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It is my pleasure to return to the ACS Green Chemistry Institute® as a result of the organizational realignment announced last month by ACS Executive Director and Chief Executive Officer Tom Connelly. The ACS GCI is part of the newly formed Scientific Advancement Division, which also includes the Office of Research Grants, ACS technical divisions, and technical programming at ACS National Meetings. This new structure will enable the Society to address its mission “to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and its people” by better coordinating and focusing its activities related to advancing the chemical sciences.

 

While much has changed since I served as Assistant Director of the Institute from 2001-2004, several key initiatives remain strong. The Presidential Green Chemistry Challenge Awards continue to recognize outstanding green chemistry technologies through the partnership between the U.S. Environmental Protection Agency and the ACS Green Chemistry Institute®. The Institute awards the Ciba Travel Awards in Green Chemistry, Joseph Breen Memorial Fellowship and the Kenneth G. Hancock Memorial Award to students for their outstanding contributions to green chemistry. The annual Green Chemistry & Engineering Conference, now in its 21st year, saw record attendance last year in Portland, Oregon. The call for papers for this year’s conference is open through Monday, February 13, and I encourage you to submit a paper aligned with the symposia themes.

 

A critical ACS GCI initiative in recent years has been the creation of Roundtables, which are designed to accelerate industrial adoption of green chemistry. Current Roundtables address five key areas of the chemistry enterprise: Pharmaceuticals, formulators, chemical manufacturers, hydraulic fracturing, and biochemical technology. The Roundtables have been very effective in identifying research needs within their respective sectors and developing tools and strategies to address these needs.

 

I am delighted that ongoing support from the ACS Petroleum Research Fund will enable the ACS Summer School on Green Chemistry and Sustainable Energy to be held once again at the Colorado School of Mines, from June 20-27, 2017. The Summer School is the highlight of my professional year thanks to the commitment to and passion for green chemistry and sustainability demonstrated by the graduate students and postdoctoral scholars who participate in this program. The future of chemistry is in good hands!

 

Another education initiative of the ACS Green Chemistry Institute® is the Green Chemistry Education Roadmap. Two workshops held in 2016 produced draft green chemistry core competencies, which have recently been revised in response to stakeholder input. These competencies will serve as the foundation for the roadmap, and we will be seeking additional input from the community in the coming months.

 

I have much to learn in my new role at ACS and I would encourage you to share your ideas regarding all aspects of the ACS Green Chemistry Institute® with me at m_kirchhoff@acs.org. Thank you and I look forward to hearing from you.

 

All the best,

 

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“The Nexus Blog” is a sister publication of “The Nexus” newsletter. To sign up for the newsletter, please email gci@acs.org, or if you have an ACS ID, login to your email preferences and select “The Nexus” to subscribe.

 

To read other posts, go to Green Chemistry: The Nexus Blog home.

Contributed by K. E. Hernandez, Ph.D. candidate working for Professor Frances Arnold, Division of Chemistry and Chemical Engineering, California Institute of Technology

 

Catalysts are important tools in green chemistry because they enable reduced-waste manufacturing methods by accelerating reactions where every reactant is incorporated into the product. Many catalysts that facilitate enantioselective bond formation are made from rare and non-renewable materials, such as palladium or rhodium; replacing these catalysts with renewable alternatives would allow for the more environmentally-friendly production of key chemicals. We believe that enzymes can meet this acute need for new, low-cost, sustainable catalysts, and in doing so, further advance and expand green chemistry.

 

In Frances Arnold’s lab, we start from natural proteins to develop new enzymes. Though a major drawback to enzymes is their limited reaction scope, expanding the range of reactions that can be catalyzed enzymatically will facilitate the widespread adoption of biocatalysis. Our team of chemists, biologists and engineers has expanded the reactions catalyzed by naturally-occurring proteins to include reactions unknown in the biological world using a process called ‘directed evolution.’

 

The powerful algorithm of evolution allows organisms to continuously update their catalytic repertoires with useful, new capabilities — think antibiotic resistance, or the ability to degrade many manmade compounds. Humans have been capitalizing on evolution to engineer desirable traits into biological systems for thousands of years: Everything from corn to cats has had its genomes altered through artificial selection and breeding to produce favorable phenotypes. Our innovation in Frances Arnold’s lab is that we do it with molecules. In the lab, we evolve enzymes by putting pressure on them to perform non-native functions that may not be useful to a bacterium, but are useful to us. Directed evolution mimics evolution through artificial selection accelerated in the laboratory setting by focusing on individual genes expressed in fast-growing microorganisms. We introduce mutations to parent proteins sourced from nature and screen the daughter proteins for increased activity for a desired reaction. We then use the ones with increased activity as parents for the next round of mutation and selection, and continue until we reach the desired activity and selectivity.

 

Although we can greatly enhance activity with directed evolution, a new enzyme activity has to come from somewhere. Thus, our starting proteins have to have at least small levels of the new activity in order to act as a starting point for the evolution of a novel enzyme. This is how nature creates new enzymes – we just follow the same recipe.

 

We have found that cytochrome P450s, whose native functions include monooxygenation, are a wonderful source of non-natural activities. We have engineered these proteins to carry out carbene and nitrene transfer reactions known to chemistry (e.g., olefin cyclopropanation, aziridination), but not found in biology. In recent projects, we have used a wider range of heme proteins as starting points to further expand the reactions catalyzed by biocatalysts.

 

Picture1.pngOur lab has made a cyclopropanating enzyme that produces the chiral precursor to the antidepressant medication levomilnacipran (1), and we have pushed these industrially relevant biocatalysts to synthesize pharmaceutical precursors at larger scales. One recent project focused on making a chiral cyclopropane intermediate used in the synthesis of ticagrelor, a medication used to prevent the reoccurrence of heart attacks. We identified a truncated globin from Bacillus subtilis that catalyzes this reaction (Figure 1) at low levels and also showed some selectivity for producing the desired diastereomer of the ticagrelor cyclopropane precursor from ethyl diazoacetate and 3,4-difluorostyrene (2).

 

This enzyme variant underwent evolution through the mutagenesis of many residues within its heme-binding pocket. Screening libraries of mutant enzymes identified beneficial mutations Y25L, T45A and Q49A, which improved the activity and selectivity of the catalyst so that it yields the desired ticagrelor cyclopropane almost exclusively. The catalyst does not even have to be purified because the reaction proceeds well in whole bacterial cells that express the evolved enzyme. After testing a range of reaction conditions, we found that the slow addition of the whole-cell catalyst and ethyl diazoacetate solutions to 3,4-difluorostyrene gave virtually a single isomer (>99 percent dr, 98 percent ee) of the ticagrelor precursor in 79 percent yield in preparative scale reactions. This work demonstrates how directed evolution can rapidly optimize a newly discovered biocatalytic activity, olefin cyclopropanation, to synthesize useful products in high selectivity and yield.

 

Picture2.png

Another recent project has focused on engineering a biocatalyst with a novel carbon-silicon bond forming activity that has also never been found in nature. C-Si bonds are seen in medicinal chemistry, imaging agents, elastomers, and high tech consumer products, such as televisions screens. Until now, the only methods used to create these bonds enantioselectively have relied on multistep chemical syntheses to prepare chiral reagents or chiral transition metal complexes. An iron-based catalyst had never been reported for this carbene insertion reaction. Then, postdoctoral researcher Jennifer Kan and her team discovered that cytochrome c from Rhodothermus marinus could catalyze the reaction between ethyl 2-diazopropanoate and phenyldimethylsilane to form the chiral organosilicon product with high enantioselectivity (Figure 2A, 3). They performed saturation mutagenesis on three residues within the active site that they thought were likely to influence enzyme activity, and through this, discovered the triple mutant V75T M100D M103E, which allowed the catalyst to form the C-Si bond with very high turnover numbers and enantioselectivity (>1500 turnovers, >99 percent ee).

 

Testing the engineered enzyme against a panel of silane and diazo reagents, Kan’s team discovered that the mutations in the triple mutant were broadly activating. The engineered enzyme was shown to catalyze the formation of 20 organosilicon products, most of which were obtained as a single enantiomer (Figure 2B). The triple mutant was also shown to have high selectivity for carbon-silicon bond formation over the formation of carbon-nitrogen bonds in the same substrates.

 

It is fascinating to see that at least some of nature’s vast catalog of proteins can be evolved — with only a few mutations — to efficiently create chemical bonds not known in biology and that the new biocatalysts can access areas of the chemical space that biology has not explored.

 

The future for biocatalysis is bright – companies embrace the technology to replace wasteful stoichiometric processes and catalytic processes that rely on costly and unsustainable rare metals (4,5). As the community continues to discover and develop new enzymes, the applications of biocatalysts for sustainable chemical production will grow. This year, our lab has explored a wide range of natural protein diversity to develop useful enzymes with wide-reaching applications. Through this, we have demonstrated that nature has the capacity to quickly produce and optimize catalysts for novel reactions — all we have to do is ask the right question and then evolve.

 

Citations:

  • (1) Wang, Z. J.; Renata, H.; Peck, N. E.; Farwell, C. C.; Coelho, P. S.; Arnold, F. H. Angew. Chem. Int. Ed. Engl. 2014, 53, 6810-6813.
  • (2) Hernandez, K. E.; Renata, H.; Lewis, R. D.; Kan, S. B. J.; Zhang, C.; Forte, J.; Rozzell, D.; McIntosh, J. A.; Arnold, F. H. ACS Catalysis. 2016, 6, 7810-7813.
  • (3) Kan, S. B.; Lewis, R. D.; Chen, K.; Arnold, F. H. Science. 2016, 354, 1048-1051.
  • (4) Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Science. 2010, 329, 305-309
  • (5) Bornscheuer, U. T.; Huisman, G. W.; Kazlauskas, R. J.; Lutz, S.; Moore, J. C.; Robins, K. Nature. 2012, 485, 185-194.
  • (6) Stelter, M.; Melo, A. M. P.; Pereira, M. M.; Gomes, C. M.; Hreggvidsson, G. O.; Hjorleifsdottir, S.; Saraiva, L. M.; Teixeira, M.; Archer, M. Biochemistry. 2008, 47, 11953-11963.

 

 

“The Nexus Blog” is a sister publication of “The Nexus” newsletter. To sign up for the newsletter, please email gci@acs.org, or if you have an ACS ID, login to your email preferences and select “The Nexus” to subscribe.

 

To read other posts, go to Green Chemistry: The Nexus Blog home.

News Roundup Dec31-Jan13.jpg

The Importance of the Circular Economy in Business

January 9, 2017 | Green Biz

Rather than solely using a bottom line (even a triple bottom line) and largely linear approach to growth and development, we must imagine, analyze and quantify how circular growth augments our conventional business models.

 

Using Biomimicry to Make Artificial Spider Silk

January 9, 2017 | Forbes

An international team of scientists has devised artificial silk that becomes a slim yet tough fiber, with help from a machine designed to mimic the spinning spiders do naturally. The silk isn’t quite as strong as the real thing, but the researchers have a few ideas for fine-tuning the technology so it can move a step closer to the market.

 

New Tech from Carbon Clean Solutions Cuts the Cost of CO2 Capture and Utilization

January 8, 2017 | Quartz India

Carbon Clean Solutions built a plant in Tuticorin in southern India that captures carbon dioxide from its coal-fired boiler and converts it into soda ash. The commercial-scale plant, set to capture 60,000 tons of CO2 annually, does it so cheaply that it did not need any government subsidies.

 

The E factor 25 Years On: The Rise of Green Chemistry and Sustainability

January 7, 2017 | Royal Society of Chemistry Journal

Following an introduction to the origins of green chemistry and the E factor concept, the various metrics for measuring greenness are discussed. It is emphasized that mass-based metrics such as atom economy, E factors and process mass intensity (PMI) need to be supplemented by metrics, in particular life cycle assessment, which measure the environmental impact of waste and, in order to assess sustainability, by metrics which measure economic viability.

 

Nanowires Offer Low-Cost Printed Electronics

January 5, 2017 | IEEE Spectrum

Researchers at Duke University have discovered that silver nanowires are able to achieve the desired level of conductivity for printed circuits without needing to be heated to the point where they would harm the less expensive substrates.

 

Hairprint is Nontoxic by Nature, and by Design

January 5, 2017 | San Francisco Chronicle
Hairprint is the first hair care company to receive the Made Safe certification — an independent third-party nontoxic certification program that puts products through a rigorous screening to test for potentially harmful ingredients.

 

Natural Catalyst Mimics Nature to Break Tenacious Carbon-Hydrogen Bond

January 4, 2017 | Phys.org

A new catalyst for breaking the tough molecular bond between carbon and hydrogen holds the promise of a cleaner, easier and cheaper way to derive products from petroleum, says a researcher at Southern Methodist University, Dallas.

 

 

“The Nexus Blog” is a sister publication of “The Nexus” newsletter. To sign up for the newsletter, please email gci@acs.org, or if you have an ACS ID, login to your email preferences and select “The Nexus” to subscribe.

 

To read other posts, go to Green Chemistry: The Nexus Blog home.

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