Making medicines in an energy-deprived world | 91TV
Transcript
- Thank you so much for coming. It's wonderful to see you all. I hope you don't mind,
- I'm a bit of a walker, so I'm going to be sort of strutting across the stage. I promise I won't
- sing anything. It's really humbling, and such a privilege to be here to share some of the work
- that we've been doing back in South Africa. It's such an interesting topic, this idea of living
- in a world without power. I think if you look at the title of the slide, you might think it's a bit
- dramatic, but we'll get into why it's a little bit dramatic, but first, let's get orientated for with
- where we all are. So this is where we are, the United Kingdom, currently, and I am from Africa,
- which is this over here, and specifically I'm from the creatively-named South Africa,
- which is the southernmost part of Africa, and more specifically, I'm from Cape Town,
- which is the southernmost part of South Africa, which is this part over here. So
- I think most people kind of know where Africa is, but I think what most people don't know is
- just how big the African continent actually is. I came across this image from Scientific America,
- which actually highlights just this fact. So it's quite impressive that you can place nearly all of
- the US, China and India on the African continent and then still have so much space left over for
- a couple of other European countries. Most maps don't actually represent this in all its glory,
- and also is why it takes 11 hours to fly direct from London Heathrow all the way to
- Cape Town. So that's a little bit about that. Maybe just to share some beautiful photos of
- Cape Town. If you've never been there, please do go. It's absolutely fantastic. One of the
- most beautiful cities you'll ever visit. The iconic aerial photograph of the FIFA World Cup
- Stadium that was built in 2010. That's the famous Table Mountain, and on top of the Table Mountain
- is the National Park where you can find these king proteas, our national flower, and you can
- even see some amazing views if you sort of just go down the back of Table Mountain to something
- like this, which is the Hout Bay area. It's really beautiful. You really should go visit and see it.
- Coming sort of closer to the chemistry is at the foot of the mountain over here,
- at this section over here, is where we find the University of Cape Town. A really beautiful aerial
- shot of Cape Town here. So you can imagine the views, when you're working late at night in the
- lab with all the students, of the city. So I'm an organic chemist. What does this mean? If somebody
- were to ask me, or you were to think about what an organic chemist might be or do, if you think about
- the word organic, you would say, maybe it's got to do with something natural, but I assure you,
- it's got nothing to do with farming. I don't know how to farm at all. Another interpretation
- of what organic chemistry might be is all we do is we spend all day in a lab mixing things and
- dreaming stuff up, and honestly, that is the most accurate description of what organic chemistry
- is probably. We obviously try not to create too many hazards in the lab while we are doing that.
- Historically, though, or at least traditionally, in the context of what an organic chemist was
- traditionally known as, is if we look at the expanse of the periodic table, we are really only
- concerned with sort of a couple of elements or atoms, and the main one being carbon. So in truth,
- organic chemists only care about the carbon atom. You'll find a couple of ones here and there,
- but what's really unique about the carbon atom is, as we all know, we're all carbon-based
- species and so are plants, and so are animals. A lot of the things we encounter in life are
- all based on carbon. So in essence, I can be somewhat biased and say that organic chemists
- like to study life and how molecules affect our lives today, because everything about our life
- involves this element of carbon. So these are some of the amazing structures that you'll find
- in the world that we live in, and if this looks a bit strange to you, don't get too bogged down
- with what's going on - I do apologize the slide - but the important take-home message is that a lot
- of these organic molecules, or these carbon-based molecules have wide-ranging biological properties.
- This is really what's sort of fascinating me about organic chemistry and organic synthesis,
- this idea that you could place arrangements of carbon atoms in different orientations and
- different arrangements, and you could stitch together these other types of atoms, like this
- nitrogen atom over here, and depending on how you actually move them in space, you could start
- eliciting a whole bunch of biological properties. For example, this type of molecule here might have
- some anti-tumour properties, another one might be an anti-platelet, another one might be, you know,
- some very important penicillin. So it's really this type of idea that - and to me it was just
- magical that you could almost manipulate a molecule in space and you could try and elicit
- whatever function that you might want to bring out in the therapeutic space, for example - but
- what blew my mind even further was that many of these molecules are derived from nature.
- Why that is amazing is because, if you think about chemical synthesis or what we try to do
- to actually make these molecules, we go into the lab and we mix those things together. The
- whole idea or the whole reason we're trying to do this is so that we can invent new
- ways of developing strategies to make these molecules, but because they're so important,
- we have to continuously think really carefully about how we want to ultimately challenge these
- molecules. Mother Nature is really what organic chemists look to as a benchmark for some of
- their strategies and some of their methods that they use to sort of test their mettle,
- if you will, if you want to speak of it that way, because if nature can do it, so can I,
- type of a thing. I suppose that's what scientists have historically been doing, this sort of using
- physical properties and physical phenomena that they see out in nature, and trying to see if they
- can beat it or do the same thing that nature can. We've seen this in many examples, things like
- aviation. We've learned how to study the properties of lift by looking at animals,
- and by using those types of examples, we can make aeroplanes get us to London, as an example.
- Obviously, these are the types of examples, things like echolocation that we know bats and plants do.
- I'm sorry, whales. Another interesting story, which I like a lot is the invention of Velcro,
- which was George de Mestral, a Swiss electrical engineer, who figured out or discovered as he was
- walking in the field one day, these plants of this burdock flower stuck to his shirt,
- and when you zoom-in to one of these flowers, you actually find the hook on the end of it,
- and that's actually what sticks to the Velcro, and there you go - or sticks to your clothing
- and ended up inventing Velcro. So all these really cool, natural inspirations that come
- from nature, which I find really fascinating. We also have indications of people learning
- about nature and how natural products affect their world. For example, you have things like
- the willow tree, which is where aspirin comes from, and opium, morphine, comes from the opium
- poppy flower. We've known this for years and years and years. I suppose maybe the people at the time
- didn't know exactly what they were looking at, at the time, but obviously they've learned that these
- types of compounds exist in everyday life. This is where it starts getting quite interesting. We
- obviously want to decide to figure out ways to make these types of important molecules so we
- can start making really cool natural products so we can start making medicines. So what you
- might find, as I mentioned, that chemists like to use nature as a benchmark. If we consider
- some typical morphine synthesis or standard synthesis that you might find, this is one
- of the - if I just show you the structure of morphine, which this is - of course, we know
- it's an opioid type of medication, and you can actually do this in the lab. There's a
- really amazing piece of work that came out a couple of years ago, that shows how you can
- actually synthesize morphine in the lab, and it's a really impressive synthetic sequence.
- I'm not going to get into the details, but there's a lot of steps going on here. I want to point out
- a couple of things. You'll notice that there are things like this thing over here in n-BuLi,
- and PD, which is palladium metal. You go through all these steps A, B, C, D, whatever,
- you get to this really cool intermediate over here, and then you continue on with the sequence,
- and then you get all of these fantastic chemistry that happens, and you ultimately produce morphine.
- This synthesis is really impressive. It's one of the most fascinating things that I've read,
- and the beauty of that synthesis is I find really exciting. So we can do this. Chemists can do this,
- but let's look at the competition. So how does nature do this? As we said,
- it comes from the flower. So nature uses a process called photosynthesis to, essentially, extract
- light from the atmosphere, or extract light, and by using carbon dioxide and a bit of water you can
- generate these sugars, and it starts synthesizing molecules. That's how nature, or how plants,
- generate all these molecules that are confined in nature. I think it's kind of like magic, right?
- So this is how nature makes morphine. It captures the light, uses it as energy, starts the whole
- transport chain, and ultimately, you can take a whole bunch of these small molecules, and it
- has its own series of steps, and a whole bunch of other steps too, and out pops morphine. So if you
- think about it, we can do exactly what nature can do. So, yay, humans. Humans are the best.
- As I said, we like to test out our scientific discoveries largely against nature, and most
- of the time human beings do this significantly better, or can sort of outperform nature. Take
- the bird example, for example. Human beings have figured out how to have an aeroplane fly, but
- we've also figured out how to fly outside of our atmosphere and into the sky, which I don't recall
- any animal being able to do just yet. Maybe it's still happening, but there's something special
- about the way nature does some of these types of chemistry, and when us as chemists start thinking
- about really pushing the boundaries because we're doing things really - or outcompeting nature.
- The one thing that I've noticed, at least in my own work, that I've been introspecting a
- lot about over the past couple of years, is that we've actually been ignoring one really, really
- important piece of information. Yes, nature, we can do a whole bunch of chemical reactions,
- but the one small detail that we're forgetting is nature doesn't do it the same way we do. The way
- nature does it is renewable, usually, using renewable energies, it uses a circular type
- of economy, so there's very little waste, and it actually does it in harmony with the environment.
- It doesn't offer to destroy the planet at the same time as making important molecules for
- human life or for its existence. So this is how we make morphine. We need some lights to turn on,
- we need air conditioning, lots of equipment, heating, and that's how nature does it. Now,
- this is the critical point, and this is what I've been really fascinated about over the last few
- years. It doesn't use high-reaction temperatures. I point out that one over here as an example. We
- have reactions that go at 80 degrees 90 degrees; you use all these organic solvents. All it does
- is it uses a plant, room temperature. It doesn't use palladium metal, for example. There's no waste
- and it doesn't destroy the plant at the same time. So this is a really interesting question, or this
- is really what struck me about my chemistry. So if everything needs to sort of act in balance,
- I think most people can agree that if I told you that resources are declining and we are sort of
- a consumer. Human beings are increasing their consumption. I suppose you can imagine that if
- there was a scale, as the consumption goes up, the resources go down, and obviously there's
- some negative effects of climate change by using a whole bunch of resources. Something that really
- struck me, and I love this movie, Jurassic Park, was this quote of the year, which says, 'Your
- scientists were so preoccupied on whether or not they could, that they didn't stop to think whether
- they should actually do it.' So what do I mean by that? So we know how to make morphine in the lab,
- as an example, but we also know that nature can do it without using excessive heat, without using
- expensive reagents and those types of things. So just because we can do it, should we do it?
- This is the question that's really been bothering me for the last five years, the
- question of what happens in a scenario where we are so heavily reliant on an essential resource,
- and we aren't keeping track of how rapidly it's declining, and one day we reach that day
- when we no longer have a resource available to us that has allowed us to operate at the
- efficiency and at the magical level that we've been operating. Have we thought about that and
- have we planned for those types of scenarios? It's a bit drastic. I know it's a bit drastic,
- but coming to the point of today's lecture is really what a lot of African countries, a lot of
- developing nations start to experience. So this idea of load shedding, what is load shedding?
- Load shedding, as it's affectionately called in South Africa, are routine power cuts that happen,
- because the energy grid is fragile. This is just a snapshot of the app that we have in South Africa,
- and depending on the day and how severe the power cut is, you have these various stages,
- one through six or eight, or whatever it is, and the higher the stage, the more the power goes out.
- So I've taken a snapshot here of some date a couple of years ago, and in that period of time
- we were going through stage six load shedding. So if you can effectively count all those hours,
- it's somewhere between 10 and 12 hours per day that your power goes out. Today, it seems like
- it's quite fair, at stage three, so it's only four hours or so. So then you can ask yourself,
- 'Okay, if I need to make an antibiotic,' as an example, 'and the one way we do that is by
- stirring reaction at 100 degrees overnight, but the power turns off, how do we need how do we
- continue making this antibiotic?' So there's those types of questions that have really been keeping
- me up at night, like, how do we do chemistry when we don't have resources, something as
- essential as electricity? It's a bit dramatic, as I said, but this is the reality that we had
- been working with in South Africa, and to be honest, it's not a South African problem really.
- One of the benefits of South Africa, I suppose, we have this schedule that tells us where the
- power is going to go out, but there are some other countries in Africa where they don't
- get the schedule and the power just stays out for days. So if they also need access to some
- of these important things, how do they do it? So the question becomes, are we as scientists, really
- thinking about how practical our chemistries are, and are we making sure that we are adjusting them
- to plan for some of these types of, of events? So this is really what I've been looking at, and
- this is a photo of one of my second-year lectures. There was no power during load shedding, but the
- lecture wanted to continue, and the students took their phones out and they sort of just
- helped the lecturer out. It's endearing, but it's crazy when you when you see a photo like this,
- right? It makes you really think about stuff. Anyways, so the challenge then, really,
- to set the stage here, the challenge really becomes, okay, Wade has this absolute passion
- of making these types of molecules, but how can we do it in a way that doesn't tap into loads of
- chemical resource? Also, in a small little group out of Africa, there's not a lot of
- money to spend on expensive reagents, so we have to be really creative about resources.
- Can we make those molecules cheaply? Can we make them using room temperature strategies,
- so not needing to reflux excessively - and I'll come to why that's important in a second - and
- try and minimize waste wherever we can? The way we've achieved this, or the way we've tried to
- achieve this, really, is through the use of light energy, so taking inspiration from nature again
- using photosynthesis. So can we, essentially, hold the light that uses light energy as we want to,
- and ultimately, apply it to chemical synthesis? Now this isn't a new field, of course. This has
- been studied for years. One of the, I suppose, the fathers of photochemistry and green chemistry,
- the Italian chemist Giacomo - I can never pronounce his name correctly - Giacomo Ciamician.
- I think that's how you say it. He was really fascinated about this field of green chemistry,
- and he was really fascinated by putting a whole bunch of this iconic photo, chemical reactions,
- on the balcony of his university, University of Bologna, and really studying how light
- could affect chemical transformation or chemical properties. This was a really inspiring lecture
- that was published in Science in 1912, where he speaks about the photochemistry of the future,
- and there's a couple of really interesting things about it, given that it's in 1912. Just to read a
- couple of comments here. It starts off in 1912 with, 'Modern civilization is the daughter of
- coal.' I'm not going to make this about coal, so don't worry about that, but the interesting
- thing here that struck me about this lecture is that he was almost talking about the same
- things that we're talking about today, and this was 100 years ago, which is really interesting.
- I really do encourage you to read this. It's really a fascinating read. The other thing
- that he also mentioned, he does this really interesting calculation about how much light
- comes and hits the atmosphere, and in essence, he has estimated that the desert of the Sahara,
- with its six million square kilometres, receives a daily solar equivalent to six billion tons of coal
- in a six-hour period. Effectively, that's what he's calculated how much energy hits the earth
- in a six-hour period, accounting for a couple of things, obviously. I think the estimate from the
- IAEA, I think it was, is that I think in 2022, the average global coal consumption was about
- six billion. So it's really interesting. Just food for thought. There are, obviously, some challenges
- with taking your reactions and leaving it out in the sun. There's a lot of unwanted reactions. So
- we have to be able to control a lot of these photochemical reactions, and since the advent
- of LED technologies, we've really learned how to make more focused light sources. We've been
- able to take advantage of this field of using light energy to catalyse chemical reactions.
- So this is a standard reactor that we might use. And simply what happens is we take a little LED
- light, shine it onto our reaction, and by virtue of using a small molecule, like photosynthesis
- does with chlorophyll, we can do a whole bunch of chemical transformations. I know you're thinking,
- but wait, you're using electricity and the electricity goes out, how do you do the reactions?
- The beauty of this type of field is that LEDs are really low power-consuming, so what that means is
- you can actually take your LED lights, hook it up to a couple of car batteries so if your power does
- go out, you can still carry on doing synthesis. So this is what we've done. This is our lab set up:
- couple of car batteries, a couple of lights and away we go. So this has been really cool, really
- fun, and of course, you can see the implications that this might have, that you can hook that up to
- solar cells. and then you could, essentially, be completely free of the grid, and things like that.
- So just quickly how this field of photochemistry works. The important thing here is that we need
- some light, of course. We also need a molecule called a photocatalyst or photosensitizer, and
- not to bore you with the details, but essentially the light hits this photosensitizer, some magic
- happens in the middle, and that promotes the photosensitizer to some excited state,
- and once it's there, it can start catalysing really interesting organic transformations.
- So ultimately, what we want is light to hit the photosensitizer and transfer that energy to a new
- type of molecule. So can we use photochemistry to make some of these types of scaffolds? So
- what I'm going to do is ,I'm going to share two or three stories about how we've managed
- to do that. So the first one is about these dihydroquinolines, and this is these types of
- six membered ring systems over here. What we wanted to do - and this is
- the PhD student, [?Minaje 0:22:28.7], from Zimbabwe, he's now in the States I believe,
- doing a postdoc at Harvard Medical School I think - and what we wanted to do is really take some of
- these really simple precursors and make these types of molecules. The way Minaje figured out
- how to do this, was you can take this metal salt, some silver nitrate, in the presence of a really
- cheap chemical oxidant and cook it up to 100 degrees, and it was fantastic. We could make
- these types of heterocycles and it goes via this double decarboxylative type of radical reaction,
- but I'm sure you can already see the problem, given the long story that I've just given you
- about sustainability and all these types of things. Obviously we're heating it to
- 100 degrees, we're using metals. It's, obviously, the opposite to everything that I've just said.
- It was actually at this point that my career took the turn that meant that all of these
- philosophical ideas about sustainability actually came up, because that photo that I
- showed you about the load shedding schedule being at stage six was when we started working on this.
- So the power would go out for 12 hours systematically at different times during the day,
- and what we needed was to reflux these reactions for 48 hours. So we needed to heat the reactions
- for 48 hours at 100 degrees, and as you can imagine, if the power goes out for 12 of those
- 24 in a day, this chemistry is not going to work. So we really needed to figure out how
- can we get the same transformation to happen, but at room temperature, and that's where we really
- invoke the work of photochemistry. So what we did, inspired by some of the work by Corey Stephenson,
- where he reported that you could, essentially, get the same type of chemical activation by adding a
- second cycle, or second catalytic cycle, which uses some type of small molecule photocatalyst.
- That's quite important. We were able to, essentially, do exactly the same transformation
- now at room temperature by virtue of just adding a photocatalyst and light. What that meant was we
- could carry on doing this work, so when the power goes out, now that we're at room temperature and
- we have the batteries, we can still actually make exactly the same molecule that we could
- at 100 degrees. So that was really, really, really cool for us. We really enjoyed that work.
- So I'm not going to get too much into the details of this, but as I mentioned before, it was
- really this was this sort of thermal part of the reaction, and by adding a second bit that involved
- the light, we could, effectively, allow the chain to carry on, and ultimately make the molecule
- that we wanted. We did some mechanistic stuff to figure out exactly how this reaction was working
- in real life, but I think the most important part, or the most exciting part of this slide,
- for Minaje, at least, was that if you count the number of bonds we're creating in a single step,
- you can see that these red ones, so that one is one, this two, and essentially, installing this
- other line, double-bond over there, is three steps. So this is Minaje's favourite part,
- that we could actually make three bonds in one step. So this was really, really fun,
- and that also comes to this idea of circular economy. You kind of want to have minimal waste,
- so if you can do multiple reactions or a cascade of reactions in a single reaction, that actually
- helps towards sustainability. So not only could we get this reaction to work at a lower temperature
- using a small organic molecule and light, but we could also make multiple bonds at the same time.
- Please don't let the question be, 'Which bond is the best bond?' because that's not going to that's
- not going to go down. All right. So that area of chemistry or photochemistry is two main activation
- modes. That one as about electron transfer type of processes. I'm going to switch gears a little bit
- and speak about energy transfer catalysis, just a little bit. This is a slightly different form
- of photochemistry or activation mode, in that we don't use electrons or single electrons through
- radical processes, which we do in the other one. So the way energy transfer catalysis works is a
- little bit different, and I've been becoming a lot more interested in this field as my career
- progresses. So if you just have a look at this curve over here, this is a standard energy profile
- of what the reaction would look like. We started with some reactant over here, it goes through some
- activation barrier, or it needs to overcome some type of activation barrier, this hill over here,
- and then, ultimately, it ends up as a product which is a lot lower in energy than the
- starting material. That kind of makes sense. It wouldn't make sense if your product was
- high energy. It would be like you going to sleep, but having more energy while you're sleeping than
- when you're actually moving. You sort of want to be at rest. So the reason why we actually need a
- lot of the heat and increasing pressure and all that stuff, is really just to climb this initial
- mountain of this energy profile of our chemical transformations. So we have to get this molecule
- up this hill, so we're sort of pushing it, and by pushing it we have to use energy. We have
- to input something, so that once it gets to this part here, it can, ultimately, just slide all the
- way down. That's the way normal thermal types of reactions work. What's interesting when you start
- using light energy, there are higher levels of energy that you are able to access, high-energy
- levels that you're able to access. So as an example, this might be some type of system that
- you would access under normal thermal conditions, but perhaps somewhere up here is what we call an
- excited state. This is when the molecule absorbs light and gets promoted to a new type of state.
- If we can get this molecule through photoexcitation, so shining some light on the
- molecule up to some higher state up here, you can then see that, if it's over here, everything is
- downhill all the way to get down to the product, and we've just established that we can use light
- in photochemistry to get molecules into higher activation states. So why this is really cool is
- because we can take a molecule through energy transfer catalysis, heat it with some light,
- or using some type of physical phenomenon, get it to an excited triplet state, and from that point
- it goes all the way down until it gets to that point that you might want to promote it to through
- heating, as an example. Then, once it gets there, it goes all the way down. So we can go from here,
- all the way up to there through the use of light, and from there it's all downhill,
- so it becomes energetically more favourable. So the way this kind of works - I'm not going
- to get into too much of what goes on here - but naturally, if you take an organic molecule and you
- shine some light on it, nothing happens, usually. It would be hugely inconvenient if we were to
- walk outside into the sun, and every time the sun hits us we start getting excited into an excited
- state. So there's obviously some thermodynamic issues here that that we need to consider, but
- let's just say that that is generally the case. The sun hits us and it doesn't really change our
- behaviour too much, but we do still want it to get promoted to an excited state, so what we use is
- our magical photocatalysts. What the Photocatalyst does is ,denoted by this thing over here, it says,
- 'Actually, I'm happy to take the energy, because I like it,' so it gets promoted to an excited state,
- and really, in a sort of cartoonistic way of thinking, the photocatalyst has its energy and
- simply just throws it over onto the molecule. By doing that, the photocatalyst goes back
- down to its ground state, and your molecule that you're trying to activate now enters an excited
- state. Now it's in that high-energy profile, and now it can tumble all the way down and form some
- really interesting products along a new reaction pathway. Of course, there's hard science behind
- this as well, and we can view it as a double electron transfer process. I've deliberately
- drawn this molecule out in this type of way, because I've actually become fascinated with
- these small molecules called thioxanthones. As I mentioned, a lot of these photocatalysts you saw
- in the first slide require iridium or these platinum or these really expensive metals.
- What intrigued me about these types of small molecules over here, is not only are they cheap,
- but they actually have very similar properties to iridium in terms of its photodynamics. What was
- really interesting to me at the time, was when we looked at how many synthesis applications
- there were in this field to use these types of molecules, we only found a handful of reactions,
- which are all these ones that are currently on the board, and largely, they are more or
- less belong to the same class of reactions. This work was really amazing work pioneered,
- predominantly, by Thorsten Bach, who did a lot of these types of chemistry,
- these two-plus-two type cycloaddition reactions, and that was in 2014. 2018 was really when he
- started pioneering this work, but after that initial work, it was only until 2020, 2021,
- you can see that these types of photosensitizers were used in different types of applications. So
- 2022, 2021. This was, essentially, the limit of what had been done with these types of molecules.
- So we really thought we wanted to expand the reaction profile of these small organic
- molecules to see how far we could actually push it, to make some other interesting types
- of scaffolds. So what we thought, again coming to our heterocycles - this is my PhD student, Megan,
- came onto the project - and what we wanted to do was, essentially, take this type of
- really simple precursor and, effectively, create this bond over here in red using thioxanthone.
- Now, there was precedent for this in literature, some amazing work by Martin Smith out in Oxford,
- where they could do a similar type of bond connection using an iridium photocatalyst
- and some blue light. So we figured iridium is about the same energy as these types of small
- molecules. These types of small molecules, arguably, are a little bit high in energy,
- so they should work, kind of. Of course, there were some other indications that this type of
- reaction would work as well, again using iridium for this type of reaction. So as we were working
- on this in about 2020, these two papers came out that showed that they could do exactly
- the same reaction that we were trying to achieve, but what we noted about it is,
- if you look at the catalyst that they used, once again, that's iridium, and again, that's platinum,
- and not even - I was going to say not even counting costs because these metals are extremely
- expensive - I could never afford a platinum metal catalyst in my lab - but we knew we were
- onto something, is really what I'm getting at. They still required really expensive metals,
- and ultimately, what we ended up doing is publishing the first metal-free version of
- exactly the same reaction, and our postdoc, Daniel, helped us finish this work. So we've
- made a whole bunch of molecules. I'm not going to go into the details of that, but I do want
- to highlight the first row that that was that was over here, because we were really wondering what
- is happening in the world that, if we're trying to do these types of reactions, that the default
- stance is to grab an expensive metal catalyst. So it's obviously a reason, and the reason is
- that these metals work really, really well, but we wanted to actually just test it in our reaction,
- to see if maybe we were missing something. Maybe we were getting lucky, or whatever that is with
- this particular system. So we compared them just using three arbitrary selected substrates,
- comparing our photocatalyst to just a standard iridium photocatalyst, and you can see here the
- yields at the top is [?ours/hours 0:34:22.6] - or not ours [unclear words 0:34:23.8] thioxanthone,
- and the bottom is iridium, and you can see that the reaction yields are pretty much the same.
- That's not really that impressive. What is impressive is the cost of these two catalysts.
- So the thioxanthone is about US$27 per gram, whereas this is about close to $1,000 per gram. So
- it stands to reason, then, that there's obviously better ways to do this. So what we're currently
- looking at in our lab is, essentially, trying to figure out cataloguing various reactions to
- see is there a way that we can showcase this idea to the world, and not just to chemists I suppose,
- that there's possibly an alternative organic small molecule that we could use that's a lot cheaper,
- that could do the same transformation that you're trying to achieve, so we don't have
- to use a whole bunch of expensive metals for reactions that don't really need them,
- when we can get away with using things that are lot cheaper and reserve the expensive
- metals for more important types of processes. All right, so let's not get too much into the
- applications, but the one thing that I find was really cool was really this example over here. So
- what we did was, we did the same reaction, and one of the disadvantages of metal catalysts is
- they're not usually recoverable. So once you do the reaction - and this
- is true of industry - once you do a chemical reaction, you normally discard the metal waste,
- and you gather your product and on you go. What we wanted to do was really demonstrate if we
- could start recycling our catalysts, so what we did was, we did one reaction on a gram scale.
- We covered that catalyst and threw it straight back into another reaction, and we could do this
- again. So we sort of demonstrated that we can actually cover our catalyst, and then actually
- use it again in a related chemical process. We also then demonstrated in this work that we
- could also oxidize this molecule to produce this double bond over here, this quinolinone molecule,
- through the use of a copper catalyst and some heat. Again, I know what you're thinking,
- you're using a metal and you're using heat again, right? So what we ultimately done is we noted
- that we didn't like this, so we tried to think about, can we stick to our own principles and
- try and design this type of process to ultimately produce this molecule, but a lot more cheaply and
- not using metals, if we can? Why this was really cool for us, is because if you recall that first
- bit of work that I showed you with requiring a lot of silver and you could get away with
- 100 degrees, but ultimately, what we're looking at here is, we could, essentially, access a
- similar type of system through potentially one reaction. So what do I mean by that? So this
- was the reaction that we ultimately used to do this oxidation chemistry for this double bond,
- and we thought that, in this example we used this thermally, we heated it with a copper catalyst,
- could we do the same thing with a copper photocatalyst at room temperature? Yes we can.
- So we can take a copper catalyst with some other type of oxidant using one equivalent right now and
- light, and we can get the same type of bond. Copper is not our catalyst. Copper is really
- great, because it's more environmentally friendly and it's more abundant in the world, so it's much
- better than iridium, but we're really interested in seeing if the chemistry would work with this
- small molecule that we ultimately were fans of. A long story short, it does actually work, and we
- can actually form this double bond oxidation on some selective substrates. What you'll
- notice here, if you're familiar with this type of chemistry, is that formally, what we were able to
- achieve is the direct coupling of this bond over here to this aromatic system over there, and what
- that's known as is the Fujiwara-Moritani reaction, which is a variation of a Heck cross-coupling.
- The only difference is the Heck cross-coupling requires some type of halogen here on the ring.
- So formally, what we could do in a single step, and this is what we're currently working on, so
- this is unpublished, so formally what we are doing is really using the same thioxanthone molecule,
- having it undergo this cyclization reaction, which we know works really well, and then at some other
- point later in the reaction, throwing in some NFSI, and in one part, we can ultimately get this
- type of reaction going. Why that's really neat is because the Fujiwara-Moritani reaction requires
- high temperatures and palladium metal catalysts. Traditionally, it requires high temperatures,
- and it definitely requires palladium. So this is really a neat thing that we think was really cool
- about trying to do this work. This is my favourite one actually, because it actually highlights
- something that I'm really passionate about, which is this idea of antimicrobial resistance. I'm not
- passionate about resistance, I'm passionate about tackling the problem of resistance.
- So we know that these penicillin antibiotics, or antibiotic resistance, is becoming an increasing
- problem through overprescription, or the bug is getting smarter, or whatever it is,
- but we really need to figure out ways to make these types of molecules, and the penicillins,
- or the antibiotics, have these four-membered ring structures in the molecule. So what we were able
- to do is just really modify our reaction that I showed you the first time, the first time we did
- the cyclization type of chemistry on aniline, by simply placing an extra carbon bond over there.
- We were, ultimately, able to make a whole bunch of these four-membered ring molecules,
- again through the use of photochemistry, use of light, and this organic small molecule
- photocatalyst. What's really exciting is, we could make a whole range of these types of what we call
- beta lactam molecules. Let's, again, not get into the details, but why this is really cool for us,
- is because this allows us to then start making a whole range of these molecules.
- We could think about starting to test them for various properties, medicinal chemistry
- properties, for antimicrobial resistance, but also what it's allowed us to do is take away a lot of
- the costs involved at upfront medicinal chemistry type of programs. So because we can access these
- types of molecules quite cheaply, we can get away with doing a whole bunch at a time.. Not going to
- get into the reaction mechanism too much over here, but if you are interested, it goes via a
- typical type, nourished type, photochemistry type of reaction, and this was published alongside my
- colleague, [?Roal 0:41:07.9 ], who is in the audience over here. It was really, really fun
- working together on this project. To sort of finish up, I want to sort of share a couple of
- maybe just final thoughts about where I'm going with trying to look to the future of this field,
- and what I'm trying to achieve here. It's really trying to think about ways we can design better
- photocatalysts that we could either use any type of light source or the sun directly,
- according to Giacomo's vision for photochemistry. So this over here is a typical photochemical
- cycle. The way it works is we take the molecule, as I said, we heat it with some light, it gets
- excited, promotes - or gets excited over here, and then it does its energy transfer to a molecule,
- and from there it can start doing some really cool stuff. From an organic chemistry point of view,
- we are really only concerned about how the 1a, what I have over here, the organic molecule,
- ultimately behaves after the energy transfer process has occurred. What what I started
- thinking about, really, is that I actually need to get involved on this side of the
- equation, which is what is actually happening fundamentally with the photocatalysts themselves,
- and that requires a lot of physical chemistry and physics type of knowledge, which I do not have,
- or did not have. When you read the physics, or you try to read the physics literature,
- it's quite mathematical, which is not very common of organic chemists to start reading.
- One thing that's actually stuck with me in the physics literature, the old physics literature,
- through El-Sayed's work, was this idea of the heavy atom effect, and it might explain why these
- iridium metals work so efficiently. Essentially, what it says is a whole bunch of maths. That's not
- important. I mean, it is important, but it's not important for us. There's this Z term, the Z to
- the four, and the Z to the four is, essentially, saying that the heavier your atom is, the better
- you are going to get these excited-state photocatalysts to populate your reaction and
- enable it to do these energy transfer reactions. So we were quite intrigued by this, and that then
- stands to the reason why those iridium, or those very expensive metal catalysts, worked so well. So
- that's possibly one of the hypotheses that people usually use to say why they work, because iridiums
- are heavier metals, have a higher atomic number, they have better intersystem crossing, better
- photodynamics, and that's why they work well. So my idea, based on this old physics literature
- was could we then apply some of those types of principles to small organic molecules so we can
- ultimately design better photocatalysts. So what we did was, we replaced sulphur with selenium,
- and what we noticed, if we did the same type of transformation, we could, essentially, reduce the
- catalyst loading by four. So instead of using 20 mole percent of catalysts we could use a lot less,
- and there are some initial indications that the rate, if you do sort of a study over time,
- the reaction rate is greatly enhanced. So this was really cool, this was really exciting, because it
- allows us to actually derive or do some rational design from fundamental physics principles, for
- us at least, but we were probably thinking that maybe we're reading too much into this because
- it was a result that we really wanted to actually happen so we could design better photocatalysts.
- So at this point, we were completely out of our league, and what we actually noticed was
- that there might be something a little bit more trivial at play that makes these photocatalysts
- work a lot better, and that's simply that the light has a match with the actual photocatalyst.
- So the photocatalyst actually absorbs the energy of light that's going on. So what we think is
- actually going on, is that the selenium catalyst actually absorbs the light a little bit better,
- rather than the solid catalyst, and that's all that's happening. We don't think that there's
- any fundamental physics phenomenon unfortunately, but the reason why we know that is because I did
- some work over at the University of Bristol with Andrew Orr-Ewing, where we tried to study some of
- these advanced physical chemistry, all these types of photodynamics, through laser spectroscopy. Now,
- this was quite fun for me because we could use lasers, and I think that's just cool. It doesn't
- matter; like just using lasers as cool. The way this actually works is, if you want
- to study molecules in atomic level and how they evolve over time, you can think about photography.
- So you sort of take a snap of light and you can capture a photo, so the light, essentially,
- allows you to take the photograph, but if you want to study things that happen at a really fast time,
- you need a light that can flash really, really quickly, and that's, essentially, what the laser
- does. It allows you to, essentially, generate images like this, that you remember the old races,
- you wanted to figure out who won, and there's this camera flashing away as the runners go past,
- and you can slowly track in slow motion by taking multiple photos, how the system evolves
- over time. That's essentially what you do with a molecule, but using a laser. What's really cool
- about this - and again, I'm not going to bore you with the details - but blue is early time and rede
- is later time. What it actually shows us, is we can actually monitor in real time how our
- photocatalyst evolves through time, and actually changes from one excited state to the other,
- and from that we can start deriving some really exciting types of conclusions from
- them. From these studies is where we actually came to potential conclusion that maybe the
- heavy atom is not what we thought it was, but we found some really other cool stuff.
- I think I'm running out of time here, so I'm actually going to just sort of move along quite
- quickly, to come to my wish list and actually what is this five-year journey that I've been on,
- really. What have we really learned, or what am I really trying to think about going forward? So
- I've come up with this sort of wish list, and this idea of a wish list is that can we, ultimately,
- make drugs or do advanced drug synthesis, completely renewable, including low lights,
- and we're going to come to low light applications, and develop more off-grid labs? So rather than
- using these massive labs that we require air conditioning and all these things, is
- it possible to take a simple container like this, put it in the middle of nowhere, and through the
- use of light energy by coupling two solar cells or wind turbines, can we ultimately make massive
- industries and actually shrink them down so much because we don't need massive infrastructures,
- and we can use this on a small scale? I think this is really cool for me because
- it would be benefit to both actual scientific research, but also education. If you start
- thinking about designing chemistry experiments in remote areas where they don't have access to a lot
- of chemical experiments, by nature, by virtue of our experience abilities to run labs and
- things like that. So you can start doing really cool, sort of school experiments out in the open,
- and you can actually learn about these various photochemistry things. So really, ultimately,
- taking all this land mass and converting that to that, I think that'll be really cool. So there was
- a report on sustainable labs in the RSC. If you haven't read it, I encourage you to read it. It
- was quite eye opening. Essentially, what it says is that lab buildings account for about 60 per
- cent of a university's total energy consumption, which makes you feel really guilty as a scientist.
- One Final thing, though. So we obviously said that we're trying to utilize light energy,
- but I went deep-sea diving once in Bali, and it actually occurred to me that how - don't ask how
- this occurred to me while I was deep-sea diving - we tried to get light to catalyse reactions,
- but how do we get around the problem that some countries don't have lots of light,
- like the UK, for example? How can we still do chemistry outside using light, if the light is
- very low or there's no availability? this is where deep-sea diving comes into play. It got
- me thinking about how do they do it. If you look at these coral reefs that's down below,
- they look beautiful. They are flourishing. All these colours are there. How is it possible that
- they can thrive with very little light down there? These aren't my photos, by the way. This is from
- Unsplash. It's a stock image. What had occurred to me is that there are some species in the world
- that emit light naturally, from fireflies to plankton, to the coral reefs down below.
- So is it possible - this is a pie-in-the-sky idea, but I think it's really cool to dream about these
- types of things - but is it possible to utilize these types of technologies, or utilize these
- types of properties that we find in nature - again, taking inspiration from nature - and
- ultimately, use bioluminescence so we can get away from the light bulbs and maybe get away
- from direct sunlight, if you don't have direct sunlight. So could you imagine a system where
- you maybe have a whole bunch of plankton floating around, around button plants emitting light, and
- inside you have a reaction vessel that actually allows you to still continue doing chemistry,
- if you don't have access to vast amounts of light? So this is the reaction that I actually
- set up using a glow stick. I sort of snapped the glow stick open and it's emitting blue light,
- and my reaction is sort of in there. It didn't work, so we had to challenge.
- That's a challenge that we're still trying to overcome, but it's really this idea, can we,
- essentially, use chemiluminescence or the idea of bioluminescence as another way to generate light
- for these types of chemical transformations? At the moment, I'm actually based at the University
- of Sydney doing some really cool stuff on larger molecules, seeing how we can use photochemistry
- and also apply them to more complex systems like proteins, as an example. So I'm running
- out of time here, so I'm going to just quickly acknowledge my research group, which has been
- absolutely fantastic. This is one of the most recent snapshot. All my collaborators, Richard
- Wall, you guys are there, James in the audience as well, and also Andrew Orr-Ewing in the audience.
- Guys, thanks very much for all your support. My two students, ex-students I guess, are in the
- audience as well here. [?Partu 0:51:36.8] up top, is currently doing a postdoc at the University of
- York and Jonathan [?Déluge 0:51:40.8] doing a PhD at Manchester University, and all the
- funders for the money, but specifically the Royal Society, all your generous support has
- been enormous to my career as a scientist. As you know, as you heard earlier on, I was
- a recipient of the FLAIR fellowship, and that was a substantial grant that really allowed me to do
- all of this research. So it's really amazing to be standing back here again to win the Africa prize,
- to show what benefit the Royal Society actually gave to me as a scientist coming out of Africa.
- So I'm really grateful for that. Here's some really cool photos. Everyone in the audience,
- you'll see them. Also, going through this journey, you wouldn't be without your friends.
- These are all my 12 closest friends. We're all scattered around the world right now,
- but if you're watching, you guys are the best. My family as well. If you're also watching, thanks
- so much for all your support through the time, and of course, my lovely wife is in the audience
- as well. She had to put up with me through my PhD in 2011, and somehow she managed to stick with me
- and she's still here, so for all your support and your love and motivation for those late nights.
- Of course, coming back to Giacomo as a final thought, another part of his lecture that he
- spoke about was this, which is really interesting. Again, this is 1912. Just remember the time,
- 1912. 'The photochemistry of the future should not or ever be postponed to such distant times.
- I believe that industry will do well in using from this very day all the energies that nature puts in
- at its disposal. So far, human civilization has made the most use of fossil solar energy field,
- so coal fields. Would it not be advantageous to make better use of radiant energy?' And this is
- in 1912. Fast forward 111 years, and I think we're still there at the moment. Just food
- for thought. Thank you very much for your attention. I'm happy to take any questions.
- Thank you very much. That was a wonderful talk, and thank you for sharing your journey
- as well. It's now open for some questions, either from the audience - behind you,
- there's a microphone - or if there are any questions online as well.
- Hello. Testing. Okay, cool. Thank you so much for the opportunity to ask the question. My
- name is Aslan. I'm a technology scientist, and an actor currently working on a free universal
- healthcare system integrating DARQ technologies with nano. We've got really exciting news in
- technology space. We've got quantum computing. We now have the technological prowess to simulate
- intricate experiments that traditionally require extensive time, for example, a year,
- and resources are very expensive, as you know. Now we can do it online in a matter of minutes,
- and Microsoft got one, and we can even test for free. This approach can significantly accelerate
- the identification of promising photocatalytic materials before moving to laboratory validation,
- thereby expediting the overall discovery process. As you were talking, how do we better design this?
- So how do you envision the integration of quantum computational simulations
- with traditional chemical research to transform the future of sustainable
- and efficient photocatalysts, particularly in developing cost-effective materials for
- environmental remediation and energy conversion? There we go. Thank you.
- Thanks. Did you write that question just now? No, no, it's an important one as well. So actually,
- part of our photocatalyst design that we are trying to achieve, is actually through using
- computational modelling, computational data. So a lot of these energies and properties that you see,
- through experiments that we use with, for example, the ultrafast laser spectroscopy, a lot of those
- properties you can compute and you can, for example, predict the UV absorption spectra and
- all those things using, quantum chemistry or using computational models, but we're always going to
- need the empiricism there to confirm that those models are real, because the computer will just
- tell us what we want to hear a lot of the time. Yes, I think it's going to be vital going forward
- in rational catalyst design. The other thing is also we need to feed better information to these
- computers. So I think it will definitely help expedite things going forward, but there are a
- couple of things that we also do need to consider. As an example, there are some reactions that work
- well with one photocatalyst, and doesn't work well with another photocatalyst, and we don't really
- know the reasons for it. So we're also trying to first learn something about why that is, and
- then seeing if the computer can actually predict that ultimately. I'm not sure if I'm answering
- your question, but I think it's going to play an important role. Yes, we definitely need it.
- Thank you.
- Are there any other questions from the audience?
- Well, first, can I say, what a fantastic lecture? What a fantastic lecture. Very impressive work.
- Thank you.
- I think you said that one of the reasons you use these heavy atoms is because of
- the high-spin orbit coupling. It must be hard to kind of get around that with light atoms,
- so it's especially impressive as to what you've achieved. I mean, do you see ways in which you
- really can, using these relatively light atoms, improve the magnitude of the spin orbit coupling?
- So that's one of the things that we are looking at. As a first thought,
- and this is why reading some of this literature was a bit disappointing for us, because we figured
- that one of the reasons that those heavy atoms work was because of the spin orbit coupling term,
- by virtue of the heavy atom effect, but preliminary experiments say that's not the case,
- or not necessarily the case with light atoms. There's a lot more things that we need to start
- thinking about. So what we are trying to do is design the thioxanthone molecules with different
- push/pull effects, placing the atoms at different positions around the ring, to see if we can learn
- something about it first, but I agree, it's remarkable that they can do the same thing.
- Yes, and just to follow up the previous question,
- I think this field would have a lot to learn from teaming up with computational chemists.
- Absolutely, yes.
- Any other questions? One final question over there. Thank you.
- Hi. Good evening. Doctor Wade Petersen, my name is [?Tanisa 0:58:34.1]. I'm from
- the South African High Commission in London. Normally I would run off to go to my kids,
- but my husband's taking care of them, so, you're very lucky to be in my presence. No.
- I'm kidding. I'm very lucky to be in your presence. This is not a question
- about organic chemistry. My idea of chemistry is watching Breaking Bad and hating Walter White,
- but I just want to say to you, in my job, as a South African diplomat, I'm often asked,
- 'You're like the leading economy in Africa. Why do you have load shedding?' I mean, because we didn't
- grow up with load shedding, right? It's a recent phenomenon. So your presentation is one of the
- first times I've actually come across something that's a positive reaction to a very negative
- thing that's taking place in our country. I just want to say that you make us all so very proud.
- Our high commissioner couldn't be here. He's trying to mediate peace in South Sudan. Good
- for him, and for South Sudan - sorry, I'm not the best diplomat - but, your pictures of Cape
- Town make us all very homesick, and you fly the flag so high and so beautifully, and with your
- lovely wife and now you're in Sydney. I'm just so grateful that you've won this award. And thank you
- to the Royal Society, and thank you on behalf of all South African expats living in the UK.
- Thank you. I appreciate that.
- I think on this note, a very, very positive note as well, I will - I'm almost at the point
- of closing, but we have a little award to present to you. So if you'd like to come over? The award,
- as we know, is the Royal Society Rising Star Africa Prize 2023,
- and it's awarded to Doctor Wade Petersen for his research into new methods for the
- construction of molecules relevant to drug discovery, using visible light as a source
- of energy. Very many congratulations. And here is your certificate and also your medal as well.
- Thanks very much.
- Congratulations.
- Thank you.
Join us for the Royal Society Rising Star Africa Prize Lecture given by 2023 winner Dr Wade F Petersen.
Chemists have provided the world with an abundance of enabling synthesis methods for the construction of molecules significant to human life; specifically crucial medicines. Many of these methods utilise rare and expensive metals and/or require significant heating processes. In a world of rapidly declining resource, both in terms of energy and materials, a very sobering question emerges:
‘How will we make critical medicines if some resources are no longer available — say in the middle of a blackout?’
In this talk, Dr Petersen will share some of his experiences working under such conditions in Africa, as well as describe his research endeavours toward achieving sustainable and energy efficient syntheses of therapeutically relevant small molecules: mimicking photosynthesis and using light energy in pursuit of chemical synthesis perfection.
About the Royal Society
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