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Organocritical Suzuki

20 March 2021 - Counter reports

Remember when in the beginning of the year Hai-Zhu Yu and Hua-Jian Xu (call them team A) reported an organocatalytic Suzuki (aromatic amine plus potassium carbonate) reaction? (blog) The claim was met with skepticism because surely there must have been some trace palladium (the staple metal in a Suzuki) in the vicinity, for example accumulated through the synthesis of the amine catalyst in a palladium catalyzed Buchwald-Hartwig amination? We already have one counter-report from catalysis detectives Gonda, Tolnai and Novak (team B). (blog) The key piece of evidence they presented to the jury was the palladium-free synthesis of the same catalyst which subsequently was found to be catalytically inactive. They also re-did catalyst synthesis and did find trace amounts of palladium where team A did not find any.

Robin Bedford is one of the authors in 24 (!) person team (team C) of a second counter-report that is now available on ChemRxiv (DOI). The Bedford group is totally dedicated to catalysis and the result of their investigation is also negative.

The first thing team C did was to repeat the catalyst synthesis and Suzuki reaction according to the original procedure. They were able reproduce the results but also noted that the Suzuki reaction actually improved in the presence of water. Now the reaction mechanism proposed by team A is featuring an organopotassium intermediate which can impossibly co-exist with water. For this reason alone team C discredits the proposed reaction mechanism.

Detecting trace metal can be tricky! Team A relied on IPC-MS and to the best of their efforts they did not find any (< 1 ppb). In the new report team C arrives at 7,5 million ppb which corresponds to half the palladium used in the synthesis. The new report also describes a combination of reductive electrolysis and energy-dispersive X-ray spectroscopy by which palladium again was found. Electrolysis was also used to "clean" the catalyst from any metal. Post-treatment, the catalyst was again not active. Where team A spent a lot of effort to remove metals by dedicated scavengers it was also possible to remove all metal by a simple recrystallization step. This again rendered it inactive. Like team B in their report, the authors note that a clean catalyst sample is colorless and not colored as in the team A samples.

Team C also performed a palladium-free catalyst synthesis, this time based on a Chan-Lam coupling (SI not yet available). The catalyst made in this way was also found to be catalytically inactive.

In the meanwhile the journal Nature Catalysis, home of the original paper has issued a warning that "the conclusions of this paper are subject to criticisms that are being considered by the editors".

When calcium met nitrogen

17 March 2021 - Inorganic chemistry

nitrogenactivationbycalcium2.PNGThis is an interesting research theme. Reduce an alkaline earth metal to it's plus one oxidation state and watch what happens next. End of last year there was Cameron Jones exploiting magnesium dimer L-Mg-Mg-L with each magnesium a reactive plus one (blog) and there was also from the boron group Philip Power with a plus one R-Al aluminium compound (blog).

The Frenking / Harder groups have now set their sights at calcium. They report their attempt to create a L-Ca-Ca-L dimer in a similar way as Jones where L is a beta-diketiminate ligand (Rösch et al. DOI). The outcome was unexpected. The dimer was predicted to materialize by reducing the corresponding L-Ca iodine dimer but whatever monster came out was just too reactive and escaped isolation.

The authors explain that instead it takes on whatever is available. With potassium metal as reducing agent it rather reacts with solvent benzene or any other aromatic solvent. More surprisingly, in absence of an aromatic solvent (all-aliphatic methylcyclohexane) and with potassium dispersed on potassium iodide a complex with nitrogen is formed from the "protective" nitrogen blanket.

The compound can be stabilized with tetrahydrofuran and the crystal structure confirms de nitrogen unit has a double bond and is a dianion. Heating this compound to 60 degrees results in alpha hydrogen abstraction from the THF ligand with the hydrogen atom ending up with nitrogen and the complex then breaks down into ethylene, the acetaldehyde calcium enolate and diazene. The latter byproduct eventually forms hydrazine. That almost sounds like nitrogen reduction but calcium is of course not doing a real catalytic Haber-Bosch reaction (HB).

In traditional HB a transition metal can use partially filled d-orbitals to interact with empty pi-star orbitals at nitrogen in a concept called the Dewar-Chatt-Duncanson model. The authors propose that calcium mimicks the transition metal by doing the very same. But d-orbital participation in an alkaline metal is controversial! In 2019 Frenking unveiled calcium octacarbonyl (see blog here) but his suggestion in 2019 that this compound owes its existence to pi backbonding was met with criticism and an angry article (DOI) In the new work Frenking did the calculations and sticks to his guns.

The authors slyly remark that although the calcium dimer did not materialize, the new nitrogen adduct is a strong reducing agent by itself by ejecting nitrogen in addition to the electrons and even stronger than the aforementioned magnesium dimer. The Jones lab is notified.



Organocatalytic Suzuki update

06 March 2021 - Forensics

The report of a metal-free Suzuki-Miyaura reaction by the Hai-Zhu Yu and Hua-Jian Xu labs in January must be the organic chemistry sensation of 2021 (blog here). In it, palladium is replaced by an aromatic amine as an organocatalyst. The report has been met with disbelief though (example here) because in this reaction type the general consensus is that it is nearly impossible to exclude the presence of at least some metal.

An 11 person strong team from Hungary and Germany took it on themselves to check the published procedure and they report about it in an article on ChemRxiv. Co-authors Gonda, Tolnai and Novak are not newbies when it comes to catalysis, for example, back in 2010 they unmasked a reported copper-catalyzed Sonogashira as well, a pbb-level palladium driven reaction. And the news is again not good, palladium was again found to be present in "homeopathic" quantities.

In the Yu / Xu procedure the organocatalyst was prepared in a classic Buchwald-Hartwig reaction with a relatively high palladium loading. The Hungarian detectives argued that If palladium had sneaked its way into the coupling reaction it must have been via this attack vector. They decided to make the catalyst in three different ways.

First they repeated the catalyst synthesis as reported by Yu and Xu (2-methylbenzene-1,3-diamine ,PdCl2(PCy3)2 ,1-bromo-2-methylbenzene ). By ICP-MS they found 512 mg/Kg of residual palladium in this sample, a figure much higher than that reported by Yu and Xu. More damaging was the find of quantities of phosphorous as well.

Another batch was synthesized using 0.01 equivalent of palladium instead of 0.03 equivalent (bis(cinnamyl palladium(II)) chloride , tBuXPhos and a polyethylene oxide surface surfactant). The new residual palladium level was 10 mg/Kg without any phosphorous present.

The catalyst was also prepared without the use of palladium at all using 2-methylbenzene-1,3-diamine and di-o-tolyliodonium tetrafluoroborate. The three batches were then tested in a typical Suzuki reaction with batch A resulting in a 98% yield, batch B in a 93% yield and batch C reporting no yield. The last result would certainly put the organocatalytic Suzuki hypothesis to bed, there may be other research groups on the procedure replication trail, we will have to wait and see.


A tetraimido sulfuric acid

03 March 2021 - Chemical Zoo

tetraimido sulfuric acid Jung 2021.PNGThe Stalke group (University of Göttingen) has recently reported the synthesis and isolation of a tetraimido sulfuric acid (Jung et al. DOI). Where regular sulfuric acid has a central sulfur atom, two hydroxyl groups and two oxo groups, in the new compound the substituents are two formal amino NHtBu groups and two formal imido NtBu groups. Both compounds are therefore structurally related and because the arrangement of valence electrons is unchanged you can regard the compounds as isoelectronic.

The starting compound for the 2021 synthesis has been sitting on a shelf in the Stalke lab since 1998 (DOI). The synthetic route can be sourced back to sulfur chloride which in a well-known reaction reacts with tert-butylamine to the sulfur diimide di-t-butyl-sulfurdiimide. Addition of lithium tert-butylamide followed by oxidation with bromine gives access to an compound S(NtBu)3 and another round with the lithium amide gives butterfly compound dilithium-N,N',N,N'-tetrakis(tert-butyl)tetra-imidosulfate.

In the new work this compound was stirred in THF for 2 minutes with tert-butylammonium chloride to yield the tetraimido sulfuric acid compound. Sometimes developing new chemistry can be that simple. The new compound is stable if kept below 35 degrees below zero otherwise it's fate is conversion back to S(NtBu)3 which is an equivalent of sulfur trioxide.

Structural analysis: from the crystal structure the bond lengths of the amido S-N bonds and the imido bonds are not surprising. From QTAIM computations, the shorter imido bonds are also found to be more polarized towards nitrogen. It is tempting to draw the imido bond as a double bond e.g. S=N but, surprise, according to the analysis, it is a polar single bond just as the amido bond.