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.

There were 9 general lab safety topics raised by the audience.

These answers are Ralph Stuart’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.)

Can you talk more about the safety & health issues in the laboratory? Specifically, what are the general policies for the hazards of broken glassware and dealing with students cut by broken glassware?

General laboratory safety issues, as well as glassware specifically are well covered by the ACS publication Safety in the Academic Laboratory. A reminder: Remember to check with the host institution for its protocols related to providing first aid before lab work starts, as glass cuts are one of the most common laboratory injuries.

How do I access or subscribe to the Journal of Chemical Health and Safety?

The Journal of Chemical Health and Safety (this link will take you to the Journal’s web site) is a member benefit of the Division of Chemical Health and Safety and is also available in many academic libraries. 

I am most concerned about the Risks (vs Hazard) within chemical reactions.

This is an important point. The risks associated with a chemical reaction are often not clear from a review of the Safety Data Sheets for individual chemicals, so further safety analysis of the process as a whole is necessary. This issue was identified by the Chemical Safety Board’s 2011 report and the ACS is working hard to support this process with the technical resources outlined in the webinar.

Two related questions:

• Another thought is treating students like workers and getting them OSHA protection – never saw this in my time in academia, but in industry, I got a benign chemical splash between glove and coat and the reporting on that went on for 12 months and involved a lot of discussion and meetings around chemical practices
• In 2003, U. Iowa Dept. Chemistry had an explosion from one of the grad students running a solvent still, where he was burned (3rd degree) and hospitalized.  There was a lot of controversy afterwards, because the university did not intend to cover medical bills, stating that student insurance did not cover graduate teaching assistants that were involved in lab research (only graduate research assistants were covered).  Eventually the student union became involved and this was resolved.  However, does this continue to be an issue in academia?  With respect to hazards for graduate/undergraduate research, has there been any legislation to cover students injured in an accident by workers comp/disability?

The academic laboratory is an interesting challenge in this respect. Traditionally, higher education has been what the former head of OSHA, among others, has referred to as a “fissured workplace”. This phrase describes workplaces in which employees and students work together under a wide variety of institutional relationships (e.g. full time employees, visiting scholars, tuition-paying students, volunteers, etc.). This situation presents an interesting challenge to developing and sustaining an active laboratory safety culture because the legal requirements applicable to each group will vary depending on their status and the legal jurisdiction that applies.

Do you follow OSHA 1910. 1450 requirements?

This question refers to the OSHA Lab Standard found here. This question is answered on an institution-by-institution basis. We have a Chemical Hygiene Plan at Keene State and the University of Cincinnati.

How do you apply process safety management principles in the research lab environment?

This issue is well explored by a 2009 article in the Journal of Chemical Health and Safety by Neal Langerman entitled Lab-scale process safety management. Dr. Langerman expanded on this article in a 2015 JCHAS column entitled Expand Process Safety Management

Can you explain Control Banding, and how effective it is?

Control banding is an area of active research in laboratory safety profession. The concept is to address control of laboratory hazards for a group of chemicals, rather than a process-by-process basis, in a more general way than allowed by tools such as a Job Hazard Analysis. However, control banding is complicated by the variety of physical and health hazards associated with chemical processes used in the research setting. To be effective and sustainable, an ANSI Z10 style Management System should be developed to support the control banding process.

Can we design our safety assessment checklist or we have to follow yours?

It is best practice for checklists to be as specific as possible to the laboratories that use them. General guidance for the best use of checklists can be found on the ACS hazard assessment web site here.

Any feedback from educators and researchers about the ACS Hazard Assessment webpage and tools?

The tool is still new to the world (it was released on the web in 2016), so Kendra’s case study of its use is one of the earliest we in ACS have found. We are very interested in other feedback on the tool; e-mail safety@acs.org to provide your comments.

There were four related questions and comments relative to Lab Safety Culture. 

• Who is responsible for chemical safety in the lab? (Everyone is a fine answer, but also a dodge). I feel it starts with the supervisor/mentor and I dislike the way accident blame tends to get pushed towards the victim.
• University chemistry depts operate funded largely by NIH/NSF/DOE grants. In awarding these grants, there are requirements to follow bio-safety, radiation safety animal welfare, student mentoring guidelines. But chemical safety is left to the local university and fire marshals to regulate. BUT there could be chemical safety requirements IF they could be clearly codified and agreed to. The enforcement comes from losing grant support BUT the key is they have to be clearly defined for what are wide ranging activities and there has to be reporting back to the granting agencies.
• It would be good to note that Prudent Practices and Safe Science from the National Academies came out of the Board on Chemical Sciences and Technology. They also have a publication on producing Laboratory SOPs. All of them are available for free through the National Academies Press. http://dels.nas.edu/bcst/Reports-Academies-Findings
• From my understanding, PIs are primarily responsible for ensuring that researchers who participate in their laboratories receive proper safety training prior to participating in the lab. This coincides with the outcome to the incident that occurred in California when a researcher died due to lack of training.

These comments and questions point to an interesting challenge – the decentralized, entrepreneurial nature of lab work within a larger organization.This issue is the focus of many of the safety culture resources I identified during the webinar, in particular Safe Science from the National Academies Press.  The ACS Hazard Assessment web site outlines the roles and responsibilities related to lab safety here. It is clear from the literature that chemical safety requires both leadership from lab management and empowerment of individual lab workers to be effective and sustainable over time.

What role can lab informatics and Electronic Lab Notebooks play in creating the culture of safety?

This is a very active area of research collaboration between the DCHAS and the ACS Division of Chemical Information. We are using the RAMP paradigm to identify resources and gaps in the electronic lab safety resources available to the laboratory chemist. It is important to note that education for chemists in both laboratory safety and chemical information skills is an important part of a scientific education, both in terms of the sciences of information management and risk management and in practice of these skills while chemistry lab work is being practiced.

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