Nobel Prize in Chemistry 2021 Part 2, Asymmetric Organocatalysis, Enantioselective Organic Chemistry

Explaining more of the science behind the Nobel Prize for Chemistry in 2021 on asymmetric organocatalysis, won by Prof. Benjamin List and Prof. David MacMillan. This video focuses on the use of imidazolidinone catalysts in Diels-Alder reactions that give high enantioselectivity for these cycloadditions (MacMillan). These transformations evolved the organic chemistry techniques that had previously been studied using transition metal catalysis as Lewis acids that can carry chiral ligands.
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For control in Diels-Alder reactions, it is required that a dienophile with an electron-withdrawing group attached is used in reaction with a diene. This is to assist in molecular orbital energy matching and preventing over-reaction. The electron-withdrawing group is most effective it is part of a pi system that can conjugate effectively with the dienophile pi system, and so lower its LUMO in energy (LUMO = lowest energy molecular orbital). Cycloaddition reactions then proceed in a smooth and predictable way in high diastereoselectivity. These reactions tend to proceed via an endo transition state, rather than an exo transition state, as this one is relatively lower in energy due to additional secondary orbital interactions - a pi stacking interaction between an electron-rich pi system and an electron-poor pi system.
The LUMO of the dienophile can be further lowered in energy by coordination of this electron-withdrawing group to a Lewis acid. The Lewis acid can be used as a catalyst and could be based on either a main group element or a transition metal. Both of these options allow a chiral Lewis acid to be used by embedding an electron-deficient element (such as boron) in a chiral molecule or by employing designed chiral ligand specific for a metal centre and its preferred coordination geometry. If you ensure that the chiral Lewis acid structure is as one enantiomer, you can induce enantioselectivity into your Diels-Alder reaction as the chiral catalyst will be held close to the reacting centres in the transition state for the cycloaddition.
To introduce organocatalysis into the Diels-Alder reaction, it was recognised that you could turn a pi-conjugating electron-withdrawing group on a dienophile such as an aldehyde into an iminium ion which would drastically lower the LUMO energy of the dienophile’s pi system, not least that an iminium ion bears a full positive charge. If the iminium ion is made from a secondary amine that is chiral and has sufficient steric bulk to restrict conformation of molecules, chiral information can be brought very close to the reacting centres in the Diels-Alder transition state. As the iminium ion system lowers the LUMO energy of the dienophile so much, when it is formed the Diels-Alder reaction will be a lot faster than the equivalent reaction with the parent aldehyde-bearing dienophile, and so it is possible to use a secondary amine as an organocatalyst. Pyrollidine has long been used for forming both iminium ions and enamines in organic chemistry for tempering reactivity for selective reactions. The imidazolidinone catalysts developed by the MacMillan group are an evolution of the same idea using an amine catalyst based on a five-membered ring. It is possible to make imidazolidinone ring systems relatively easily from parent amino acids and the first generation catalysts developed for the asymmetric organocatalysis of the Diels-Alder reaction were derived from phenylalanine. Further work by MacMillan and other groups explored how to optimised this type of asymmetric organocatalysis for higher enantioselectivity and yields, but also explored how the same key transition state structure and reactive intermediate could be used in many other nucleophile/electrophile chemistry, such as asymmetric Michael additions and Friedel-Crafts reactions. The organic chemistry in this video explains some of the early successes in this widely expanded area of asymmetric organocatalysis since the turn of the millennium. Small molecule organic catalysts, particularly chiral ones in high optical purity (high ee), tend to be much cheaper and environmentally friendly when compared to their transition metal counterparts and equivalents. The environmental factors have attracted attention in identifying asymmetric organocatalysis as a field of study that has big applications in green chemistry largely as the need to dispose of often toxic and/or environmentally destructive metal waste is completely removed from any synthesis. Additionally, the organocatalysts can often be separated easily from reaction products and recycled whereas transition metal catalysts are often destroyed in work-up.

[@kendalldoer5466]

This video was excellent!! It's my second day of advanced organic chemistry in undergrad and we are covering a David MacMillan paper exactly on this topic. This video helped me understand MUCH better. Keep up the good work!

[@CasualChemistry]

Many thanks for the feedback and glad you enjoyed the video. I'll be getting on to more when my in-person teaching load decreases a bit in the next few weeks. I have lots of ideas on related topics/ideas.

[@suneelgaur5246]

These videos are great! Very clear and concise explanations of some difficult concepts. After watching this, all of my confusion has vanished...fantastic!😃👍

[@CasualChemistry]

Many thanks for the feedback - much appreciated 🙂

[@campbeja001]

Your videos are by far the best I have seen in balancing detail with easy comprehension. Nice job!

[@CasualChemistry]

🙂 thanks for the feedback - glad you enjoyed the videos!

[@leopoldvisions1079]

Great video! Thank you very much! I'm still in High School and doing a presentation on asymmetric Organocatalysis and your videos already helped me a lot! I'd be very thankful if you could explain the Hydrolysis at the end (Minute 12:00) to me in more detail (please also tell me where the OHC group is coming from)? I hope you see this and can find the time to answer me. Have a great day!

[@CasualChemistry]

Many thanks - glad the video has been helpful :) For the hydrolysis of the iminium ion to the aldehyde, I'll try and explain the steps in text below. You might find my video on Acetals useful as it's essentially the same mechanism with a N swapped in for a O. (R)(H)C=N(R)(R)+ gets attacked by water at the carbon (like a carbonyl) to give (R)(H)C(OH2)+(NR2) A proton is transferred to make the amine a leaving groups to (R)(H)C(OH)(NHR2)+ Then the oxygen lone pair comes down and kicks out NHR2 an an amine and forms the C=O double bond.

[@JBry_]

Fantastic video, I'm definitely going to watch some of the others on your channel and I'm looking forward to more content from you in the future :). I'm actually in the process of writing my third year literature project on MacMillan's catalysts and their applications in the synthesis of biologically active products. With regard to the extra pi stacking from the Ph due to the CH2, I think you've even went beyond what MacMillan explained in his papers.

[@CasualChemistry]

Thanks :) Glad you enjoyed the video and I definitely have a list of new videos I want to make as soon as I can. Some of the rationalisation of these mechanisms can come much later after other research groups have played around with similar ideas, and then you can start inferring why certain other catalysts have e.g. decreased enantioselectivity over other.

[@JBry_]

@@CasualChemistry Glad to hear it! Yeah I suppose that makes sense, I'd guess computational studies would also need to be done to verify that those stabilising interactions actually do exist as well.

[@sincostan2396]

good explanation sir, am curious about racemic mixture. would you tell how the isomers in tlc? does the spot closed to each other?

[@CasualChemistry]

Many thanks for the feedback🙂 If you have a racemic mixture of enantiomers, on standard TLC they will be exactly the same Rf. If you had some special silica which has been functionalised with a chiral organic (for example certain sugars are common for this) you would see some separation of spots. This is how enantiomers can be separated on scale without too much effort by chiral HPLC, though that often requires optimisation for specific molecules. On normal TLCs, you would expect to see separation between spots for diastereoisomers with sensible solvent systems as these are chemically distinct isomers.

[@victordonchenko4837]

Very nice, very helpful.

[@CasualChemistry]

🙂 Thanks

[@m.jadidinejad6727]

excellent💖💖

[@danielyanes5510]

Great video! Please at some point can you show kinetic versus thermodynamic control in synthetic applications?

[@CasualChemistry]

Sure. I have some plans on my to-do list that will lean into these ideas quite heavily. I’m planning a variety of discussions on alkene formations with defined geometries etc

[@helpmereach1ksubswithoutan997]

Thank you very much. 😍🥰

[@CasualChemistry]

Glad you enjoyed the video 🙂

[@mayurpawar9324]

Such a brief And Nice explanation! Thank you sir 🤗. Please make a video on fukuyama coupling 🙏

[@CasualChemistry]

🙂 Many thanks for the feedback - glad you enjoyed the video. I have a few ideas for future videos on metal catalysis in a more general sense so I'll see if that reaction can fit nicely in one of those discussions.

[@poatatoecouch7]

Perfect videos, much appreciated!

[@CasualChemistry]

Many thanks 🙂 Glad you’ve enjoyed them

[@m.jadidinejad6727]

Thanks alot💕💕

[@CasualChemistry]

You’re welcome 🙂 glad you enjoyed the video

[@yudhabudiman3050]

Thanks for your excellent explanation. In the minute 11.03, if the imminium does not have phenyl group, it will give two types of endo products... So it will give the final product with phenyl in the backward and CHO in the forward, and phenyl in the forward and CHO in the backward,,, is that what you mean?

[@CasualChemistry]

Many thanks for the feedback - much appreciated 🙂 With your question: yes that is the point I’m trying to make there. If you don’t have the stereocentre on the organocatalyst, you get a mixture of the two enantiomers of the 1,2-syn diastereomer (as you’ve described) in a 50:50 mixture - a racemic product, rather than a preference for one enantiomer as intended

[@AmanKumar-dg9nf]

what about if we have the Z dienophile??... How the transition state will look like... I am kind of thinking exo product will be formed but confused about the transition state.\

[@CasualChemistry]

Well I think it's not so clear so that's a recipe for just getting poor selectivity. I'm assuming that you mean a Z-geometry for the C=C bond (not the C=N bond): in which case there are a few things to think about. When a Z- alpha,beta unsaturated aldehyde is in the the presence of these catalysts, they might isomerise to E anyway by conjugate addition and subsequent rotation and E1CB-type mechanism. If you've locked in a Z-geometry (e.g. using a ring) I agree things are less likely to be so selective for endo:exo. There will be a fight over the electronic preference for pi-stacking and the steric constraints, which you could only work out by doing the experimental work and finding out. Often, if there is any fighting for selectivity ("mismatched" reactivity) the most likely outcome is just poor selectivity, which in this case would be low ee. Though I'm sure people have found ways to make particularly large steric effects that totally override the pi-stacking effect and favour an exo product - but arguably those situations aren't particularly general and so less useful as a methodology.

[@Abdulkalam-sy5gl]

Sir , please make a video basic organic chemistry level in undergraduate degree student.

[@CasualChemistry]

I have a few videos pitched at different levels mainly through different undergrad stages, particularly some of the things in the retro synthesis playlist explain some key ideas. More of these videos are on the way. I hope you find them useful 🙂

[@Abdulkalam-sy5gl]

@@CasualChemistry thank you

[@wabslayz5272]

Hey I’m a big fan, please help me find the PH of Phenacetin 😭 please!

[@CasualChemistry]

Thanks for the feedback :) I assume you mean pKa here which I would estimate at about 15. You might find the Evans tables useful for this sort of thing: ccc.chem.pitt.edu/wipf/MechOMs/evans_pKa_table.pdf

[@aryanranka4765]

Nice

[@CasualChemistry]

Many thanks 😊 glad you enjoyed the video