Perspective Cite This: J. Org. Chem. 2019, 84, 4580−4582
pubs.acs.org/joc
Greening Organic Chemistry with Process Chemistry Kai Rossen* H. Lundbeck A/S Ottiliavej 9, 2500 Valby, Denmark
J. Org. Chem. 2019.84:4580-4582. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 04/19/19. For personal use only.
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by the chemist who understands both the chemistry and the societal needs that have to be addressed. Unfortunately, needs are not always for positive reasons, and sometimes even the fulfillment of positive needs incurs unintended consequences. The perception of chemistry in general and organic chemistry in particular began to turn negative beginning in the 1960s. Many times, business decisions were made that emphasized economic gain over other considerations. Chemical production gone awry and environmental contamination of the environment gave the public the feeling that chemistry is primarily harmful and responsible for many societal ills. As a consequence, two types of responses developed, as the economic and societal needs for products resulting from the chemical processes remained unchanged. The first response, coming from outside the chemical community, was increasing regulatory oversight, not just for production processes but also by more closely examining the fate of chemicals ending up in the environment. The combination of public demand for responsible chemistry, the regulatory codification of this demand, and the awareness of the chemical community for the need to minimize environmental impact have made chemical production much safer and less polluting than it has ever been. It is a positive development that this emphasis on responsible chemistry has now become global today. The second response, which came from within the chemical community, was the coinage of the term “Green Chemistry” by Paul Anastas and John Warner in 1997.7 Their book is fascinating reading, as it clearly describes the dichotomy in which we chemists operate. The book defines 12 Principles (Figure 4.1, p 30) outlining how chemists should think and do better. These principles have helped sensitize the chemical community to the fact that we practitioners share responsibility both for the products we design and make and the way we make them and, thus, need to be cognizant of their short- and long-term health and environmental impacts, regardless of their usefulness to society. Although Anastas and Warner deserve credit for increasing awareness of the ideas of “Green Chemistry”, the concepts are rooted in the approaches industrial process chemists have taken for a significantly longer time.8 Some 20 years after the publication of “Green Chemistry”, it may be time for us to look again at these concepts and apply them in a manner that will lead to further progress. I believe that Green Chemistry is synonymous with well-executed and practiced process chemistry and is also equivalent to “cost efficient”. Cost efficiency is easily construed to imply the irresponsible
fter having been an industrial process chemist for more than 30 years, I was honored to be asked to share my personal view of organic process chemistry, the subset of organic chemistry that scales up reactions to industrially useful volumes, for this Special Issue “Excellence in Industrial Organic Synthesis 2019.” Oftentimes the visibility of industrial chemistry research is limited, not making it onto journal pages but instead appearing in patentsif it appears anywhere publiclybecause of the proprietary nature of the work. Indeed, industrial chemists are often discouraged or even prevented from publishing their research. Academic chemists, on the other hand, often do not peruse the patent literature. This “lack of communication” dampens the advancement of chemistry research and development to a certain degree. That is why a Special Issue in an academic journal focusing on research carried out in industry is important to help open new channels for communication. I think it is important to step back and look at what organic chemistry is all abouta brief look at the past is instructive for looking toward the future. Organic chemistry is inherent in Nature. In its most basic sense, life on Earth is a complex and fascinating exercise of nonequilibrium applied organic chemistry. Nature uses organic chemistry to achieve function. Microorganisms, plants, and animals in turn invest heavily in organic chemistry to gain advantages for survival.1 As we have evolved, humans have used whatever was at our disposal to improve our chances for survival and well-being. In this context, we have used large-scale organic chemistry for millennia in a purely utilitarian manner without understanding the underlying processes. For at least 9000 years people have utilized biotechnological processes to prepare aqueous ethanolic solutions from various sources of sugar that increase our chances of survival by improving social interactions.2 Documented use of plant extracts by Chinese physicians to treat malaria goes back over 2000 years.3 The Vikings were only able to travel in ships from Europe to North America some 1000 years ago because of the large-scale production of tar from wood.4 The knowledge of craftsmen and alchemists of a bygone era was not scientific by today’s standards, but a deep and sophisticated knowledge enabled them to use organic chemistry on scale to achieve practical benefits. The shift toward fundamental understanding of science for knowledge’s sake began in the 18th century and developed rapidly during the 19th century. Curiosity to understand the functioning of our world was a key driver. But applications, both for the creation of wealth and for the power of the state, may have been even more important. An incredibly insightful analysis of Marcellin Berthelot in 1887 described chemistry as being able to create its own objectsalmost at willso that chemistry is more than just a descriptive science but a creating art.5,6 This ability to create is the real power of chemistry: Chemistry is able to provide function and purpose as created © 2019 American Chemical Society
Special Issue: Excellence in Industrial Organic Synthesis 2019 Received: February 1, 2019 Published: April 19, 2019 4580
DOI: 10.1021/acs.joc.9b00344 J. Org. Chem. 2019, 84, 4580−4582
Perspective
The Journal of Organic Chemistry
academic researchers and be complemented by a set of costs used all over the world.17 This tool would allow all organic chemists to use a common language for “cost”, which, since all principles would carry a cost, would equate for “greenness”. It would have to provide a universal guidance for the many cost contributions to a process, such as the starting materials and reagents and catalysts, solvents, penalty for energy-consuming reaction conditions, waste disposal, etc. When used systematically, such a program will also help to answer the frequently debated question of which synthetic route is “best”not necessarily the one with the least number of steps or the highest yield, but indeed the “greenest” (and by inference the cheapest). More important, it could help teach students on which aspects to consider to “green” their chemistry. A second proposal toward good communication between academia and industry centers on publications. The series of articles from pharmaceutical process research groups that are in this Special Issue is a positive example. Such articles bring topics and strategies to the attention of academic researchers that can be a starting point for further dialogue and that also demonstrate the very high level of scientific quality of the work performed in industrial settings. Communication also needs a continuous forum, and in that regard, the ACS journal Organic Process Research & Development, for which I am happy to serve as Editor-in-Chief, has benefited the process chemistry community for more than 20 years. Research that describes large-scale applications of organic syntheses, the great science that is necessary to prepare complex organic compounds on scale, and the strategic and tactical aspects of achieving the “greenest” process possibleall are excellent fits to OPR&D. The two ACS journals JOC and OPR&D complement each other and, I hope, benefit both academic and industrial communities and thus ultimately organic chemistry. Academic chemists will continue to be at the forefront of scientific innovation, including the very important generation of knowledge without immediately obvious applications. Industrial process chemists will continue to steer the field into practical use of those innovations that pass the green and sustainable test and lead to more economical chemistry with reduced environmental impact to deliver products needed by society. Both types of chemists have roles to play, and the more they speak to each other the more impact their work will have on the field as a whole. By embracing cost-driven/green chemistry thinking into organic synthesis, we have the opportunity to develop our field into a positive direction and maybe even help to change the public consciousness to develop the positive image that chemistry, in general, and organic chemistry, in particular, deserve based on their positive contributions to society.
avoidance of costs for waste disposal, energy, safety measuresor the use of raw materials produced under such conditions. The clear learning from both the Green Chemistry Principles and societally implemented regulations is that such behavior is simply not acceptable in the 21st century. To serve as a meaningful tool to guide research and development into a more positive direction, a holistic view of the entire process, including its scale, is critical. A single elegant and efficient step might result in a Green Chemistry claim in a publication, but if the starting materials were prepared using chemistry that resulted in large waste loads, then the overall process is not really “green”.9−11 Looking at the 12 Principles of Green Chemistry individually shows their limitations. For example, it is simply not correct that a catalytic reaction is always superior and “greener” than a classical resolution or the application of a readily available classical auxiliary. The separation of enantiomers by a classical resolution can lead to highly cost-effective and “green” processes, especially when the resolution can be performed as a crystallization-driven asymmetric transformation. When we accept the requirements of Green Chemistry we must consider that the compound we are manufacturing on scale has passed a benefit/risk assessment as being desirable to manufacture and meets the regulatory requirements for a chemical to be produced. Strict metrics using a holistic cost assessment are needed to guide us beyond the original 12 Principles of Green Chemistry, which are very valuable, but are largely qualitative. As cost accurately reflects all impacts, using cost is also more meaningful than other metrics, such as Process Mass Intensity (PMI), that have become popular lately but do not fully account for expensive but low mass reagents or catalysts.12,13 A further “greening” of organic chemistry will require the tools and expertise of the process chemistry community to perform cost calculations that reflect true cost assessment. It is fair to say that Green Chemistry has already been fully embraced by many industries.14 Indicative of this is the ACS Green Chemistry Institute’s Pharmaceutical Roundtable and Chemical Manufacturers Roundtable, where global players come together to foster the application of green chemical principles in industry and look toward greener, and ultimately also cheaper approaches. Chem21, a related public-private partnership managed by the European Union (as part of the Innovative Medicines Initiative), has invested significant resources in companies and in academic institutions all over Europe in order to develop better chemistry with less environmental impact. These initiatives have helped to increase communication between the worlds of academia and industry and increase the awareness for the need for Green Chemistry also in academia.15,16 Good communication between the (largely) industrial community of process chemists and the academic community is of importance not only to solve the continuously evolving challenges of designing inexpensive, and hopefully “green,” routes but also for the training of the new generation of scientists in these principles. There are two points that I would like to propose to foster such communication. First, I would like to challenge the community of industrial process chemists and engineers to provide guidance to the academic community about the “costs” of a process from beginning to end. A good starting point could be the recently published quantitative cost-calculation and route evaluation tool of Wuitschik, which could possibly be simplified for use by
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kai Rossen: 0000-0002-3857-0004 Notes
The author declares no competing financial interest. 4581
DOI: 10.1021/acs.joc.9b00344 J. Org. Chem. 2019, 84, 4580−4582
Perspective
The Journal of Organic Chemistry Biography
Changing the Synthetic Route. Chem. Rev. 2006, 106 (7), 3002− 3027. (11) Leng, R. B.; Emonds, M. V. M.; Hamilton, C. T.; Ringer, J. W. Holistic Route Selection Org. Org. Process Res. Dev. 2012, 16 (3), 415−424. (12) Constable, D. J. C. Green Chemistry Metrics. JOURNAL 2018, 1. (13) Li, J.; Albrecht, J.; Borovika, A.; Eastgate, M. D. Evolving Green Chemistry Metrics into Predictive Tools for Decision Making and Benchmarking Analytics. ACS Sustainable Chem. Eng. 2018, 6 (1), 1121−1132. (14) Veleva, V. R.; Cue, B. W.; Todorova, S. Benchmarking Green Chemistry Adoption by the Global Pharmaceutical Supply Chain. ACS Sustainable Chem. Eng. 2018, 6 (1), 2−14. (15) Green Chemistry Institute. https://www.acs.org/content/acs/ en/greenchemistry/industry-roundtables/pharmaceutical.html/ (accessed Mar 9, 2019). (16) Innovative Medicines Initiative. https://www.imi.europa.eu/ (accessed Mar 9, 2019). (17) Kaiser, D.; Yang, J.; Wuitschik, G. Using Data Analysis To Evaluate and Compare Chemical Syntheses. Org. Process Res. Dev. 2018, 22 (9), 1222−1235.
Dr. Rossen has worked over 30 years in process research in the pharmaceutical industry and is currently Vice President of Process Chemistry of Lundbeck A/S in Copenhagen in addition to being Editor-in-Chief of the journal Organic Process Research & Development. Photo: Alec Tremaine Photography
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REFERENCES
(1) Armaly, A. A.; DePorre, Y. C.; Groso, E. J.; Riehl, P. S.; Schindler, C. S. Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin. Chem. Rev. 2015, 115 (17), 9232−9276. (2) McGovern, P. E.; Zhang, J.; Tang, J.; Zhang, Z.; Hall, G. R.; Moreau, R. A.; Nuñez, A.; Butrym, E. D.; Richards, M. P.; Wang, C.s.; Cheng, G.; Zhao, Z.; Wang, C. Fermented beverages of pre- and proto-historic China. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (51), 17593−17598. (3) Tu, Y. ArtemisininA Gift from Traditional Chinese Medicine to the World (Nobel Lecture. Angew. Chem., Int. Ed. 2016, 55, 10210−10226. (4) Hennius, A. Viking Age tar production and outland exploitation. Antiquity 2018, 92, 1349−1361. (5) Berthelot, M. (1827−1907), Chemist, historian, philosopher, and statesman: A retrospective view on the centenary of his death. Chem. Educator 2007, 12 (3), 195−206. (6) La chimie crée ́ son objet. Cette faculté créatrice, semblable celle de l’art lui-même, la distingue essentiellement des sciences naturelles et historique. Marcelin Berthelot, La Synthèse Chimique; Alcan: Paris, 1887. (7) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press, 1998. (8) Farbwerke vorm. Meister Lucius & Brüning 1863−1913. Hausdruckerei der Farbwerke in Höchst am Main, 1913. Pages 16 and 17 describes how over 150 years ago, in 1867, the German “Meister Lucius & Brüning Farbwerke” Company in Frankfurta forerunner of Hoechst AG, which was up until the 1990s one of the world’s largest pharma, agro, and chemical companiesintroduced a “greener” process for the preparation of the red dye fuchsine. Fuchsine was at the time an economically very important product, and by replacing the arsenic acid which until then had been used to make it, a “greener” process was achieved. In 1913, a book commemorating the company’s 50th anniversary described how the company used an outside expert to argue for obtaining the permission of the authorities and made arguments very familiar to the ones described in the twelve principles of Green Chemistry of 1997. The improved process even resulted in a “green chemistry” award at the 1873 world exhibition in Vienna. (9) Zhang, T. Y. Process Chemistry: The Science, Business, Logic, and Logistics. Chem. Rev. 2006, 106 (7), 2583−2595. (10) Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.; Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W. Critical Assessment of Pharmaceutical Processes A Rationale for 4582
DOI: 10.1021/acs.joc.9b00344 J. Org. Chem. 2019, 84, 4580−4582
