PHARMACEUTICALS
Figure 2 - General structure of a YPhos ligand
Note : Where an aryl or alkyl substituent would normally be expected is the phosphine ligand as an ylide group ( coloured blue )
approach to catalyst lifecycles . Closedloop systems like Umicore ’ s ( Figure 1 ) offer an economic advantage , as the cost of recovering and processing existing palladium is lower than mining the metal .
Additionally , by using 100 % recovered palladium , companies can avoid the use of conflict material . By working closely with supply chain partners , manufacturers can implement effective precious metal recovery programmes , preserving scarce raw materials . And , as up to 80 % of precious metal value can be recovered , this reduces future catalyst spend .
Identifying ideal properties
In order to design and develop innovative and improved palladium catalysts , the target properties for cross-coupling catalysis must first be understood . Firstly , the efficiency of the catalyst can be measured by the turnover number ( TON ), the number of moles of substrate that a mole of catalyst can convert before becoming inactivated . The higher the TON , the more efficient the catalyst .
Catalysts should also endeavour to optimise the reaction conditions – ideally as close to room temperature and pressure as possible . Finally , a good catalyst will be relatively stable for reduced complexity in storage and handling .
Precious metal catalysis design is highly dependent on ligand selection . Ligands significantly impact the activation energy of a catalytic reaction , determining the temperature and pressure under which a reaction will occur . They also influence the selectivity of the reaction , improve the
solubility of metal catalysts in organic solvents for extraction and extend catalyst lifetimes by reducing the impact of degradation pathways .
Generally , the ligands chosen when designing palladium cross-coupling catalysts are sterically bulky and electron-rich . Sterically bulky ligands have two major advantages : they have increased selectivity , due to limited access to the metal centre , and provide additional structural support to the catalyst . Ligands that are electronrich increase the nucleophilicity of the palladium core , which in turn lowers the activation energy required for crosscoupling reactions .
Recent advances
In any industry manufacturers are constantly looking to improve sustainability , increase profit margins and alleviate time pressures . Focusing on the pharmaceutical pipeline , catalyst providers can support these goals by reanalysing traditional approaches and developing new solutions with green chemistry principles in mind .
One way in which researchers are looking to optimise cross-coupling catalysis is by improving the ligands within the catalytic systems . Brad Carrow ’ s group at Princeton University , US , synthesised tris ( 1-adamantyl ) phosphine ( PAd 3
). They found that , when associated with a palladium core , PAd 3 complexes catalyse Suzuki couplings with an exceptional TON of close to 20,000.1
The high efficiency demonstrated by the palladium complexes of these new phosphines allow for shorter reaction times , even without increasing the temperature of the reaction vessel . This enables a temperature range with higher flexibility for chemists to work within , thus allowing the reaction to be run at room temperature .
With milder conditions , the reaction now has increased compatibility with temperature-sensitive functional groups , which opens new greener syntheses for existing reactions and potential new pathways to form new products – making the PAd3 ligand a powerful tool for research chemists .
Additionally , recent work by Viktoria Gessner ’ s group at Ruhr University Bochum , Germany , showed how an understanding of structure-activity relationships , steric demands , and donor properties , can lead to more effective cross-coupling catalysis . By exploring new ligand structures and arrangements , Gessner and coworkers have discovered a class of ylide-containing phosphines they have termed the YPhos * family ( Figure 2 ). The ylide substituent provides strong electron-donating properties to the phosphorus donor site . The electron-richness of the YPhos contributes to a uniquely high activity in cross-coupling reactions , especially Buchwald-Hartwig aminations . Additionally , while ylides are known to be a highly reactive species , YPhos ligands tend to be stable when complexed with a metal , owing to additional reactions between the ligand and the metal species .
Outlook
As a universal tool in the pharma and fine chemical industry , the advance of palladium cross-coupling catalysis has the potential to create a real impact on the sustainability of pharmaceutical synthesis . As such , R & D teams are now leveraging the comprehensive understanding of this established field to design new , more efficient catalysts .
However , collaboration between academia , manufacturers and the wider supply chain will be vital as the pharmaceutical industry looks to enable greener drug discovery , development and manufacture . Considerations such as downstream processing and precious metal recovery are important areas for collaboration , to move towards a more circular and sustainable economy . ●
* Reference - YPhos is : a registered trademark of Umicore 1 : J . Am . Chem . Soc . 2016 , 138 , 20 , 6392 – 6395 ; https :// doi . org / 10.1021 / jacs . 6b03215
J j
Christophe Le Ret
GLOBAL MARKETING DIRECTOR
UMICORE christophe . leret @ eu . umicore . com www . umicore . com
32 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981