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Update: Improving atom economy of dehydrogenative decarbonylation

“Selective Metal-Catalyzed Transfer of H2 and CO from Polyols to Alkenes” Verendel, J. J.; Nordlund, M.; Andersson, P. G. ChemSusChem, 2013, 6, 426-429. DOI: 10.1002/cssc.201200843

In a recent post I commented on the byproducts of dehydrogenative decarbonylation, namely H2 and CO.

1st reaction scheme

I wondered whether this gas mixture, syngas, could be used in a subsequent reaction. This would improve the atom efficiency of the reaction and potentially also improve the safety (of both the syngas-producing and syngas-using reactions). Both are goals of green chemistry and I especially appreciate avoiding rolling cylinders of toxic and/or flammable gases around the lab.


Rh-catalyzed Alcohol Deoxygenation

“Acceptorless Photocatalytic Dehydrogenation for Alcohol Decarbonylation and Imine Synthesis.” Ho, H-A.; Manna, K.; Sadow, A. D. Angew. Chem. Int. Ed. 2012, 51, 8607-8610. DOI: 10.1002/anie.201203556

The use of biorenewables as feedstock chemicals for commodity chemicals as well as fuels requires mild, selective removal of oxygen-containing functional groups. This is in direct contrast to the production of these chemicals from petroleum products, which, at least for highly functionalized target molecules, necessarily involves oxygenation of hydrocarbons.

There are a large amount of methods development currently underway and I highlight the recent report from the Sadow group on the decarbonylation of alcohols under Rh catalysis. I think the described reaction is a good example of green chemistry, as the reaction is high-yielding, selective, and performed at room temperature under photocatalytic conditions. One serious drawback is the use of benzene as the solvent, although toluene works as a solvent in at least some cases.

Reasoning that photolysis would prevent catalyst inhibition by CO binding, the researchers first screened Rh(I) catalysts under photocatalytic conditions with the test substrate cyclohexanemethanol. Unfortunately, no cyclohexane was observed under these reaction conditions. The group then tested Rh and Ir compounds known for C-H activation, such as Cp*Ir(CO)2 and Tp*Rh(CO)2, and did observe cyclohexane for one of the tested catalysts, albeit in low yield (36 % NMR yield with Tp*Rh(CO)2). CO and H2 were also observed, consistent with the targeted alcohol decarbonylation reaction. Interestingly, using their previously reported rhodium tris(oxazolinyl)borate complex ToMRh(CO)2 (1) improved the yield to > 95%. Furthermore, the related dihydride, ToMRh(H)2CO (2) was roughly three times slower and the Ir complex ToMIr(CO)2 was inactive for this reaction.


Raging Hormones – Gram-Scale Synthesis of Prostaglandin PGF2α

“Stereocontrolled organocatalytic synthesis of prostaglandin PGF in seven steps” Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature 2012, online view. DOI: 10.1038/nature11411

In my very un-scientific survey of the green chemistry-branded journals, I see way more new methodologies than I see total syntheses. I hope to single-handedly change this, and show how green a total synthesis can be by writing about the awesome recent synthesis of prostaglandin PGF by Aggarwal and coworkers. First, a few words on the target molecule. Being hormones, prostaglandins such as PGF are involved in tons of biological processes. Interestingly, instead of being synthesized by some important gland and acting in far-off regions of the body as are endocrine hormones, they are autocrine or paracrine hormones and are synthesized “on-site.” The first structural characterizations of prostaglandins came in the 1960s, some 30 years after their initial discovery. Soon after, they became the subject of numerous syntheses, the first of which was achieved by E. J. Corey in 1969. A series of syntheses followed, but even 40 years later, the structurally-related glaucoma drug latanoprost is synthesized in 20 steps using Corey’s 1969 prostaglandin strategy.

That’s right, the prostglandin structural motif is medicinally relevant. So, not only would an improved synthesis be cool from a fundamental science perspective, it might actually be moved into industrial production and have an immediate impact! (more…)

A “Designer” Surfactant for Cross Couplings of Hydrophobic Reagents in Room Temperature Water

“TPGS-750-M: A Second-Generation Amphiphile for Metal-Catalyzed Cross-Couplings in Water at Room Temperature” Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. J. Org. Chem. 201176, 4379-4391. DOI: 10.1021/jo101974u

I occasionally run reactions in water, and it is awesome. I LOVE not worrying as much about cancer. Unfortunately many interesting chemicals are simply too hydrophobic to allow reactions to be run in aqueous solution. As anyone who has ever scrubbed a greasy pan will know, one way to get around the solubility problem is with soap. Also called emulsifiers, surfactants, amphiphiles, a soap by any name is pretty much the same thing in my mind (though others will disagree I’m sure). Molecules with hydrophilic and hydrophobic ends can form micelles in water, creating variously-shaped and sized particles with hydrophobic cores. Using those hydrophobic cores as reaction media is a concept known as micellar catalysis. The Lipshutz group was not the first player in this arena, but they have been at it for some time. They recently teamed up with the medicinal chemistry company Kalexsyn and came out with a new amphiphile that caught my eye, dubbed TPGS-750-M. 


Inherently Flame-Retarding Polymers

“Preparation of flame-retarding poly(propylene carbonate)” Cyriac, A.; Lee, S. H; Varghese, J. K.; Park, J. H.; Jeon, J. Y.; Kim, S. J.; Lee, B. Y. Green Chem. 2011, 13, 3469-3475. DOI: 10.1039/C1GC15722A

During graduate school in California I was very aware of the tremendous amount of household furniture loaded with flame retardant polybrominated diphenyl ether chemicals. Those chemicals do a great job of reducing the flammability of numerous petroleum-based products. Unfortunately their non-covalent incorporation in the polymers speeds their environmental release.  Once in the environment, they break down slowly and bioaccumulate. Additionally there are numerous human health and ecological concerns with these chemicals, including their association with decreased fertility in humans (ref). That is why this paper on flame-retarding poly(propylene carbonate) (PPC) caught my eye. Another reason could have been the flames in their graphical abstract!

TDI = toluene 2,4-diisocyanate; TPU = thermoplastic polyurethane

As luck would have it the chemistry is neat too, flames aside. The researchers begin by highlighting (bragging about?) the fact that they have an actual pilot plant in which they use their cobalt-salen-based catalyst to polymerize CO2 and propylene oxide to PPC (Note: experiments from this study were not performed in the pilot plant). The catalyst displays high turnover frequency (15,000/h) and produces high molecular weight polymers (Mn = 300,000).


Metal-free, Organocatalytic Intramolecular C-H Amination

“Organocatalytic, Oxidative, Intramolecular C-H Bond Amination and Metal-free Cross-Amination of Unactivated Arenes at Ambient Temperature” Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem. Int. Ed. 2011, 50, 8605-8608. DOI: 10.1002/anie.201102984

For constructing aryl C-N bonds, the traditional synthetic sequence (i.e., what we teach undergrads) involves nitration followed by reduction, the nitration requiring harsh conditions and the reduction generating a stoichiometric amount of Sn waste.


More recently, Buchwald and Hartwig have improved on this through the use of catalytic Pd. This reaction, however, requires a pre-oxidized aryl halide, which must be prepared prior to coupling.

C-H bond amination has been highlighted recently as a method to streamline the synthesis of aryl C-N bonds (see the work of White or Dubois for examples of allylic and aliphatic C-H amination reactions, respectively). Fewer synthetic steps means less waste and an overall greener reaction. Most catalytic C-H aminations, however, require the use of Rh, an expensive heavy metal. The Antonchick group recently reported the metal-free, organocatalytic synthesis of carbazoles by aryl C-H amination. This chemistry is novel and complements the work others are doing to use earth-abundant metal complexes as C-H amination catalysts (esp. Fe and Cu).

The Antonchick group starts by optimizing the conditions for the synthesis of N-protected carbazole 2a from the precursor 2-aminobiphenyl 1a in 81 % isolated yield from a 12 hr reaction in hexafluoro-2-propanol (HFIP) at room temperature.

They then improve their conditions by using catalytic amounts of iodoarene in the presence of peracetic acid as their oxidant avoiding the generation of a stoichiometric amount of iodobenzene waste from their initial conditions. Note that their optimized conditions require a mixed solvent system consisting of HFIP and methylene chloride.


Oxygen, Nature’s Oxidant for Nature’s Feedstocks.

“Selective catalytic conversion of biobased carbohydrates to formic acid using molecular oxygen”R. Wolfel, N. Taccardi,  A. Bosmann, P. Wasserscheid, Green Chemistry, 2011, DOI: 10.1039/c1gc15434f

Graphical abstract: Selective catalytic conversion of biobased carbohydrates to formic acid using molecular oxygen

All of us have a very personal relationship to the oxidizing power of oxygen. We use oxygen to turn our food into energy, CO2 and water. There are a number of enzymes and pathways that aid this process, each aiding the reaction of food and oxygen toward the creation of CO2 and water.  Now the key to turning complex biomass into usable small molecules is the ability to control this reaction so that we can extract usable chemical building blocks without ending up back at CO2 and water. As you can see in this video over-oxidation can be a real concern.  This paper demonstrates the use of a polyoxometalate (POM) catalyst to promote the oxidation of biomass to formic acid.


Iron-catalyzed intermolecular cycloaddition

“Iron-catalyzed Intermolecular [2π-2π] Cycloaddition” Russell, S. K.; Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc. 2011, 133, 8858-8861. DOI: 10.1021/ja202992p

As the cost of precious metals increases dramatically along with concerns over the toxicity of 2nd and 3rd row metals, chemists are increasingly turning to employing earth-abundant metals in catalysis, especially iron.

In their recent contribution in the area of base metal catalysis, the Chirik group at Princeton reports an intermolecular, iron-catalyzed cycloaddition reaction. In addition to building on the intramolecular version of the reaction they had previously reported, the current contribution is also notable for their isolation of a catalytically competent intermediate.

The chemistry starts with their remarkable iron bis(dinitrogen) complex 1 (or a related bridging diiron dinitrogen complex), a formally zero-valent compound with an electronic structure better described as a dianionic bis(imino)pyridine ligand bound to an intermediate spin iron(II) ion.

The redox non-innocence of the supporting ligand enables the iron center to do two electron chemistry (required for oxidative addition and reductive elimination), reactions usually reserved for 2nd and 3rd row transition metals. In Chirik’s system, iron generally stays in the preferred ferrous oxidation state, while the ligand undergoes two electron reactions cycling between a neutral donor and a dianionic form during catalysis.

The bond-making and bond-breaking events still occur at the metal center (as for more traditional organometallic reactions, think Pd(0)/Pd(II) chemistry), the trick is that the accompanying redox changes occur at the ligand.

The bis(dinitrogen) complex 1 can catalyze the intermolecular cycloaddition of 1,3-butadiene with ethylene to form vinylcyclobutane. By introducing a methyl group into the butadiene substrate (isoprene), the 1,4 addition product is formed instead.


Catalytic Directing Groups in Hydroformylation

“Synthesis of Quaternary Carbon Centers via Hydroformylation”  Sun, X.; Frimpong, K.; Tan, K. L. J. Am. Chem. Soc. 2010, 132, 11841.  DOI: 10.1021/ja1036226

Just as the advent of protecting groups opened up new chemical space accessible by current synthetic techniques, so too did the advent of the directing group.  Both however come with the downside of often requiring additional synthetic steps for the installation and removal of these groups.  For example, the past decade or so has seen a number of efforts at using directing groups such as phosphines to affect the course of hydroformylation reactions.  I should mention here that people are so interested in the hydroformylation of alkenes in part because it is such an industrially important reaction, with 9 million tons of aldehyde products being produced in this way per year (ref).  The challenges with this reaction are selectivity, one of the foremost issues being that terminal alkenes preferentially give linear products.  Shown below is a 2001 example from the Leighton group where a phosphine directing group on allylic ethers yields the branched hydroformylation product (Markovnikov addition), whereas the linear product (anti-Markovnikov) would be favored in the absence of the directing group:

The Up-Side: this method offers access to substrates not previously available through hydroformylation.   The Down-Side: it is hard to imagine an industrially-relevant product containing that specific phosphine moiety, so it would undoubtedly have to be cleaved, making the overall process highly atom un-economical.  This latter point could be addressed by somehow using the phosphine group in a catalytic, instead of stoichiometric, fashion.  This is exactly what the research group of Kian Tan at Boston College has been up to lately.  They have developed what they term a “scaffolding ligand” that coordinates to the organometallic catalyst as well as rapidly and reversibly (two important things for this type of catalysis) forms covalent bonds with alcohols.  In doing so it brings the substrate (in blue below) and catalyst (in red below) in close proximity and influences the course of the reaction.


Hydrogen-Mediated C-C Coupling to form Allylic Alcohols

“Direct Vinylation of Alcohols or Aldehydes Employing Alkynes as Vinyl Donors: A Ruthenium Catalyzed C-C Bond Forming Transfer Hydrogenation”  Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009131, 2066-2067. DOI: 10.1021/ja809456u

In their 2007 JOC perspective on hydrogen-mediated C-C bond formation, Krische and co-workers point out that “upon consideration of the E-factor for various segments of the chemical industry, a strong inverse correlation between process volume and waste generation is observed.”(1) Given that the lower volume fine chemical and pharmaceutical sectors typically focus on the production of chemicals with higher degrees of molecular complexity then their bulk chemical counterparts, the authors propose that there is a persistent need for the development of selective, atom-economical reactions capable of producing these relatively specialized chemicals. As luck would have it, the Krische group has come to the rescue with a number of reactions that might fit the bill.

One such reaction is their recent report of the ruthenium-catalyzed vinylation of alcohols or aldehydes using alkynes as the vinyl donors (shown above).

I think this reaction is neat because it represents a departure from how people have typically gone about bringing alkynes and alcohols together to form allylic alcohols. In this early example from the Wipf group, (more…)