- Silvio Cornuto: Valeria Messalina Institute, UC Milan, Italy
- Alexander Thwacker: Organischmetallischchemieabteilung, Univeristät von Wankendorf, Germany.
- Henri de Pampelmousse: École de Chimie Banale, Gauloises Université, Brest, France.
- Aap Tsagay: Kuchu Chethay University, Bajoling, Bhutan.
- Günther Schlonk: Department of Pyrofrolics and Inorganometallics, University of West Failure.
We spent way too much time on this.
Specific: The Over Reaction is the most fiendishly complicated transformation in modern synthetic chemistry. It features nine discrete catalysts, visible light and electrochemical oxidation, which cooperate to convert obstannyl sulphosphoxides, aryl moronic esters, cumulenes, homopropargylic ethers and cyanodiazetidines into elseviammonium dismylatesin one step. The mechanism of this reaction has perplexed chemists since its discovery reaction in 2005. Now, for the first time, we propose a catalytic cycle for the Over Reaction.
The history of science is riddled with happy accidents.
Naturally, such occurrences are referred to as “serendipitous discoveries” rather than “lucky fuck-ups,” because it sounds more intelligent. Chemistry has seen its fair share of these stories play out: the discovery of iodine, mauve dye and penicillin are some of the more famous examples. Though our half-arsed search of the illiterature was inconclusive, we assume that the discovery of pyrrole was also accidental, as no sane individual would set out to work with such an obnoxious molecule.1 The Über–Furious–Bob–Paul–(and so on and so on)- Wang–Fukovski reaction is another such child of serendipity, more commonly referred to as “The Over Reaction” for the sake of brevity.2
In June 2005, Aggravated Professor Frank Furious was attempting to perform the hydrogenolysis of benzyl triflate 1. This molecule features both an obstannane group and a sulphosphoxide moiety, which while reactive, are typically stable towards hydrogenative conditions.3 Furious was observing a complete lack of reactivity, despite a literature procedure claiming to obtain 85% conversion in 15 minutes.4
Furious cranked the temperature and dialled up the H2 pressure, let the reaction run overnight and returned the next morning. Nothing. He consulted Dr Grundle’s paper, noticed that he’d claimed a 98% isolated yield, and snapped. One of Furious’ students recounts the events that followed:
‘Frank always had a case of nominative determinism, but this was next-level. He thundered “0.01% catalyst loading my arse” and upended a box of metal complexes and a fistful of sample vials into the flask. Then he threw a 9 V battery into the reaction mixture, squawking something about “electrocatalysis,” and connected the vessel directly to the H2 cylinder without a regulator, while humming the tune to Under Pressure. AsI was running for shelter, I saw him grabbing the UV lamp off the TLC box and strapping it to his flask: “visible light is piss-weak anyway, it can’t even give you cancer.” The last thing I remember was watching Furious flip a lab bench, shout “cock blaster” at his reaction and storm out the door. We didn’t see him for three weeks, and we were too scared of that reaction to go near it.’5
Frank returned from his impromptu stress-leave and disassembled his creation, which had miraculously remained intact. On discovering that none of his students had been in the lab during his absence, his ire was stirred to life once more, and he instructed Klaus Über to work it up as punishment. Über began this process by smashing the flask and recovering a charred black solid, which he placed in a ball mill for a week. The residue was extracted with DMSO and subjected to a medically inadvisable amount of chromatography. From the ashes of Furious Frank’s failure, Über isolated 17 mg of molecule 3, which he dubbed Phoenoxide A (Figure 2).6
Phoenoxide A was fully characterised, and its structure was assigned by X-Ray crystallomancy. It features the fused, polycyclic core of a class of molecules known as “Elseviamines,” so called for the tremendous difficulty encountered in accessing them.7 This difficulty is primarily associated with the pentavalent carbon centre at C5. These Elseviamines are a subset of the Pandammonium Alkaloids, a large and chaotic family of natural products.
The impact of this finding was obvious: Furious and Über had discovered a one-pot synthesis of Elseviamines. But there was a problem: neither of them could remember how. Frank’s vision was red-shifted at the time, and everyone else was running for cover. The subsequent carnage made it impossible to determine which catalysts Furious had added to the reaction. It took the Furious group three years to reproduce their original reaction, which they eventually managed in collaboration with nine different labs in 16 different countries (Figure 3A).8,9 The result was the longest named reaction in the IOUPAC Brown Book, which is catalytic in scandium, uranium, molybdenum, iridium, rhenium, copper, ruthenium, palladium, visible light, invisible light, and electrical current (Figure 3B). It is stoichiometric in tin, molybdenum and suffering, and is one of the least atom-economical reactions known.
Five years of painstaking mechanistic investigation by our group and our collaborators has resulted in the first tentative catalytic cycle for the Over Reaction (Figure 3D). Full experimental conditions are detailed in the electronic unsupported information.10
The Over Reaction is the coupling of an obstannyl sulphosphoxide 1 with a homopropargylic ether 4, a cyanodiazetidine 5, a cumulene 6, and an arylmoronic acid (pinacol ester) 7. The product of this unholy union is a highly substituted elseviamonium dismylate zwitterion.11 The reaction forms nine new bonds and five contiguous stereo centres. It is conducted under a high pressure of H2, with a 9 V battery functioning as both electrochemical oxidant and stir-bar. Yields are typically between 0.5 and 3%, rating between an 8 and an 11 on the Browning Index.12 The low yields of this transformation reflect both the horrendous inefficiency of the reaction itself, as well as the nightmarish workup. Most of the catalysts and their associated intermediates are completely incompatible, giving rise to a menagerie of side-products and off-cycle intermediates. Under the harsh reaction conditions, these undesirables breed and multiply until a material resembling brown coal is produced. The product is obtained by milling this deposit followed by Soxhlet extraction with refluxing DMSO.
Half of the periodic table is involved in the catalytic cycle of the reaction, but the first metal involved is scandium. This Lewis acid is complexed with a crown-of-thorns-ether to improve its solubility, and functions to both activate and moderate the promiscuity of the sulfoxide moiety throughout the reaction. A polyhydridic uranium complex (9) serves as a powerful reductant and as a shuttle for H2, which it uses to partially hydrogenate the aromatic ring of the obstannyl sulphosphoxide. The nitrogenous portion of the product is incorporated via a nitrinidinium radical cation. These fickle and fleeting intermediates are derived from the one-electron oxidation of nitrenes, which are themselves highly reactive. The only oxidant capable of such a challenging transformation is a photo-aroused perfluoridium cation [Ir]+*. The catalyst perfluoridium PF6 enters this state upon the absorption of a
photon of invisible light, and rips electrons off anything it can get its LUMO’s on. The parent nitrene must be trapped as a metal complex until this oxidation is performed, lest it become distracted and wander off. Molybdenum complexes are capable of stabilising them, provided that the Mo-bound ligand is itself a rock of stability. The Focker ligand has such stability, and thus MoFocker is a suitable nitrene transfer catalyst for this reaction.13 Rhenium possesses an affinity for the pi-systems of alkynes and serves to convert homopropargylic ether 16 into !, #- unsaturated carbene 17. Rhenimine B is a soluble rhenium source, supplied as a single enantiomer for purely decorative purposes.14 Pendant isopropyl groups adjacent to the imines shield the metal centre from rapacious solvent molecules, preventing decoordination and rhenial failure. The Thwaker Reagent [CuHL] is a mild hydride source, selective for cyclopropanes. The ring-closing olefin-metathesis step of the catalytic cycle is sterically demanding, and requires a highly active catalyst. Grubbs’ Other Catalyst II (patent rejected), is one of the most efficacious. The thermodynamic incentive for its reactivity is the ejection of its pyrrole, which is barrierless even at 12 K.15
A palladium-ArsePhos complex performs the migratory arylation of alkene 20. The ArsePhos ligand (sometimes referred to as Y-O-YPhos) incorporates a labile, bulky arsine (a fat-arsine) and electron-rich phosphine, separated by an osmocene unit. It’s catalytic activity in Mitsubishi couplings is matched only by its acute toxicity.16 The final catalytic step in this marathonic mechanism is the photoarousal of dismyl anion 22. Acridazole is an organic photocatalyst, known for its efficacy in such energy transfer reactions, albeit only on days with a prevailing north westerly breeze.
Density Dysfunctional Theory
Initially, we sought to probe the mechanism of this bizarre transformation with computational methods, because it was cheaper than using the catalysts themselves. Using the Hartree Fück level of theory, the MLF06-XXX functional and the 2G1C LYP basis set, we were able to successfully model the chelation of scandium by substrate 1. This interaction was found to be favourable by 14.7 kflop/mol. However, modelling the interaction of uranium hydride 9 with the substrate proved to be exceedingly difficult. When the 6-31(f)+_+ basis set was used to model uranium, the simulation ETA was in mid-2047. By switching to RANDL2DZ, the computation time was lowered to three weeks, but the resultant energy was 28,000 kflop/mol higher than expected. A compromise was reached with the LANL2DZ-D97DEP31G-OSX10-WD40-6-3211111G(dp)*^* basis set, which took six months to tell us that the energy of 10 was something like 50 kflop/mol. To achieve this shorter computational time, it was necessary to model uranium as a really big chromium atom. At the time, we intended to submit our work to Nature, and we figured that we could send the initial manuscript and append the calculations six months later before it had been sent out for review. Modelling the next mechanistic step (the radical scission fission), proved to be beyond the capacity of modern computational methods. Our initial attempts were met with “Error 424: spontaneous decomposition” followed by a total system crash of all servers on the network, and legal action taken against us by Facebook for disrupting their service.17
Kinetic Isotope Defect
The most informative of our numerous mechanistic studies was an isotopic labelling experiment. We exposed deuterated obstannyl-sulphosphoxide D2-1 to standard Over Reaction conditions, and observed the distribution of deuteration in the product by 1-and-a-bitHNMR. A significant kinetic isotope defect was observed. 85% of the original 200% was scattered across the product in a seemingly random distribution. The remaining 115% is still missing, please contact us if you find it. These results are evidence for rapid and promiscuous hydrogen exchange, facilitated by at least one of the nine catalysts.
In the beginning, there was scandium. And Frank knew that it was good. A scandium chelate 8 is formed from the sulphosphoxide portion of 1. Uranium hydride 9 enters the stage, and forms four agnostic interactions with the pi-system of 9. Adduct 10 undergoes radical scission-fission (also called a radical-dance) with nitrinidinium cation 11, while contained in a solvent-maze. The nitrogen is quaternized, while an equivalent of triflyl sulphobstannane 16 is expelled. Concomitantly, uranium delivers an equivalent of H2 to the pi-system, and shuffles a couple of the other protons around. The result of these processes is the partial hydrogenation and triple-ring closing cyclisation of 13 to give pandemonium cation 14. The formation of nitrinodinium 11 begins with the thermolysis of cyanodiazetidine 12, which generates a nitrene. The MoFocker complex stabilises the nitrene (13), until it is oxidised by a photoaroused perfluoridium cation [Ir]+*. The reduced form of perfluoridium [Ir] is reoxidised by the 9 V battery.
Rhenimine B serves to cleave homopropargyl ether 16 and generate !, #-unsaturated carbene 17, via vinylidene formation, 1,5-hydride transfer, and $-hydride reallocation. The carbene attacks pandemonium cation 15 in a cyclopropanation. The resultant cyclopropane 18 undergoes reductive ring opening mediated by the Thwacker Reagent, which is regenerated with an equivalent of sodium trifutylborohydride. Grubbs’ Other Catalyst II performs a ring-closing olefin metathesis on diene 19, furnishing most of the elseviamine core. Alkene 20 is arylated with phenylmoronic ester 21, in a classic example of the Mitsubishi Redistribution.18 Penultimately, dissociation of scandium reveals the lone pair of dismyl zwitterion 22. An energy transfer process occurs between 22 and a photoaroused acridazole [Ac]*. The result is an excited triplet (23), bearing an sp4 hybridised carbon. This transition, while not spin-forbidden, is strongly spin discouraged. The triplet is trapped with cumulene 24, and after dissociation of the scandium complex from the resultant zwitterion (25), the product elseviammonium dismylate 26 is liberated.
The final mechanistic feature, and the only one to elude us thus far, is the role of triphenylphosphine. One equivalent of PPh3 is essential for the “success” of the reaction, and a proportionate amount of OPPh3 is recovered during the workup, but we don’t know why. Our best guess is that it functions as an oxygen scavenger, or perhaps a votive offering to the capricious chemical gods.
We have proposed the first plausible mechanism for the Over Reaction: a catalytic cycle so contrived that even The Goodies would struggle to ride it. The rate limiting step in this mechanism is finding the catalysts and reagents. After that, it’s a dump-and-stir in its purest form. The number, complexity, and obscurity of catalysts for this reaction mean it would be significantly cheaper if it were stoichiometric in rhodium instead. It does, however, provide a one-pot route to elseviammonium dismylates. The most remarkable aspect of this work is that despite featuring almost every buzz-word in the chemical lingua wanka, this still wasn’t good enough for Nature. Still, beat that Krebs!19
The authors wish to acknowledge their students, who, despite having done all the grunt work for this paper, somehow didn’t merit inclusion as authors. Günther Schlonk wishes to acknowledge whoever drew the catalytic cycle for the Wacker Process page on Wikipedia. The file name is visible as “wackonwackoff.tiff”, which made him chuckle for an hour.
Silvio Cornuto and Alexander Thwacker conducted the mechanistic experiments. Henri de Pampelmousse performed the DDT calculations. Aap Tsagay prepared the starting materials. Günther Schlonk devised the catalytic cycle during a seminar on WHS, and prepared the manuscript.
About the Authors
Cornuto, Thwaker, Pampelmousse and Tsagay are successful academics in their fields, despite being entirely fictional. Recently, Günther Schlonk was almost killed by a flying shard of glass from an exploding solvent still. Luckily, he had a Safe Working-Procedure folded in his breast pocket, which was thick enough to stop the shrapnel from reaching his heart. Thus, he continues in his capacity as Imperial Editor in Perpetuity of The Journal of Immaterial Science.
Conflicts of Interest
Günther Schlonk has so many things he should be doing with his time instead of writing this nonsense. Yet he continues to churn out manuscripts due to a procrastinative disorder, a pathological compulsion to take the piss and a troubled relationship with his research.
Notes and references
- F. F. Runge, J. Brown Chem. 1834, 156, 5704–7954.
- The IOUPAC Brown Book, 34, 4673.
- F. Mercury, D. Bowie, J. Mus. Chem. 1981, 2:31.
- A. Grundle, M. Taint, V. Gooch, Org. Memos. 3, 460–461.
- “A Lab Maiden’s Tale” by A. N. Nonymous, Sysiphos Publishing.
- K. Über, F. N. Furious, Wangew. Chem. Int. Ed. 6, 60–71.
- G. Marius, L. C. Sulla, J. Unnat. Prod. Online (accessed: never).
- Don’t think about it too hard, you’ll hurt yourself.
- F. N. Furious et al. et al. et al, J. Am. Chem. Sox. 3524, 5–15.
- The electronic unsupported information: tinyurl.com/3m6s7n3h
- “Dysfunctional Groups” by Eileen Dover, 2009, Sysiphos Publishing.
- Next week’s manuscript
- W. A. Focker, J. Inorganomet. 2002, 77, 98–97.
- S. Forkbeard, H. Bluetooth, 980 C.E. J. Scand. Chem. 4, 1–3.
- R. H. Grubb, A. H. Darthveyda, 2005, Omnihedron, 23, 63–70.
- S. Cluckwald, J. F. Birchtwig, 2012, J. Inorganomet. 54, 7–12.
- Error messages via AtomSmasher’s Generator, CC BY-SA 3.0
- J. Mitsubishi, K. Toyota, N, Subaru, 1995, Rhombus, 3, 57–102.
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