Two groups of researchers have recently reported a new light-powered method in which readily available chemical building blocks are coupled to produce useful complex molecules that cannot be easily found or made. Because these metal-catalyzed reactions require only visible light and mild conditions, they could be incredibly useful new methods for the cheap and environmentally friendly synthesis of pharmaceuticals and other valuable materials. 


Everything in the world around you (including the tea you are drinking, the ceramic mug from which you sip it, the fibers in the worn-in PJ’s you are wearing, and the detergent you used to wash them) is a complex assembly of infinitesimally small molecules. The structures and three-dimensional shapes of these individual molecules are responsible for the properties of the substance as a whole, including its material properties such as flexibility, temperature resistance, and durability, and its biological activity such as taste and smell, medicinal effects, and toxicity [1]. Many useful substances, like the cellulose in paper and cardboard, can be easily extracted in large quantities from biomass such as plant matter, algae, or yeast. However, many complex molecules, like the potent anti-tumor drug candidate discodermolide, cannot be isolated in useful quantities from natural sources. Still others, like the Teflon™ coating your favorite nonstick pan or the anti-influenza drug Tamiflu™, do not occur in nature at all and were invented entirely by chemists attempting to develop new substances with certain desirable properties [2].

Many organic chemists seek to develop practical methods to produce useful complex molecules that cannot be isolated efficiently (or at all) from other sources. This process of complex molecule synthesis stitches together simple materials through a planned series of transformations. Syntheses are designed to take place in the shortest possible sequence of steps, maximizing yield and purity as well as minimizing waste [3].

Figure 1 ~ A typical catalytic cycle in the synthesis of a complex molecule. A) A small amount of a catalyst converts a simple starting material into a more valuable product. B) Over the course of the transformation, the catalyst is regenerated, enabling it to repeat the process many times on a large amount of starting material.

Catalysis serves an important role in these syntheses because employing a catalyst can substantially minimize waste while enabling transformations that would not otherwise occur on a reasonable timescale (Figure 1A). By definition, catalysts are regenerated during reactions, so they can be used many times over; this process is represented as a catalytic cycle (Figure 1B) [4]. As such, in catalytic transformations, the starting material can be transformed into product by a much smaller amount of the catalyst, often minimizing the formation of unwanted byproducts typical of non-catalytic reactions. Furthermore, because the catalyst is only used in very small quantities, even expensive catalysts are not cost-prohibitive.

While organic synthesis has been revolutionized by the emergence of several modes of catalysis over recent decades, just this year two popular catalytic methods have been united to enable unprecedented, powerful chemical transformations. The combination of these two methods, cross coupling and photoredox catalysis, will facilitate the discovery and production of novel materials in a resource- and energy-efficient way.

Cross Coupling

The 2010 Nobel Prize in Chemistry was awarded for a catalytic method called cross coupling, which has matured since its conception in the 1970’s into a staple of complex molecule synthesis []. In a typical cross coupling reaction, a metal catalyst activates two different, initially inert starting materials, facilitating controlled formation of a new bond between them (Figure 2) [5,6].

Figure 2 ~A typical cross coupling catalytic cycle. In each round of the catalytic cycle, a metal catalyst stitches together two different starting materials. The reaction proceeds very efficiently if both starting materials are flat (having bonds to other atoms all aligned in a plane). If, however, the second starting material (blue) is tetrahedral (having bonds to other atoms extending in all directions), it can be difficult to activate. In these cases more reactive (potentially dangerous and cumbersome to work with) starting materials must be employed.


The advent of cross coupling methodology opened up a range of different ways to join molecules and fundamentally simplified the routes used in complex molecule synthesis. Cross coupling is now used in the discovery or production of many pharmaceuticals and remains a staple in the synthesis of organic materials used in solar cells and LEDs.

Although cross coupling has enabled unprecedented formation of challenging bonds, it is not failsafe. The success of a cross coupling reaction is highly dependent on the shape and location of the reaction site within the larger molecule. In particular, it can be difficult to trigger a reaction at an atom that is not in a flat area of the molecule, especially if that atom is in the middle of a strand of atoms rather than at the end of the chain. To overcome this obstacle, the second starting material (Figure 2, blue) must be highly reactive. In practice, such reactive starting materials can be difficult to handle. A reliable cross coupling method that could employ stable, conveniently available starting materials would provide a major advance for complex molecule synthesis. Fortunately, as we will see, some significant advances are well underway.

Photoredox Catalysis

Visible light photoredox catalysis is another recently developed method for forming chemical bonds. In this method, a metal catalyst absorbs light, such as that from a common household light bulb or even ambient sunlight, giving it the energy necessary to add or remove an electron from a starting material. This generates a reactive intermediate that can then undergo further reactions with itself or any other molecules that may be present. Photoredox catalysis typically allows chemists to avoid using the toxic reagents or harsh conditions that were historically required to generate some types of chemical bonds. Because photoredox catalysis simply harvests the necessary energy from light, it provides an environmentally friendly alternative to these traditional approaches [].

On its own, photoredox catalysis is fundamentally limited to a rather narrow range of starting materials—ones that can easily undergo the correct sequence of electron transfers. However, it has seen growing application when used in tandem with other catalytic methods. As we will see in the next section, these combined methods can modulate the reactivity of the starting materials to enable electron transfer and/or subsequent steps that would not have been possible with the photoredox catalyst alone [].

Tandem Photoredox Cross Coupling Catalysis

In back-to-back papers from the labs of Dr. Gary Molander, Dr. Abigail Doyle, and Dr. David MacMillan recently published in Science [9,10], two research teams independently reported the first applications of tandem photoredox cross coupling catalysis to overcome the difficulties of cross coupling in geometrically challenging starting materials [].

Both research teams used the same two catalysts that work together during the reaction: iridium for photoredox catalysis, and nickel for cross coupling catalysis. The iridium photoredox catalyst absorbs light, enabling it to remove an electron from one of the simple starting materials. This generates an unstable radical intermediate, which is immediately fed into a nickel-catalyzed cross coupling reaction (Figure 3, step 1). After one round of cross coupling has been completed (Figure 3, steps 2 and 3), the photoredox catalyst has an extra electron and the cross coupling catalyst is missing an electron. The two catalysts then swap electrons in order to start on another round of the reaction (Figure 3, step 4). Because the catalysts rely on each other twice in their epicyclic catalytic cycles, they remain completely in sync, avoiding potentially messy side reactions.

Figure 3 ~ Tandem photoredox cross coupling catalysis. In each round of the catalytic cycle, the photoredox catalyst (iridium = [Ir]) absorbs light, which then enables it to remove an electron from the starting material to generate an unstable radical intermediate. This intermediate is immediately captured by the cross coupling catalyst (nickel = [Ni]), circumventing the tricky step in the isolated cross coupling cycle. After the cross coupling is complete, the photoredox and cross coupling catalysts exchange an electron to return to their starting states and repeat the process on new starting material.


Tandem photoredox cross coupling allows the use of stable and readily available cross coupling partners without sacrificing the good reactivity typically seen only with less stable building blocks. The research teams employed diverse starting materials including amino acid derivatives, which are the building blocks of proteins and are easy to isolate from biomass.

This novel method utilizes mild conditions, easily obtained starting materials, and a simple light source, and may be readily adopted for synthesis of valuable products on a large scale (Figure 4). Furthermore, because these reactions require only visible light to generate the reactive intermediates, waste is minimal, making the procedure favorable from both an environmental and a cost perspective.

Figure 4 ~ Tandem photoredox cross coupling catalysis enables synthesis of valuable products. Even simple starting materials derived from biomass and petroleum can be converted into molecules with useful properties for applications in pharmaceutical and material development.


These reports are groundbreaking demonstrations of a potential solution to some of the current limitations in cross coupling. With further development, these methods could offer sustainable and environmentally benign routes to valuable complex molecules [8,11]. While only time will reveal the true impact of this method, it offers a promising expansion to the reaction repertoire used to prepare structurally diverse molecules to address unmet pharmaceutical needs.

C. Rose Kennedy is a Ph.D. candidate in the Department of Chemistry and Chemical Biology at Harvard University.


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One thought on “Light-Powered Construction of Valuable Molecules from Simple Chemical Building Blocks

  1. Very interesting – the idea that you can introduce light to combine molecules together will definitely help reduce the costs and upkeep for the pharmaceutical company. This means that companies that aid in the logistics of pharmaceutical companies will also be positively affected as well.

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