Last summer I was faced with the decision of what subfield of Chemistry my final year project was going to revolve around. Following a six-week summer internship in the Complex Chemistry labs of the University’s Advanced Research Centre (ARC), I was particularly keen about the possibility of tackling areas that deviated a bit more from our base curriculum or areas that one may initially associate with the field of Chemistry. I was eager to witness and understand more about the ever-evolving incorporation of automation and digitisation into the field, and learn some new, relevant skills along the way. As such, I selected “Complex Chemistry” as my top preference for my Honours project and was fortunate enough to join Dr. Hessam Mehr’s research group as a result.

Brief project background

My seven weeks in the Mehr Group revolved around the exploration of aerosol microdroplets as a reaction medium for chemical synthesis. The idea behind this stems in part from the successful applications of other departures from traditional “flask-based” synthetic approaches, such as flow chemistry and microfluidics, with their own sets of advantages. The two main incentives for performing chemistry in the aerosol medium, i.e. in “spray” form are:

1. The potential of different chemical pathways/reactivity as a result of substantially confined volumes — reaction acceleration in microdroplets has been a prominent observation in literature.
2. Performing chemistry within this medium is inherently “stochastic”. Is there potential for novel pathways for a given set of chemical building blocks based on the probabilistic nature of droplet interactions within an aerosol cloud?

My experience

More specifically, my experience in the lab was very much focused on demonstrating the feasibility of some known organic reactions via an ultrasonic atomiser-based apparatus for droplet generation. The “reactor” (photographed below) was connected to a computer via a MicroPython circuit, and any chosen reaction was controlled and tuned via a Python program. One thing I very much appreciated and enjoyed was getting to assemble a physical circuit from scratch, coupling it with a script and seeing it all come to life when testing out the spraying of a solvent of choice. Hessam was very helpful and keen to demonstrate processes such as soldering and laser-cutting (for the assembly of the acrylic box, as seen in the photograph), as well as explaining the unfamiliar features of the algorithm and circuitry.

The biggest challenge within the project certainly had to do with my choice to explore organic reactivity in the medium, coupled with our primary method of droplet detection — microscopy. The droplets generated during a given aerosol reaction were allowed to settle onto a glass slide for visualisation under a Raspberry Pi-based RGB microscope. A reaction is deemed to have proceeded if distinct reagent and product droplets can be identified. This distinction is typically attributed to a significant difference in colour between the two — something that organic chemistry is not particularly known for. As such, my resilience was certainly tested when scouring the lands for an organic reaction that would undergo a distinct colour change in a reasonable timeframe under mild conditions. What this meant was that the eventual sight of a beautiful contrast between distinct red/orange and colourless droplets following an ado-dye synthesis in the aerosol medium put a big smile of excitement and relief on my face.

Nearing the end of my project, with the help of Dr. Mehr’s programming expertise, I had the opportunity to witness the seemingly simple, yet promising potential of changing up the algorithm loop to facilitate multi-step reactivity involving an unstable intermediate, i.e. stoichiometric spraying in a sequential manner, as opposed to the simultaneous spraying of two atomisers as per a simple binary reaction. Starting to see the extent of how such an affordable apparatus could be tailored and fine-tuned through the power of code to facilitate a truly hands-off approach to performing mainstream chemistry in an atypical medium was, needless to say, a very rewarding way to wrap up my project.

Final thoughts; what next?

It is an understatement to say that I am incredibly grateful to Dr. Hessam Mehr for all the patience and guidance throughout my time here. The group provided me with a refreshing look at a different side of Chemistry that aims to take full advantage of where the world is heading technologically — and it’s doing so with accessibility and ease-of-communication in mind. While my time in the group is now over, with the prospect of exploring various other yet-unclear endeavours, the experience I have gained working in Mehr Research is nothing short of invaluable, and the skills I’ve developed will undoubtedly aid me in any facet of Chemistry, or many other potential career path for that matter.

At the time of writing this post I’m preparing for my final degree exams coming up in just under three weeks, so fingers crossed! What keeps me going are some great destress socials with friends; playing some great games and talking for hours about Japanese animation and graphic novels! Following graduation I hope to take some time to enjoy some lovely (hopefully!) sun with my family in Poland, as well as take my partner around some places she’s not seen there yet!

That’s all, folks!

Two years ago, I came to Glasgow after finishing my undergraduate studies in China. For my program, I learnt the synthesis technology and characterisation (such as atomic force microscope, transmission electron microscope, etc.) of some popular advanced materials (such as quantum dots, perovskite batteries, etc.), which will be the basis of my research work in the future.

When Hessam pitched the idea of using microdroplets as reactors, I was attracted by this crazy idea, and so embarked on a project to create micron-sized soft materials out of seaweed. This blog post is to share with you why these materials are so interesting and how we hope to use them to make the next generation of chemical containers.

What really is a chemical container?

When it comes to chemical reactions, many people think of two solutions mixed in a beaker or test tube, changing from one colour to another. The function of beakers or test tubes is to isolate the reaction from the environment. As a traditional reaction container, they have the advantages of low price and easy operation, but the disadvantages of only carrying out one kind of reaction at the same time are also obvious. If I need to do four chemical reactions and try five reactant ratios for each reaction, assuming I need 5 mL of reactant for each reaction, then I need 20 beakers or test tubes and 100 mL of reactant solution. This soon starts to become impractical when we need to examine a larger number of reactions and conditions.

Perhaps you can say that, under the premise of constant total volume, if the interior of a container is divided into several smaller partitions, the above problem can be solved. This is true and indeed it’s the design idea behind more modern reaction vessels like 96 well plates.

You can even go above 96 wells and well plates with 384, 1536, and even 12,000 wells are available commercially. However, this idea soon runs into limitations. Not only would tinier wells become prohibitively expensive to manufacture, manually using them would be cumbersome and time consuming, even with the help of automation, such as robotic pipetting machines.

This is where our idea of using aerosols comes in: if we are able to turn individual aerosol particles (each just a few microns in size) into chemical containers, it would provide a fast and easy way to make millions of tiny containers that we would never be able to create manually.

Why calcium alginate?

Let’s look more closely at how exactly we are planning to create our next-generation reaction vessels. In order to build a container around an aerosol particle, the easiest way is to form it within the medium where the reaction will take place, called in situ in chemistry. Can this strategy address the challenge of building microscopic isolated chemical environments?

This puts forward new requirements for the chemistry used to form our reaction vessels: the reaction generating the container needs to be robust and reliable (not easily affected by the reaction conditions such as temperature, pH, etc.), and it should be possible for small molecules to enter and leave the container.

In my project, we focused on alginate-based materials to meet this challenge. Alginate is a natural polysaccharide derived from brown seaweed. Due to its unique properties such as biocompatibility, biodegradability, and the ability to form gels in the presence of divalent cations like calcium, alginate is widely used in various industries, including food, pharmaceuticals, and biomedical applications.

Calcium alginate happens to meet all of the above conditions. It is produced by cross-linking alginate using calcium ions, which works under a wide range of conditions. As a bonus, the soft structure generated this way can be rapidly dismantled in the presence of compounds like ethylenediaminetetraacetic acid (EDTA), so that we can easily release the contents of our container.

What does cross-linking mean?

In chemistry and biology a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. Cross-linking leads to gel formation, which improves the mechanical strength and stability conpared to uncross-linking solution. The cross-linking is widely applied in drug delivery, tissue engineering, food encapsulation, etc.

How did we do it?

Usually, calcium alginate is produced by reacting sodium alginate solution with calcium chloride solution. In order to obtain micron-scale calcium alginate, though, we needed to create tiny sodium alginate droplets (smaller than the diameter of a human hair). Obviously, these droplets wouldn’t be practical to make manually, so we turned to a somewhat unusual method instead: using an ultrasonic atomiser.

What is an ultrasonic atomiser?

Ultrasonic atomisers are devices that using ultrasonic vibrations to create a fine mist or spray of liquid. They are commonly used in various applications such as humidifiers, medical nebulisers, spray-coating systems, and even in certain types of fuel injectors used in cars.

Here is how our atomiser setup works. First, we have a very cool electronic component called a piezoelectric actuator. What does the actuator do? It moves in response to an electric potential (aka voltage). If we change the voltage very rapidly (say a few hundred thousand times a second), the actuator starts to vibrate fast enough that any liquid that comes into contact with it is smashed into microscopic droplets. Second, we need a way to bring the solution in the bottle to the actuator. For this we use a wick made of cotton. One end of the wick is in contact with the liquid in the bottle and the other end touches the piezoelectric element at the mouth of the bottle. The solution is diffused through the cotton wick to the top. To summarise, when sodium alginate solution is poured into the vial the cotton wick draws it up and brings it into contact with the actuator.

Next, we energise the piezoelectric element. We can control exactly when this happens using a computer program that can be customised according to our experiment. When activated, the actuator undergoes periodic deformation, producing sound wave. But these sound waves are very high in frequency, so we cannot hear them; that’s why they are called ultrasonic pulses. The overall result is that our sodium alginate solution is broken up into microscopic droplets and ejected upward.

In our experiments, we tried two different methods of preparing calcium alginate. One was to make sodium alginate and calcium chloride solution form droplet, which reacted after collision in the air and collected by glass sheet; The other is to allow a solution of sodium alginate to form droplets, which are collected in a petri dish or beaker containing a solution of calcium chloride. We found that the second method works better when there is no intervention (such as using an electromagnetic field to control the movement of the droplets). This is probably because the likelihood of alginate and calcium droplets colliding in the air is not very large in the first method.

We didn’t only use sodium alginate and calcium solutions in our experiments. The table below shows some of the other combinations that we tried (there were many many more!). Some of these combinations gave us very interesting results that you can see in the microscopy pictures at the bottom.

Then, we tried to introduce the reaction of iron ions into the formation of calcium alginate reaction vessel to verify that the calcium alginate generated in situ can serve as the reaction vessel. When sodium ferrocyanate solution is mixed with ferric chloride solution, the mixed solution will change from light yellow to blue. We added sodium ferrocyanate solution to sodium alginate solution so that the resulting droplets were a mixture of sodium alginate and sodium ferrocyanate, and a mixture of calcium chloride and ferric chloride was added to the petri dish. At the end of the reaction, the blue droplets can be clearly observed under the light microscope at 5.6 times magnification. This means that the reaction can be carried out in calcium alginate reaction vessels.

The next question that came to our mind was whether we could put anything, such as solid particles, inside our microscopic containers. To see if this was possible, we added iron oxide powder to the above solution of sodium ferrocyanide and sodium alginate. After the reaction, the solid particles can be clearly observed under the optical microscope (see picture c below).

Finally, we added EDTA (Ethylene Diamine Tetraacetic Acid) to the petri dish after the reaction was completed, and after a few seconds, all the blue products previously appeared disappeared, which means that the cross-linked structure of calcium alginate can be destroyed in a short time.

Looking to the future

Many thanks to Dr. Hessam Mehr for his unwavering support and patient guidance, which enabled me to complete this project. Making tiny chemical containers is a very exciting area of research and we think that we have only begun to scratch the surface in the short period working on this project. We need to try more types of reactions to understand what other unique materials can be made using our aerosol-powered and computer-controlled techniques.

We had to tackle many challenges in this project. For example, when forming sodium alginate droplets, we found that different components of the solution require adjusting parameters such as voltage and frequency, and finding the optimal values seems to be tricky, which is also the challenge of this technology.

These days, I spent the weekends visiting some small towns around Glasgow, and enjoying the beautiful scenery, which always gives me the energy to continue my experiment with the complete enthusiasm when back in the lab.

At the same time, this project has allowed me to face everything that happens in scientific experiments with peace of mind. Not all experiments are a success but you can always learn something from each one, and there are always new challenges when you least expect them. I regard this period as a gentle prelude to my future academic life.