Roundtable Review

Cross coupling: The Palladium Solution
Posted 21 June '13

What is Cross Coupling?

Carbon is the most abundant element in the chemical composition of organic matter. Stability is the boon and bane of carbon structures: once made, they can persist for a long time, but it is hard to persuade them to break old bonds in favour of new ones. Chemists have long been interested in reactions that build carbon-carbon bonds as these allow them to build new molecules to their liking.

Valsartan, anti-hypertensive drug. Biaryl in red. Bold red bond made by cross coupling.

Valsartan, anti-hypertensive drug.
Biaryl in red. Bold red bond made by cross coupling.

A number of Nobel Prizes have been awarded to chemists who found new ways to make carbon-carbon bonds. The latest Nobel Prize in Chemistry for carbon-carbon bond forming reactions was awarded in 2010 to three of the developers of a palladium-catalyzed reaction called ‘cross coupling’.

Cross coupling reactions are used to make interconnected, cyclic (aromatic) structures called biaryls, from the connection of two, aromatic hydrocarbons, also called arenes. These structures are an intrinsic part of many bioactive molecules like Valsartan, a drug used to treat high blood pressure with global sales of about $4 billion . Before cross coupling, Valsartan and similar compounds were difficult to make, but with a handy palladium catalyst, we can now easily produce not only drugs, but also agrochemicals and functional materials.

How does it work?

Catalytic Cycle of the palladium-catalyzed cross-coupling reaction

The catalytic cycle of palladium (Pd) in the cross coupling between two arenes (Ar).

Catalysts are usually used in tiny amounts compared to the molecules they transform as they are not actually consumed during the reaction. The small (catalytic) amounts necessary make modern cross coupling reactions versatile and economic. If the same number of palladium and substrate molecules had to be used, cross couplings would probably be too expensive to ever succeed on an industrial scale as pure palladium costs approximately $60 per gram. Not cheap!

In metal catalysis it’s all about balance. Palladium perfectly balances stability and lability when it comes to forming bonds with carbon. The metal has to be able to bind the substrate in order to act upon it, but it also needs to be able to depart from it after the reaction and return to its original state in order to bind to a new substrate molecule. This is the reason palladium is superior to nickel or (platinum) equivalents. Their bonds are either too unstable or too stable to establish an efficient catalytic cycle.

In coupling reactions it is important to distinguish between homocoupling, meaning reacting two of the same molecules together, and cross coupling, meaning reacting two different molecules. A catalyst, thrown into a mix of two different molecules, needs to be able to distinguish between the two types of molecules in order to produce the desired cross coupling event over the generally undesired homocoupled product.

 

What’s the story?

The remarkable discovery of palladium’s cross coupling catalyst potential didn’t even start with the famous metal itself, but with copper.  In the beginning of the 20th century, a chemist called Fritz Ullmann found that copper, when used in stoichiometric amounts, could mediate carbon-carbon bond formation. His reactions, despite having a bad reputation for being non-reproducible or resulting in erratic yields, held a twist that later became important for cross coupling reactions. Prior to this, chemists had  performed carbon-carbon bond-forming reactions on ‘unfunctionalised molecules’. This means, the reacting carbon atoms didn’t have any special substituents but were only bonded to other carbons and hydrogens. Ullmann put a halogen substituent (e.g. chlorine, bromine) in place where he later wanted the new carbon-carbon bond to be, introducing the concept of pre-functionalisation.

Pre-functionalisation in palladium-catalyzed cross coupling

The concept of pre-functionalisation.
The blue arene is functionalised with a halide (chloride Cl).
The red arene is functionalised with a metal (zinc Zn).

Modern cross couplings are based on this concept: both coupling molecules are pre-functionalised in a way that makes them easily distinguishable for the catalyst, producing almost exclusively the cross coupling product. This is usually done by functionalising one coupling partner with a halogen and the other with a metalloid or main-group metal.

Palladium is a relatively ‘young’ element compared to copper, cobalt or nickel. Discovered as a new element in 1804, it was thought to be a useless oddity at that time. Its discoverer, the London Chemist William Hyde Wollaston, had a hard time even proving that he found a new element and that it wasn’t merely an alloy of other, already known metals.

In the late 1950s, the later-to-be Nobel Prize winner Richard Heck set out to study the mechanism behind the then recently discovered palladium-catalyzed reaction.  What he found during his investigation was one of the first palladium-catalyzed cross couplings. His series of breakthrough communications in 1968 was followed by renewed interest in cross coupling reactions and opened the gates for a flood of new processes, concepts and ideas.

By 1975 palladium’s role as a flexible and handy catalyst for a multitude of carbon-carbon bond-forming reactions had been firmly established. Negishi and Suzuki published their respective ideas on the subject in 1976 and 1979, promoting the use of easy-to-handle organometallic coupling partners in the form of organozinc and organoboron reagents. After that, researchers went about to refine existing reactions, aiming for ever lower catalyst loadings; milder conditions, meaning lower reaction temperature or ‘greener’ solvents like water; and higher scope towards both coupling partners.

 

Where do we go from here?

Cross coupling is now an established process both in industry and in chemical research labs. Despite tremendous advances made since the golden age of cross couplings, there are still questions to solve, improvements to be made.

From cross coupling to C-H activation: what palladium can do

C-H activation (top) vs classic cross coupling (bottom): What palladium can do.

In an ideal world, one could take any two carbon-containing molecules and, with the right catalyst, selectively break and form new bonds on one particular, unfunctionalised carbon. However, not having pre-functionalisation in one or both coupling molecules leaves a major problem: which of the carbon atoms are going to react if none of them are distinguished from the others ones in the molecule, i.e. carrying a particular substituent?

There’s a plethora of research going on in an exciting area called: C-H activation. The idea is to eliminate pre-functionalisation and instead use the unfunctionalised compounds to substitute either or both pre-functionlised coupling partners. This would make the overall process cheaper and greener, as pre-functionalising a molecule often requires several reaction steps, consumes time and resources, or results in toxic waste products. Fantastic advances have been made in the last twenty years in this area, particularly in replacing organometals.

History is repeating itself while chemists now turn their gaze beyond palladium, looking at the abilities of other metals as potential candidates for the ultimate super-selective, active, economic, and ecologic catalyst.

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