The first green chemistry metrics - the E-Factor and Atom Economy (AE) - were introduced in the early 1990s. However, such mass-based metrics needed to be augmented by metrics that measure the environmental impact of waste, originally referred to as the Environmental Quotient, EQ. Various metrics for assessing the sustainability of chemicals such as life cycle assessment (LCA) and for assessing economic viability are discussed. The development of a sustainable bio-based production of chemicals meshes fits well with the concept of a circular economy, based on resource efficiency and waste minimization by design, to replace traditional linear, take−make−use−dispose economies.

The invention of the E-Factor in 1992 was a game-changing moment in the development of sustainability and green chemistry that completely changed our perception of waste. Prior to this revolutionary event waste management was focused on waste remediation. The E-Factor focused attention on the amount of waste formed, in particular the prodigious amounts formed in the manufacture of fine chemicals, such as flavors and fragrances and active pharmaceutical ingredients. It resulted in a paradigm shift in the concept of an efficiency in chemical processes, from an indicator based solely on yield to one that assigned value for eliminating waste.

The general perception in the early seventies was that catalytic reactions in aqueous media employing water-soluble organometallic complexes of transition metals to produce commodity chemicals could not take place despite (1) the discovery in 1827 of the first water-soluble transition metal complex, Zeise’s salt, K[PtCl3(η-C2H4)]·H2O [1] and (2) the industrial application in 1959 of water-soluble cobalt sulfonated phthalocyanine catalytic complexes in the UOP Extractive Merox™ thiols oxidation process for upgrading oil refining products [2]. Notwithstanding these early contributions, in 1974 two groups independently showed that water-soluble organometallic complexes of transition metals can catalyze different reactions in this green aqueous reaction medium. The group of F. Joó and M.T. Beck carried out the aqueous-phase hydrogenation of pyruvic acid to lactic acid catalyzed by water-soluble Ru/TPPMS complexes [TPPMS, sodium salt of monosulfonated triphenylphosphine, PPh2(C6H4-m-SO3Na)], while E.G. Kuntz at Rhône-Poulenc achieved the proof of principle showing that the hydroformylation of propene to butyraldehydes catalyzed by water-soluble Rh/TPPTS complexes [TPPTS, sodium salt of trisulfonated triphenylphosphine, P(C6H4-m-SO3Na)3] can be done on a laboratory scale in aqueous/organic biphasic systems. The industrial scale aqueous/organic two-phase propene hydroformylation process using a water-soluble Rh/TPPTS catalyst was developed after successful pilot plant scale tests in 1984 by Cornils et al. at Ruhrchemie which is well known as the Ruhrchemie/Rhône-Poulenc (RCH/RP) process [3], [4]. This first major success was followed by additional industrial biphasic processes that, today, have led to an exponential increase of new applications of several water-soluble transition metal complexes modified by numerous ligands, such as sulfonated and carboxylated phosphines, phosphines containing hydroxy and ether functionalities, phosphines with amino, ammonium, phosphonium, phosphonate and phosphate moieties, sulfonated amines, phthalocyanines, porphyrins, phospholes and thioethers or sulfone-based phosphines, and nitrogen-containing ligands. Also included are tenside ligands that catalyze diverse reactions, such as hydroformylations of lower, midrange, higher and functionalized olefins, hydrocarboxylations, carbonylations, alternating copolymerizations of olefins with CO to polyketones, hydrogenations, hydrogenolyses, oxidations, epoxidations, dehydrations, isomerizations, epimerizations, ring-openings, alkylations, and telomerizations, etc. to produce commodity chemicals in aqueous/organic two-phase systems [3]. [...]

The chemical industry of the future will use waste, as carbon dioxide, lignocellulose, plastic and food waste, as the raw material and renewable electricity as the energy source. In order to achieve this lofty goal it is essential to have simple and reliable metrics for measuring and assessing waste. The most well-known metric used for this task is the E-Factor. Other possible mass-related metrics, such as process mass intensity (PMI) are discussed. Energy is also mass-related and can be measured in kgs of CO2 equivalents and as such incorporated in the E-Factor. It will also be essential to identify renewable vs non-renewable energy used in the process.

Keto reductases are crucial NAD(P)H-dependent enzymes used for the enantioselective synthesis of alcohols from prochiral ketones. Typically, the NADPH cofactor is regenerated through a second enzyme and/or substrate. However, photocatalytic cofactor regeneration using water as a sacrificial electron and hydrogen donor presents a promising alternative, albeit a challenging one. Herein we fabricated several nitrogen-doped carbon dots (CDs) with visible light absorption properties, good water solubility and biocompatibility for photocatalytic regeneration of NADPH. The CD with a smaller size and suitable redox potential gave the highest NADPH yield (55.7 %). Based on this, NADPH-dependent aldo-keto reductase crosslinked aggregates (AKR-CLEs) were initially applied as a stable biocatalyst to reduce the prochiral ketone. (S)-1-(2-Chlorophenyl) ethanol, an intermediate for LPA1R antagonists, was obtained in 65.3 % yield and 99.99 % enantiomeric excess (ee) under visible light irradiation. The isotope tracer experiment confirmed that water is the hydrogen donor in this light-driven, photo-enzymatic asymmetric hydrogenation system. This method is useful for the sustainable synthesis of chiral alcohols. Moreover, the general principle of utilizing water as the sacrificial hydrogen and electron donor holds potential for application in other redox cofactor regeneration systems.

Enzymatic reductions catalyzed by reductases generally depend on reduced nicotinamide cofactors as a hydride source. However, for industrial viability, it is more cost-effective to use water as the hydrogen source, bypassing the requirement for the cofactor. Here we report a hybrid photo-biocatalyst system based on infrared (IR) light and responsive reductive graphene quantum dots (rGQDs), for performing the direct transfer of hydrogen from water to prochiral substrates. The photo-biocatalyst, assembled from rGQDs and cross-linked aldo-keto reductase (AKR), mediates the synthesis of the pharmaceutical intermediate, (R)−1-[3,5-bis(trifluoromethyl)-phenyl] ethanol ((R)−3,5-BTPE), in 82% yield and >99.99% ee under IR illumination. Our photo-enzymatic systems can also be effectively used to drive the enzymatic reduction of imines and alkenes. Since the hybrid photo-biocatalysts are insoluble, they can be readily recovered and recycled. This work opens new avenues to create artificial photo-biocatalyst systems, enabling the facile coupling of renewable solar energy and sustainable chemical production.

The development of sustainable chemistry underlying the quest to minimize and/or valorize waste in the carbon-neutral manufacture of chemicals is followed over the last four to five decades. Both chemo- and biocatalysis have played an indispensable role in this odyssey. in particular developments in protein engineering, metagenomics and bioinformatics over the preceding three decades have played a crucial supporting role in facilitating the widespread application of both whole cell and cell-free biocatalysis. The pressing need, driven by climate change mitigation, for a drastic reduction in greenhouse gas (GHG) emissions, has precipitated an energy transition based on decarbonization of energy and defossilization of organic chemicals production. The latter involves waste biomass and/or waste CO2 as the feedstock and green electricity generated using solar, wind, hydroelectric or nuclear energy. The use of waste polysaccharides as feedstocks will underpin a renaissance in carbohydrate chemistry with pentoses and hexoses as base chemicals and bio-based solvents and polymers as environmentally friendly downstream products. The widespread availability of inexpensive electricity and solar energy has led to increasing attention for electro(bio)catalysis and photo(bio)catalysis which in turn is leading to myriad innovations in these fields.

The design and orderly layered co-immobilization of multiple enzymes on resin particles remain challenging. In this study, the SpyTag/SpyCatcher binding pair was fused to the N-terminus of an alcohol dehydrogenase (ADH) and an aldo-keto reductase (AKR), respectively. A non-canonical amino acid (ncAA), p-azido-L-phenylalanine (p-AzF), as the anchor for covalent bonding enzymes, was genetically inserted into preselected sites in the AKR and ADH. Employing the two bioorthogonal counterparts of SpyTag/SpyCatcher and azide–alkyne cycloaddition for the immobilization of AKR and ADH enabled sequential dual-enzyme coating on porous microspheres. The ordered dual-enzyme reactor was subsequently used to synthesize (S)-1-(2-chlorophenyl)ethanol asymmetrically from the corresponding prochiral ketone, enabling the in situ regeneration of NADPH. The reactor exhibited a high catalytic conversion of 74 % and good reproducibility, retaining 80 % of its initial activity after six cycles. The product had 99.9 % ee, which that was maintained in each cycle. Additionally, the double-layer immobilization method significantly increased the enzyme loading capacity, which was approximately 1.7 times greater than that of traditional single-layer immobilization. More importantly, it simultaneously enabled both the purification and immobilization of multiple enzymes on carriers, thus providing a convenient approach to facilitate cascade biocatalysis.

The designed and ordered co-immobilization of multiple enzymes for vectorial biocatalysis is challenging. Here, a combination of protein phase separation and bioorthogonal linking is used to generate a zeolitic imidazole framework (ZIF-8) containing co-immobilized enzymes. Zn2+ ions induce the clustering of minimal protein modules, such as 6-His tag, proline-rich motif (PRM) and SRC homology 3 (SH3) domains, and allow for phase separation of the coupled aldoketoreductase (AKR) and alcohol dehydrogenase (ADH) at low concentrations. This is achieved by fusing SpyCatcher and PRM-SH3-6His peptide fragments to the C and N termini of AKR, respectively, and the SpyTag to ADH. Addition of 2-methylimidazole results in droplet formation and enables in situ spatial embedding the recombinant AKR and ADH to generate the cascade biocalysis system encapsulated in ZIF-8 (AAE@ZIF). In synthesizing (S)-1-(2-chlorophenyl) ethanol, ater 6 cycles, the yield can still reach 91%, with 99.99% enantiomeric excess (ee) value for each cycle. However, the yield could only reach 72.9% when traditionally encapsulated AKR and ADH in ZIF-8 are used. Thus, this work demonstrates that a combination of protein phase separation and bio-orthogonal linking enables the in situ creation of a stable and spatially organized bi-enzyme system with enhanced channeling effects in ZIF-8.

Effective photolytic regeneration of the NAD(P)H cofactor in enzymatic reductions is an important and elusive goal in biocatalysis. It can, in principle, be achieved using a near-infrared light (NIR) driven artificial photosynthesis system employing H₂O as the sacrificial reductant. To this end we utilized TiO₂/reduced graphene quantum dots (r-GQDs), combined with a novel rhodium electron mediator, to continuously supply NADPH in situ for aldo-keto reductase (AKR) mediated asymmetric reductions under NIR irradiation. This upconversion system, in which the Ti-O-C bonds formed between r-GQDs and TiO₂ enabled efficient interfacial charge transfer, was able to regenerate NADPH efficiently in 64 % yield in 105 min. Based on this, the pharmaceutical intermediate (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol was obtained, in 84 % yield and 99.98 % ee, by reduction of the corresponding ketone. The photo-enzymatic system is recyclable with a polymeric electron mediator, which maintained 66 % of its original catalytic efficiency and excellent enantioselectivity (99.9 % ee) after 6 cycles.

The pressing need to mitigate climate change and drastically reduce environmental pollution and loss of biodiversity has precipitated a so-called energy transition aimed at the decarbonization of energy and defossilization of the chemical industry. The goal is a carbon-neutral (net-zero) society driven by sustainable energy and a circular bio-based economy relying on renewable biomass as the raw material. It will involve the use of green carbon, defined as carbon derived from terrestrial or aquatic biomass or organic waste, including carbon dioxide and methane emissions. It will also necessitate the accompanying use of green hydrogen that is generated by electrolysis of water using a sustainable source of energy, e.g. solar, wind or nuclear. Ninety per cent of the industrial chemicals produced in oil refineries are industrial monomers that constitute the precursors of a large variety of polymers, many of which are plastics. Primary examples of the latter are polyolefins such as polyethylene, polypropylene, polyvinyl chloride and polystyrene. Polyolefins are extremely difficult to recycle back to the olefin monomers and discarded polyolefin plastics generally end up as the plastic waste that is responsible for the degradation of our natural habitat. By contrast, waste biomass, such as the lignocellulose contained in forestry residues and agricultural waste, constitutes a renewable feedstock for the sustainable production of industrial monomers and the corresponding polymers. The latter could be the same polyolefins that are currently produced in oil refineries but a more attractive long-term alternative is to produce polyesters and polyamides that can be recycled back to the original monomers: a paradigm shift to a truly bio-based circular economy on the road to a net-zero chemical industry.

The increasing role of biocatalysis in the green and sustainable manufacture of chemicals is discussed. In the last two decades the breadth and scope of biocatalysis has increased enormously as a result of remarkable advances in metagenomics, protein engineering and bioinformatics. Moreover, the use of enzymes has become more cost-effective through advances in immobilization technologies and the application of the immobilized enzymes in continuous flow operation in packed bed reactors. Consequently, biocatalysis is already the method of choice for the synthesis of enantiopure chiral products for the pharmaceutical and fine chemical industries. Further applications in commodity chemicals manufacture are currently being stimulated by the increasing maturity of biocatalysis and the ongoing transition to a bio-based circular economy based on the valorization of organic waste on the road to net zero manufacturing.

The introduction of the E Factor in 1992 focussed attention on the problem of waste generation, defined as everything but the desired product, in chemicals manufacture and gave rise to a paradigm shift in our concept of efficiency in chemical processes, from one based solely on chemical yield to one that assigns value to eliminating waste. Thirty years later, it has become clear that waste is the underlying cause of the major global environmental problems, from climate change to plastic pollution and that the solution to this ubiquitous waste problem is pollution prevention at source enabled by green and sustainable chemistry. The role played by (bio)catalysis, alternative solvents, the emergence of a carbon neutral circular economy based on renewable resources and the electrification of chemicals manufacture based on renewable energy in the drive towards pollution prevention and sustainable industries is delineated.

The discovery that enzymes could function efficiently in organic solvents revolutionized their use in industry but represented a change from the natural “green” solvent, water, to a host of environmentally undesirable solvents. Considerable effort is being devoted to making such processes greener again. Bio-based solvents, derived from waste biomass, possess the desirable attributes of traditional organic solvents but are more conducive to a circular bio-based economy. Although biocatalytic oxidations have only been tested in bio-based ether solvents, there is considerable scope for expanding this to include bio-based ester solvents. Alternatively, both ionic liquids and deep eutectic solvents, with tunable properties, are proving very interesting solvents for biocatalytic oxidations. In particular, oxidative depolymerization of lignin, catalyzed by laccases, has been extensively investigated. Finally, designer amphiphiles can facilitate the formation of micelles that act as hydrophobic nanoreactors for performing biocatalytic oxidation processes while surrounded by aqueous buffer as solvent.

The use of engineered ketoreductases (KREDS), both as whole microbial cells and isolated enzymes, in the highly enantiospecific reduction of prochiral ketones is reviewed. The homochiral alcohol products are key intermediates in, for example, pharmaceuticals synthesis. The application of sophisticated protein engineering and enzyme immobilisation techniques to increase industrial viability are discussed.

Two non-canonical amino acids (ncAAs) with bio-orthogonal reactive groups, namely, p-azido-l-phenylalanine (p-AzF) and p-propargyloxy-l-phenylalanine (p-PaF), were genetically inserted into an aldo-keto reductase (AKR) and an alcohol dehydrogenase (ADH), respectively, at two preselected sites for each enzyme. The variants were expressed in the genome recoded bacterium Escherichia coli C321.ΔA. Supernatants of the individual cell lysates were subsequently mixed to produce orderly combi-crosslinked enzymes (O-CLEs) of AKR and ADH by co-polymerization of the two variants through their reactive bio-orthogonal groups. The site-specific cross-linked enzymes (S-CLEs) and cross-linked enzyme aggregates (CLEAs) were produced using dibenzocycloocta-4a,6a-diene-5,11-diyne (DBA) and glutaraldehyde as the crosslinking agent, respectively. The catalytic efficiencies of the O-CLEs, S-CLEs and combi-CLEAs were determined using the water soluble dihydro-4, 4-dimethyl-2, 3-furandione as a surrogate substrate in aqueous solution at 37 °C. The O-CLEs exhibited the highest catalytic efficiency (K_cat/K_M = 11.36 S⁻¹ mM⁻¹) that was 4.24 and 22.27 times that of S-CLEs and combi-CLEAs, respectively. In the asymmetric cascade synthesis of (R)-1-(2-chlorophenyl) ethanol the product yield after 14 h using the O-CLEs, S-CLEs and the combi-CLEAs was 93%, 55% and 16%, respectively. Moreover, high activities and selectivity (ee > 99.99%) were maintained at high substrate concentrations in prolonged operation.

In the movement to decarbonize our economy and move away from fossil fuels we will need to harness the waste products of our activities, such as waste lignocellulose, methane, and carbon dioxide. Our wastes need to be integrated into a circular economy where used products are recycled into a manufacturing carbon cycle. Key to this will be the recycling of plastics at the resin and monomer levels. Biotechnology is well suited to a future chemical industry that must adapt to widely distributed and diverse biological chemical feedstocks. Our increasing mastery of biotechnology is allowing us to develop enzymes and organisms that can synthesize a widening selection of desirable bulk chemicals, including plastics, at commercially viable productivities. Integration of bioreactors with electrochemical systems will permit new production opportunities with enhanced productivities and the advantage of using a low-carbon electricity from renewable and sustainable sources.

Acylated Morita-Baylis-Hillman (MBH) adducts were synthesised and subjected to enzymatic kinetic resolution (EKR) by hydrolysis employing various lipase enzymes: from P. fluorescens, P. cepacia (PCL), C. antarctica A (CAL−A), C. antarctica B (CAL−B) and Novozyme 435. In a number of instances enantiopure Morita-Baylis-Hillman acetates or butyrates and their corresponding hydrolysed MBH adducts were obtained with ee values of >90 %, at ca. 50 % conversion, corresponding to enantiomeric ratio (E) values of >200. Enantioselective transesterification reactions on MBH adducts was achieved using acyl anhydrides in THF or the greener organic solvent 2-MeTHF in the presence of CAL−A. This is the first report of successful lipase-catalysed EKR of aromatic MBH adducts by transesterification in organic medium.

The increasingly apparent negative impact of human activities on the environment has heightened the urgency for the chemistry community to adopt greener and more sustainable practices. The E-factor can still be considered a valuable tool in this drive, particularly because of its broad acceptance and familiarity amongst both industrial and academic chemists. An important factor in broadening the adoption of green principles is ensuring that the academics responsible for training the next generation of chemists prioritise green and sustainable practices in their undergraduate and post graduate laboratories. Green metrics must be easy to use to motivate the broader chemistry community to develop greener syntheses. For maximum impact to be achieved the detail of the exact green metrics applied are less important than their adoption by the broader chemical community. Of growing importance is the replacement of fossil resources with renewable alternatives to reduce greenhouse gas emission that is a significant driver of climate change. The C factor is used to compare the carbon footprints of different routes to a particular product.

The covalent immobilisation of enzymes generally involves the use of highly reactive crosslinkers, such as glutaraldehyde, to couple enzyme molecules to each other or to carriers through, for example, the free amino groups of lysine residues, on the enzyme surface. Unfortunately, such methods suffer from a lack of precision. Random formation of covalent linkages with reactive functional groups in the enzyme leads to disruption of the three dimensional structure and accompanying activity losses. This review focuses on recent advances in the use of bio-orthogonal chemistry in conjunction with rec-DNA to affect highly precise immobilisation of enzymes. In this way, cost-effective combination of production, purification and immobilisation of an enzyme is achieved, in a single unit operation with a high degree of precision. Various bio-orthogonal techniques for putting this precision and elegance into enzyme immobilisation are elaborated. These include, for example, fusing (grafting) peptide or protein tags to the target enzyme that enable its immobilisation in cell lysate or incorporating non-standard amino acids that enable the application of bio-orthogonal chemistry.