A catalyst is something that speeds up a reaction without getting used up in the process. We talk about them a lot in biochemistry, and typically when we do so we’re talking about enzymes. Enzymes are biochemical catalysts – they’re often proteins, sometimes RNA, and sometimes a complex of protein + RNA – and they make it waaaaay more likely that a reaction will occur. They can do this by holding the substrate(s) (things that are going to react and/or change) in the optimal position to reaction, donating or holding onto protons (H⁺), or other tricks of the trade. And, at the end of the reaction, the enzyme is back to its old self and ready to do it again. This makes them incredibly valuable. But they can be complex and sensitive to reaction conditions, therefore alternative, simpler, catalysts are often used (and desirable) when possible. But these catalysts, lacking the greater context provided by the big ole enzyme structure, are often more promiscuous in the reactions they catalyze and the spatial orientation of molecules they help synthesize (think left vs right hands). This year’s Nobel Prize in Chemistry laureates, Benjamin List (currently at the Max Planck Institute in Germany) and David W. C. MacMillan (currently at Princeton University), found ways to get around this “stereochemistry” problem – in ways that are more environmentally-friendly than traditional synthesis routes.
Their prize was formally given “for the development of asymmetric organocatalysis”
let’s de-jargon this…
“asymmetric” – this refers to that stereochemistry thing – these catalysts allow scientist to make mostly a single stereoisomer (like only right hands or only left hands)
“organo” – in chemistry, “organic” refers to molecules that are based upon a carbon-hydrogen backbone
“catalysis” – here’s that key word I started out mentioning, which refers to something speeding up a reaction without getting used up in the process
As I will discuss later, their key, “proof-of-concept” discoveries were published in 2000, and since then the field has taken off. It is considered a “third type of catalyst” – in addition to the metal and enzyme catalytic classes.
but a key thing to know for today is that what makes enzymes even more valuable (in comparison to other catalysts) is that they’re super specific in which reactions they catalyze – as well as *where* on a molecule and with what “stereochemistry.” Stereochemistry refers to what direction various atoms in a molecule stick out in 3D space. And what “3D version” (stereoisomer) a molecule will have will depend on
- the stereochemistry of the pieces its made from and
- how those pieces were put together
quick background: Molecules are collections of atoms (individual carbons, nitrogens, oxygens, hydrogens, etc.) held together by strong, covalent bonds, which involve the sharing of pairs of negatively-charged subatomic particles called electrons. much more here:
What you need to know for today is that, if you have a linkage hub, typically a carbon, with 4 different groups attached, which we refer to as a chiral center or an asymmetric carbon, you can end up getting stereoisomers, where those groups are sticking off in different directions. A special name is given to stereoisomers that are non-superimposable mirror images of one another (think right hand vs left hand) – we call these enantiomers. Non-mirror-image stereoisomers are called diastereomers. Each asymmetric carbon provides an opportunity for stereoisomer formation, so there can be tons of possible combinations of stereoisomers for a single molecule (making this an even more drastic problem for synthesists), but for simplicity I will just refer to the whole right-hand, left-hand thing.
There are countless possible stereoisomers. Yet, in our cells, and the cells of all living organisms, you’ll typically only find a single stereoisomer of each molecule. This is largely thanks to enzymes. Almost all molecules our cells synthesize are made through series of enzymatic reactions. Each of these reactions generates a stereospecific intermediate product that gets passed onto the next enzyme, and the next, and the next … with that stereochemistry preserved throughout. How do they do this?
Firstly, they have binding sites which are ideal for binding a single stereoisomer, “rejecting others.” It’s like they’re a bunch of right-handed gloves. Therefore they start with already-biased precursors. Then, to make sure that stereochemistry is preserved, enzymes provide a lot of contextual information, such as holding the molecule in the exact “right” orientation to get the desired enantiomer. For example, covalent bond formation (which involves sharing pairs of electrons, remember) often occurs via the electrons of one atom “attacking” another atom. Which enantiomer you get often depends on which side the attack comes from. An enzyme can sort of hide one side and put the other side on display in order to bias where the attack will come from.
But other, “simpler” catalysts like those traditionally used by synthetic chemists, can’t provide that info. As a result, a piece often gets added on in its non-superimposable mirror-image form (enantiomer). Like Frankenstein’s maker stitching on a left hand instead of a right hand. When Frankenstein goes to put on gloves there’s a problem!
Similarly, if the body were to try to use one of those enantiomeric compounds, there would be a problem. Potentially many problems. For example, they wouldn’t fit into all of the enzymes the cell would normally use to work with them and/or break them down or modify them. Remember, the level of specificity of enzymes includes specialization for working with specific enantiomers. It’s like your cells have a bunch of right-handed gloves so you can’t use left hands.
So why not just use enzymes all the time for in vitro (“in a test tube”) chemical synthesis? Although enzymes are awesome, they can also be pretty complicated. Our body’s main RNA polymerase, RNA Pol II, is actually made up of 12 protein subunits!
So, typically, although we use enzymes for many purposes in the lab – like polymerase chain reaction (PCR) and in vitro transcription (IVT) which pieces together DNA or RNA letters, respectively, based on a template – for many other purposes, such as building those building blocks, alternative catalysts are often used (and desirable) when possible.
These catalysts are frequently what we call “small molecules” – they’re pretty much what that sounds like they’d be. Little molecules, not big ole enzymes. But this means they lack the context enzymes can provide. Remember, in an enzyme, although only a small part of the enzyme might be directly contributing to the catalysis, that small part is perfectly positioned, and the substrate is perfectly positioned to react – in a very specific way.
Say you want to add a piece to a specific location on a molecule. Synthetic chemists can do things like add “protective groups” to parts of the molecule that they don’t want to “accidentally interact” – but even if they can get the reaction to occur at the site of interest, the piece often gets added on in its mirror-image form (enantiomer). Like Frankenstein’s maker stitching on a left hand instead of a right hand. When Frankenstein goes to put on gloves there’s a problem!
Similarly, if the body were to try to use one of those enantiomeric compounds, there would be a problem. Potentially many problems. For example, they wouldn’t fit into all of the enzymes the cell would normally use to work with them and/or break them down or modify them. The level of specificity of enzymes includes specialization for working with specific enantiomers. It’s like your cells have a bunch of right-handed gloves so you can’t use left hands.
For pharma companies, this can be a huge problem. For some drugs, it’s not so bad. Take ibuprofen, for example. Only the “S” stereoisomer is active, but your body can convert the “R” form to the S form, so if there’s a mix in your pill, that’s okay. But with thalidomide, your body can once again interconvert between its R & S forms, but they’re both “active” in different ways – the R form can serve as a sedative whereas the S form is responsible for causing severe birth defects. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869253/
If a synthesis is giving you a 50/50 mix of enantiomers, 1/2 the product is “useless” and could even be harmful (as is the case with thalidomide). Manufacturers can use purification methods to isolate the desired enantiomer and prevent detrimental effects, but there’s still that big resource (and profit) loss. And if you have a step-wise synthesis where you’re losing half of the goods each time… not a good yield…
To get around this problem, synthetic chemists have traditionally turned to metal-based chiral catalysts. Metals are great because they have big “fuzzy” electron clouds that can give and take electrons. note: electrons are the negatively-charged subatomic particles that atoms (individual carbons, nitrogens, oxygens, hydrogens, etc.) swap and share to form bonds. Enzymes also frequently make use of metals as “cofactors” (helper molecules). But in an enzyme, there’s a lot of context… Chemists can provide a small bit of context by using these metals complexed to a small molecule.
note: “complex” here refers to an organometallic coordination complex which is where the organic compound part donates a pair of electrons to the metal, helping hold it in place.
These complexes can provide some context, and they can sort of “hide one side” of the metal to sway the reaction to happen in a way that will bias one of the stereoisomers.
So, before 2000, we had 2 ways of making chiral compounds
- metal-based catalysts
But both of these strategies had problems…
Enzymes are complicated, requiring expression, purification, etc. And you can’t easily “redirect” them to do other things because they’re so specialized for their substrates. And they’re really picky and sensitive to reaction conditions. They’ve evolved to function best in cellular conditions, not harsh test tube conditions.
And metals are a non-sustainable resource. Mining them can be environmentally costly. And the metals themselves are really sensitive to things like moisture and oxygen (they can easily change their oxidation state and “go bad”). So metal-catalyzed reactions often have to be performed in glove-box type contraptions.
This is where our Nobel laureates come in. They figured out a way to use organic small molecules (so way less complicated than enzymes) to catalyze enantiomerically specific reactions. And these molecules are better for the environment that the catalysts that are traditionally used.
What’s really powerful is when organocatalysts are used in sorta chain reactions. In your body, reactions aren’t happening in isolation. When your cell makes a molecule from smaller pieces, those stepwise reactions can happen sequentially, with the molecule kinda handed off from one enzyme to another. Some enzymes (often multi-subunit ones) even are able to catalyze multiple steps. But when scientists synthesize a molecule in vitro, they’re typically doing it one step at a time. With different reaction conditions optimized for each step. And in between each step they’re purifying out the product. Not very efficient.
But, with organocatalysts, when the reactions are more specific, you don’t have nearly as many byproducts to weed out along the way, so you can actually set up chain reactions in vitro.
So, what are these magic molecules?
The first was actually one that your body knows quite well – proline!
You might remember proline from our discussion of amino acids (protein letters). Proline is probably like the biggest weirdo of the protein world. All amino acids have a generic backbone that allows them to link together and a unique “side chain” or “R group” that sticks off and gives them special properties. Proline’s side chain actually circles back on itself and bonds to the backbone like a ring. This is important in protein structures because it can kinda lock a conformation (shape) into place, etc. What makes it important as a catalyst is that, unlike the other amino acids, it has a secondary amine (a nitrogen attached to 2 carbons).
List got the idea to use proline from the structures of enzymes themselves. Although enzymes are often big, bulky molecules, usually the catalytic action usually just involves a couple of amino acid side chains sticking out into the active site.
note: this is not to say that the rest of the enzyme isn’t super important for positioning the substrate, increasing local concentrations, altering local pH, etc. But working in vitro the chemists can better control those other factors to make reaction conditions more ideal overall (without having to worry about messing up a whole enzyme, cell, etc. – small molecules are much more tolerant of extremes).
What if, List thought, you could just supply those catalytic amino acids? If you supplied them as a single enantiomer, they should be better at catalyzing the reaction in a way that results in a single enantiomer.
There was even a paper from the 1970s that had tried using proline to catalyze a reaction.
List, working in the lab or Carlos F. Barbas III at Scripps Research Institute in San Diego, California, decided to test whether proline could catalyze a different kind of reaction, known as an “aldol reaction.” In our bodies, aldol reactions are carried out with the help of enzymes called aldolases. List found that proline could act as a “micro-aldolase.” https://pubs.acs.org/doi/10.1021/ja994280y
As the term suggests, an aldol is a molecule with an aldehyde and an alcohol. An aldehyde is something with a carbon double-bonded to an O (this is called a carbonyl) and also linked to an H and another carbon, so something like R-(C=O)-H, where “R” is a hydrocarbon-based “rest of the molecule.” And an alcohol is something with an -OH group.
In an aldol reaction, an aldehyde or a ketone (a ketone is where the carbonyl has R’s on both sides, instead of an H on one side) reacts with the carbonyl carbon of another molecule. The result is a joining of the molecules with the production of a molecule that has a carbonyl next to a hydroxyl group. So you go from
-R1-(C=O)-H + R2-(C=O)-R3 -> -R1-(C-OH)-(C=O)-R2&R3 (it’s really hard to try to write this without being able to show multiple things connected to that carbonyl carbon!)
What makes this reaction super duper valuable is that it allows you to form a new carbon-carbon bond. And carbon-carbon bonds are literally the backbone of all organic molecules! So, most of the stuff in our bodies. Part of what makes them great backbones is that carbons are generally stable and unreactive. But that also makes it hard to get carbons to react to one another to join up. So reactions that can do this are really valuable.
List, Lerner, & Barbas III found that L-proline could act as an enamine catalyst to form bonds between acetone CH3-(C=O)-CH3 and a variety of aldehydes. https://pubs.acs.org/doi/10.1021/ja994280y
An enamine is a combo of an aldehyde or ketone & a secondary amine and it it can act as a nucleophilic “Lewis base” (electron pair donor). The reaction using the proline catalyst proceeds via an enamine intermediate, where the catalyst is covalently stuck to the substrate. This helps dictate how the reaction proceeds stereochemically. And its chemical makeup makes it highly nucleophilic and thus reactive towards the electrophilic carbonyl carbon of the aldehyde.
jargon note: if an atom has more electron density that its protons can comfortably reign in, it seeks out the help of additional protons from another atom. Since protons are found in the nucleus, we call such proton-seekers nucleophilic. Other atoms are more likely to want to help out if they’re wanting more electron density (i.e. they’re electrophilic). To fulfill their desires, a nucleophile can “attack” an electrophile, leading to the formation of a new bond. And where it attacks from can influence the stereochemistry of the resulting product.
Around the same time, David MacMillan and his colleagues found a different small organic molecule could catalyze a different reaction, the Diels‒Alder reaction. This is another one of those fundamental reactions crucial to organic chemistry – it takes an aldehyde and a diene (something with 2 carbon-carbon double bonds) and forms a ring.
MacMillan found that a derivative of a different amino acid, L-phenylalanine, could serve as a chiral imidazolidinone catalyst (a form of iminium ion catalysis/Lewis acid catalysis). In this case, the aldehyde & the catalyst join up to form a charged (ionic) intermediate with a higher reactivity towards the diene. This idea was inspired by how metal-based catalysts typically work. Both act as “Lewis acids” or electron pair acceptors, which lowers the barrier to nucleophilic attack. And the surrounding bulky atoms in the catalysts MacMillan used biased the attack to yield mostly one enantiomer.
Since then, the field of organocatalysis has really boomed and scientists have found more and more ways in which small organic molecules can catalyze a variety of fundamental reactions. https://www.nature.com/articles/nature07367
Pharma companies have embraced the techniques and are working to streamline the production processes of drugs including Tamiflu and some antidepressants.
One cool application is combining organocatalysis with other forms of catalysis such as photocatalysis, which uses light. Another is “total collective synthesis” which uses common intermediates to produce a range of compounds, similarly to what enzymes in our body do. https://www.nature.com/articles/nature10232
I hope this helps get people excited about chemistry and shows that organic chemistry isn’t just a hard class that your school forces you to take. It’s awesome!
For a good overview of the award recipients & their work, I recommend this ASBMB Today article by Laurel Oldach, https://www.asbmb.org/asbmb-today/people/100621/2021-nobel-in-chemistry
Also check out the Nobel Prize committees’ publications
here’s the popular science background: https://www.nobelprize.org/uploads/2021/10/popular-chemistryprize2021.pdf
and the more technical detailed scientific background: https://www.nobelprize.org/uploads/2021/10/advanced-chemistryprize2021-3.pdf
And note that the whole lemon/orange thing is a myth. Both lemons and oranges have 96-99% of (R)-limonene & only 1-4% (S)-limonene. So yes, lemons and oranges do smell different, but it isn’t because of the limonene. Instead it’s because of differences in other molecules they have. https://www.youtube.com/watch?v=W9JpRg8M1qk&ab_channel=Reactions