The people at Dart NeuroScience and Accela ChemBio have been treating us to a true laboratory poison mystery in the latest OPR&D (DOI). Who said that commercial organic chemistry could not be fun? Making money and do science! An otherwise unremarkable Suzuki reaction (coupling two aryls together with palladium) suddenly failed just when upscaling from a one kilogram batch to a 6 kilogram batch (academics, say those words aloud: 6 kilo-gram batch).
After eliminating the usual suspects (water, air, additives) it was down to a nicotinate precursor (street name: methyl 5-bromo-6-chloro-nicotinate ) to to take up the butler role in this Suzuki murder drama by poisoning the palladium acetate catalyst. But in the initial NMR / HPLC-MS / CHN elemental analysis interrogations the compound came up clean leaving the investigators empty handed. It must be said the probe was sabotaged by the shady vendor of said nicotinate: he refused to disclose its origins. Pressing it a bit further (torture?) he did make one confession: thionyl chloride was used in the manufacture, giving the researchers a vital clue: sulfur!
But spiking a batch with thionyl chloride itself did not do anything. The purification process took care of this intruder. Then the researchers turned their gaze on mother liquor...From a nearby precinct ICP-OES was summoned and yes: after concentrating and recrystallisation from hexane there was lurking just below the sulfur detection limit of ordinary machines like elemental analysis: 0.13% of sulfur. But again no signals from NMR / HPLC-MS / elemental analysis! What was this, something alien? Exhausted, the researchers turned to GC-MS who finally delivered clue number two: it was elemental sulfur (street name: S8). That evening, drowned out by the cheers of celebrating chemists, humble TLC complained he had arrived at that conclusion already on day one by matching the Rf value of a suspicious blot to S8s mugshot. If only anyone had listened.
But then were did S8 come from? It was eventually traced back to some illicit going ons between thionyl chloride and the solvent DMF somewhere upstream in the synthetic pipeline. Incidentally a reaction that was catalysed by pyridine-like compounds. Unlike thionyl chloride, S8 did manage to evade all detection attempts and purification elimination rounds and thus was able turn an ordinary Suzuki reaction into a crime scene.
In the end the researchers came up with a sulfur-free nicotinate and demonstrated a reaction to completion with just 0.02% catalyst loading. Case closed!