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Multidimensional thinking: Exploring Chemical Space to Optimize Reaction Conditions and Boost Your Yield
Phosphine ligands and their subsequent metal complexes are synonymous with homogenous catalysis. The ability to tune a catalyst through the modification of the steric and electronic properties of its respective phosphine ligand is highly advantageous and as ligands, their effectiveness is evident through their wide-spread use in academia and industry.1,2
When trying to decide what phosphine ligand to use in your catalytic reaction, you may ask “what is the most efficient way to screen my ligand library?”
Techniques such as high throughput are becoming more commonplace in chemistry, with the shift towards automation and digitalization, but what does that mean for us in the laboratory? Herein, we use the example described by Allen et al.3 to take a brief look at how the use of high throughput differs from traditional reaction optimization.
Figure 1 - Reaction scheme - palladium-catalyzed carbonylative esterification
When faced with the target transformation, shown above, we have multiple options including solvents, bases and importantly, the ligand on our palladium catalyst. Traditionally in the laboratory, we keep all conditions the same, changing one variable at a time. This method was used in the case of this reaction; the results of which are tabulated below.
Table 1 - illustrates the process of exploring the impact changing the phosphine ligand on the palladium catalytic center has on yield, using the traditional technique of changing one parameter at a time.
As shown in table 1, the first 16 experiments examined which phosphine ligand would be the most effective. Xantphos, experiment 16, gave the highest yield with 81%. From here, the lab chemist would make the assumption that Xantphos was the best candidate and start to change other parameters, such as the base and solvent (experiments 17 -21). However, this is linear thinking and does not consider that the variables are interdependent.
High throughput allows the reaction to be explored in a multidimensional way. Below, in table 2, the team3 illustrates the results obtained using high throughput. This shows that in fact the best ligand in this case was dcpe (1,2-bis(dicyclohexylphosphino)ethane), when toluene is used as a solvent with potassium carbonate as the base. Without high throughput the chemical space would not have been fully explored and the optimal conditions would not have been efficiently identified.
Table 2 - illustrates the use of high-throughput to screen multiple reaction conditions. (Conditions from left to right are: Solvent - Acetonitrile, Base - DIPEA, K2CO3, KOAc; Solvent - Toluene, Base - DIPEA, K2CO3, KOAc.) The success in terms of yield is represented by the color gradient - red is 0% conversion, yellow is 50% and green is 100%.
“New” techniques such as high throughput is optimizing the way we do chemistry. Many laboratories are investing in this area, however for companies or institutes without these capabilities, there are a number of partners with whom you can collaborate, such as Solvay’s Laboratory of the Future. Looking more specifically at phosphorus chemistry, the Strem Catalog, in partnership with Solvay, is well-placed to provide a wide phosphine ligand library for exploration in your reaction.
Some ligand candidates to consider are depicted below in Figure 2. These include CYTOP® 216X (Strem Catalog: 97-1310), which can be utilized in cross-coupling reactions (DalPhos ligand family); adamantyl based functional group alternative CYTOP® 282T (Strem Catalog: 15-7535); CYTOP® 242T (Strem Catalog: 97-1044), a ligand that can be used in Suzuki-Miyaura cross coupling reactions; CYTOP® 241 (Strem Catalog: 97-1030), a versatile building block for catalysis applications; and finally CYTOP® 266 (Strem Catalog: 97-1120) which can be used in the synthesis of dcpe.
Figure 2 - Showcases a few examples of possible ligands you could explore.
Explore the Strem Catalog for phosphine ligands, today, and read more about phosphines in catalysis on the Strem blog.
References:
Featured Products
97-1310 2,4,6-Trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane (~32% in xylene) [CYTOP® 216X ORGANOPHOSPHINE] (26088-25-5)
97-1044 Di-t-butylphosphine (50% in Toluene) [CYTOP® 242T ORGANOPHOSPHINE] (819-19-2)
15-7535 9-Phosphabicyclononanes in toluene, mixture of isomers, CYTOP® 282T (13887-02-0)
97-1120 Dicyclohexylphosphine, 98% [CYTOP® 266 ORGANOPHOSPHINE] (829-84-5)
97-1030 Di-i-butylphosphine, min. 97% [CYTOP® 241 ORGANOPHOSPHINE] (4006-38-6)
