Webinar Questions: Green Chemistry Techniques

There were 14 Green Chemistry technique questions raised by the audience.

These answers are Dr, Denlinger’s; feel free to share your thoughts and follow up questions in the comments section below. (Note: the comments section is moderated, so there may be some time delay before your question shows up.)

1.) What safety practice is applied when opening the Ball Mill vials after the reaction? 
After taking the vial out of the ball mill, it is usually clamped in a vise and the cap is removed using a wrench. This is also done under a snorkel, since in some cases gas or vapor escapes when the vial is opened.
2.) What is the largest scale at which you have run a ball milled reaction? 
The largest scale I’ve personally run one of my reactions produced 500 mg of my desired product. Our standard stainless steel vials are about 3.5 mL in volume, and our large stainless steel vials are about 64 mL in volume.
3.) What are the limitations or downfalls to ball-milling?
It would be difficult to perform a reaction that required a gas as a reagent, since we rely on the motion of the ball to grind our reagents together during ball milling (though there are also advantages to this: see “Conducting moisture sensitive reactions under mechanochemical conditions”). Creative solutions might be found, though, such as using dry ice as a CO2 source (see “The solvent-free and catalyst-free conversion of an aziridine to an oxazolidinone using only carbon dioxide”). We have also tried reactions that occur through radical mechanisms and have not had any success with those yet.
4.) What about oxidizers?
One of my projects is the oxidation of alcohols under ball milling conditions, and several oxidizing agents were tested (ex. TEMPO, Oxone®, mCPBA). No accidents have ever occurred, and nothing was out of the ordinary with these reactions as compared with others that did not involve oxidizing agents.
5.) I assume based on reactivity arguments that there are some reactions that may not be amenable to solvent-free solid state reactions.  Have you encountered such situations (reactions that went out of control, etc.)? 
We haven’t encountered any reactions that went out of control in our system. For the most part, the research process is the same for us as any other organic chemists. We try something, and if it doesn’t work at all or we observe low conversion to product, we change the system and try again. There are certainly reagents that we would not put into a ball mill, but in those cases we look for safer alternatives that can carry out the same transformation (using Cs2CO3 as the base for the Wittig reaction instead of n-BuLi is one example).
6.) I am using THF for GPC, how can I change that to a GC solvent? 
The simplest change you can make is to switch to 2-methyl-THF, but there are some other options available if that wouldn’t work for you (see “Updating and further expanding GSK’s solvent sustainability guide “ for examples).

7.) How easy to separate solid solid compared to liquid liquid in terms of green chemistry?
We still use solvent to extract our reaction mixtures from our vials, so for separations it’s a matter of choosing a solvent that will dissolve the product. Solvent selection guides can be used to help make the greenest choice possible for separations, especially if chromatography has to be used. I’m working on my project with polymer resins so that we can green up the separation process as much as possible. Avoiding solvent for the reaction phase of the process still helps prevent waste, but we also want to expand that philosophy as much as we can to the isolation/purification process.

8.) How difficult is material removal from the Ball Mill vials?  Does it require any liquid aids?
Removal of material from the ball mill vials is not that difficult as long as an appropriate solvent is chosen (see question 7). Yes, we do use solvent to aid the removal of material from the vials and subsequent isolation (whether it’s gravity filtration, liquid-liquid extraction, or chromatography).

9.) Has anyone assessed particle exposure around the ball-milling set-up?

No, but that might be a good thing to analyze just to make sure we have the safest set-up possible. We usually tighten the caps onto the vials with a wrench to ensure no reactants leak out, but it is possible to smell highly volatile reagents while they are being ball milled. That definitely indicates that vapor at least is able to escape, so very small particles might be able to escape as well.

10.) Ball-milling – I have heard of but never tried it – is it truely a solid-solid reaction or is it more like a melt where under heat/friction you get a liquid phase?
Our indirect evidence suggests that our reagents react with each other whether or not they melt under our conditions. Using an iButton to measure the temperature of the vial during the reaction indicates that the vial reaches a temperature of about 45°C. So any reagents with melting points lower than that are probably melting, but anything with a melting point higher than that probably is remaining as a solid.

11.) Are the polymer resins you’re using recyclable? 
Yes! For the Wittig reaction, we don’t reuse the polymer because it has changed from triphenylphosphine to triphenylphosphine oxide. For some of my other projects, however, a catalyst is attached to the polymer. This catalyst is not used up or changed during the reaction, so I can scrape it off the filter paper after gravity filtration, save it, and use it again. In one project it is possible to use the same polymer-bound catalyst sample at least 5 times with no change in its activity.

12.) Are the ball mills safe when dealing with crystal morphologies and materials that could decompose explosively (shock)?
I have not used any reagents that would fall into that category, and in general we try to find alternative routes in order to avoid specifically hazardous chemicals. There is one example of using azides under ball milling conditions (see “Scratching the catalytic surface of mechanochemistry: a multi-component CuAAC reaction using a copper reaction vial”), and no safety issues arose.

13.) A sequestering solid support will not have much resolving power for separating related components so it has limited utility BUT more importantly a lot of solvent goes in to making these resins so it is questionable how green they are – have you done such an analysis?
These solid-supported reagents are tools in the green chemistry toolbox—they cannot be applied in every chemical process, but there are certainly many processes that would benefit from them. In cases where a reaction or process would not benefit from a re-design using solid-supported reagents, other tools in the green chemistry toolbox could be applied. This might consist of choosing safer solvents, choosing different reagents, using photochemistry or microwave chemistry, or any of the myriad ideas published in journals such as Green Chemistry and ACS Sustainable. The fact that we cannot fix everything immediately does not mean that we shouldn’t try to fix what we can. Even making a small change to be safer or greener is better than what we were doing before, and making many of these small changes can result in a big change overall.

Not only is solvent used to make these resins, but many other reagents that may or may not be particularly safe are used as well. My work on the Wittig reaction was an extension of a proof-of-principle project to understand how these solid-supported reagents behave under ball milling conditions. In order to address the problem you mentioned, I also investigated the possibility of using ball milling to functionalize a polymer itself. This would give us more control over the greenness of the functionalization process. Furthermore, I investigated using a polysaccharide backbone instead of polystyrene, so that the solid support employed would be biodegradable and derived from renewable resources. We plan to publish that work this summer.

14.) what amount (mass) of reagents are used in ball mills?
The amount used can vary from one ball milling group to another, but in our group we usually try to work on the 1 mmol scale (so producing about 100-200 mg of product, depending of course on the specific compound). We can vary that number a bit, but we are constrained to the approximately 3.5 mL volume of the regularly used stainless steel vials.