Archive for October, 2013


Went to look for material on C-H microwave-assisted insertion reactions and was quite surprised that so little has been published. With all of the aromatic, heteroaromatic and constrained aryl compounds, I figured people would be licking their chops to get at it — as the holy grail of organometallic catalysis. Well then — one would think that the lack of functional leaving groups needed or aryl boronic acids, halides and or a stoichiometric catalyst who wouldn’t give it a go. Maybe all of you are, but it is simply too boring to publish. Enough of my context: let’s look at a pretty cool C-H microwave insertion. Although this is not that new, it certainly makes me think there is work that can be applied in medicinal chemistry groups — c’mon just look at those screening hits begging.

Out of Bob Bergman and John Ellman labs at UC Berkeley in 2003, the C-H insertion under microwave irradition was investigated as a replacement for a high-temp sealed tube reaction. Several things were modified 1) Wilkinson’s catalyst to the Rh (coe) catalyst shown in the scheme which provided lower loading 2) solvent was swtiched to dichlorobenzene with acetone (for microwave absorbing power — but can be modified now to move away from acetone if needed but at 6-12 minute reaction times, who’s telling them to change and 3) reaction times from hours to minutes. Enjoy the reading — I will have more of a review on this transformation in the future.

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Microwave Intramolecular C-H insertion

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Every time I come across a new polymer microwave synthetic route I have to think of all the gooey mess that I have made in many of my reactions. Maybe I have been a polymer chemist for a lot longer than I imagined. Many of the traditional concepts we learn as synthetic chemists apply across all of the disciplines, but polymer chemists have to deal with additional complications that are not often the part of the curriculum. The added viscocity and quasicrystalline nature provide the interest — just look at all of the special properties, but it also makes it more challenging.

Microwave approaches for polymer methods is relatively new. Early examples in kitchen microwaves showed moderate success — and certainly a lack of control for a structured development…..making it difficult to repeat and gain insights for progressing the field of study. With the success of commercial microwaves for the lab, this has changed dramatically……to the point now where we witness 100s of microwave polymer publications each year. Several reviews will bring you up-to-date on the current state of research: Wiesbrook Hoogenboom and Schubert 2004  Hoogenboom and Schubert 2007 and Bogdal 2007

There are three main categories that are usually talked about: Step Growth Polymerization, Ring-Opening Polymerization and Free Radical Polymerization. Without shoving too much over the fence, I will show a few examples and at least one in each category.

Step Growth

Watanabe Macromol. Chem. Rapid Commun. 1993, 25, 209.

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Polyamides open vessel mw in high boiling high dielectric solvents

Chiral pyromellitoyl polymers a column materials Mallakpour J. Appl. Polym. Sci. 2004, 91, 516.

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Poly(amide imide)s

Polyanhydride synthesis is typically a two-step conventional approach over several days. This was shortened to one-step microwave method which took place in minutes. Mallapragada Macromol. Rapid Commun. 2004, 25, 339.

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Polyanhydride microwave approach

And just to let you know that pretty standard C-C coupling reactions work just fine Carter Macromolecules 2002, 35, 6757.

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microwave C-C coupling polymerizations

Ring-Opening

Significant rate enhancement over conventional heating Ritter Macromol. Rapid Commun. 2005, 26, 160-163.

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Cationic ring opening microwave polymerization

Free Radical

Microwave and microwave under radical generating conditions promote different pathways — both accelerated reactions considerably (in an oil bath the acrylamide formation did not occur, both polymerized in minutes). Ritter Macromol. Rapid Commun. 2005, 206, 349-353.

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Free Radical microwave polymerization

Now go take a look through some of what these chemists do and see if you can find some reactions that might be used in their world. It’s fun to see if the things we do day-to-day can be transfered into other areas of research.

Let’s talk about what most would consider a pretty easy metal-organic framework – MOF-5. Before we jump into this specific compound, it would probably benefit everyone why. Most of the research centered around these compounds came at the result of zeolite work, as porous materials with a lot of functionality (water purification, catalysts for cracking — but mostly in detergents). Unlike the adsorbing qualities of zeolites, MOFs are generally studied because of their ability to trap gas, such a H2 and CO2 — so these buggers can be used in gas separation, purification and sensing selective gases. The nice thing about such an experimental science, there is much to be learned — varying ligand, metal, and pore size to study their effectiveness in action.

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MOF-5 ZnO4 polyhedra with 1,4-benzenedicarboxylates

Typically, MOFs are synthesized by mass transfer techniques or traditional hydrothermal and solvothermal methods, which take days and even weeks for mass transfer reactions. Although recently these have become an attractive prospect for microwave irradiation — with the hope of faster reaction times and more uniform structures (the idea would be to increase the surface area and compound which would trap CO2). A current method (Chemical Engineering Journal 2010) for synthesis and evaluation: 2.93 g of zinc nitrate hexahydrate (Zn(NO3 )2 ·6H2 O and 0.55 g of terephthalic acid (H2 BDC) in 50mL of NMP were mixed together and transferred to sealed Teflon pressure vessels followed by heating for 30min under irradiation. Two methods: 1) first included a ramp to 105C and holding the temperature, 2) ramping to 105C followed by a shallow ramp to 130C. As a comparison, MOF-5 was also prepared by conventional relux over a 4h period. The morphologies from method 1 and conventional reflux is shown in the SEM images below. Higher quality crystals were formed under microwave conditions.

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a) MW 105C 30 min b) relux 4 h

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Take a look through the XRD patterns to recognize impurities formed under reflux conditions and how MOF-5 is conditioned following the reaction methods (washing and solvent exchanges). What remains is — which one traps CO2 more efficiently?

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Surface area and CO2 absorption properties

The mw method produced MOF-5 with 12x the surface area and 3x the CO2 absorption power. Honestly for me, the most interesting part of the article is in the application. Several cycles of capture and release and recapture gives you an idea how good the thought process and application can be for breakthrough materials in chemistry.

Check out Chemistry by Design by Jon Njardarson at the University of Arizona. If you want to keep up your skills and have fun in a group, this virtual flashcard synthesis website is one-of-a-kind. To be honest, I had to pull out a couple books on the first one I tried. Nice work Jon. I will try and contribute in some way from some microwave steps at some point.

Carrying with the theme of using reactive gases in a microwave reactor will quickly lead to hydrogenation and hydrogenolysis techniques. There has been much written on the subject – too much to account for, but I will mention some of the key features and improvements over the last several years. As far back as 1999, Professor Bose at the Stevens Institute of Technology published a paper on transfer hydrogenations for synthetic reactions. In the paper, several considerations to using hydrogen as well as reaction set-ups are discussed: the ability to use an open-system from the in situ generation of hydrogen from a hydrogen donor (ammonium formate, cyclohexadiene, formic acid), specific hydrogenation reactions with the need for higher pressure and elaborate equipment. This was an excellent paper showing CTH applications — ammonium formate with RaNi in ethylene glycol at atmospheric pressure producing high yields in the following azetidinones below. To set the stage correctly however, it should be noted that reactor, closed-vessel technology and the addition of H2 had not yet developed.

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Moving forward — Kappe’s recent books and reviews will provide the most up to date examples of reactions under H2 pressure and CTH methodologies. I have also included an example from his work as well (free access from Angewandte Chemie 2004).

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MW CTH NO2 hydrogenation

OK — we have the starting point and the present, but several things went in between. As I mentioned, several events had to take place. For one, there was a strong belief in the organic community that H2 in a closed microwave reaction was not all that safe. One thing was clear, if the vessel can not handle the pressure or temperature, this was not a good starting point. This was more of a “gas and pressure thing” than the type of reaction itself. A reasonable recent review by Elena Perticci and Maurizio Taddei goes into some detail of some of the developments pre-2007. To set the record straight, all of the commercial vendors have developed safe set-ups to use H2 gas and it comes down to scale, pressure requirements and and the additional chemistry research needs. Heck, even I have fun using the tank and filling the reaction chamber.

Presently there is a need for both type of reaction techniques. Microwave transfer hydrogenations are constantly used — especially with the development of new catalysts. A recent example of 1,4-cyclohexadience with Pd/C used for hydrogen transfer for double-bonds along with N-Cbz  and OBn deprotections (TL 2008). If you feel like reading some more — there is a nice publication on microwave transfer hydrogenations of ketones with Ru(xantphos) complexes to provide the alcohol in near quantitative yield (ChemCatChem 2012). Tying back to earlier thoughts on ionic liquids (IL), CTH under microwave irradiation takes place in an IL medium as well (Synthesis 2002).

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MW CTH in ILs

The use of H2 gas under higher pressure also has its’ place on the bookshelf, and there are still many examples where the pressure needs to help the reaction along, even when accelerated by microwave irradiation. Some recent work reflects several examples where much higher pressure is required, even a dearomatization (not such a simple transformation) reaction with 60 bar H2.

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MW CBZ removal H2

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Dearomatization MW H2

Give these techniques some consideration while digging in the organic toolbox, both microwave and reactive gases can be combined as an innovative technique.

In my last blog post I talked about solid reagents used for CO generation in situ. Although that is a nice workaround and very creative for doing a number of transformations, there is still nothing like being able to use reactive gas to carry out the chemistry. If you took a look at the post — I still would like to be able to a number of modifications in the microwave at the same time, switching Pd sources, solvents and even reactions — wouldn’t it be cool to run heteroaryl triflates with Hermann’s palladacycle in one vessel and Pd(OAc)2 with halides in the next vessel — with different solvents and different amines and alcohols so that at the end you came out with a slide with arrows to fifteen different products in one microwave method…..ok before I get off the point.

Recent work from Leadbeater and Kromos indicate that hydroxycarboxylations and alkoxycarboxylations can be performed under microwave conditions under a pre-loaded atmosphere of CO in a multimode microwave. It is worth noting that solvent, CO loading and aryl iodides had the most striking results. Since CO is more soluble in alcohol over H2O, these reactions tended to need less temperature. The systems were loaded with 10 bar (for esters)and 14 bar CO (for acids).

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Microwave CO insertion with reactive gas addition (acids and esters)

Leadbeater was also able to show how this process could be scaled up to the 1 mol scale using single reaction chamber (SRC) technology microwave design (shown below). Several things of note: 1) they flushed the system with N2 followed by CO then reloaded with N2 and added on top of that the amount of CO needed for several reactions (6 reactions on the 50 mmol scale) run simultaneously, then the same process was used for the larger scale reactions (scheme 2).

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UltraClave microwave SRC CO insertions

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Evolution of gaseous CO microwave approaches

Newer SRC designs (see SynthWAVE in previous posts) enable multiple gas inlets that can expand the work done here to include flushing and loading with ease as well as mechanical stirring. As the technology changes so should the possibilities — in the article, they are able to perform several reactions simultaneously so it gives me pause for thought that we should be able to do several independent unique reactions under microwave conditions. For SRC, there is a pool of liquid absorbing the microwave energy and controlling the temperature and conditions — with the right solvent in the pool and pre-pressurization, the boiling point of each solvent and the liquid pool is raised, giving the possibility to run different reactions that are otherwise not a good idea in multimode reactors. Although I have started to see this mainly from the inorganic chemists, there is certainly room to play for everyone. We should start to see higher pressure hydrogenations and carbonylations. A recent publication out of Cravotto’s lab indicates that this thinking is ongoing (a nice picture of multiple reactions in the SynthWAVE).

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Multiple microwave Heck reactions with cross-linked cyclodextrin catalysts

The ability to utilize gaseous reagents and expand microwave capabilities has been underappreciated in many regards. The amount of research in this area pales compared to the need to perform these transformations and understand what can and can’t be done. The focus for this will be carbonylative insertions on aromatic halides to prepare carboxylates or amides.

The apprehension and lack of microwave capability for performing reactions under what I would call reasonable pressure is evident in the literature. Because of this, several researchers have used reagents that can generate CO in situ. An intriguing report from Mats Larhed helped shed some light on some of what can be accomplished. Mo(CO)6 has been used to generate CO in situ for a number of reactions over the years (Pauson-Khand reaction comes to mind).

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Competition between two pathways

The initial design, with Mo(CO)6, used excess allyl amine with iodobenzene under a variety of microwave time and temperature studies to show that the fast CO insert step followed addition of the nucleophile was the dominant pathway over the Heck reaction. Taking these results a number of aryl and heteroaryl iodides were used to exemplify the idea (scheme 1).

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Scheme 1: In situ microwave CO insertion – amidation

Expanding the scope to include less reactive aryl halides and aryl triflates and tosylates offers several opportunities to functionalize rings systems.

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Aryl halides CO amidation under microwave conditions

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Aryl and HetAr-triflates/tosylates CO amidation under microwave conditions

Dr. Larhed’s work has recently expanded this to additional areas of functionalization. One thing they were able to show was a larger scale reaction of scheme 1 to 25 mmole scale in a large scale Biotage Advancer system. I know that doesn’t impress the process chemists — I am sure they are sneering at me now. Stay tuned — I will turn this to advances on the microwave side next — with much larger scale possibilities.

I am always looking for funny ways people apply the latest technology or methodology in the literature. Just do an analysis of the number of papers that come out after the big papers on metathesis, Buchwald-couplings, click chemistry……ok you get it, even I ran around trying some cascade reactions (in my case it was Pummerer derived). Funnier things take place — try and perform a 6-10 step synthesis with only Pd couplings — it’s a fun way to spend a few hours coming up with something. For my literature reference of the week (2011)– I found a convergent 6 step microwave synthesis of a 2-{4-[2-(N-Methyl-2-pyridylamino)ethoxy]phenyl}-5-Substituted 1,3,4-oxadiazole  library….I mean every step included a microwave step. I had to double check. It was a nice process for producing a library of analogs (could be done at a few different places, although this group had a specific left-hand piece) and even concluded with a cycloaddition step at the end to form the oxadiazole.

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Microwave steps abound

There’s nothing much more to say other than…see if you can give me examples where someone has used a specific reaction, reagent or technology to run multiple steps throughout the entire process — it has to be several steps though. Maybe next week I will use microwave synthesis to set up the northern warhead of a complex total synthesis…..hehehe, some of the vernacular that gets picked up makes me think that I will start using cartoons to name starting materials coming together.

Another nice report on the utility of ionic liquids:  an organic synthetic approach to tetrahydrobenzo[a]xanthen-11-ones. This was a nice idea to combine the ionic liquid with an acid functionality to see if the combination of the two would promote the 3 component sequence with attack of the aldehyde, alpha to the OH on the arene, spitting out water and reaction with the enol for of dimedone and intramolecular attack for the OH to give the desired Xanthene product.

Green Chemistry Letters and Reviews 2011

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3 component reaction with catalytic IL

In addition to using the IL (or Task Specific as referred to in the article), they wanted the reaction to be catalytic in the acid — so the IL was studied in mole percent/time to develop the chemistry (5-20%, so not a solution phase reaction) for 10 min provided comparable results.

The approach was nice enough, but I get a little chapped when I don’t see temperatures defined as part of an optimization. Isn’t that a pretty key variable? Was this a multimode microwave? With a time of reaction from 8-15 minutes, temperatures can get pretty high, especially in the presence of an IL as part of the medium…….I get the utility, but would just like a little care given to pushing a technique. Anyway not to end on a down note, they did note some standard conditions with the current method and have shown a significant reduction in time while maintaining high yields.

Ionic liquids have been called many things: green, recyclable and non-volatile, an answer to many of our wows in organic synthesis. I liken the interest to nanoparticles or carbon nanotubes…..very interesting, and everyone scrambles to make and use, and publish (oh how many Buchwald amine-couplings did I perform after those first couple of publications). All of that said, I have mixed feelings on what can be done…or which one do you use? But hey maybe I waited long enough to jump in the deep end.

Since  I am not going to do an exhaustive literature dump on all of you, I thought I would impress upon the audience how these buggers can be used to enhance microwave chemistry. For starters, if you have a reaction that is normally performed in a non-polar solvent (an a kicker would be conventionally at high temp in a non-polar or non-microwave absorbing medium), the addition can help make the method a microwave method instantly. The following are a few examples of this idea:

Materials Research

Chem. Commun., 2010,46, 3866-3868

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Microwave Reaction Help with IL

Organic Reactions: Intech Open-Source Jan 2013

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IL added to non-absorbing solvent

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IL in Toluene under MW conditions

OK, so you can look at these and get the idea. These authors are on the money, but the idea of a susceptor is not a new concept for helping a non-absorbing reaction work under MW irradiation (they use the terms doping agents), but it certainly does get us to think how we might use ILs. Additional examples can be found in Rafael Palou’s review of IL/MAOS processes, both as a comparison and with some synergism. Among the many examples in the review, Kay Brummond’s [2+2] intramolecular methods employ doped-IL in toluene to the desired fused bicycle. There is also a table of references of named reactions that have utilized this approach.

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[2+2] intramolecular cycloaddtion IL-doped-MAOS

The other advantage of ILs as a medium for a microwave process has to do with the low vapor pressure these materials give during heating. They do require some getting used to on the work-up (isolating product away from the IL), but the advantage of mixing a solvent with a high vapor pressure with an IL can help the overall process in low-to-medium pressure vessels used in some of the microwave reactors.

My thought process is a little different (and I have detailed a new way to think of MW reactions in a single-reaction chamber SRC)– I want to take full advantage of the solvents used in traditional approaches but utilize the ILs as a liquid absorbing pool in a single reaction chamber where several different reactions can be done under MW conditions in their typical solvents (THF, toluene, DCE) and use the IL to absorb the MW surrounding the reactions. One of the great things about this would be that the system will be pre-pressurized to raise the b.p.s of the solvents and the IL can be recycled from one reaction to another, because it isn’t really a part of the reaction other than to absorb the MW energy. So don’t scoop my idea, LOL!

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