Archive for July, 2014

New Synthetic Database

Just came across a new database — SynArchive… it’s pretty cool, new and different. Adds to the tool box we keep stashing all the new gadgets. ENJOY!


Better get out your name reaction book — this is a mouthful….and dig back to your Berichte der deutschen chemischen Gesellschaft to find examples of some of the earliest examples of metal mediated couple reactions (loved that I got to goof off in German a bit — it’s the only other language I can speak in the house with an echo since the other three speak a little Tagolog.

Anyway — the scheme below depicts the Glaser Cu(I) homocoupling reaction

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Glaser coupling of 1869

If we add a nice coordinating base like TMEDA to the copper and do the entire step in the presence of the oxidant (keeping the sequence catalytic to the metal), we have the Glaser-Hay coupling. One of the nicest features of this reaction is that it is extremely resilient to functionality and takes place in a number of solvents.

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Glaser-Hay — Examples for Synthesis 2010, 3461

No let’s mix in the pot — macrocylization and microwave and see what kind of meal we make. Over the next few blog inserts I will stick to some of these macromolecules out of interest in what people have been recently improving.

Macrocyclizations are a wild lot; there’s all sorts of things that can go wrong from the get go — and some nifty techniques to orchestrate the right pieces to come into play. Included in the list of challenges: competing oligomerization, lack of ability to increase the scale because the dilutions necessary to produce product and the general need for heat to promote the ring closure……whereas, increased temperature would normally get me jazzed to run it in a microwave, often times the slow addition techniques often found in these preps present an obstacle to the technology.

Shawn Collins at the University of Montreal was able to develop a way around high dilution and low-yielding conventional procedures through a phase separation strategy (he was able to utilize a two-phase system that could handle heat and shuttle the desired product away from undesired reactions and starting materials — this group chose PEG400/MeOH but mentions that other phase separations are viable). Inserted below is the strategy on a first shot comparison using phase separation vs. traditional thermal heating under high dilution (Figure 1/Scheme 1).

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Since this was a side-by-side, the goal was to look for the phase separation to work — so the yield needed to be better (11 vs. 73% and a 150x factor on dilution) — WOW! OK so now the stage is set — can the 2 day reaction be improved upon with the aid of microwave heating. Taking the same 16-membered ring formation some optimization provided a path for microwave’s benefits.

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Optimization of the ligand and improvement in time

There is a lot to be said for cutting the time down to 6/12 hr from 2 days, but the group marked forward with larger rings sizes and shortened time studies to make a number of exiting molecules featuring the 1,3-diyne moiety within the marcocycle…and the table illustrates it nicely.

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I cant take you away from reading the article so I will leave you to read through the studies on concentration compared with conventional heating….quite incredible actually to see the differences….and it really goes back to my thinking about the things that are in play in different reactions — keeps me excited that people are pushing the boundaries of accepted reaction techniques and practices.

Enjoy the read — and as a note, on Shawn’s website, he lists a number of his strategies — and kind enough to provide copies on request. Kudos, Shawn. Vive Shawn, je vous dois un verre!

Normally I would leave the literature alone on the production of ZnO — it has been explored on a number of occasions, and with several processes — including solution phase microwave. A recent publication (Journal of Materials 2013) intrigued my interest: this group detailed several parameters in their development of ZnO nanoparticles — and discussed at length the morphologies associated with the different conditions.

Let’s back up a bit — ZnO is a critical component in paints, plastics, ceramics and adhesives. It’s properties open the number of applications were it can be used. Hence the importance of looking into good ways to reproducibly make the material with the desired morphology. For this paper, the group utilized microwave radiation for the production of ZnO by studying the temperature effect, precursor variation, post-wash, base precursors, stoichiometry and power/irradiation time. Each contributes to the variation in products formed and provide some guidance for those interested in using mw for their research.

We are all familiar with the general advantages — rate acceleration, wide range of conditions, selective morphology formation, reproducibility of the instrumentation, easy-to-use and fast instrument optimization. However when it comes to inorganic microwave conditions the key performance factor relates to keeping the variable temperature gradient profiles to a minimum over the bulk of the reaction — and the microwave heating the solution and materials, rather than the vessel and relying on convection heating to transfer the heat…..serves as the prevailing reason for using the technology.

Before getting into some of the key parameters: the products we characterized by FE-SEM and XRD — pretty normal in the field.

Temp: Conditions were set to a range of 80-140C

Products formed at 80-100C were impure and contained a considerable amount of precursor starting materials. At 120-140C strong defraction peaks appear corresponding to wurtzite ZnO and a homogeneous distribution of particles from the conditions at 140C. Looking at the table 1 (Click on image to zoom) and characterizations 2, it is interesting to see differences in particle size at 140C depending on the amount of power that was administered — it was postulated that an increase in power could help reach the desired temperature quicker. While that is a good dose of handwaving, nucleation and crystal growth play a role in the formation of the the products so further studies would be needed to tweak out conclusively.

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Table 1: Microwave parameters

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100C, 120C and 140C

Particle size and precursor effect: For the zinc nitrate and zinc acetate, the distribution of particles is homogeneous whereas the ZnCl2 produced some aggregation and non-uniform distribution. Depending on ligand coordination or lack there of in the starting materials, the counter ion has a pronounced effect on the crystal growth — and this allows some control of over the type of ZnO desired…..Characterization 2

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ZnO with different starting materials with mw at 140C 600W

Base effect: Each of the bases used: NaOH, KOH and NH4OH provided different morphological products depending on conditions: the differences are attributed to the changes electrostatic properties of the hydrated ions Na+, K+ and NH4+ — and their effect on crystal growth on the surface (a good example is K+ producing more than one type of crystal depending on the concentration).

Power and irradiation time: Here is where I found the studies to be the most interesting — YOU HAVE TO READ! For time, there is a comparison at the 140C at 5, 10 and 20 min timepoints including the set-point temperature reached — so this is time at 140C. Looking at the Characterization 3, it is easy to see that some product formation happens during the ramp to temperature and more well defined particles are achieved at the late stage timepoint — or 10 minutes at 140C.

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Product once reached 140C, 5 min at 140C and 10 min at 140C

However, when looking at the power — the increase in power to reach 140c over the same time period produces less defined structures. Perhaps not so intuitive a result considering all of the parameters studied. From this it sounds like I should use less power, shallower ramp profile and hold the temp a bit longer to produce the ideal product. Give this a read, it certainly has me thinking. I firmly believe that the complexity of the reaction system and the mechanisms of nucleation and crystal growth makes this type of experimentation necessary in tuning desired product and morphology in nanoparticle design.



Well I did say all things microwave…..a buddy of mine said I should review it, but I thought you might get a better kick out of looking at it yourself.

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Microwave magnetron on a stick with a directional antenna

Check it out

Two things I like to see: Reactions that I don’t often come across and having a functional handle to utilize in some of the chemistry I am interested in… imagine my delight in this paper (Molecules 2013) –Efficient Synthesis of Boron-Containing α-Acyloxyamide Analogs via Microwave Irradiation — Boron in the final compound — I can use it again, well all….right (in my Dazed and Confused voice) AND the α-Acyloxyamide which is often formed via a Passerini reaction.

Although this group was actually looking to make boron containing compounds to study cytotoxicity, I thought about the handle that it provided (although pointed out that there is a boron containing compound commercially available as a drug, I can’t imagine non-cancer targets would provide too much opportunity for this functionality.

First things first” Passerini: below

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Multicomponent Passerini reaction (Acid, aldehyde and isocyanide)

Applying this to the aldehyde or the carboxylic acid gives us a way to functionalize two different sides of a fragment — come on you combichemERS.

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Boron on the carboxylic acid

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Boron on the aldehyde starting material

Although not exhaustive, there were a few solvents screened, H2O provided the best set of conditions in the microwave –55C, well maybe not so much. I would have to look into additional solvents and temperatures — must be some hydrolysis somewhere.

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Small solvent screening sample

It’s a quick read, but think about the utility. Could show some potential for adding an additional starting material and coupling post pinacol-boronate formation.



Interesting new article (Beilstein JOC 2014) on a microwave optimized approach to 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles via a 3-component reaction combination, The group decided that 3 possible combinations were feasible to provide the final compounds depending on how the starting materials were reacted together, Path A — 2 step with the triazole ring formed first then cyclocondensation with the diamine….Path C forms the benzimidazole first followed by   the cycloaddition of the azide to the acetylene susbstrate……and Path B were each of the reactions are taking place under the same set of conditions in one-pot.

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Interestingly —  most people would likely use the same thought process and see if the conditions for forming the benzimidazole or the triazole would work best and what order the strategy should provide the best pathway. In  the process, they reasoned that the conditions would be suitable by simply having all 3 components together in a one-pot reaction…..good for them. If you take a look at the conditions for the imidazole formation, the solvent choice was toluene but in the Cu-mediated triazole formation THF,H2O was used…….and therefore the group next moved to a solvent screen to optimize conditions

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A total of 11 reactions were performed to conclude that some H2O was needed for the reaction to proceed well….solubility likely from the CuSO4. There were some differences in reaction time and temp so it took some time to conclude (see my thoughts on SRC screening and this would have taken 30 minutes tops running all of the reactions at 110C for 20 min).  Once the solvent combination was chosen a series of compounds with changes on both ring systems were made — although there was a little discussion on group substitutions and reaction yields, all products were formed in good to excellent yield — providing an accelerated approach using microwave technology to speed up the reactions, but also to introduce strategic thinking into how the technology could be applied creatively.

Dig into the article a bit — they formed some mechanistic reasoning to the possible pathways for the reactions……which is always fun, and for me, where I take the info and see how it can be applied to other reactions of interest. THERE SHOULD BE A BOOK OF REACTION CONDITIONS, TRANSFORMATIONS…PERFORMED IN MICROWAVE REACTORS…..make it searchable and chemists will devour the chemistry in a number of creative ways.

Enjoy the read.

Fantastic new review in Chemical Reviews 2014 (Microwave-Assisted Preparation of Inorganic Nanostructures in Liquid Phase) summarizing some of the latest work in microwave inorganic nanoparticle synthesis. Below are a few of the important bullets discussed in the article….lots of interesting research being done in this arena — tremendous number of applications in this field:


1. Microwave Chemistry and Microwave Effects

Microwave-Assisted Hydrothermal/Solvothermal Methods

2. Microwave-Assisted Preparation of Nanostructures in Aqueous Solution

3. Microwave-Assisted Preparation of Nanostructures in Polyols

4. Microwave-Assisted Preparation of Nanostructures Using Ionic Liquids

5. Microwave-Assisted Preparation of Nanostructures in Other Solvents (and Mixed solvents)

6. Microwave-Assisted Self-Assembly of Nanostructures

7. Comparison of Microwave Heating with Conventional Heating

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The first thing I will say in this post is: you won’t find me using O2 in a microwave reaction…..well with recent developments utilizing better methods of introducing reactive gases to microwave systems…see SRC microwave synthesis, I find that we are seeing more controlled and safer ways to use H2 and O2 in a microwave reactor…..which is great because it is greener and the atom economy approach will help broaden reagents that are useful for these powerful transformations (see scheme below)

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A recent publication (love the open access journals btw, although I can appreciate the difficulty in making sure these stay on the up-and-up) on the conversion of a variety of alcohols to aldehydes and ketones indicates that simple Pd/C in the presence of MeOH, base and molecular oxygen (gas addition to SynthWAVE) converts alcohols into esters with ease. That find was impressive, but what stands out in the article is how they arrived there. Going back several posts I introduced the SRC design and how people are starting to use it — in this research, they  really went into screening mode: what Pd reagent, what base and what combination would work best for the transformation — If I am doing DOE or feasibility studies, I want to quickly get to the best set of conditions possible.

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SRC Cartoon of reaction sequence

Below I have placed the first set of conditions looking for microwave conditions with a few Pd catalysts.

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The reaction chamber was loaded with oxygen (2.5 bar) and pressurized with nitrogen (up to 20 bar) [57]. Reactions were performed in the presence of benzylalcohol, K2CO3 in methanol and numerous different reaction conditions were screened

Without going too heavily into his paper — you have to read it — I have included a table of the bases and catalysts which were screened.

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Enjoy the material — another example of running a few sets of microwave conditions to arrive an an optimized route to a variety of esters. One thing to note — pay attention to the utility of using O2 in a N2 blanket inside the microwave reactor — moving us forward in what is possible using microwave technology for synthetic operations

Wanted to post some interesting reads — always fun to see scientists move from reactions taking 1-2 days down to an hour or minutes. Many times however, when we see this, there is a strong desire to understand it. Hey I can’t hit an 85 mile/hour curve ball either but I am ok not knowing all the details — suffice to say there are more and more publications on the “strangeness” of microwave accelerated reactions — especially those that take place in solution.

Here is a list of a few recent publications that are worth reading:

1. Org Lett – Ru-mediated ring-closing metathesis of an oligopeptide was sluggish with oil-bath heating—taking hours. But it proceeded rapidly—that is, in two to five minutes—with microwave heating. Paper

2. Early 2014 discussion from FSU researcher, Dudley

3. JOC 2010: Challenging Ru-catalyzed ring-closing metathesis transformations leading to eight-membered-ring systems and Ni- or Co-catalyzed [2+2+2] cyclotrimerizations were evaluated at elevated temperatures applying microwave dielectric heating or conventional thermal heating in order to investigate the role of wall effects.

4. Kappe’s microwave effects review late 2012:

and the Buchwald paper from the previous post….

5. Paper pdf link

Glad to see that C&E News is reporting who is still trying to get to the bottom of microwave effect and reaction rate acceleration. The June 16th issue of CENews mentioned that a group at Idaho State looked into studies on Buchwald-Hartwig amination reactions and their differences in reaction rates — thermal differences or microwave effects….

The detailed account can be found:  Much of the rub is the discussion on the early differences in rates with subtle thermal differences between microwave and conventional thermal conditions. After detailed study, the group postulates that the two sets are actually in close agreement.


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