Catalysis is common across industries, and it is estimated that over 90 % of commercial goods are made using catalysts during some point of their manufacturing.

For a process that is so widely used, you might still have some questions but not to worry, we have some answers.

Understanding Catalysts and Catalysis

1. What Are Catalysts?

Catalysts are substances that help reactions (influencing the rate or the outcome) without getting consumed or incorporated into the product. They can help speed things up, but they can also help when different conditions are needed such as a lower reaction temperature.

A majority of SiliCycle’s customers use transition metals as catalysts in the form of organometallic complexes, i.e., compounds with a carbon-metal bond. Some popular ones are copper, ruthenium, and of course palladium.

Since the catalysts are not consumed by the reaction, they must be eliminated otherwise to conform to regulations.

2. What Is Catalysis?

If catalysts are what helps the reaction move along, catalysis is the process of using a catalyst. Catalysis is one of the principles of green chemistry. In general, increasing the amount of catalyst does not significantly affect the reaction. For this reason, they can be used in “catalytic amounts” instead of “stoichiometric amounts”.

3. Why Do We Use Catalysis?

Many transformations of chemical functions cannot be achieved without catalysts. For example, without using transition metal catalysts, the formation of carbon-carbon bonds on aromatics can be difficult, if at all possible.

Some of the frequent cross-coupling reactions necessitate metal catalysts. Among these well-known reactions, examples of Suzuki-Miyaura, Direct Arylation, Sonogashira, Kumada, and Buchwald-Hartwig are presented below (question 8).

Catalysts give access to molecules that cannot be otherwise synthesized.

4. How Do Transition Metal Catalysts Work?

When it comes to metal catalysts, the empty d-orbitals of the metals allow them to bond reversibly with functional groups. This opens the door for reactions that were previously difficult or unobserved. The electropositive nature of the metal influences the reactivity of the catalyst.

When looking at a chemical process, focusing on the catalyst versus focusing on the reactants and products can be very different. Having the catalyst in mind, the linear reaction between a reactant and a product becomes more like a cycle. Throughout the reaction, the catalyst is modified before going back to its original structure.

During the catalytic cycle of a cross-coupling reaction, the same transformations happen to the catalytic complex: oxidative addition, transmetalation, and then reductive elimination.

During the oxidative addition, the metal complex inserts itself into a covalent bond with one of the reactants.

In the example pictured, the palladium (attached to the first reactant from the oxidative addition step) will bond with the other reactant during the transmetalation step.

Then, the reductive elimination is the opposite of the oxidative addition, the metal is eliminated from the covalent bond, leaving a covalent bond now linking the two reactants. Cross-coupled.

5. How Much Catalyst Do You Need?

Catalysts are used in, wait for it, catalytic amounts. However what that means depends on many things, including the reaction type and the catalyst used.

Palladium catalysts are the most common for cross-coupling reactions. Other metals might be more abundant than palladium (so easier to source), but often not as efficient. Then, larger quantities (but still catalytic ones) are necessary.

Various research is conducted to reduce the dichotomy of using either very effective palladium catalysts in extremely small loadings, or the less-efficient-more-environmentally-friendly other abundant metals (i.e., nickel, copper, etc.). In some cases, higher catalyst loadings of the other metals will be needed to get the same efficiency, which increases the residual metal contamination in the final products.

6. When Are Catalysts Used?

Catalysts are used all the time. In the lab, they are especially useful for coupling reactions: for the synthesis of Active Pharmaceutical Ingredients (API), for polymerizations, etc. There are also natural catalytic processes occurring in our bodies daily. These involve biologic catalysts like enzymes, not organometallic ones. Unless you are an android...

7. What Are the Drawbacks of Using Metal Catalysts?

Since the metallic catalyst is not consumed in the reaction, residual metal can find its way in the final product. Such residual metals usually want to be avoided.

On the other hand, without the metal catalyst, the final product might not even be attainable. Metal scavengers remove residual metal impurities, making the catalytic reaction followed by a scavenging treatment the best option to complete the total synthesis of the desired product free of undesired impurities.

Fortunately, most metals used in catalysis can be scavenged by SiliaMetS Metal Scavengers. (Check here for help selecting a Metal Scavenger)

8. What Are Common Cross-Coupling Reactions and their Clean-Ups?


One of the most common cross-coupling reactions, Suzuki-Miyaura, is used for the coupling of aryl halides with aryl boronic acids. Different palladium sources can be used as catalysts, and Pd(PPh3)4 is among the frequent ones employed. But residual palladium can find its way in the crude product and needs to be removed.

In two Application Notes (EP001-0 and EP002-0), the E-PAK technology was used to remove residual traces of the Pd(PPh3)4 catalyst for two examples of Suzuki cross couplings. Let’s explore the two Suzuki reactions and their clean-ups.

For the Suzuki coupling featured in the Ceritinib synthesis (below), SiliaMetS Thiol and DMT proved to be best scavengers for Pd scavenging in this Suzuki coupling in bulk while SiliaMetS DMT was the most efficient in E-PAK mode.

In a model reaction used in the synthesis of the kinase inhibitor AKN028 (below), treatment with SiliaCarb C-CA first decreased the Pd level. SiliaMetS Imidazole proved to be the most efficient scavenger to remove up to 95 % of the remaining Pd. The optimized conditions were transferred to E-PAK SiliaMetS Imidazole, providing similar results.

Direct Arylation

Direct arylation is an alternative to Suzuki cross-coupling that circumvents the need of boronic acid derivatives, while still using palladium as a catalyst.

Helal et al. synthesized the analog PF-05180999, a preclinical candidate targeting cognitive impairment associated with schizophrenia by C-H arylation. 1

It was found that C-H arylation chemistry was superior to Suzuki coupling for heteroaromatic derivatives, likely due to the instability of the required heteroaryl boronates. SiliaMetS Thiol was used to remove palladium from the crude product.

Direct hetero arylation polymerization is also a strong coupling strategy for the synthesis or conjugated polymers as demonstrated by Imae, et al. 2

The Pd residues were removed with SiliaMetS DMT.


The Sonogashira reaction couples terminal alkynes with aryl halides by using palladium as a catalyst and copper as a co-catalyst. In the Application Note EP007-0 'Scaling up a Sonogashira Reaction with E-PAK'

SiliaMetS DMT is used to remove residual palladium (8,360 to 4 ppm) and copper (895 to < 5 ppm) for the product pre-treated with SiliaCarb C-VW.


Kumada cross coupling can be catalyzed by either palladium or nickel for the coupling of aryl and alkenyl halides.

In the Application Note EP005-0 'Efficient method for the removal of nickel with E-PAK', the product of a Kumada coupling was contaminated with residual traces of NiDPPPCl2 catalysts.

SiliaMetS Triamine and DMT gave the best scavenging results with a pre-treatment of SiliaCarb C-CA. The entire E-PAK process allowed to decrease nickel levels from 7,785 ppm to 41 ppm.

Buchwald-Hartwig Amination

Buchwald-Hartwig is a Pd catalyzed amination for the formation of C-N bonds, coupling amines with aryl halides, pseudohalides and aryl esters.

Vaidyanathan et al. have shown that zinc salts promote the Buchwald-Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1-H-azaindoles and 1-a-aryl-1H-azaindazoles (below). 3

SiliaMetS Thiol successfully removed traces of residual catalyst.

In another study, Caille et al. developed a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale featuring a Buchwald-Hartwig amination using BrettPhos as a ligand. 4

After the screening of potential scavengers, SiliaMetS Thiourea was selected as the scavenger of choice. It afforded product in 90 % with less than 2 ppm of residual Pd.

Another kilogram scale Buchwald-Hartwig amination was conducted by Magano et al. (below). 5

The material was treated with SiliaMetS Thiol to produce the HCl salt with only 2 ppm of Pd.

There are examples in the literature where the palladium catalyst is promoted by a cocatalyst. For example, Li et al. used tin acetate (n-Bu2SnO) to promote Buchwald-Hartwig couplings of heteroaromatic amines (below). 6

The desired product was obtained with 1,530 ppm of tin, which was reduced to less than 20 ppm by treatment with SiliaMetS Cysteine or TAAcONa. The isomeric purity remained unchanged after the scavenger treatment.

9. How Green Is Catalysis?

We already discussed that catalysis is one of the principles of green chemistry. But it is more than that. It also contributes to the prevention principle of green chemistry stating that it is better to prevent waste than to treat the waste after it was created; using catalytic amounts means there is less waste created in the process, so less waste to treat afterwards.

Catalysts influence the course of an organic reaction by

  • Finding an alternative reaction pathway ;
  • Orienting the molecules in such a way that it maximizes the probability of collisions ;
  • Temporarily bounding to the molecules, hence forming an intermediate that has a lower activation energy.

These processes mean that the activation energy of a synthetic step is lowered, which may contribute to

  • Atom Economy ;
  • Less Hazardous Chemical Syntheses ;
  • Energy Efficiency Design.

All of which are principles of green chemistry. This happens when the unique way the catalyst works allows an overall simpler pathway for the total synthesis (on top of the principles of catalysis and prevention).

Among the different ways to make a reaction more efficient and environmentally friendly, changing the catalyst or reducing the amount of catalyst used are possible solutions. Some catalysts are made of more abundant metals, making them more environmentally friendly to use. On the other hand, using a very efficient catalyst that requires very little loading but is made of less abundant metal could still be environmentally efficient if using very little loading.

Bonus Question: Where can I get chemical catalysts?

Finding the right type of catalyst is important. You may need to hunt around for the best ones. A comprehensive source of organometallic complexes is offered by eMolecules, a chemical search-and-fullfillment platform often used by drug discovery researchers that aggregates and sells commonly-used and hard-to-find chemical structures from a global network of chemical vendors, so finding what you need is made a little easier. eMolecules has over 9.5k transition metal-based compounds in its database from over 85 suppliers.



1 Helal, C. et al. J. Med. Chem., 2018, 61, 1001-1018
Research API, Pfizer Global Research & Development, Connecticut, United States

2 Imae, I. et al. RSC Adv., 2015, 5, 84694-84702
Hiroshima University, Hiroshima, Japan

3 Vaidyanathan, R. et al. J. Org. Chem., 2017, 82, 7420-7427
Chemical Development and API Supply, Bristol Myers Squibb Research and Development Center, India

4 Caille, S. et al. Org. Process Res. Dev., 2015, 19, 476-485
Amgen Inc., Thousands Oaks, California

5 J. Magano et al., J. Synth. Commun., 2008, 38, 3631-3639
Pfizer Global Research and Development, Connecticut & Michigan, United States

6 Li, X. et al. Org. Process Res. Dev., 2017, 21, 1653-1658
Process Development & Process Chemistry, DOW AgroSciences, Michigan & Indiana, United States

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Eliane, M.Sc

Eliane is the Scientific Content Specialist here at SiliCycle, with years of experience both in the lab and client support. She studied at Laval University, for both her Bachelor’s and Master’s in Chemistry. In fact, her thesis was in organic electronics in which purity is of the utmost essence, making her in-tune to the purification needs of chemists.