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Innovations in Chemical Catalysis Will Revolutionize the Future

How New Nonmetallic Chemical Processes Will Change Industry and Reduce Toxic Waste 

Organocatalytic processes are particularly appealing, as they are sustainable and remove the need to employ costly, toxic, and nonrenewable metals.  ©David MacMillan/HJIFUS
Organocatalytic processes are particularly appealing, as they are sustainable and remove the need to employ costly, toxic, and nonrenewable metals. ©David MacMillan/HJIFUS

The following article is the second part of Prof. David MacMillans keynote presentation, entitled “New Catalytic Strategies for a Sustainable Future,” at the Twenty-Eighth International Conference on the Unity of the Sciences (ICUS XXVIII) in 2022.   

Discovery of Organocatalysis

When I arrived as an assistant professor at the University of California at Berkeley in the summer of 1998, I really did not know how I would accomplish my goal of developing a general method for organocatalysis [the process of using organic, nonmetal, nontoxic catalysts to facilitate chemical reactions]. But I had faith in the stellar, devoted, and incredibly hardworking group of young graduate students who joined my lab that first year. Fortunately, my confidence in my team was well placed.


In the spring of 1999, a first-year graduate student in my group, Kateri Ahrendt, found that a small organic molecule was capable of catalyzing a well-known reaction called the Diels-Alder cycloaddition. Most excitingly, as Kateri wrote in her notebook …  the organocatalyst was able to preferentially form the desired mirror image of the product.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

In the absence of this catalyst, the reaction generates both mirror images of the product in equal quantities. Although this preliminary result was far from publication-ready—we would ultimately need to modify the structure of the catalyst and optimize reaction conditions in order to achieve really useful levels of selectivity—Kateri’s pivotal experiment on April 3, 1999, represented the first demonstration in my lab of an asymmetric organocatalytic reaction.


Following a great deal of experimentation, we ultimately hit upon a highly effective, generalizable organocatalyst scaffold: the imidazolidinones.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

From a sustainability standpoint, the imidazolidinones are really desirable catalysts since they can be made easily and inexpensively by combining phenylalanine, an amino acid, with acetone, a bulk chemical commonly used as a paint stripper.


Imidazolidinones also have the important advantage of being highly tunable; that is, their structures can be easily modified to meet the particular needs of different types of chemical reactions. This tunability would allow us to ultimately realize the grand vision of developing a generic activation mode: a single organocatalyst scaffold that could be applied to hundreds of different chemical reactions. In fact, the emergence of organocatalysis as a major mode of asymmetric catalysis can be traced to this key catalyst design feature.


Following our landmark 2000 publication, in which we reported the first asymmetric organocatalytic Diels-Alder cycloaddition, we went on to develop a series of asymmetric organocatalytic reactions using the imidazolidinone scaffold.


A second-generation imidazolidinone catalyst, brilliantly engineered by graduate students Joel Austin and Chris Borths, proved even more versatile than our original scaffold, allowing us to quickly develop dozens of powerful new asymmetric organocatalytic reactions.

Expansion of Organocatalysis

Around this time, other academic researchers began to make important contributions to the growth of this new field, most notably Karl Anker Jørgensen and Yujiro Hayashi (see image below). Meanwhile, Ben List and Carlos Barbas were conducting elegant research in the related area of enamine-based organocatalysis.

This was an incredibly exciting time, as our group and others around the world were inspired to invent a wide swath of powerful new reactions that made use of the asymmetric organocatalysis framework.


This was an incredibly exciting time, as our group and others around the world were inspired to invent a wide swath of powerful new reactions that made use of the asymmetric organocatalysis framework. Of course, all transformational scientific advances are built upon the foundations of their forebears, and the field of asymmetric organocatalysis is highly indebted to the many outstanding chemists who have made fundamental contributions in adjacent areas of catalysis. Without the discoveries of these pioneers, the field of asymmetric organocatalysis simply could not exist.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

As the field of asymmetric organocatalysis continued to grow, we also began to branch out in exciting new directions. Of particular interest to our group, from a sustainability standpoint, was the possibility of merging multiple organocatalytic reactions together within a single reaction vessel as a way to quickly—and with minimal waste—build up a high degree of chemical complexity from simple starting materials.

This general strategy, which we termed cascade catalysis, would actually emulate the way that Nature makes complex molecules. In Nature, simple building blocks are shunted through a biochemical assembly line wherein each enzyme catalyzes a distinct reaction in a controlled sequence to quickly generate complex end products.

Of particular interest to our group, from a sustainability standpoint, was the possibility of merging multiple organocatalytic reactions within a single reaction vessel…This general strategy…we termed cascade catalysis.


Our analogous cascade catalysis strategy, which used simple organocatalysts in place of Nature’s enzymes, proved highly effective. In a key demonstration, we accomplished a rapid total synthesis of strychnine, a naturally occurring molecule that is also commonly used as rat poison.


This central complexity-building transformation was accomplished in a single reaction vessel, as a very simple starting material was fed through three consecutive organocatalytic cycles, each of which added an element of complexity to the molecule, to generate a highly elaborated end product.


This product was easily converted to strychnine, allowing us to achieve a rapid synthesis of this challenging natural product in just twelve steps from commercially available starting materials. Cascade organocatalysis has since been further validated as a sustainable, waste-efficient, and highly economical strategy for building complex molecular architectures.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS


In 2007, Teresa Beeson, an outstanding third-year graduate student in my lab, developed a novel mode of asymmetric organocatalysis, which we termed SOMO catalysis. This would ultimately launch our research group into some really exciting new directions, culminating in the development of a new type of sustainable catalytic platform that combines organocatalysis with visible-light catalysis. This new area, called photoredox catalysis, was first demonstrated by an excellent postdoctoral researcher in my group, Dave Nicewicz.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

The ability to merge organocatalysis with visible-light catalysis represented an extremely important advance, and over the past fourteen years, photoredox catalysis has matured into an important field of research in its own right. In fact, today, the field of photoredox catalysis is as influential as the field of organocatalysis, and I feel very fortunate to have been deeply involved in the conceptualization and advancement of both of these crucial areas.

Organocatalysis and Society

I am proud of the ways in which asymmetric organocatalysis has influenced the field of synthetic organic chemistry over the past twenty years. The impacts of organocatalysis can also be felt beyond the confines of the academic research community. In industrial settings, where environmentally responsible practices are emerging as a major corporate priority, organocatalytic processes are particularly appealing, as they are sustainable and remove the need to employ costly, toxic, and nonrenewable metals. As such, organocatalytic solutions are increasingly applied to modern, large-scale industrial processes.

In industrial settings, where environmentally responsible practices are emerging as a major corporate priority, organocatalytic processes are particularly appealing, as they are sustainable and remove the need to employ costly, toxic, and nonrenewable metals.

Today, bulk-scale organocatalysis is used in the environmentally friendly synthesis of scented fragrances, particularly those manufactured by the Swiss company Firmenich.


Organocatalysis has also found application in the recyclable plastics economy. For example, Prof. Bob Waymouth of Stanford University and Dr. James Hedrick of IBM have developed organocatalytic processes that break down polymers to their component monomeric building blocks. Since these monomers can then be transformed back to polymers, such organocatalytic processes have the potential to render plastics completely recyclable and sustainable. Needless to say, the widespread adoption of such technologies would have an enormous impact on our oceans and other threatened ecosystems.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

Perhaps not surprisingly, asymmetric organocatalysis has been heavily adopted across the pharmaceutical industry, where the need to access single-mirror-image versions of medicinal molecules is paramount. Merck’s chronic migraine drug, Telcagepant, for example, is manufactured using asymmetric organocatalysis techniques developed in our laboratory.

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

Beyond industrial applications, organocatalysis has influenced our broader society in somewhat surprising ways. It turns out that organocatalysis has played an important role in democratizing the field of chemistry. Organocatalysts are inexpensive, and organocatalytic reactions can be carried out under atmospheric pressure without special equipment. For that reason, organocatalysts are uniquely accessible to scientists and educators around the world.  

©David MacMillan/HJIFUS
©David MacMillan/HJIFUS

Across the globe, students and researchers have the unique opportunity to gain hands-on experience in cutting-edge asymmetric organocatalysis technologies and, perhaps more importantly, to make their own innovative contributions to this field of research, regardless of the financial and instrumental resources available to them.

The accessibility and ease of use of organocatalysis stands in stark contrast to many other modern synthetic methods, and the implications of this democratizing effect are exciting to consider. I would argue that the next revolutionary advances in organocatalysis will emerge not from the most well-resourced labs but from those researchers who have the best and most creative ideas.

The Future of Catalysis

I am often asked what the future holds for organocatalysis. I do not have an answer to that question, but I know that we must provide for our expanding global population in environmentally responsible ways. I believe that the solutions to many of our most pressing challenges will depend upon scientists’ ability to develop powerful and sustainable catalyst systems. These solutions will include organocatalysis and biocatalysis, but they will also include emergent sustainable technologies, such as photocatalysis and electrocatalysis.


Prof. MacMillan is the James S. McDonnell Distinguished University Professor of Chemistry at Princeton University. He shares the 2021 Nobel Prize in Chemistry with Dr. Benjamin List for the “development of asymmetric organocatalysis.”


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