Blue pill or Red pill: We need a fast

reaction!

Serendipity and opportunities in chemistry

Professorial Inaugural Lecture

Reinout Meijboom

Salutation

Dear Vice Chancelor – Prof T Marwala; the University of Johannesburg Management

Executive Committee; The Executive Dean of the Faculty of Science – Prof Debra Meyer;

Heads of Departments; all professors; all UJ and non UJ Academic staff; students of the

University of Johannesburg; Family and friends; all invited guests.

Acknowledgements

It is customary to end a presentation with a word of thanks, but I will start with several words

of gratitude to those who contributed to who I am today. Let me start with my family. My

appreciation goes to my parents – Carel and Riky. Thank you for everything you have done for

me over the years. It cannot be easy to have a child on the other side of the world. I think it’s

important to mention here that my parents flew from the Netherlands to attend this occasion,

and this is something that I really appreciate. I also have to acknowledge my siblings who

would have wanted to be here, but could not attend for several reasons.

My gratitude goes to my wife – Prof Lizelle Piater, whose beauty is only surpassed by her

intelligence. We have been together for 11 years now and moved together to Johannesburg at

the start of 2009. While she works in the related field of Biochemistry, it is astonishing how

the jargon of the fields differs. The same instruments have different names in Chemistry and

Biochemistry, and it has taken me almost 10 years to decipher what is meant with some of the

Biochemistry terms. Lizelle is always there for me, to council in difficult situations or to

comfort me when students drive me crazy. Thank you for everything!

A special word of thanks goes to all my teachers, mentors and collaborators. There are too

many to mention here, so I will only mention a few. These are the mentors whom I worked

with during my MSc, PhD and post-doctoral research. The first is Prof Jan Teuben, my

undergraduate supervisor at the University of Groningen. He taught me the finer details of air

sensitive synthesis, a basis that has served me well in my career as a researcher. The second

mentor is my PhD supervisor, the late Prof John R Moss. I was certainly not the easiest student

during my PhD studies. Finally, my post-doctoral host, Prof André Roodt. I have learned a

tremendous amount of knowledge from you, including crystallography and kinetics. Thank you

for educating me in chemistry and the world.

Having mentioned only three mentors, it is important to say that numerous others were mentors

and teachers to me. Time prevents me to mention everybody, but that doesn’t mean that I didn’t

learn from you. Numerous mentors are used as a mirror to discuss issues and research on a

daily basis. Thank you everyone!

Thanks to all my friends, for their roles in my life. Again, I will not mention any names as there

are too many to mention here.

The research group; all past and present students: I am grateful for all you have done, and proud

to be associated with you. You are all outstanding researchers, as can be evidenced from the

papers you have produced.

Thank you to all the sponsors of the research. The University of Johannesburg has sponsored

parts of my research. In addition, several grants from the National Research Foundation of

South Africa as well as Sasol and Eskom are highly appreciated. The research would not have

been possible without these grants! A special word of thanks is also given to some of the

companies who have helped me tremendously. Shimadzu South Africa has put an incredible

amount of equipment in my lab as ‘permanent demonstration’ equipment. This has really

propelled the research productivity. Similarly, I need to acknowledge Wirsam Scientific for

their generous access to their demonstration site, just off campus. Some of my former students

were at Wirsam every week to do some measurements on their equipment. Poretech has helped

me tremendously with a demonstration piece of equipment, as well as assistance in organizing

the CATSA2016 conference. Finally, Frontier Labs in Japan donated a catalyst screening fixed

bed reactor to our research group. Thank you everyone!

Finally, my gratitude goes to this amazing country, South Africa! I toured South Africa in 1993

as part of a student group visiting several universities and industry. During this tour I met a

number of mentors and colleagues with whom I still have contact. After my studies in the

Netherlands, I tried my luck and got a PhD position at UCT! Now 21 years later, I am a

Professor of Chemistry in South Africa! South Africa is my home now, and I am committed to

the development of South Africa through teaching and research.

1. Blue pill or Red pill: we need a fast reaction

In life, and in research, we are not following a linear road. Many times we find something

serendipitously, showing us a side path. Serendipity, is the discovery of something you are

not actively searching for. The word was derived from the medieval Persian story of the

three princes of Serendip, current day Sri Lanka, who continued to discover things they

were not looking for. When we discover these serendipitous side roads, we have to make a

decision. We either follow the same road and ignore the discovery, or we take the side road

to a completely different place. We have to make the decision though.

This rather strange title was inspired by the 1999 movie ‘the matrix’ In the movie, the main

character was offered the choice between a blue pill and a red pill. If you take the blue pill;

you stay on the same road. Everything is as it was and you continue the way things are.

You stay in your comfort zone. If you take the red pill, however, if you take the side road,

you stay in Wonderland and you can see how deep the rabbit hole goes. In other words,

you have to make the decision. Incidentally, Vice Chancellor, the person modeling here for

the actor Laurence Fishburn is Dr Mulisa Nemanashi. He was my first graduate at UJ. In

my research and life I have taken a number of red pills, going down the rabbit hole into the

research equivalent of Wonderland. This is obviously a reference to the wonderful Lewis

Caroll book ‘Alice in Wonderland’.

Figure 1: Dr Nemanashi and Mrs Mogudi as Morpheus and Alice.

Here we see Alice peeking down the rabbit hole. Modeling Alice here is Ms Batsile

Mogudi, my current oldest PhD student. Ms Mogudi dropped out of education in 1976. She

then started her education the moment she could not help her children with their homework.

After going through high school, and a BSc at Unisa, she did her BSc(Hons) at UJ and a

MSc at the University of the Free State under Prof Roodt, which I co-supervised. Now at

the age of 60 she is about to finish up her PhD in chemistry. A truly amazing and inspiring

story!

In my life, I have made a number of these blue pill or red pill moments. I suppose that the

first one was to come to UCT to do my PhD 21 years ago. That was a red pill moment;

completely out of my comfort zone, doing a degree in a country far away from where I

grew up. Taking the red pill makes life interesting, but difficult. Several of my colleagues

are well aware of my favorite picture – as I have drawn it on their boards on numerous

occasions. It is outside your comfort zone where the really interesting things, and

interesting research is happening!

2. We need a fast reaction

Most of the research I have been involved deals with catalysis. Catalysis is the process of

increasing the rate of a reaction by adding a substance called a catalyst, which is supposedly

not consumed during the reaction. The normal way of depicting the catalytic process is

shown here. This, however, in my mind does not depict the process of catalysis properly. I

prefer the picture by Gadi Rothenberg depicting a mountain. The uncatalyzed route is over

the mountain, and the catalyzed route is around the mountain. Catalysis is by definition

taking a different route to your destination. This different route is faster, but you have to

take a completely different route, take the side road.

My PhD work started off with something called dendrimers. Dendrimers are tree like

molecules, which are completely symmetrical. The synthesis of these molecules takes a lot

of effort. We prepared a range of these symmetrical molecules, and the chemists in the

audience would appreciate the simple spectroscopy caused by the symmetry. It is also clear

that any impurities would show up immediately in the spectra. The target was to use these

dendritic molecules as a way of connecting a number of catalysts together. In the process

of preparing these molecules, we designed and prepared so-called lithiated dendrimers.

Alkyl lithium reagents are pyrophoric, in other words they spontaneously burn when

exposed to oxygen from air. These lithiated dendrimers were especially sensitive and it

took a tremendous effort to synthesize and isolate them. Again, the chemists in the audience

will appreciate the effort of preparing and handling these molecules. The reason I am

mentioning dendrimers at this point is because they would re-appear about ten years later

when I started my independent research work at UJ.

Figure 2: Schematic dendrimer representation and lithiated dendrimers.

2.1 Heterogeneous catalysis

When I was asked to apply for a vacant position at UJ in 2008, the question was posed to

me if I would like to perform research in heterogeneous catalysis. This was an obvious ‘red

pill’ moment for me; I had no knowledge of heterogeneous catalysis nor any formal training

in heterogeneous catalysis. The department, however, had decided that heterogeneous

catalysis was one of the fields that it should move towards, due to its importance for the

chemical industry. This was a way of improving contact with the chemical industry. Since

this was a completely unknown area of research to me, my answer was: YES, I’ll do

research in heterogeneous catalysis.

This research started off using my experience in dendrimers. If we take a dendrimer as a

template for the synthesis of a nanoparticle, then we get exceptionally well defined

nanoparticles with a narrow size distribution. These would then, hopefully result in a well

behaved mechanism in catalytic reactions. The nanoparticle synthesis needs to be

performed carefully, otherwise the nanoparticles form outside the dendritic template, and

aggregate.

The first part of this work was published in 2013 in the Journal of Colloid and Interface

science. That paper was immediately popular, and ended up being one of the highest cited

papers published in the journal that year. This paper has been cited almost 150 times now.

Subsequent work focused on the determination of the mechanism of a model reaction: the

reduction of nitrophenol to aminophenol. Nitrophenol is an environmental pollutant, but

reduction to aminophenol converts this pollutant to an innocuous substance. The

mechanism involves absorption of the reagents onto the surface on the nanoparticle,

followed by reaction on the surface and desorption of the product. We were able to follow

this reaction using simple spectroscopic techniques. The data is then fitted to the rate

equation and modeled appropriately.

The real target, however, are not the model reactions but industrially relevant reactions. In

order to achieve this, we attempted to immobilize the nanoparticles on a support. Our initial

attempts resulted in aggregation of the nanoparticles after burning the template from the

support. We had to come up with a different idea!

Figure 3: Immobilization of dendrimer templated nanoparticles on a support.

The thought was to synthesize ‘molecular beakers’ or ‘molecular tubes’. These materials

are known as mesoporous materials. The idea was to immobilize the nanoparticles inside

these pores and this would prevent them from aggregating. However, we were interested in

mesoporous transition metal oxides, rather than conventional silica.

The initial attempt at the synthesis of mesoporous metal oxides using a hard templating

method resulted in nanorods with nanoparticles on them. This method was not optimal,

since the yield is rather low. We then found a literature method to prepare mesoporous

metal oxides using a soft templating method. This synthesis results in small crystallites

packed together in such a way that there are regular pores between the crystallites. This

method showed great promise and we started using it for several projects.

We found that the materials prepared using this method were catalytically active

themselves. One of the model reactions, the reduction of nitrophenol again, was catalyzed

by mesoporous cobalt oxide. Something that was not reported in the literature. Smaller

crystallites catalyze the reaction faster, and presumably most people who tried the reaction

used bulk material. We could play with the composition of these materials as well, and we

found that doping the mesoporous cobalt oxide with various base metals could increase the

rate of reaction even more.

When immobilizing a nanoparticle on these materials, the redox couple of the support

material assists the reaction on the nanoparticles. This results in an increase of the rate of

reaction, when normalized to the metal surface. The increase of the rate of reaction of

nitrophenol reduction was about 16 fold. However, for some other reactions we found up

to a 240 fold increase of the rate of reaction. We are currently expanding the types of

reactions that can be catalyzed by these materials.

3. The silver bullet

Around 2006-2007 I was involved in writing a review article on the coordination chemistry

of silver(I) compounds. While writing this review, I realized that silver chemistry is a mess.

There are no formal rules for the coordination environment, and nobody was actively

working in the field. I also realized that based on the commercially available starting

materials, there is a compound space of over 3000 compounds to be investigated. At that

moment my main interest was in crystallography of these compounds, and we must have

made approximately 150 of these compounds over the years. Crystallography shows us

what the ‘shape’ of the molecule is, and can pinpoint the atoms of the molecules. We

published widely in this area.

Around 2011, when my rating feedback came back, one of the comments from the panel

was that we should find an application for the silver compounds that we were preparing –

this research was still ongoing next to our venture into heterogeneous catalysis. I mentioned

this over a glass of wine to Prof Cronje, and she suggested that she will investigate the anti-

cancer properties of these compounds. I was convinced that this wouldn’t work, as several

reports in the literature indicated that there were no anti-cancer properties of these

compounds.

Lo and behold, the first five compounds showed apoptotic behavior! Apoptosis is the

programmed cell death – suicide – of cells, something a cancer cell evades. Our compounds

not only induced apoptosis in cancer, but were not inducing apoptosis in normal, healthy

cells. This was a breakthrough! We had some compounds in our hands that were selective

for cancer cells, at a concentration 10 times lower than that of the related commercial anti-

cancer drug. Initial mouse toxicity screens indicated that the compounds are well tolerated

up to 3 g of compound per kilogram of bodyweight. The research didn’t go to higher

amounts due to the large amount necessary to feed the mice.

Figure 4: We propose that silver complexes target the mitochondria of cancer cells.

After six years we have now screened about 120 compounds, and it appears that the first

five compounds are the best – so far. We quite literally stepped with our bare feet on the

needle in the haystack! The work is now patented worldwide, and a complete class of 3000

compounds is protected! We have still a lot of work to do in this field and numerous

compounds to screen for activity.

Following the patent protection, we published some of the work in the scientific literature.

One of these papers attracted a tremendous amount of attention worldwide. This resulted

in several TV (Carte Blanche) and radio (SABC SAFM) interviews, and the news of the

compounds was shared via numerous popular media articles. The paper has currently the

highest Altmetric score of any paper published in Biometals, and 90% of the popular media

articles were not picked up by Altmetric. The upcoming issue of Momentum, a Shimadzu

publication, is also highlighting the research at UJ. Indeed, this research generated a lot of

attention for UJ!

Figure 5: Feature article in Momentum magazine on silver anticancer drugs developed at

UJ.

4. The future of Chemistry

When we are looking at the future of chemistry, it is indeed a bright future. Currently, most

of chemistry is analogue. Perhaps the most used glassware in chemistry laboratories are

named after 19th and 20th century scientists. Some examples would be the Erlenmeyer flask

and the Schlenk tube. Recent developments have shown that chemistry could go ‘digital’.

We are currently already digitizing our teaching by using 3D printed molecular modeling

kits for the first year students. This brings the price of these kits down from approximately

R200 to R10, and enables all our undergraduate students to better understand the

geometrical concepts used in chemistry.

Some of the projects being developed in our laboratory currently are on the border line of

chemistry, catalysis and engineering. For example, we have developed 3D printed syringe

pumps, and 3D printed reactors for the inclusion of catalysts developed earlier. Using these

home-built devices, we could show that a model reaction can be performed efficiently. The

beauty of this system is that it is low cost, and we only use in house built equipment.

Similarly, we have developed a mold for the casting of catalyst support materials. These

molds are 3D printed from poly-lactic acid, a low melting plastic. After casting the support

material, we remove the mold by simply melting it away from the monolithic support pellet.

Subsequent precipitation of an active metal phase results in a monolithic catalyst pellet

which has been evaluated for a model reaction. Thus the pressure build up, experienced in

fixed bed reactors is prevented.

Within synthesis, we need to understand what the problem is first. In the literature, typically

only the successful syntheses are published. There is no journal of failed experiments! Most

of these syntheses are found by intuition and luck, with the researcher building on his or

her experience in order to produce the desired molecule. However, it is important to realize

that the chosen conditions are not necessary the only conditions for the synthesis of

molecules. There might be other conditions which lead to the desired products. However,

because it takes too much time to investigate all reaction conditions, most researchers stick

to what has worked in the past and never try other conditions due to time limitations.

Laboratory robotics would be able to investigate the complete condition and product space,

but were up to recently too expensive. Since the introduction of so called ‘open source

hardware’ based on low cost 3D printers, the price of laboratory robotics is coming down

rapidly. There is, however, one caveat: you have to build them yourself! Currently we are

building a liquid handling robot which could examine more of the potential product space.

This robot is open source, and is relatively low cost compared to the commercial

alternatives. Building the equipment for your research obviously enables one to understand

the hardware properly, with the possibility of repairing the hardware when it breaks down.

It also allows us to expand the functionality of the equipment, when necessary. Finally, this

could lead to a type of ‘scientific cottage industry’ where a number of small companies

could produce the equipment for sale in South Africa.

More of chemistry will go digital. The current state of the art are synthesis robots who

collectively explore the synthesis space. These robots are connected via Twitter and direct

each other so as to not repeat a synthesis. While this sounds expensive, the hardware was

made completely open source, and each synthesis robot would cost about R7500,- Thus,

we could foresee a rapid expansion of chemistry, where researchers are relatively rapidly

exploring the complete compound space of their interest. For us to keep up, it might be an

idea of starting a ‘digital chemistry’ research focus, with the appropriate support of course!

Chemistry as a subject has a bright future here at UJ. With the pending marriage of the

Department of Chemistry with the Department of Applied Chemistry, one of the largest

departments in Africa is created. This would encourage more collaboration between

colleagues, and potentially increase the research output and drive the teaching towards

excellence. When this is combined with the establishment of the Shimadzu Innovation

Center, the future is indeed bright!

The passion of every academic is to develop people that will change the world. We train

the leaders of tomorrow and equip them for the future. As part of the training, we have

started an ‘Undergraduate Research Academy’ several years ago. Here we take in

undergraduate students, and teach them research skills. This improves the chemistry

knowledge of the students, but also enables PhD students to supervise others. This way we

have increased the knowledge of the undergraduate students, added to the skill set of the

post-graduate students and enabled our students to get excited about research and further

their degrees!

The future of chemistry at UJ looks bright indeed!

Figure 6: Undergraduate researchers in the laboratory.