Abstract
Palladium-catalyzed reactions are among the most commonly used procedures in organic synthesis. The products have a range of uses, including as intermediates in total synthesis and as screening compounds for drug discovery or agrochemical projects. Despite the known and potentially deleterious effects of low-level metal impurities in biological assays, the quantification of metal remaining in reaction products to verify the effective removal of the transition element is rarely reported. Using palladium as an exemplar, we describe a pilot study that for the first time quantifies residual metal levels in reaction products following increasingly rigorous purification protocols. Our results demonstrate that significant levels of residual palladium can remain in isolated reaction products following chromatographic purification, and only by using a subsequent metal scavenging step are they reliably reduced to a low level. Finally, we provide a set of simple guidelines that should minimize the potential for issues associated with residual palladium in reaction products.
Highlights
Palladium-catalyzed reactions are among the most commonly used procedures in organic synthesis
Whereas it is usually straightforward to quantify impurities that are present at higher levels (1−5 mol %) using conventional techniques such as nuclear magnetic resonance (NMR), trace-level impurities (
This is surprising given the frequent use of transition element catalysis,[18−22] along with recent notable examples where the presence of trace impurities has proven problematic.[23−26] The deleterious effects of trace-metal impurities on high-throughput screening (HTS) readouts are well described.[27−31] The fact that assay interference can occur during lead optimization seems unappreciated,[15,32] and aside from process development chemists,[33−39] few chemists publish proof that their reaction products are metal-free (Figure S1 and Tables S1 and S2).[40]
Summary
The experimental protocols, workup, and isolation procedures for all reactions were standardized during this study and were based on described procedures. (See the Supporting Information.) Reactions were conducted by different chemists drawn from a team of six, each having ∼5+ years of synthetic experience following a chemistry degree or equivalent to best mimic real-world project conditions. Maria Chatzopoulou − Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom; Present Address: UCB Biopharma U.K., Slough, U.K; orcid.org/0000-0003-1886-7705. Madden − Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom; Present Address: Department of Chemistry, Newcastle University, U.K. Liam J. G. Galan − Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom; Present Address: Evotec (U.K.) Ltd., Abingdon, U.K.; orcid.org/0000-0002-6241-0238. Notes The authors declare the following competing financial interest(s): G.W. and A.J.R. are minor shareholders of OxStem Limited (U.K. company number 07711860)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
