In drug discovery, chemodivergent reactions have recently attracted great interest because of their involvement in the synthesis of libraries of small molecules. The concept of diversity-oriented synthesis relates to the selective formation of various well-defined products from only one readily available starting material. This can be achieved by steering the reaction’s selectivity through fine-tuning of the catalyst, solvent or reactions conditions. In the past years, several chemodivergent approaches have been developed to create molecular diversity from common starting materials, However, it still represents a challenge as the existing methods generally involve the use of different catalysts or drastically different reaction conditions.
In this light, a recent article published in ACS catalysis from a collaboration between the groups of Haijun Jiao and Mathias Beller (DOI: 10.1021/acscatal.0c03614) reports the development of a palladium catalyst performing either the hydroformylation or the semi-hydrogenation of alkynes in nearly equal conditions. The outcome of the reactions could be easily switched by changing the the acid cocatalyst used. In the catalyst, the palladium is bearing a pyridylphosphino ferrocene ligand which appeared essential for the observed behavior. A very detailed mechanistic study unraveled the origin of this unusual product selectivity, showcasing that the pyridyl group on the ligand acts as a proton shuttle during both reaction mechanisms. Furthermore, a combination of DFT and experimental evidences could further highlight the exact role of the acid cocatalyst in directing the reaction toward hydroformylation or semi-hydrogenation.
Initial studies and conditions optimization
The authors initially intended to explore the reactivity of a series of palladium catalysts into the hydroformylation of alkynes. The palladium catalysts tested were previously developed for the reaction of alkoxycarbonylation and for which it was already demonstrated that the pyridyl group in the ligand acts as a built-in base, influencing the selectivity of the reaction. For the preliminary studies, diphenylacetylene was used as model substrate to produce the corresponding α,β-unsaturated aldehyde. Interestingly, the authors observed during a series of initial experiments that, using the pyridyl-based palladium catalysts, the hydroformylation was occurring in high yield and high selectivity (up to 92% yield, selectivity of 94/6 aldehyde/alkene) and outperformed the catalyst systems that lacked the pyridyl group. The unusual switch in the catalyst behavior was found when the various acids having different pKa’s were tested. Surprisingly, the use of of triflic acid as cocatalysts induces a complete switch in the product selectivity selectivity from aldehydes to the formation of the trans-alkene product, (yield (98%) and a high selectivity (E/Z>99/1)). Interestingly, no over-reduction to the alkane product was observed, which is normally a common side-reaction occurring in the hydroformylation of alkynes.
Influence of the acid on the chemoselectivity
Next, the effect of the acid on the chemoselectivity was studied by performing the reaction with different acids and at different loading. For all tested acids, the modification of the acid loading shows a similar effect: at low acid concentration, the aldehyde product is formed while at higher concentration the yield of alkene increases (and the yield of aldehyde decreases). The experiment also shows that the acid with the strongest pKa, triflic acid, clearly leads to the formation of alkene while the acid with lowest pKa, CF3COOH, leads to the aldehyde product. Interestingly, a kinetic study performed with triflic acid as cocatalyst shows that, during the reaction, the Z-alkenes is formed initially, which then slowly isomerizes into the E-alkene, ultimately leading to the observed high E-selectivity. Further experiments were performed to understand the equilibrium between the Z and E products, showing that during isomerization, the β-elimination into E-or Z-alkene is faster than the reductive elimination, hence restricting the alkane product formation.
In depth mechanistic study: DFT and kinetic experiments
The origin of this change in chemoselectivity was thoroughly investigated by performing control experiments, kinetics and extended DFT studies for both catalysts (with and without pyridine group in their ligand structures). The catalyst lacking the pendant pyridyl group behaves according to the well-established palladium-hydride route which was taken as a reference for this study. The various possible mechanistic pathways for the base-containing catalyst were calculated to evaluate the role of the pyridine group. From the extended DFT studies, it was concluded that the presence of strong acid lowers the barrier of hydrogenation and raises the barrier of hydroformylation to a large extent, which ultimately results in a chemoselectivity switch. To illustrate this, the authors proposed two interconnecting catalytic cycles, which share a common palladium(alkenyl) species which can either react with the strong acid to enter the semihydrogenation route or can react with CO to enter the hydroformylation route. For both routes the pendant pyridine group is involved in the hydrogen activation.
Finally, an extended substrate scope for both the hydroformylation and the hydrogenation of alkynes was performed, showing the great applicability of this method to the synthesis of a very large range of products from a single starting material.
From this study appears several interesting points. First, this paper highlights that the design of catalysts is crucial in the development of new synthetic tools, notably to create diversity in the available building blocks librairies used in drug discovery. This paper also reflects the power of a screening approaches in finding unusual reactivity. We hope this work will encourage other groups to explore new efficient and sustainable methods of synthesis.
About InCatT (www.incatt.nl): InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical and Bulk chemical industry to solve their most challenging projects.
Article: “Tuning the Selectivity of Palladium Catalysts for Hydroformylation and Semihydrogenation of Alkynes: Experimental and Mechanistic Studies”
By: Jiawang Liu, Zhihong Wei, Ji Yang, Yao Ge, Duo Wei, Ralf Jackstell, Haijun Jiao and Matthias Beller
ACS Catalysis 2020, 10, 12167−12181