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Alternatives assessment frameworks

A big part of implementing green chemistry in industry is the task of identifying and selecting product or process chemistries that are safer, less resource-intensive, and also functionally better than those we currently use. That involves complex judgments and comparisons with many dimensions. Figuring out how to make multifaceted comparisons to support scientifically informed judgments is the domain of alternatives assessment (AA). Anyone involved in green chemistry should be familiar with this idea.

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Chemical Footprinting: New tools for tracking green chemistry business practices

Chemical Footprinting: Identifying Hidden Liabilities in Manufacturing Consumer Products

In an unassuming low-rise in the Boston suburbs, Mark Rossi tinkers with a colorful dashboard on his laptop screen while his border collie putters around his feet. Rossi is the founder of BizNGO and Clean Production Action, two nonprofit collaborations of business and environmental groups to promote safer chemicals. He’s also the creator of tools that he hopes will solve a vexing problem—how to get a handle on companies’ overall toxic chemicals usage.

Consider the screen of Rossi’s laptop. Chances are the company that manufactured the product has crunched the numbers on the total amount of carbon, water, and land associated with getting it into the office—from the manufacturing of the electronic components to the packaging and transportation to retail outlets. But the total amount of toxic chemicals that contributed to the screen’s design and production might be a more difficult question to answer….

Read the entire story, by Lindsey Konkel, at  http://ehp.niehs.nih.gov/123-a130/

Green Chemistry via Continuous Flow

“Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906” Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Proc. Res. Dev. 2012, ASAP. DOI: 10.1021/op200340c

“Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin.” Lévesque, F.; Seeberger, P. H. Angew. Chem. Int. Ed.. 2012, 51, 1706-1709. DOI: 10.1002/anie.201107446

“Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy” Cervera-Padrell, A. E.; Nielsen, J. P.; Pedersen, M. J.; Christensen, K. M.; Mortensen, A. R.; Skovby, Dam-Johansen, T. K.; Kiil, S.; Gernaey, K. V. Org. Proc. Res. Dev. 2012, ASAP. DOI: 10.1021/op2002563

A little while back I wrote about an aerobic oxidation which was greatly improved by switching from a traditional round bottom flask setup to a continuous flow reactor – basically, continuous flow reactors are much better at handling oxygen, especially on scale.  But most of the advantages of the flow reactor were specific to that reaction, and it wasn’t clear to me how a flow process would improve a reaction that doesn’t use oxygen, or some other gas.  Fortunately, a lot has been published since then to help me get a handle on how continuous flow reactions can contribute towards greener processes.  In particular, this review covers continuous processing within a green chemistry context, and Organic Process Research and Developement has a continuous flow themed issue in their ASAP section, including this process-oriented review (speaking of OPRD, check out this recent editorial concerning solvent selection and green chemistry).  It turns out that flow chemistry can improve processes in a bunch of different ways, and it’s hard to get a sense for how this can work by just looking at one reaction.  So I’ll cover a few different reactions that illustrate different green aspects of continuous flow reactors.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture.  This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale.  One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative.  The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

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High-Yielding Semi-Synthesis of an Artemisinin Precursor

“Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin” Westfall, P.J.; Pitera, D.J.; Lenihan, J.R.; Eng, D.; Woolard, F.X.; Regentin, R.; Horning, T.; Tsuruta, H.; Melis, D.J.; Owens, A.; Fickes, S.; Diola, D.; Benjamin, K.R.; Keasling, J.D.; Leavell, M.D.; McPhee, D.J.; Renninger, N.S.; Newman, J.D.; Paddon, C.J. Proc. Natl. Acad. Sci. U.S.A. 2012109, E111-E118. DOI: 10.1073/pnas.1110740109.

Malaria, caused mainly by the parasite Plasmodium falciparum, leads to nearly a million deaths and 250 million new infections each year. The sesquiterpene lactone endoperoxide artemisinin, derived from Artemisia annua, is very effective as an antimalarial drug, and widespread resistance hasn’t yet developed. Artemisinin is the only high-volume drug that is still isolated by extraction from its native plant producer in a low-yielding (around 10 μg per g plant material), resource-intensive process that uses volatile solvents (most commonly hexane).

Artemisia annua. Photo credit: Jorge Ferreira via Wikimedia Commons.

As a result, supplies of the drug are short, and those who need it often can’t afford it. The development of new processes for artemisinin production would therefore advance both public health and green chemistry interests. Total synthesis of the drug hasn’t been considered as a viable alternative because of low yields, but a lot of effort has been directed toward developing semi-synthetic sources of artemisinin using a combination of microbial fermentation and chemical synthesis. Toward this end, the Keasling lab reported a few years ago that they had constructed a biosynthetic pathway for the artemisinin precursor amorpha-4,11-diene in yeast with yields of ~200 mg/L—already impressive given the complexity of the molecule. Amorphadiene synthase (ADS) comes from Artemisia annua; the rest of the genes are from yeast. Here is the existing pathway:

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Iron-Catalyzed C-H Amination

“Iron-Catalyzed Intramolecular Allylic C-H Amination” Paradine, S. M.; White, M. C. J. Am. Chem. Soc. 2012, 134, 2036-2039. DOI: 10.1021/ja211600g

In their recent communication, Christina White’s group at Illinois reports a new allylic C-H amination catalyzed by iron. This builds on previous work from their group in Pd sulfoxide catalyzed allylic amination and iron catalyzed C-H oxidation. In addition to showcasing an exciting reaction, this paper is a great contribution from a green chemistry perspective: they use a cheap, non-toxic metal catalyst to do a highly selective C-H oxidation reaction, one that streamlines the synthesis of C-N bonds directly from the (relatively) unreactive C-H bond. Interestingly, quantitative comparisons are made throughout the paper to the more commonly used Rh2(OAc)4 catalyst.

They start by screening Fe catalysts for intramolecular allylic amination reactivity of sulfamate substrates. Although the polypyridyl Fe complex they have used previously for hydroxylation and desaturation chemistry gave a low yield of product, the phthalocyanine Fe complex 1 gave a good yield (and better than a tetraphenylporphyrin iron complex) of allylic amination. Importantly, they obtained only trace quantities of the aziridination product, showing the high selectivity of the iron-catalyzed reaction (>20:1).

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Chemical Feedstock Production by Fermentation

“Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol” Yim, H.; Haselbeck, R.; Niu, W.; Pujol-Baxley, C.; Burgard, A.; Boldt, J.; Khandurina, J.; Trawick, J. D.; Osterhout, R. E.; Stephen, R.; Estadilla, J.; Teisan, S.; Schreyer, H.B.; Andrae, S.; Yang, T. H.; Lee, S. Y.; Burk, M. J.; Van Dien, S.  Nature Chem. Bio. 2011. 7, 445-452. DOI: 10.1038/nchembio.580

The production of chemicals from biologically-derived feedstocks is a major goal of green chemistry research, but despite a lot of work that’s been done, it’s going to be hard to make the switch from petroleum-derived chemicals to bio-based ones.  This is especially true for high-volume commodity chemicals – many of these chemicals have been produced from petroleum for a hundred years, the processes have been optimized to work efficiently on enormous scale, and they are really, really cheap.  So the bar is set pretty high, and most papers from academic labs on microbial or enzymatic chemical production are too low-yielding to ever be commercialized (although to be fair, the same could be said for most synthetic chemistry papers).  That’s why I was a drawn to this paper published by Genomatica, a company based in San Diego, on the production of 1,4-butanediol by an engineered strain of E. coli – first they got the bug to produce 1,4-butanediol, then they engineered it to produce lots of the stuff.  Currently one million tons of 1,4-butanediol (BDO) are produced each year, virtually all of it derived from petroleum-based feedstock chemicals.

Apparently 40% of this is used in the production of Spandex, and the rest of it is used to make other polymers and THF.  If Genomatica’s BDO production works according to their plan, all those tons of spandex could be bio-based!

The future of spandex?

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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.

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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.

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More Stahl Aerobics

“Highly Practical Copper(I)/TEMPO Catalyst System for Chemoselective Aerobic Oxidation of Primary Alcohols” Hoover, J. M.,; Stahl, S. S.  J. Am. Chem. Soc. 2011. ASAP. DOI: 10.1021/ja206230h

To quickly follow up yesterday’s post on aerobic alcohol oxidation, I thought that this new paper from the Stahl lab on the same topic was worth mentioning.  While their continuous flow process for alcohol oxidation was a pretty big improvement over many existing methods, the reagents necessary were not ideal.  Toluene and pyridine are both toxic, and palladium is not extremely abundant, especially compared to 1st row transition metals.  So there was plenty of room for improvement, which is why I was really psyched to see this new catalyst system for primary alcohol oxidation that was published a few days ago. Virtually all of the reaction components have been replaced by greener reagents:  acetonitrile instead of toluene, N-methylimidazole instead of pyridine, and catalytic TEMPO/(bpy)Cu(I) instead of palladium acetate.  Unlike most aerobic alcohol oxidations, an atmosphere of pure oxygen was not necessary – the oxygen present in ambient air was enough for the reaction to run efficiently.  And the reaction is run at room temperature to boot.  It’s hard to imagine that this reaction would be more difficult to scale up using their flow reactor than the Pd-catalyzed version, although you never know I suppose.

There’s loads more in the paper on their catalyst development studies, and on the chemoselectivity of this process for primary alcohols versus secondary ones – definitely worth reading!

The Problem with Oxygen

“Development of safe and scalable continuous-flow methods for palladium-catalyzed aerobic oxidation reactions” Ye, X.; Johnson, M. D.; Diao, T.; Yates, M. S.; Stahl, S. SGreen Chemistry, 2010, 12, 1180-1186.  DOI: 10.1039/c0gc00106f

We’ve had a pair of posts recently about using oxygen as an terminal oxidant in cross-coupling and biomass degradation, and as a green oxidant, it’s pretty hard to beat.  So I was a little surprised to learn that of the many cool aerobic synthetic methods that have been developed in the last decade, very few are used in industry.  The big drawback, especially on large scale, is safety – oxygen is usually the limiting reagent in the combustion reaction, and things can get pretty crazy when you have an oxygen-enriched atmosphere (and much crazier with liquid oxygen – check out this awesome video, and this one that Marty had in his last post).  So while stirring 100 mL of toluene under a balloon of pure oxygen might be fine, doing the same thing with 100 L is problematic.

This setup doesn't scale up very well

Safety aside, these reactions suffer because proper gas-liquid mixing is more difficult to achieve as you scale up.  All of this prompted a collaboration between Eli Lilly and Shannon Stahl‘s lab to develop a scalable continuous-flow method for aerobic alcohol oxidation, which avoids these problems. (more…)

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.

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