Organocatalysis – a chemical revolution assisted by NMR

In this article, we describe how this field has developed in the 20 years since it was discovered and highlight the special role that nuclear magnetic resonance (NMR) has played in helping List and MacMillan’s teams unlock the potential of organocatalysts to make chemical transformations more environmentally friendly.

Organocatalysis – a chemical revolution assisted by NMR

Although catalysis as a concept has been around for centuries, the field continues to evolve, with a major landmark being the award of the 2021 Nobel Prize for Chemistry to Prof. Dr Benjamin List and Prof. David MacMillan for their work on asymmetric organocatalysis. In this article, we describe how this field has developed in the 20 years since it was discovered and highlight the special role that nuclear magnetic resonance (NMR) has played in helping List and MacMillan’s teams unlock the potential of organocatalysts to make chemical transformations more environmentally friendly.

What makes an organocatalyst?

Up until 20 years ago, the prevailing notion was that there were just two types of catalyst. Metal-based catalysts use the special complex-forming and electron-sharing powers of certain metals to bring together the reactants and facilitate the breaking and formation of bonds. Enzymes achieve the same result in living organisms by enveloping the interacting molecules within complex protein structures, and by invoking cascades of small steps to overcome the energetic barriers to reaction.

But in 2000, this long-established perspective on catalysis changed, when Prof. Dr Benjamin List (then at the Scripps Research Institute) and Prof. David MacMillan (then at the California Institute of Technology) independently developed organocatalysts. These are small, carbon-based molecules that perform their catalytic role without involving a metal atom. As a result, organocatalysts avoid the toxicity and expense of many metal-based catalysts, making it easier for chemists to devise environmentally friendly syntheses of important molecules.

A new concept: organocatalysts for asymmetric reactions

In recognition of the impact of this new class of catalysts, in October 2021 List and MacMillan were jointly awarded the Nobel Prize in Chemistry “for the development of asymmetric organocatalysis”. Asymmetric catalysts – those that help a reaction generate more of one enantiomer of a product than another – have been a major topic of study for over 50 years, but what List and MacMillan did was to realize that the catalyst could be a simple organic molecule. MacMillan devised amines that mimicked the properties of traditional electron-accepting metal catalysts, and used them to catalyze a ring-forming reaction between an unsaturated aldehyde and a diene.1  Meanwhile, List was inspired by biological systems, and found that the naturally-occurring amino acid proline could catalyze the carbon–carbon bond-forming reaction between a ketone and an aldehyde (known as an aldol reaction).2

But it’s often the case that what drives new discoveries in science – apart from inspiration and hard work – is the tools that scientists have to hand, which is where NMR comes into the story.

Using NMR for structure determination

Thanks to its ability to probe chemical structures at the atomic level, NMR is routinely used to identify the products of all sorts of reactions, including those studied by both List and MacMillan as part of their studies on organocatalysis. For example, the MacMillan team used 1H and 13C NMR to confirm the identity of products resulting from their ground-breaking experiments on the amine-catalyzed α-alkylation of aldehydes.3

The MacMillan group went on to use organocatalysis to not only tackle challenging transformations, such as the α-fluorination of cyclic ketones,4  but also to develop methods involving multiple catalytic processes in a single reaction. One method achieved the enantioselective α-benzylation of aldehydes, using a strategy involving activation not just by organocatalysis, but by a radical-mediated ‘spin-center shift’ upon the alcohol.5  The group also demonstrated that this concept could be further expanded to merge three processes – enamine organocatalysis, photoredox catalysis and hydrogen-atom transfer catalysis – for the enantioselective α-alkylation of aldehydes by simple olefins.6

In the above cases and many more, 1H NMR was often used not just for determination of the overall structure, but to determine the stereochemical purity of the product. In cases where the product contains more than one chiral center, this is often done by integrating the signals from certain distinctive protons, but other techniques can also be brought into play – for example, using the nuclear Overhauser effect to determine whether a particular proton–proton pair sits on one side of a molecule or the other.

Understanding reaction mechanisms

But beyond its use for routine structure determination, NMR has played a special role in the development of asymmetric organocatalysis, which has been the focus of particular study by the List group.

The first of these roles is improving the understanding of organocatalyzed reaction mechanisms. When List first described his proline-catalyzed aldol reaction, there was of course great interest in understanding how it worked. The breakthrough was made eight years later by the team of Prof. Dr Ruth Gschwind at the University of Regensburg, Germany, who used NMR to identify an elusive and highly debated reaction intermediate.7  By probing the exchange of protons during the course of the reaction, they not only confirmed predictions that the intermediate was an enamine, but they deduced its stereochemistry and mode of formation too.

Another notable result was the asymmetric hydrogenation of unsaturated aldehydes, catalyzed by an ammonium phosphate,8  in which NMR was used to show that rapid double-bond equilibration preceded the hydrogenation step, confirming earlier observations of similar reactions that the double-bond configuration of the starting material had no impact on the chiral purity of the product (known as ‘stereoconvergence’).

Since then, there have been numerous examples where NMR has been used to examine the stereochemistry or conformation of organocatalysts. Techniques used by the List team center on the above-mentioned nuclear Overhauser effect, as illustrated by investigations into organocatalyzed Diels–Alder-type reactions,9 epoxidation of carbonyl compounds,10  ring-opening of epoxides11 and aziridines,12  and carbocation activation13,  amongst others.

The team has also investigated organocatalyzed reaction mechanisms directly, using techniques such as diffusion-ordered NMR spectroscopy (DOSY) to observe the association of a catalyst with its substrate,14  so-called ‘in operando NMR’ to follow reactions in situ with standard NMR experiments and reveal their kinetic order,15  and 13C kinetic isotope effects (KIEs) to uncover the slight preference of a reaction for one isotope over another at the key reacting site.16

From solutions to surfaces

A particularly interesting breakthrough was made by the List group in 2013, when they described how a variety of organocatalysts could be immobilized on nylon using light, and reused more than 250 times with scarcely any reduction in performance.  It allows the catalyst to be easily recovered from the reaction mixture, enabling higher loadings to be used without problems.

Importantly, this study stands out from most of the work on organocatalysis because it shows that the concept can also be applied to reactions taking place at surfaces, not just in solution. Such heterogeneous catalyst systems can be difficult to study but, despite this, NMR still proved useful in this case, with magic-angle spinning 19F NMR used to determine the catalyst loading in situ.

Following reactions on the small scale

A major benefit of NMR is that it is inherently quantitative, enabling the concentrations of reagents, intermediates, products and side-products to be followed over time – as shown by List’s team in a kinetic study of the synthesis of enol silanes.18

And because NMR doesn’t destroy the sample, the reactions need not be run in a conventional reaction vessel. A major change in NMR over the last 20 years is that improvements in sensitivity now mean that samples at typical reaction concentrations – often much lower than those normally used for NMR experiments – can be studied in a regular NMR tube. This enables short-lived (and hence low-concentration) organocatalytic intermediates to be investigated as they form. There are several ways of achieving this sensitivity boost, with a particularly useful development being dynamic nuclear polarization (DNP), in which microwaves are used to transfer spin polarization from electrons to nuclei, increasing the signal-to-noise ratio. Another approach uses cryoprobes, which reduce the background noise by cooling down the instrument’s electronics to about –270 °C.
In fact, the ability to run reactions in NMR tubes links is another example of improving the environmental credentials of reactions, by simply reducing the quantities of chemicals used. The principle is simple but powerful, and is nicely demonstrated by List’s recent work on reducing organocatalyst loadings for an asymmetric aldol reaction to less than 1 ppm.19

NMR: Helping organocatalysis fulfil its potential

In conclusion, organocatalysis has undergone dramatic advances in the last 20 years, spearheaded by the work of List and MacMillan, and assisted by the atom-level information provided by NMR. By allowing researchers to identify reaction products, and distinguish stereoisomers of reagents on small scales and in real-time, NMR has helped uncover and optimize the mechanisms of organocatalyzed reactions.

By doing this, it should become easier to move chemical transformations away from metal-based catalysts, and towards more sustainable organocatalysts, while simultaneously improving the ability of chemists to work on the applications that society demands – whether inventing life-saving pharmaceuticals, manufacturing new high-performing polymers, or developing more efficient systems for energy storage.

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  1. K.A. Ahrendt, C.J. Borths and D.W.C. MacMillan, New strategies for organic catalysis: The first highly enantioselective organocatalytic Diels–Alder reaction, Journal of the American Chemical Society, 2000, 122: 4243–4244.
  2. B. List, R.A. Lerner and C.F. Barbas, Proline-catalyzed direct asymmetric aldol reactions, Journal of the American Chemical Society, 2000, 122: 2395–2396.
  3. D.A. Nicewicz and D.W.C. MacMillan, Merging photoredox catalysis with organocatalysis: The direct asymmetric alkylation of aldehydes, Science, 2008 322: 77–80.
  4. P. Kwiatkowski, T.D. Beeson, J.C. Conrad and D.W.C. MacMillan, Enantioselective organocatalytic α-fluorination of cyclic ketones, Journal of the American Chemical Society, 2011, 133: 1738–1741.
  5. E.D. Nacsa and D.W.C. MacMillan, Spin-center shift-enabled direct enantioselective α-benzylation of aldehydes with alcohols, Journal of the American Chemical Society, 2018, 140: 3322–3330.
  6. A.G. Capacci, J.T. Malinowski, N.J. McAlpine, J. Kuhne and D.W.C. MacMillan, Direct, enantioselective α-alkylation of aldehydes using simple olefins, Nature Chemistry, 2017, 9: 1073–1077.
  7. M.B. Schmid, K. Zeitler and R.M. Gschwind, The elusive enamine intermediate in proline-catalyzed aldol reactions: NMR detection, formation pathway, and stabilization trends, Angewandte Chemie, International Edition, 2010, 49: 4997–5003.
  8. S. Mayer and B. List, Asymmetric counteranion-directed catalysis, Angewandte Chemie, International Edition, 2006, 45: 4193–4195.
  9. H. Kim, G. Gerosa, J. Aronow, P. Kasaplar, J. Ouyang, J.B. Lingnau, P. Guerry, C. Fares and B. List, A multi-substrate screening approach for the identification of a broadly applicable Diels–Alder catalyst, Nature Communications, 2019, 10, 770.
  10. O. Lifchits, M. Mahlau, C. M. Reisinger, A. Lee, C. Farès, I. Polyak, G. Gopakumar, W. Thiel and B. List, The cinchona primary amine-catalyzed asymmetric epoxidation and hydroperoxidation of α,β-unsaturated carbonyl compounds with hydrogen peroxide, Journal of the American Chemical Society, 2013, 135: 6677–6693.
  11. S.H. Liao, M. Leutzsch, M.R. Monaco and B. List, Catalytic enantioselective conversion of epoxides to thiiranes, Journal of the American Chemical Society, 2016, 138: 5230–5233.
  12. R. Monaco, B. Poladura, M. D. de Los Bernardos, M. Leutzsch, R. Goddard and B. List, Activation of carboxylic acids in asymmetric organocatalysis, Angewandte Chemie, International Edition, 2014, 53: 7063-7067.
  13. R. Properzi, P.S.J. Kaib, M. Leutzsch, G. Pupo, R. Mitra, C.K. De, L.J. Song, P.R. Schreiner and B. List, Catalytic enantiocontrol over a non-classical carbocation, Nature Chemistry, 2020, 12: 1174–1179.
  14. M.R. Monaco, B. Poladura, M. Diaz de Los Bernardos, M. Leutzsch, R. Goddard and B. List, Activation of carboxylic acids in asymmetric organocatalysis, Angewandte Chemie, 2014, 53: 7063–7067.
  15. L.P. Liu, M. Leutzsch, Y.Y. Zheng, M.W. Alachraf, W. Thiel and B. List, Confined acid-catalyzed asymmetric carbonyl–ene cyclization, Journal of the American Chemical Society, 2015, 137: 13268–13271.
  16. L.P. Liu, H. Kim, Y.W. Xie, C. Farès, P.S.J. Kaib, R. Goddard and B. List, Catalytic asymmetric [4+2]-cycloaddition of dienes with aldehydes, Journal of the American Chemical Society, 2017, 139: 13656–13659.
  17. J.-W. Lee, T. Mayer-Gall, K. Opwis, C.E. Song, J.S. Gutmann and B. List, Organotextile catalysis, Science, 2013, 341: 1225–1229.
  18. H. Zhou, H. Y. Bae, M. Leutzsch, J. L. Kennemur, D. Becart and B. List, The silicon–hydrogen exchange reaction: A catalytic σ-bond metathesis approach to the enantioselective synthesis of enol silanes, Journal of the American Chemical Society, 2020, 142: 13695–13700.
  19. H.Y. Bae, D. Höfler, P.S.J. Kaib, P. Kasaplar, C.K. De, A. Döhring, S. Lee, K. Kaupmees, I. Leito and B. List, Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction, Nature Chemistry, 2018, 10: 888–894.