Expansion of the Green Chemistry Principles: Inclusion of Greenhouse Gases and Carbon Footprint

Abstract

There is growing agreement among scientists that the world may face catastrophic climatic developments in the coming decades, caused primarily by the massive emission of greenhouse gases such as CO₂ and methane. Many governments are already beginning to face the challenge on how to manage and minimize the calamitous effects. The topic is a complex interplay of many facets, and the sheer size of the successive meetings of the Conference of Parties─UN Climate Change, with tens of thousands of attendees, bears witness that the management of the ongoing climate change will require a massive input of creative ideas and resources. The topic is central to the ability of humans to survive on Earth, so minimization and mitigation of climate change will be the driver for several decisions in the next decades. It is clear that we are at the beginning of a new modern industrial revolution which will completely change the way we live and how our economies function. The coming decades will experience a massive shift to renewable energies, with replacement of energy-intensive chemical manufacturing processes such as the Haber–Bosch ammonia synthesis and the petrol-based polymer industry by renewable materials and sustainable technologies. We will also have to find strategies on how to deal with limiting supplies of critical elements such as P, Pd, and Li, and critically, the construction industry will have to find replacements for concrete. These are massive challenges and will amount to a new analogous industrial revolution that requires unabated efforts in defining our future economies that will alter the fabric of our societies. Health (new medicines) and materials (to improve living standards) are central to modern human existence. Transforming science, engineering, and technologies should play a critical role by providing solutions and new opportunities. Toward this end, chemistry will play a vital and decisive role as the central science, since the material world is dependent on finite chemical resources on and within Earth. We need to acknowledge the fact that the ability of humankind to continue living on this planet depends on chemists and their creativity to bring forward solutions. The chemical community should responsibly and proudly embrace this responsibility. How will all these demands effect the production and affordability of medicines? Let us look at how the existing processes and prevailing industrial revolution will affect the production of different types of medicines and what the decarbonized industrial landscape will mean for the manufacture of these. One should never forget that medicines should not only extend patients’ lifetimes but also improve the quality of our lives. Medicines cover a vast range of different modalities, each associated with characteristic production technologies. Very importantly, all technologies are associated with widely varying business models. Let us keep in mind that the economics of a recently launched, patent-protected antibody–drug conjugate has nothing in common with that of a blood-pressure-lowering generic medicine available in the market for decades. The sharply different economic models have stark consequences, and it is regrettable that both public and private companies blur this line in communication. This confusion may be explained by the fact that the preparation of a classical generic medicine is done using the same sophisticated high technology by highly skilled experts, often in the factory of the inventor next to an innovative new drug with a very different business model behind it. However, it is also a fact that the preparation of generic medicines is not a high-margin business. New modalities are highly complex─the effort required to prepare an antibody–drug conjugate is massively more complex than that for production of a classical drug. Similar complexity exists for a small synthetic oligonucleotide, where the synthesis of a building block alone requires more synthetic effort than for many small-molecule drugs. The intricacies require the extensive use of energy and solvents that generate vast amounts of waste─in other words, it is far from being benign and sustainable. While ideas abound on how to improve the sustainability of biologics, oligonucleotides, and peptides, it is fair to say that these modalities will never become easy to produce, and they will always have a problematic carbon footprint. It is likely that modern biomolecular medicines will be used when they provide therapeutic benefits in wealthy societies, despite their high cost and poor environmental footprint. From a global point of view, one can look at these as a luxury that society decides to indulge in. The vast majority of medicines in all countries, irrespective of their wealth, are still the classical drugs. Essentially, these are small-molecule drugs, usually prepared solely by chemical routes or by chemical derivatization of a natural product made by fermentation or by isolation from a plant. While every year pharmaceutical research adds new compounds to the list, the number of essential medicines is largely fixed. (1) These drugs will be prescribed to patients for years and decades to come, simply because they offer an efficient, efficacious, safe, cost-effective, and proven way to treat diseases. Small-molecule medicines are the bedrock of our medical system. It is thus important to focus on how they are produced and what we can expect for the production in the future. Many important medicines were discovered beginning in the middle of the last century, and their discovery reflects the chemistry available at that time. Enabling innovative reactions led to accessing vast chemical space in new drugs, such as the Suzuki coupling leading to biaryl drugs. The structures of the target drugs also reflect the chemistry and the starting materials available at the time of their discovery. It is no surprise that almost all available starting materials stem exclusively from geological petrol via the steam cracker, meaning that the bulk of our important medicines result from old chemistry with deep origin in fossil fuels. While it is important to fully follow the value chain back to the basic starting materials, it is not sufficient to go back in a synthesis to, e.g., thiophene to realize that thiophene is prepared in a high-temperature gas-phase reaction from butadiene and sulfur to arrive at the root of the material. Only a full knowledge of the value chain allows full control and risk management. The business drive to rely on starting materials of increasing complexity has created opaque supply chains with an inherently higher risk, as the global supply of a drug may depend on a tiny number of factories preparing a specific chemical. We currently do not have a full global picture of the supply chain for our essential drugs, risking the supply recklessly. This is the opposite of a diversified and derisked supply chain, something societies should demand given the importance of drugs for our health. A look into a complex global supply chain going back to petroleum-based chemistry that was developed decades ago does not bode well for the resulting carbon footprint of the production of medicines. This is reflected in the statistics that the production of drugs is perhaps responsible for approximately 1% of the global CO₂ emissions. (2,3) Access to medicines will be challenged by an important additional hurdle. The chemical feedstock was shifted from coal tar to petrol more than 100 years ago, and we are currently witnessing a new shift away from petrol to bio-based and renewable materials. This change is necessary and will provide functional equivalents to many of the products that we use in our daily lives. Replacing terephthalic acid with the corresponding furan-based dicarboxylic acid will result in an essentially functional equivalent polymer, which is bio-derived and biodegradable, i.e., independent of petrol as a starting point. Similar substitution of a phenyl group with a furan will not work for a pharmaceutical drug and is not that simple. The structures of the medicines that are the bedrock of our medical system cannot be altered without significant impact on their biological function, and we will need to continue producing them even when the whole supply chain has switched from petrol-based to bio-based products. Chemistry in general, but especially process chemistry, will be the central science to enable the transformation of supply chains toward sustainability. (4) Organic process research and development is the science that allows the safe, reliable, and economic preparation of bulk amounts of drugs in high quality while maintaining a very high environmental standard. It is important to note that this science is neither practiced nor generally taught at universities─its art is almost exclusively practiced in industrial laboratories. This creates a strange situation where industry hires university graduates who were trained in relevant areas but different from what is central to process chemistry and then trains them to become process chemists. There is also a growing disconnect between the perception of challenges in academia and what is necessarily important for industrial process research. This may have been unproductive and undesirable in the past, but it has to change now. Industry simply does not have the skills or the means to drive the shift from a petrol-based supply chain to one based on bio-derived starting materials. Industry certainly will not be able to discover sustainable reagents and reaction conditions for a large set of transformations or to find catalysts based on first-row transition metals (available in abundant amounts on our planet). It will be decisive for the academic world, too, to embrace such great challenges and to focus on delivering solutions. Overall, we will need a fundamental change in the way chemistry is taught, challenges are defined, and research is done, both in universities and industry─but rightly, it has to start in academia. Many things will have to change to achieve this goal. The concept of green chemistry was put forward over 25 years ago. Paul Anastas and John Warner coauthored the groundbreaking book Green Chemistry: Theory and Practice, (5) and it is a fascinating exercise to reread the book for all the insight and wisdom that came with the creation and definition of green chemistry. The holistic concept has shaped the chemistry discussion for the last two decades, and the 12 principles of green chemistry are put up in many chemists’ offices. It is striking to see the wisdom of the principles of green chemistry asking for the design of biodegradable products when we are facing a global crisis because of the pollution caused by the “forever” chemicals. The world would be in a much better state had the warnings been heeded earlier. Nevertheless, after 25 years it is important to reflect on whether we need an update of the 12 principles of green chemistry. From today’s perspective, one could argue that it is not necessarily true that catalysis is always better than a resolution, e.g., if one compares a dynamic resolution with concomitant racemization to an Ir-catalyzed reaction requiring a high catalyst loading. The 12 principles put a strong emphasis on the safety and toxicity of chemicals. The well-being of everyone working with chemicals is paramount, but it is possible to work with very toxic chemicals safely when the appropriate measures are taken. A good example is the industrial synthesis of the amino acid methionine, which is made on huge scale from HCN, acrolein, and methanethiol, all of which are very toxic and dangerous compounds. Chemists and chemical engineers know how to handle dangerous chemicals, and their use should be encouraged when they enable production with a decreased carbon footprint. We believe that an update of the 12 principles of green chemistry is needed for the topic of drug substance production and that this update must provide strong quantitative guidance allowing an objective and quantifiable measure for sustainability. We therefore propose the following three principles of green chemistry for API production: Understand the supply chain. Fully map and understand the synthesis of an API going back all the way to the basic starting materials (steam cracker, fermentation product) and include all reagents and catalysts in this analysis. Evaluate the greenhouse gas emissions. Determine full greenhouse gas output for all routes going back to the basic starting materials (6) and use this output as a new metric to evaluate a synthetic procedure in addition to traditional approaches such as PMI, yield, number of steps, and cost. Minimize environmental impact, including greenhouse gases. Invent chemistry that enables short preparation of drug substances with minimal greenhouse emissions. What differentiates these three principles from the conventional way of working? The first rule will create full transparency by creating the awareness of the real and objective complexity of a route. It has become a bad habit to start chemistry with the “commercially available starting material” without answering the question of what effort was invested to prepare that material. Such a strategy is problematic because it obscures the real impact of a route and outsources the synthetic challenge to an unknown producer with an unknown CO₂ and environmental footprint. The second rule provides the metrics by which we have to measure our activities in organic chemistry. It is an old adage that one has to measure things when one wants to change them. The classical metrics in organic chemistry had been the number of steps and the overall yield from a commercial starting material, and these metrics simply do not capture what is mandatory for chemists to deliver in order to achieve the required decarbonization. What is currently missing is an agreed system that allows the calculation of the CO₂ footprint with relative ease and in a globally consistent and agreed manner. Such a system will get away from “greenwashing”, where the pretense of an environmentally good approach is created. The third rule asks for a radical change the way chemists work. Curiosity-driven research to answer fundamental questions is important and needs to continue, maybe even much more than currently allowed by the academic funding system. One may regret it, but much publicly funded research has been done for some purpose designed to ultimately bring economic benefits to the country funding the research. Virtually any natural product synthesis will argue that the compound to be synthesized possesses some virtuous properties and that the total synthesis is necessary in order to benefit from the properties of the compound. The reality is that the compound was synthesized because the chemist considered the compound to be interesting and it allowed the researcher to develop and demonstrate new synthetic strategies and to demonstrate her or his creativity, inventiveness, and persistence at solving very challenging problems. In order to achieve the decarbonization of API production, it will be necessary to bring the same scientific brilliance to our real-world problems. The questions concern “industrial” research, as they have a practical underpinning, but they have nothing to do with the often-used image of industrial research as a minor tweaking of known methods for economic gains. The challenges are daunting. It is a good assumption that the production of all of our medicines is working close to the optimum in the frame of the known chemistry, and there is little benefit in minor changes. We have to invent chemistry that does not exist and is not imagined today, which demands not just a gradual change or improvement but a reinvention of what is possible. Moreover, failure is not an option─we must succeed in decarbonizing the production of medicines, and we need to change the raw material basis from petrol-based to bio-based materials. We must do this for real─just greenwashing is not good enough. Is there a simple recipe for finding the answers? The authors think that there is. Natural product chemistry flourished because the brightest and most ambitious organic chemists went into the tough field. Funding agencies should do the same with medicines: ask for novel approaches that allow scientists to shine with the metrics of minimized carbon footprint. It is sure that the chemical community will come with solutions that we cannot even imagine today. Giving human creativity resources in the form of funding while defining strict metrics of what needs to be achieved will provide the answers we need, just as it always has throughout humankind’s history. Bio-based starting materials are central to decarbonizing the chemical industry and making it sustainable. The focus is naturally on the preparation of materials that will find use in bulk products, based on the correct assumption that the biggest steps to decarbonization can be achieved by replacing the current petrol-based starting materials and products with new components that are bio-derived. The number of compounds that can be derived efficiently and effectively from straw or wood, from efficient fermentation, and from creative enzymic approaches is steadily increasing in an impressive manner. The new developments will provide a new set of available starting materials, just as the steam cracker changed what was available from coal-tar-derived chemistry. What will be needed is the translation of these compounds with efficient methods into what should be the foundation of new chemistry leading to medicines. This is far from trivial. We are facing a grand challenge that must be solved to secure the supply of medicines to patients in the decades to come. We can be optimistic that the chemical community has the skills to rise to the challenge and that politics has understood the need, so that funding agencies will support this research. A key aspect is that politics and funding agencies must create and define a globally accepted and uniform system to measure CO₂ emission in order to enable a strict application of objective metrics. Such a system is a prerequisite, and global funding agencies should see to the establishment of such as system. Innovation in the field of medicines is often protected by patents, which allow the patent grantee to stop others from applying the invention. The search for new drugs depends on the ability to protect the invention with a patent, as this is the way to justify the highly risky and expensive investment to look for new drugs. The situation is different for the production of generic medicines. Margins are much lower, and there should be an incentive to have the lowest-carbon-footprint technologies widely known and widely used. A potential solution to this need would be compulsory licensing under fair and equitable terms to all producers that meet a set of social and environmental standards. We believe that the goal of decarbonizing and securing the production of medicines for the coming generations can be achieved. The political decision is basically quite simple: funding agencies need to ask for research addressing technologies for sustainable API production but strictly using the three principles for sustainable API production as guidance. The technical challenge is everything but simple and will require innovation of the highest level─but chemists thrive on tough challenges and have an excellent track record for delivering solutions. We have all reason to be optimistic─we just need to start the journey. This article references 6 other publications. U.S. healthcare causes ca. 7% of U.S. emissions of CO₂. See: Of these emissions, 14% are emitted as result of drug production (tenofovir as an example). 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