Green chemistry, or sustainable chemistry, is the strategic drive towards green and sustainable practices in the chemical industry that aims to achieve a dual goal of greater efficiency and reduced waste.
View our full list of green and sustainable chemistry resources including case studies and industry examples. This white paper demonstrates how real-time data provided by advanced technology from METTLER TOLEDO supports green and sustainable chemistry in the research, development, and production of pharmaceutical, chemical, and polymer molecules and products.
The 12 Principles of Green Chemistry were developed in the late 1990s by chemists who wanted to make chemical processes safer and more sustainable. Following these guidelines in your lab can help you minimize your environmental footprint. A great thing about these principles is that they can be implemented anywhere from small labs to large industrial operations.
Prevent Waste: Design chemical syntheses to prevent waste, as it is better to prevent than to treat or clean up. This is a foundational principle for sustainable chemistry.
Maximize Atom Economy: Maximize the proportion of starting materials that are incorporated into the final product. This minimizes waste by ensuring few or no atoms are wasted.
Design Less Hazardous Chemical Syntheses: Use and generate substances with little to no toxicity to humans or the environment. This reduces risk at the source.
Design Safer Chemicals and Products: Develop chemical products that are fully effective and perform their desired function while having minimal toxicity.
Use Safer Solvents and Reaction Conditions: Avoid using auxiliary substances like solvents, or use safer alternatives. Running reactions at room temperature and pressure also increases energy efficiency.
Increase Energy Efficiency: Minimize the energy requirements of chemical processes to reduce both environmental and economic impact. Use ambient temperature and pressure when possible.
Use Renewable Feedstocks: Utilize raw materials that are renewable rather than depletable. Agricultural products and waste streams are often sources of renewable feedstocks.
Avoid Chemical Derivatives: Minimize the use of temporary modifications like blocking or protecting groups. These steps require additional reagents and generate unnecessary waste.
Use Catalysts, Not Stoichiometric Reagents: Employ catalytic reagents that are selective and effective in small amounts, as they are superior to stoichiometric reagents, which are used in excess and produce more waste.
Design Chemicals and Products to Degrade After Use: Create chemical products that break down into innocuous substances at the end of their function, preventing them from persisting in the environment.
Analyze in Real Time to Prevent Pollution: Develop analytical methodologies for real-time monitoring and control during syntheses to prevent the formation of hazardous byproducts. Process analytical technology (PAT) solutions are key to this principle.
Minimize the Potential for Accidents: Choose chemicals and their physical forms to minimize the risk of chemical accidents, including explosions, fires, and environmental releases.
“Green chemistry is the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances. Green chemistry applies across the life cycle of a chemical product, including its design, manufacture, use, and ultimate disposal.”
Environmental Protection Agency (EPA)
Developing efficient, sustainable, and often novel products and processes requires in-depth knowledge and precise control. In many ways, achieving green chemistry’s dual goal of efficiency and reduced waste means performing smarter chemistry. Access to detailed time-course data and fine parameter control requires the right tools.
One of the most active trends in green chemical production is Quality by Design (QbD), and one of the main tenets of QbD is the requirement to build expansive reaction and process understanding through online, real-time process analytical technology (PAT). Thus, QbD is a driver for real-time reaction analysis technology development. Furthermore, the information and process understanding that can be gleaned from the comprehensive data provided by real-time reaction analysis is greatly enhanced by the application of modeling and data analytic methods that make full use of data-rich experiments (DRE).
Another trend in green chemistry is the rapidly evolving development of new syntheses (and converting older chemistry) using continuous flow methods, which offer several advantages in terms of productivity and sustainability. Flow chemistry is best served by reaction analysis technology that provides uninterrupted, continuous measurements. Real-time analysis technology including online FTIR, Raman, Ultraviolet-visible (UV/Vis), NIR, NMR, HPLC, and MS are all routinely used to analyze flow chemistry and to ensure the stability and performance of flow systems. Also, real-time analysis enables the development of self-optimization systems for reactions and processes.
"Sustainable chemistry is a scientific concept that seeks to improve the efficiency with which natural resources are used to meet human needs for chemical products and services. Sustainable chemistry encompasses the design, manufacture, and use of efficient, effective, safe, and more environmentally benign chemical products and processes."
OECD, 2022 (Organisation for Economic Co-operation and Development)
Process analytical technology (PAT), such as in-situ FTIR and FBRM, has been a key driver for green chemistry research, allowing scientists and engineers to monitor and control reactions and processes in real time. The rich analytic data obtained provides valuable insight into reaction kinetics, physical transformations, and the effect of variables on performance, enabling scientists and engineers to make data-backed decisions that support green chemistry principles.
Of course, none of this is possible without precise control. Researchers have used automated synthesis workstations to accurately control and record all the major tasks performed around a reactor (temperature, stirring, dosing, and sampling) without any manual intervention. Conducting reactions in silico offers yet another way to reach sustainability goals, allowing scientists to screen solvents, determine optimal conditions, and test new ideas using artificial intelligence and statistics.
For over three decades, METTLER TOLEDO has developed powerful PAT and reaction analysis tools to support R&D and scale-up of green chemical syntheses and robust processes. The ability to automatically monitor, sample, and control reactions in real time around the clock and quickly turn experimental data into actionable information has revolutionized scientific inquiry. The pressing need to do more with our existing resources and reduce waste now requires leveraging these same tools to drive green and sustainable research, development, and production across the chemical industry.
Challenge: Investigate and develop a greener process for spherical particle formation and granulation of ethyl vanillin.
The synthetic flavor ethyl vanillin is widely used in a variety of consumer products, but practical challenges related to storage and caking hinder its further large-scale application. Preferentially forming spherical particles can mitigate these issues, making downstream processing more efficient and resulting in enhanced product quality. However, standard methods for spherical crystallization often involve dangerous and expensive organic solvents. This work describes the development of an oiling-out spherical agglomeration technology that eliminates the need for organic solvents, providing a greener and more cost-effective process. Researchers used process analytical technologies to investigate the oiling-out phenomenon of ethyl vanillin in aqueous solution. Mechanistic insight gained from monitoring changing solute concentration via FTIR (ReactIR), as well as particle count and morphology via EasyViewer and ParticleTrack G400 (FBRM-based probe) enabled the preferential formation of spherical particles in an aqueous solution of sodium chloride using a straightforward heating and quenching process. The resulting ethyl vanillin spherical product has excellent powder properties, high flowability and high yield, making it not only more environmentally friendly to produce, but also a higher quality product.
“In view of the current problems of too fast aroma release rate and poor powder properties of ethyl vanillin, this work systematically investigates the oiling-out phenomenon and the formation mechanism of spherical particles of ethyl vanillin in an aqueous solution. With the help of process analytical technologies (ATR-FTIR, FBRM and EasyViewer), two types of oiling-out phenomena of ethyl vanillin in water are found to occur with temperature changes. Further, the results of IR spectra showed that the intrinsic reason for the appearance of two oiling-out phenomena of ethyl vanillin in water is the switching of different kinds of intermolecular hydrogen bonds induced by solvation…Spherical particles of ethyl vanillin are successfully prepared in the aqueous solution of sodium chloride by the oiling-out spherical agglomeration technology. This green technology eliminates the use of hazardous solvents and combines the two unit operations of crystallization and granulation, which is especially suitable for the food industry.”
Liu, Y., Wang, S., Li, J., Guo, S., Yan, H., Li, K., Tong, L., Gao, Y., Li, T., Chen, M, Gao, Z. & Gong, J. (2023). Preparation of Ethyl Vanillin Spherical Particles With Functions of Sustained Release and Anti-caking by an Organic Solvent-Free Process. Food Chemistry, 402, 134518. https://doi.org/10.1016/j.foodchem.2022.134518
Challenge: Develop a more efficient and safer ketone oxidation reaction using oxygen – a green, low-cost reagent.
Using oxygen as an oxidant is environmentally attractive, but poses safety risks when conducted in batch due to the potential combustion of solvent vapors in reactor headspace. Fava et. al. conceptualized and developed a continuous flow approach to the aerobic oxidation of a ketone intermediate in the synthesis of the anti-tumor API, AZD4635, effectively mitigating this risk. Ketone oxidation was promoted by a copper acetate catalyst in DMSO solvent, and the effect of reactor temperature, catalyst loading, and gas flow rate were investigated. Data obtained via ReactIR provided key insight into the relationship between temperature and conversion, enabling easy optimization of reaction temperature. Implementing the optimized continuous flow reduced the overall API synthesis to three steps (as opposed to five in batch), yielding a safer, greener, and more economical process.
“Having changed the concentration, we reoptimized the reaction temperature. To obtain real-time analytical data, we implemented a Mettler Toledo ReactIR 15 instrument equipped with a flow cell that was incorporated at the outlet of the continuous-flow setup. To reduce the background noise due to oxygen bubbles in the cell, a membrane separator was introduced between the outlet of the reactor and the flow cell. IR spectra for 3 [ketone] and 4 [oxidized product] showed different absorption bands at 1689 cm−1 and 1675, 1693 cm−1, respectively. The relative conversion could therefore be monitored in real time, and by varying the temperature, we found that the oxidation proceeded with excellent conversion at 120 °C, while lower temperatures led to incomplete conversion.”
Fava, E., Karlsson, S., & Jones, M. D. (2022). Using Oxygen as the Primary Oxidant in a Continuous Process: Application to the Development of an Efficient Route to AZD4635. Organic Process Research & Development, 26(4), 1048–1053. https://doi.org/10.1021/acs.oprd.1c00279
Challenge: Develop a more sustainable chemical method for synthesizing fluorinated compounds using rhodium and iridium complexes as catalysts. Measure reaction times and determine the effects of aryl substitution on fluorination rates.
The pharmaceutical industry has increased strategic interest in developing clean catalytic methodologies to synthesize fluorinated compounds. In 2020, 37% of all small molecule pharmaceuticals approved by the FDA contained at least one fluorine moiety – a marked increase from 26% between 2011 and 2020. However, common existing synthetic methods often require the use of highly reactive fluorinated reagents. Researchers assessed the activity of recently discovered organometallic complexes towards catalytic fluorination and developed an efficient protocol for using [(η5,κ2C-C5Me4CH2C6F5CH2NC3H2NMe)-RhCl] to catalyze fluorination of a range of acyl chlorides, as the fluoride donor. The developed protocol resulted in excellent yield (94%) in a little as one hour and enabled recovery of the catalyst, further increasing the atom economy of the synthesis. In-situ FTIR (ReactIR) measurements verified the clean conversion of substrates to products, as well as provided the rich time-course data for necessary for computational investigation leading to a proposed a mechanism involving the formation of a new Rh–F bond.
Morgan, P.J., Saunders, G.C., Macgregor, S.A., Marr, A.C. & and Licence, P. (2022). Nucleophilic Fluorination Catalyzed by a Cyclometallated Rhodium Complex. Organometallics, 41, 883−891. https://doi.org/10.1021/acs.organomet.2c00052
Challenge: Develop a greener synthetic route for an opioid antagonist molecule using an electrochemical-based synthesis. Gain insight into the mechanism of the oxidation of a N-CH3 group to an iminium.
Increased demand for lifesaving medications that can reverse opioid drug overdose has led to a significant increase in their price. Recent research aimed at reducing production costs via more efficient synthetic routes has focused on the most challenging steps in the preparation of many opioid antagonists—the selective N-demethylation of a 14-hydroxymorphinan precursor. At large scale, N-demethylation is carried out with stoichiometric amounts of hazardous chemicals such as cyanogen bromide or chloroformates. Researchers developed a catalyst- and reagent-free electrochemical method for the N-demethylation step based on the two-electron anodic oxidation of the tertiary amine, thereby providing a far more sustainable and inexpensive approach. Initial reaction condition screening using the electrolysis of oxycodone in an undivided cell at room temperature as model was carried out. Using a graphite anode and stainless-steel cathode in acetonitrile with LiClO4 as the supporting electrolyte achieved 29% conversion to oxazolidine with very good selectivity. In-situ FTIR provided real-time monitoring of the iminium ion, leading to a proposed mechanism for the electrochemical oxazolidination and demethylative O,N-acyl transfer of several important opioid precursors. The developed protocol has been transferred to a flow electrolysis cell, enabling scale-up.
“…direct observation of the iminium ion by infrared spectroscopy was also attempted, again using the “cation pool” methodology. In this case, an FTIR probe was immersed in the anodic chamber of the divided cell. Oxycodone derivative 6-oxyodol, with the ketone group reduced to an alcohol, was used as the substrate to eliminate interference of the carbonyl signal from the IR. Gratifyingly, under electrolysis, a weak peak appeared at ca. 1657 cm–1 that could be ascribed to the C═N stretch of the intermediate. The weak signal observed supported the hypothesis that the iminium cation is not sufficiently stable at −45 °C.”
Glotz, G., Kappe, C. O., & Cantillo, D. (2020). Electrochemical N-Demethylation of 14-Hydroxy Morphinans: Sustainable Access to Opioid Antagonists. Organic Letters, 22(17), 6891–6896. https://doi.org/10.1021/acs.orglett.0c02424
Challenge: Develop a green, robust and highly efficient process for synthesizing enantiomerically-pure hexenoates.
Enantiomerically pure (3R)-3-hydroxyl-5-hexenoates (1) are important chiral intermediates in the synthesis of a variety of pharmaceutical compounds. Synthetic strategies for accessing (1) based on chemical methods hanve significant drawbacks related to productivity and sustainability. Biocatalysis offers a sustainable alternative. The dual-enzyme system composed of a mutant KRED (i.e., KRED-06) and Lactobacillus kefir alcohol dehydrogenase (LkADH) coupled with in-situ cofactor recycling provides excellent yield and enantioselectivity of (1), but practical issues for industrial application remain.
To address these issues, researchers developed a green continuous-flow process to produce (1) by co-immobilizing KRED/LkADH into a polyvinyal alcohol (PVA) carrier via entrapment and loading it into a tubular reactor with inline microfluidic liquid-liquid extraction and membrane separation units. Testing of different carriers revealed that PVA yielded the highest catalytic activity as well as mechanical and physical stability. Subsequent rapid optimization leveraged inline FTIR and GC-MS analysis. ReactIR was used to establish that steady state was reached after the reaction stream exited the flow reactor and that ideal plug flow was formed inside the flow reactor, confirming that the reaction solution was well-distributed while flowing through the packed KRED/LkADH@PVA.
“Rapid flow reaction optimization was carried out by exploiting inline FTIR monitoring and GC−MS analysis. The continuous-flow synthesis with the model substrate can afford a marked process intensification in comparison with the corresponding batch reaction... The results of this work not only underline the robustness and usefulness of KRED/ LkADH@PVA but also provide a greener and more sustainable continuous-flow process for highly efficient production of enantiomerically pure (3R)-hydroxyl-5-hexenoates that can be readily realized at scale.
Hu, C., Huang, Z., Jiang, M., Tao, Y., Li, Z., Wu, X., Cheng, D., & Chen, F. (2021). Continuous-Flow Asymmetric Synthesis of (3R)-3-Hydroxyl-5-hexenoates with Co-Immobilized Ketoreductase and Lactobacillus kefir Dehydrogenase Integrating Greener Inline Microfluidic Liquid–Liquid Extractors and Membrane Separators. ACS Sustainable Chemistry & Engineering, 9(27), 8990–9000. https://doi.org/10.1021/acssuschemeng.1c01419
Challenge: To eliminate the harsh reaction conditions and aggressive reagents used for methylation of organohalides, a new approach was developed that uses trimethyl orthoformate as the methyl source in a nickel/photoredox catalysis.
This novel approach to methylation of organohalides can be performed under relatively mild conditions, without aggressive or highly toxic chemicals, using the common organic reagent trimethyl orthoformate as the source of the methyl group and is consistent with the goals of green chemistry. ReactIR and NMR support the ß-scission mechanism for the reaction.
Once the scope of the reaction was thoroughly explored, the mechanism of the reaction was investigated via in-situ FTIR. Tracking the reaction indicated that dimethyl carbonate and 4'-methylacetophenone are generated in a 1:1 ratio, from the 4'-chloroacetophenone starting material. Quantitative 13C NMR also showed that the formation of the products was in a 1:1 ratio. The IR and NMR experiments were considered to be indicative of overall non-zeroth order kinetics. The formation of stoichiometric quantities of dimethyl carbonate byproduct is consistent with a ß-scission mechanism.
Kariofillis, S. K., Shields, B. J., Tekle‐Smith, M. A., Zacuto, M. J., & Doyle, A. G. (2020). Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source. Journal of the American Chemical Society, 142(16), 7683–7689. https://doi.org/10.1021/jacs.0c02805
Real-time analysis uses modern probe-based technology that can be placed directly into process streams to enable analytical profiling of the material during the reaction. Some examples of real-time analysis technology include:
