these. His concentration in the lecture was on ionic liquid chemistry and included both microwave and flow methodology for the synthesis and use of ILs.

Back to the question of effective monitoring: I will illustrate using the Anton Paar dual temperature control on the Monowave 300, because this system provides a number of options to control the temp/power of a reaction.

The first slide indicates that effective agitation using an IR sensor plays a key role in the temperature being measured in a reaction and that FO monitoring is somewhat less critical to stirring as it is in the reaction medium being measured. One thing to keep in mind throughout the slides is that these will be using ILs, and as a highly absorbing material the set temp can easily be overshot during the course of the reaction. As we see in the graph below, with the power delivered in this set-up, the actual temperature reached is 120C over the set temp (WOW!), and depending on what is being measured, a dramatic difference in temperature is measured (in this example, you can see both biotage  and CEM utilize different IR sensor engineering for their measurements.

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Simultaneous measurement can help improve the control of the chemistry being used. As shown in the slide below, measurements of the internal and external temperatures are be monitored and feedback to adjust the power — in this example the master slave control was set to each independently with an overshoot in the temperature internally when IR control is used…again notice the difference in the outcome for ILs. I should mention that the studies used here can be found in Org Biomol Chem 2011.

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ILs are still reasonably new and have been used sparingly compared with the solvents utilized in most synthetic transformations but the field is growing. Taking a look deltaTan values listed below, we can see that ILs are a bit off the normal functioning organic and aqueous environment with absorptivity that rivals metal catalysts (and often we see the increased reaction rates of organic reactions, but can’t measure the surface of the heterogeneous metal on the surface — perhaps this is why the inorganic chemists benefit from high reaction rates at higher temperatures on the surface of the nucleation and the aqueous or organic media temperature is being measured). It takes very little time for the temperature to go beyond the set point here (notice that no more power is being delivered). The good news is that ILs have very little vapor pressure associated with them, so an overpressure here will not be an issue — but depending on your chemistry, be aware of going to extreme temperatures if you don’t have the appropriate vessel materials. So where is the solution for using ILs and being comfortable with the temperature of the reaction?

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The answer is found in the same way we circumvent the ability of a microwave to be used with solvents that do not absorb microwave energy….by the appropriate choice of vessel material. You see when we use a hydrocarbon solvent or something like THF, the microwave simply delivers energy without getting the solvent up to temperature so we need to add a co-solvent (there are some tricks to this) or a susceptor so that there is something in the reaction absorbing the microwave energy and converting it into heat. Depending on the company, a version of Si-Carbide or Teflon impregnated with Carbon can be used to absorb microwave energy and not interfere with the reaction. Furthermore, their absorption properties outweigh that of the IL, so let’s take a look at the result. As we see here, pyrex shows the same issue of the lack of temperature control in the bmimBr synthesis, whereas the Si-Carbide vial absorbs the energy in a more controlled way, allowing for the reaction and temperature to stay on track with the reaction parameters.

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Hopefully this will help shed some light on temperature (and pressures generated) control in a single-mode microwave reaction. Certainly the ability to monitor both with control is something Anton Paar has built into their system for chemists to depend on their chemical environment and the use of Si-Carbide vials go along way in building in a way to help chemists move forward into different areas of research. Hope you enjoyed the slides (I thank Oliver Kappe for continued progress in the development of this field of research and development, and always looking for solutions to microwave development).

 

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Microwave Flow Advancements

I have spoken about this area in the recent past, but some of the enhancements for flow chemistry has put some pressure on microwave engineers to push the envelope for large production scale chemistry. While batch has taken precedent, and there certainly is a place and need for that (med chem, kilo labs, scoping, etc), most will agree that microwave flow reactor development has been most discussed. With that, C-Tech industries has developed and put together some trials of their contribution to these developments. A quick look at their site will help you understand the thinking: 0.3 to 1l/hour flow with the capability of handling 250C and 30 bar of pressure and a production rate of >100 kg of product/day with an innovative way of delivering the required power to maintain a transfer over solvent and reactants moving through the piped system.

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Examples of their work are easily downloadable from the website and include an article from Specialty Chemicals magazine, a case study from lab to plant, and a collaborative poster illustrating improvements in production scale and impurity profiles in Pd-mediated coupling reactions and a supported project aimed at process scale-up while minimizes and chemical method development. Developments of this nature will help sustain the technology as a choice in today’s chemical research and development. C-Tech in addition to development, has set opportunities for collaborative partnerships.

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The words microwave heating and carbohydrates are usually used together to roll of the tongue when talking about microwave technology. There have been a number of times, I have worked with carbohydrate researchers who insist that microwaves destroy and don’t have a good place with their chemistry — but give it some thought, this doesn’t mean we are going to heat things to 100-200C, moving from room temp to 50C is a major change in the energy of the system. OK- enough on that: a contemporary review on microwave heating in turning carbohydrates in heterocycles (is this like going from wine to water, lol!) has just been published by Venerdando Pistara at the Dept of Pharmacy – University of Catania, Italy (Current Organic Chemistry 2014, covering the major work accomplished in the last 4-5 years…..it’s a good review and opened my eyes to some interesting ways to use carbohydrates as part of the synthetic arsenal.

Let’s start off easy with some simple methodology in the formation of optically active cis-b-lactams. In using an acid chloride and TEA, a mixture of cis/trans b-lactams with a low level of microwave heating — and higher temperature didn’t help. Moving over to a Schiff base of the carboydrate substrate provided the cis-b-lactams and could be performed on a reasonably large scale in a commercial microwave at 800W of power for 3 minutes.

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Now moving over to the formation of heterocycles. Generation of optically active pyrazoles has been in the literature a fair bit lately. Utilizing a 2-formyl glycol and hydrazines, several optically active advanced pyrazoles were provided under microwave heating (TL 2004).

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If we take this approach as a comparison to conventional heating – and exchange the pyrazole with a pyrimidine (from 2-formyl glycals and amidines, you will notice the reaction optimization illustrates the shortened reaction time utilizing microwave heating (TL 2008).

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Pd-mediated microwave couplings can also be performed on carbohydrate substrates as shown in the example of an acetylene with a b-amino glycoside substrate in a Sonogashira coupling (Carbohyd. Res. 2010)

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Additional examples of transformations highlighted in the literature (Click  chemistry) can be found with the formation of a linked carbohydrate triazoles from galactose azides in the presence of a variety of acetylenes under microwave heating, and opening the ability to substitute at the C-1 and C-6 position (Biorg Med Chem  2010).

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Stepping away from from having the sugar backbone in place, a  mulitcomponent RCM-HDAR with 2nd generation Grubb’s catalyst was an excellent entry into the construction of the pyran ring without the need for protecting group chemistry (Carbohyd Res 2009) in toluene at 80C under microwave heating.

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Several additional examples of linking, ring construction and annulated ring systems are covered throughout the remainder of the review, and if you have any interest in sugar chemistry or the possibility of using the backbone as a handle then you need to understand some of the strategies laid out in this review — and see that microwave technology is been used extensively. So my last example is the formation of a spiro substituted sugar from a nitrone-sugar olefin cycloaddition. Using exo-glycal and a variety of nitrones, the spiro-isoxazolidines could be formed under microwave heating (Lett Org Chem 2005) — of course this has been applied to the 6-membered ring variation as well. Enjoy the rest of the review — Happy Reading!

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Although I found an example in the literature in moving from a microwave method to a micro-reactor method – and placed it in my synthflow resource blog, it should also be placed here — there are advantages born out in each technology depending on the application. To give yourself something to think about, and there are going to be several more publications using this theme, follow the paper described.

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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:

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

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Cambrex Continuous Flow CaMWave

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UpScale Microwave – Floor large mw batch reactor

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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!

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.

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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).

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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.

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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.

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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).

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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).

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

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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!

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.

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.

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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.

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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.

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