How Green is Biocatalysis? - Wiley Online Library

CHEMCATCHEM MINIREVIEWS DOI: 10.1002/cctc.201300976

How Green is Biocatalysis? To Calculate is To Know Yan Ni,[a, b] Dirk Holtmann,[c] and Frank Hollmann*[a] Dedicated to Prof. Manfred T. Reetz on the occasion of his 70th birthday

Introduction Green chemistry aims to minimize the environmental hazards of chemical processes and their products. Ever since its introduction by Anastas,[1] this principle has inspired researchers to critically rethink chemistry in view of its potential impact on the environment. Especially, the 12 Principles of Green Chemistry have been an inspiring guideline for this process.[1] Biocatalysis is widely considered as one of the key technologies fulfilling the 12 principles and thereby being green chemistry per se. The reader will recognize stereotypical boilerplate statements such as “enzymes as renewable and biodegradable catalysts”, “working under environmentally benign conditions (temperature, pH, etc.)”, and “operating in water as an environmentally benign solvent” frequently found in the introductory passages to biocatalysis publications. Indeed, these are important parameters that can make biocatalysis environmentally more acceptable than “classical” chemical methods, provided the advantages are not (over)compensated by the disadvantages. Unfortunately, the latter are discussed to a much lesser extent. We also noted a certain tendency to pick a few of the 12 principles to underline the greenness of the method published, which certainly is in contrast to the envisioned use of the 12 principles as a cohesive system.[1] We believe that the time is now to transition from just claiming environmental benefits of (bio)catalysis to quantifying the environmental impact. Indeed, the potential of biocatalysis as a tool to make chemical processes greener has been demonstrated by a limited number of studies.[2] These studies mostly comprise the life-cycle assessment (LCA) of the processes. Unfortunately, LCAs are still rather complex and work intensive. Therefore, LCAs are appreciated by industry to evaluate existing processes (and to use the positive result as a selling [a] Dr. Y. Ni, Dr. F. Hollmann Department of Biotechnology Delft University of Technology Julianalaan 136, Delft (The Netherlands) Fax: (+ 31) 15278-1415 E-mail: [email protected] [b] Dr. Y. Ni State Key Laboratory of Bioreactor Engineering East China University of Science and Technology 200237 Shanghai (China) [c] Dr. D. Holtmann DECHEMA Research Institute Biochemical Engineering Group Theodor-Heuss-Allee 25 60486 Frankfurt am Main (Germany)

2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

argument), whereas research-oriented academic groups generally do not possess the expertise, resources, and interest to perform LCAs. As a result, sustainability issues are often addressed in the phase of manuscript preparation as described above. We believe that on the long term, careless, qualitative use of the term green chemistry will discredit the concept. Therefore, with this contribution we wish to promote the use of simple metrics to assess the environmental footprint of a given method in a semi-quantitative way. To calculate is to know (better). Sheldon proposed the E factor (environmental factor) to assess the greenness of a given reaction.[3] The E factor denotes the amount of waste generated per product equivalent [Eq. (1)].

E¼

mwaste mproduct

ð1Þ

On the one hand, the E factor not only gives an indication of the wastes generated, but it also gives an indication of the resources consumed (not incorporated into the product). On the other hand, the E factor neither includes energy use nor does it discriminate between different waste qualities (such as harmless and toxic wastes). Despite these shortcomings, the E factor is easy to understand and simple to apply. Therefore, we are convinced that scientists should use the E factor to assess the environmental impact of their reactions. Of course, simple metrics such as the E factor have severe limitations.[4] For example, the quality will not be the same for any waste generated. It is easy to understand that the same amounts of water, (halogenated) hydrocarbons, and acute toxins will have different impacts on the environment, and thus a more detailed evaluation of the E factor is necessary. In principle, this can be achieved by the so-called weighting factor Q, which is obtained by weighing the hazards a compound can have on the environment.[5] However, a full evaluation of the potential environmental impact (PEI) of every waste generated is rather time-consuming and often also rather subjective. Therefore, we prefer to use the E factor and to evaluate the PEI qualitatively. Another shortcoming of the E factor lies in its negligence of the energy consumed. Despite all (justified) criticism of the E factor as a “primitive” mass-balance-based metric, it is increasingly used, especially in ChemCatChem 2014, 6, 930 – 943

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Scheme 1. a) Chemical, two-step preparation of enantiopure (S)-styrene oxide compared to b) the biocatalytic route. StyAB = styrene monooxygenase expressed in Escherichia coli.

the pharmaceutical industry (which is traditionally most waste intensive), and it is also used in academic studies.[6] An interesting investigation was reported by Bhler and coworkers in which the environmental impact of various routes to enantiopure styrene oxide was compared (Scheme 1).[6b] At first sight, the chemical routes appeared to be less eco-efficient owing to their multistep nature and the fact that in the first step racemic styrene oxide was formed, from which, a maximum yield of 50 % of the enantiopure product was obtained by kinetic resolution. In contrast, the biocatalytic route yielded the enantiopure product in 100 % yield by using molecular oxygen as the oxidant. However, a quite different picture evolved from careful quantitative analysis of the different routes. In absolute numbers, the two chemical routes are significantly less waste intensive than the biotechnological process, which is mostly due to the water needed for the biotransformation. However, even if water is excluded from the calculation, the biotechnological process (3.42) lies in between the two chemical processes (1.71 and 5.73, respectively). The picture changed to some extent upon weighing the environmental impact of the single components. Particularly, the role of water is relativized if compared to problematic components such as dioctyl phthalate (used as a second organic phase in the biotechnological process). Still, the general trends observed in the simple E factor analysis (Figure 1) are also found in the more advanced (time-consuming) analysis. This motivated us to further explore the E factor at the example of biocatalytic redox reactions published recently.

How Green is Water as a Solvent? In biocatalysis, water certainly is the solvent used most frequently. At the same time, water is generally accepted to be a green solvent, as it causes no environmental concern.[9] This also is the reason why water is traditionally excluded from the E factor. This assumption is certainly true for pure water; however, contaminated water (even by low concentrations of problematic chemicals or microorganisms) is of environmental concern and needs treatment/purification prior to release into the environment. Any treatment will contribute negatively to the overall eco-efficiency of a given process. Therefore, we prefer not to categorically exclude water from E factor calculations. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Figure 1. Chemical, two-step preparation of enantiopure (S)-styrene oxide (top) compared to the biocatalytic route. A) Ti–silicate route,[7] B) MnSO4 route,[8] C) biocatalytic process.[6b] The contributions are water (yellow), styrene (red), 1-phenyl-1,2-ethanediol (green), and “miscellaneous” (blue, i.e., the cumulative contributors with single values of less than 1).

The effect of reagent concentration One major drawback of water as a solvent in (bio)catalytic transformations is its high polarity in contrast to the hydrophobic nature of many reactants of interest. Unfortunately, this apparent conflict is generally solved by the application of very low reagent concentrations, often in the lower millimolar range. Quite expectedly, the E factor of a given reaction (including water) directly correlates to the initial substrate concentration (Figure 2). Generally, water contributes more than 90 % to the E factor of the examples shown in Figure 2. If water is excluded, the correlation between substrate concentration and the E factor is much less pronounced, as other factors such as the concentrations of the enzyme and buffer significantly interfere, as does the yield. The E factor contributions of the buffers range between < 0.1 and 4 (depending on the substrate concentration), ChemCatChem 2014, 6, 930 – 943

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Figure 2. E factors of aqueous biotransformations correlated to the initial substrate concentration. The “outliers” shown in light grey represent examples with less than 75 % conversion.

and contributions from cofactors such as NAD(P) are mostly in the order of 0.05. The contribution of the enzymes is often very difficult to estimate, as many authors tend to use activitybased specifications such as U or U mL1 (to which, quite frequently, it is not clear to what substrate and what reaction conditions these values apply). A more standardized, clear, and reproducible reporting system would be highly appreciated.[10] Nevertheless, the enzyme contribution generally lies between 0.1 and 5. Again, substrate concentration and yield are the most important parameters. However, it is easy to understand that the contribution of the aforementioned contributors can also be reduced if the product amount is raised while keeping the other amounts constant. Overall, the question arises how to increase the product-to-reagent ratio to decrease the E factor. In the following, some solutions will be discussed. Neat reactions/water-deficient reaction media The best solvent is no solvent,[9a] especially if all reaction components end up in the final product (perfect atom economy),[11] as the E factor would be minimized. This, for example, is true for (catalytic) esterification reactions under neat conditions, which yield water as the sole byproduct.[12] For example, the E factor for the industrial-scale enzymatic production of myristyl myristate is extremely low at less than 0.1, which is in line with the favorable LCA of the process.[13] Next to lipases, hydroxynitrile lyases are also frequently used under water-deficient conditions.[14] The application of redox enzymes under non-aqueous or micro-aqueous conditions lags behind the use of the aforementioned enzymes. Since the pioneering works of Klibanov and co-workers,[15] water-deficient reaction systems have only recently obtained renewed interest. For example, Kroutil and co-workers reported an exceptionally solvent-resistant alcohol dehydrogenase (ADH) from Rhodococcus ruber (ADH-A) that, overexpressed in Escherichia coli, could be applied in up to 99 % organic media with substrate concentrations up to 2 m.[16] Hexane was necessary as the solvent, probably to tailor the hydrophobicity of the reaction medium, which resulted in an overall E factor of approximately 20. More recently, recombi 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 2. ADH-catalyzed Meerwein–Ponndorf–Verley reduction of acetophenone in neat reagents with lyophilized E. coli containing overexpressed Candida parapsilosis ADH (CPCR).

nant ADHs from Candida parapsilosis[17] and Rhodococcus rhodochrous[18] in E. coli, albeit under neat conditions with excellent overall E factors of 2.2 and 0.78, were reported (Scheme 2). Apparently, the water activity of the reaction mixtures plays an important role in the activity and stability of the biocatalysts, and protection of the biocatalyst within the expression host cells also appears to be crucial. Overall, solvent-free reactions represent a highly interesting approach for redox biocatalysis as both environmental and economic features appear to be most promising. This enormous potential, however, is contrasted by the relatively small number of examples, and in-depth knowledge and understanding of the factors influencing the activity and stability of the biocatalysts is still missing. Multiphase reactions Neat or micro-aqueous reaction media are essentially monophasic reaction systems and, therefore, comprise some challenges very similar to those of “traditional” aqueous reaction media. For example, substrate/product inhibition and issues related to the equilibrium of reversible reactions (e.g., ADH-catalyzed transfer hydrogenations) apply to both reaction systems. Furthermore, the insolubility of the nicotinamide cofactors excludes reaction systems necessitating diffusible nicotinamides, for example, in enzyme-coupled monooxygenase reactions. Multiphasic reaction systems in which the biocatalyst-containing reactive phase is in contact with a second phase (solid, liquid, or gaseous) to dissolve the reactants in high concentrations (Scheme 3) may be a suitable solution for many of these issues. The two-liquid-phase-system (2LPS) concept certainly comprises the most popular multiphase system. The hydrophobic substrate is used either neat or dissolved in a suitable solvent as a second, liquid phase to the aqueous, biocatalyst-containing “reactive phase” (Scheme 3). The organic phase serves as a substrate reservoir and product sink at the same time. The 2LPS overall enables high substrate loadings, even if the actual aqueous concentration may be low. This higher loading also leads to significantly reduced overall E factors. Some recent examples of the ADH-catalyzed reduction of a- and b-keto esters compared the performance of purely aqueous reaction conditions with that of the 2LPS.[19] In both cases, the ChemCatChem 2014, 6, 930 – 943

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Scheme 3. General scheme for a multiphase (bio)catalytic transformation. The second phase serves as a substrate reservoir and product sink, which enables overall high payloads of the reagents.

Table 1. Exemplary E factor analysis of an ADH-catalyzed reduction reaction conducted under monophasic conditions and in a 2LPS. E factor [kg kg1] Monophasic Biphasic Solvent water toluene Catalyst ADH (production enzyme) FDH (regeneration enzyme) NAD (Co)substrate HCO2H starting material Coproduct CO2 Buffer[a] Sum

505 0

5.41 1.35

5.05 0.51 0.17

< 0.1 < 0.01 < 0.01

4.43 0

1.16 0.15

0.21 4.9 520.27

0.21 0.06 8.43

[a] calculated as H3PO4.

use of a second phase enabled the authors to increase the overall substrate concentration significantly (by at least 10 times). The dramatic improvements are exemplified in Table 1. Similar improvements we observed for other ADH-catalyzed reactions[20] and in the sulfoxidation of thioanisole catalyzed by whole cells[21] or with the use of isolated peroxidases.[22] Clearly, toluene as a waste product is more problematic than aqueous wastes, which for a full assessment of the environmental impact needs to be taken into account (see below). In addition to the increased substrate loadings, 2LPS are also efficient handles to control the reaction selectivity, to shift thermodynamic equilibria, and to remove reactive toxic products from the aqueous layer. For example, the second phase, if chosen carefully, can selectively extract a coproduct of a reversible reaction and thereby shift the thermodynamic equilibrium towards completion, as demonstrated by Kragl and co-workers for an ADH-catalyzed reduction.[23] Similarly, product extraction can also be used to prevent further reaction of the desired product. Especially in whole-cell biocatalysis (in which various enzyme activities are present in the reaction mixtures), selective extraction was demonstrated to be suitable to accumulate reactive aldehyde intermediates originating from alcohol oxidation[24] and acid reduction[25] (Scheme 4). 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Scheme 4. Use of organic phases to selectively extract hydrophobic aldehydes in alcohol oxidations and acid reductions. In the absence of the organic phases, through-oxidation/reduction was observed.

2LPS can also be used to remove water-labile reactants such as epoxides[6b, 26] and lactones.[27] Overall, 2LPSs bear great potential for environmentally more benign biocatalysis. The increased substrate loadings achievable enable significantly increased productivities and more efficient use of the catalysts. Also, wastes originating from auxiliary materials (such as solvents) can be greatly decreased. Apparently, the nature of the organic phase has a major influence on the environmental impact of the overall reaction. Ideally, the reactants can be applied to the reaction mixture without any additional auxiliaries. If, however, an additional solvent cannot be circumvented its choice should be guided by environmental considerations including the environmental impact of solvent production and disposal.[28] For example, most solvents are not available from the environment but have been synthesized. In the course of these syntheses, resources (energy, materials) are consumed and wastes are generated (for an example, see Scheme 7 below). Furthermore, the choice of solvent may have a significant impact on downstream processing (see below). Overall, choosing a solvent that is the most environmentally acceptable remains a difficult task with many parameters (solvent preparation and disposal as well as its influence on the environmental impact on the reaction of interest) to be taken into consideration. Next to liquid substrate reservoirs/product sinks, solid alternatives (e.g., resins) are also enjoying great interest. The reactant concentration on the aqueous layer can be controlled to minimize toxic effects on the biocatalysts and to remove reactive products. For example, Schmid and co-workers removed reactive and toxic catechols from whole-cell hydroxylations of phenols by means of XAD resins.[29] More recently, Furstoss and co-workers used solid resins to control the in situ concentration of ketones and lactones in whole-cell-based Baeyer–Villiger oxidations.[30] In situ substrate feed and product removal by using solid resins appears to be beneficial from a practical point of view, as the product-containing resin can be recovered by simple filtration. Also, elution of the product and recovery of the unloaded resin seems straightforward. Provided the reagents are solids themselves, slurry-to-slurry reactions may also be a viable approach to increase the overall concentrations. The solid reagents are administered to the reaction mixture “as is”. The overall principle is very similar to that of the aforementioned 2LPS with the exception that the ChemCatChem 2014, 6, 930 – 943

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CHEMCATCHEM MINIREVIEWS second phase is solid with the advantage that no additional solvent is needed. Recently, Codexis reported slurry-to-slurry conversions of water-insoluble starting materials with great success.[31] Finally, gas-phase reactions deserve further investigation. Here, gaseous reactants are converted by solid biocatalyst preparations, which thereby largely circumvents the use of solvents (Scheme 5).[32] For example, Bchs and co-workers report-

Scheme 5. Example of a biocatalytic gas-phase stereoselective Meerwein– Ponndorf–Verley reduction.

ed the stereoselective reduction of gaseous 2-butanone to (S)-2-butanol with an excellent overall E factor of 13.2 (1.2 if N2 is excluded).[32b] Clearly, this approach is limited to volatile reactants, and it remains to be demonstrated that more complex reactions needing diffusible cofactors can also be performed by using solid enzyme preparations.

A Note on (Bio)Catalyst Preparation Enzymes, cofactors, and all chemicals used in general have been synthesized themselves. Strictly, these prechains should also be considered in environmental evaluations, which goes beyond the scope of most publications. Nevertheless, researchers should be aware of at least the rough orders of magnitudes. Enzymes and cofactors are produced through microbial fermentation in liquid media. The fermentation broths contain, next to water, supplements such as carbon and energy sources (often glucose); N, P, and S sources (as inorganic salts or amino acids); trace elements; selection markers; and oxygen (depending on the culture conditions). An estimation of the E factor [kg waste per kg cell dry weight (CDW)] is difficult, as the compositions of the cell and media are generally unknown (empirical formula such as CH1.613O0.557N0.158P0.012S0.003K0.022Mg0.003Ca0.001[33] may give a rough estimation). Nevertheless, as rule of thumb, an E factor contribution between 2 and 10 of the aforementioned supplements per kg CDW can be assumed. The exact value, relative to the contribution of water, becomes almost insignificant. Generally, cell densities up to 10 g CDW L1 can be achieved. In some cases, under optimized conditions (high cell density fermentation), cell densities of up to 50 g CDW L1 can be achieved. Depending on the final CDW, typically 10 to 250 kg water are consumed per kg of dry cell.[34] In the case of isolated enzymes, the prepa 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemcatchem.org ration of the crude extracts and, especially further chromatographic purification, can add significant amounts of water, salts, and solvents to the environmental impact of the enzyme preparation.[34] Overall, Ewater factors for whole cells and isolated crude enzyme preparations of 100 appear to be a reasonable assumption. Enzyme purification represents an environmental but also an economic burden for biocatalyst production.[35] Therefore, for practical application, whole cells or crude extracts, both originating from recombinant overexpression of the production enzyme, are desirable. Usually, the production enzyme is expressed in such high levels that conflicting enzyme activities of the host organism are outcompeted.[36] In some cases, however, the background activity by endogenous host enzymes has to be removed to obtain the desired product properties (optical purity, side products). Generally, then (partial) purification of the production enzymes is necessary. Affinity tags are now commonly used to simplify the purification procedure. Alternatively, enzymes originating from (hyper)thermophilic origins are gaining relevance. These enzymes can often be expressed in standard expression systems such as E. coli and purified in a single heat treatment step in which the “contaminating” host proteins are inactivated.[37] Considerations similar to those for cells also apply for the commonly used nicotinamide cofactors. The non-phosphorylated (NAD + /NADH) and phosphorylated (NADP + /NADPH) cofactors are present in exponentially growing cells at approximately 2.7 and 0.12 mm, respectively.[38] This roughly corresponds to mass percentages of 0.3 and 0.02 % (w/wCDW), respectively, and water consumptions (Ewater factors) of more than 3.333 kg kg1. Further contributions from chromatographic purification apply. Notably, after proper treatment these wastes are used as agricultural fertilizers and thereby represent a valuable product.[39] The treatment, however, entails sterilization, dehydration, and inactivation of the selection markers and, therefore, is an energy-intensive process. The large uncertainties in these estimations together with the product quality of the fermentation wastes make it difficult to include the numbers presented here in any E factor calculation (we have not included these numbers in any calculation presented here). Nevertheless, the example of fermentative enzyme and cofactor production demonstrates the importance of prechains. All reagents used in a synthesis have “a history” of resource- and energy-demanding synthesis and, therefore, should not be forgotten completely in environmental considerations. Clearly, these considerations also apply to chemical catalysts and reagents. The majority of compounds are prepared in multistep syntheses, and sometimes impressive prechains can be drawn. For example, platinum metal (Ru, Os, Rh, Ir, Pd, Pt) catalysts are very popular (also in industrial practice), but they are scarce resources. Also, their extraction and processing sometimes poses significant ecological and societal issues, the evaluation of which can be very difficult. Also, the chiral ligands used, for example, 2,2-dimethyl-a,a,a’,a’-tetraphenyldioxolane4,5-dimethanol (TADDOL) and 2,2’-bis(diphenylphosphino)-1,1’binaphthyl (BINAP), are prepared through rather long, energyand resource-intensive synthesis routes (Scheme 6). ChemCatChem 2014, 6, 930 – 943

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Scheme 6. Syntheses of TADDOL[40] and BINAP.[41] The chiral information is introduced either by starting from a chiral-pool compound (for TADDOL) or through kinetic resolution by diastereomeric crystallization (for BINAP). Ts = para-toluenesulfonyl.

The synthesis schemes shown in Scheme 6 start from commercially available compounds. It should, however, not be forgotten that these are derived from natural resources. A complete picture of the environmental impact must also take these into account. The complexity of these prechains, however, places such estimations beyond the scope of any catalysis research publication. For example, Jessop recently reviewed (amongst other topics) the chemical synthesis of the popular ionic liquid [bmim]BF4 (Scheme 7, bmim = 1-butyl-3-methylimidazolium) to give a glimpse at the complexity of some prechains.[28b] Jessop proposed to evaluate the greenness of a given solvent by critically evaluating the synthetic steps in the synthesis tree for the involvement of rare chemicals [e.g., depleting Xe, rare metals (such as platinum metals), P, etc.], hazardous chemicals (leading to or bearing the risk of emission of toxic compounds, eutrophication, smog formation, acid rain, global warming, and others). We feel that such a qualitative comparison might also be a simple and efficient method to compare, for example, two catalysts.

lyzed reductions/oxidations,[43] and w-transaminase-catalyzed reductive aminations.[44] From an environmental point of view, this strategy, however, is questionable, as it results in a large amount of waste that is generated from unused reagents. Figure 3 visualizes the influence of reagent surplus on the conversion of an equilibrium reaction (K = 1). A molar surplus of more than 20-fold is required to achieve conversion of the de-

Equilibrium Reactions

Figure 3. Influence of an excess amount of reagent on the conversion of an equilibrium reaction with little thermodynamic driving force.

Many (enzymatic) reactions are reversible such as esterification, alcohol oxidation, reductive amination, and aldol reactions. Often, the energy contents of the substrates and products are quite similar, which results in a low thermodynamic driving force for the reaction and in equilibrium positions that are far away from full conversion. In this section, common strategies to shift the equilibrium towards the desired products will be discussed. Excess amounts of substrates

sired substrate to more than 95 %. As a consequence, not only the coproduct (1 equiv. relative to the desired product) but also the unused cosubstrate accumulates in the reaction mixture as additional waste. However, as Kroutil and co-workers pointed out,[45] the cosubstrate in surplus often also acts as a cosolvent, which thereby increases the overall substrate loading and, as discussed above, should be beneficial from an environmental point of view.

Application of one reagent in excess amount is certainly the most common strategy used as a result of its simplicity. This technique is commonly used to drive, for example, lipase-catalyzed esterification reactions,[12, 42] alcohol-dehydrogenase-cata 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 7. Exemplary synthesis tree for [bmim]BF4.[28b]

vinyl esters also represents a resource-consuming and wastegeneration transformation.[12] In the case of alcohol-dehydrogenase-catalyzed and isoproAccording to Le Chatelier’s principle, removal of one product panol-driven reduction reactions, in situ removal of the aceleads to a shift in the equilibrium. For example, in lipase-catatone byproduct leads to significant reductions in the overall E lyzed esterification reactions, removal of water by distillation is factor.[47] An interesting example of extractive in situ product used on an industrial scale, which results in excellent overall E [46] removal was reported by Kragl and co-workers, who demonfactors. The rather high boiling temperature of water, however, also limits this approach to reagents/products with signifstrated that certain ionic liquids can selectively extract the icantly higher boiling points. This can be circumvented by (co)products and shift the overall equilibrium.[23] using vinyl esters of the acyl donor of interest. The correspondFor reductive transamination reactions of prochiral ketones, ing transesterification reaction yields highly volatile acetaldeisopropylamine is frequently used as the amine donor, which hyde as a byproduct and, therefore, is practically irreversible has to be used in huge molar surplus (10–50-fold) to shift the (Scheme 8). However, acetaldehyde is not unproblematic from unfavorable equilibrium and to alleviate enzyme inhibition.[44, 48] an environmental point of view, and the preparation of the Again, the low-boiling acetone byproduct is frequently stripped out to further shift the equilibrium.[44] Alanine represents an interesting amine donor. It originates from renewable resources and is very soluble in aqueous reaction media. More importantScheme 8. Enzymatic transesterification of vinyl esters. The primary byproduct (i.e., vinyl alcohol) of the transesly, the corresponding pyruvate terification reaction spontaneously isomerizes into volatile acetaldehyde, which thereby shifts the overall equilibricoproduct offers various possibilum. In situ product removal


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Scheme 11. Double oxidation of diols to yield thermodynamically and kinetically inert lactone coproducts.

Scheme 9. In situ regeneration of alanine to drive transaminase-catalyzed reductive amination reactions. w-TA = w-transaminase, l-AaDH = l-amino acid dehydrogenase, FDH = formate dehydrogenase.

Notably, a similar approach based on the double oxidation of ethanol by a bioenzymatic regeneration cascade (comprising an alcohol and an aldehyde dehydrogenase) to promote ADH-driven reductions was reported by Berkowitz and coworkers.[53] Also, in case of the w-transaminase-catalyzed reductive amination, a smart cosubstrate approach was reported recently by

ities for further transformation to shift the overall equilibrium.[44] For example, pyruvate can be further reduced to lactate (by using lactate dehydrogenase together with a suitable NADH regeneration system)[49] or decarboxylated.[44] More elegantly, however, pyruvate is in situ recycled back into alanine, which thereby circumvents its stoichioScheme 12. The smart cosubstrate approach to promote w-transaminase-catalyzed reductive aminations. metric use (Scheme 9).[50] Smart cosubstrates The smart cosubstrates approach represents a relatively new development in the area of equilibrium shifting. Essentially, smart cosubstrates are transformed into thermodynamically and/or kinetically inert coproducts. For example, Lavandera et al. demonstrated that a-haloketones are excellent cosubstrates for ADH-catalyzed oxidations, as the resulting halohydrins, owing to intramolecular H-bonding stabilization, are thermodynamically very stable. As a result, full conversion of the enzymatic Oppenauer oxidation was achieved with almost equimolar amounts of the cosubstrate (Scheme 10).[51]

Berglund and co-workers (Scheme 12).[54] By using 3-aminocylohexa-1,5-dienecarboxylic acid, the thermodynamically unfavorable reaction was made feasible and irreversible as a result of tautomerization of the resulting cyclic diene ketone into the corresponding phenol (3-hydroxybenzoic acid).

Cofactor Regeneration—Who is the Greenest of Them All?

As mentioned above, efficient cofactor regeneration systems have enabled a reduction in the E factor contribution (even though the general aim was/is to reduce the economic contribution) of the nicotinamide cofactors (provided the prechains are excluded). Nevertheless, a stoichiometric donor/acceptor of reducing equivalents (cosubstrate) is required in any redox reaction. Unused cosubstrate and coproducts generally represent side Scheme 10. Chloroacetone as a smart cosubstrate that turns an ADH-catalyzed Oppenaproducts without particular value and should be conuer oxidation irreversible as a result of H-bonding stabilization of the coproduct. sidered as waste. Therefore, also the choice of cofactor regeneration system should—whenever possible—be guided by environmental concerns. Common regenerRecently, we reported a similar approach in which an ADHation systems for reduced and oxidized nicotinamide cofactors catalyzed Meerwein–Ponndorf–Verley reduction was made irreare summarized in Tables 2 and 3. General statements about versible by using lactonizable diols as smart cosubstrates the environmental impact of a given regeneration system are (Scheme 11).[52] The double oxidation of the diol cosubstrate difficult to make. For example, glucose dehydrogenase based not only resulted in doubled regeneration capacity of the coregeneration generates significant amounts of gluconic acid as substrate, but the lactone byproduct was also inert in the a byproduct and consumes an edible cosubstrate, with all ethiADH-catalyzed reduction, and therefore, this also made the cal implementations related to it. The coproduct, in contrast, is overall reaction irreversible. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Even more elegantly, both production reactions can be couReference Cosubstrate Coproduct Catalyst(s) Waste pled on the product level, that [g mol1] is, the product(s) of the first reaction can serve as the starting glucose gluconic acid GDH, cell metabolism 196 [6c, e, 19b, 36a, 55–58] H3PO3 H3PO4 PDH, [Cp*Rh(bpy)(H2O)]2 + 98 [59–61] material(s) for the second reacisopropanol acetone various ADHs 58 [17, 26a, 31b, 32b, 62–65] tion. Examples of such linear cas2+ CO2 FDH, [Cp*Rh(bpy)(H2O)] 44 [26b, 66–72] HCO2H cades comprise the ADH-cata– hydrogenase 0 [25, 73–77] H2 lyzed oxidation of alcohols fol0 [78–81] cathode – [Cp*Rh(bpy)(H2O)]2 + lowed by the Baeyer–Villiger2+ [a] GDH = glucose dehydrogenase, PDH = phosphite dehydrogenase, [Cp*Rh(bpy)(H2O)] = (pentamethyl)cyclomonooxygenase-catalyzed oxidapentadienyl rhodium(III) bipyridyl. tion of the resulting ketone (Scheme 14)[90] and the ADH-catalyzed oxidation of alcohols resulting from monooxygenase-catalyzed hydroxylaTable 3. Common regeneration systems for oxidized nicotinamide cofactors tions.[91] [NAD(P) + ]. Further examples comprise the formal substitution Reference Waste Cosubstrate Coproduct Catalyst(s)[a] of OH groups by NH2 groups by a sequence of ADH[g mol1] catalyzed alcohol oxidation and NAD(P)H-dependent a-ketoglutaglutamate GluDH 147 [57b, 82] reductive amination of the intermediate ketone[92] rate and the enzymatic redox isomerization of allylic alcopyruvate lactate LDH 90 [83] hols into ketones.[93] acetone isopropanol various ADHs 60 [45b, 84, 85] H2O2 NOx; various chemical O2 [37g, 43a, 84a, 86] Driven by the desire to avoid the costly nicotinacatalysts mide cofactor completely, there has also been signifiH2O NOx; LMS [20a, 27, 86d, 87] O2 cant research dedicated to the direct regeneration of anode – various mediators – [88] oxidoreductases.[94] As with the majority of enzyme [a] GluDH = glutamate dehydrogenase, LDH = lactate dehydrogenase, NOx = NADH oxclasses, these systems are still in their infancy, but idase, LMS = laccase mediator system. their applicability has been demonstrated with old Table 2. Common regeneration systems for reduced nicotinamide cofactors [NAD(P)H].[a]

certainly less problematic than others. Similar argumentation lines can probably be made for all regeneration systems. Probably, the greenest NAD(P)H regeneration systems are hydrogenase based and are electrochemical systems. In both cases, theoretically no byproduct is generated. Indeed, in two exemplary E factor calculations, both systems excelled with very low regeneration-related E factors of 0.17 (for hydrogenase-promoted reduction)[73] and 0.36 (for indirect electrochemical regeneration of NADH).[79c] For the other NAD(P)H regeneration systems, the corresponding E factors are approximately 2, with a weak correlation with the theoretical E factor (Table 2). Recently, the regeneration of oxidized cofactors has also experienced increasing interest (Table 3). A clear trend towards aerobic and electrochemical regeneration systems, which from the E factor point of view should also be the most attractive ones, can be observed. An elegant way to avoid waste related to cofactor regeneration clearly is to use a synthetically relevant reaction for regeneration.[89] For example, Gotor and co-workers coupled the ADH-catalyzed kinetic resolution of racemic alcohols (NADPH regenerating) to NADPH-dependent monooxygenation reactions to produce two valuable products in one reaction (Scheme 13).[89c–d] Provided that separation of the products (and the remaining byproduct) does not add additional environmental burden (see below), this approach can significantly reduce the generation of waste. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Scheme 13. Example of a parallel interconnected kinetic asymmetric transformation (PIKAT) in which both reactions lead to a valuable product. PAMO = phenyl acetone monooxygenase.

Scheme 14. Example of a biocatalytic linear cascade for the double oxidation of an alcohol into the corresponding ester by combining ADH (NADP + dependent) and Baeyer–Villiger monooxygenase (BVMO, NADPH dependent) oxidations.

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yellow enzymes (OYEs). Some very recent contributions from us[94j, k, 95] and others[96] have demonstrated that OYEs can be regenerated by electron donors other than the native nicotinamide cofactors. Next to the potentially cheaper and more robust synthesis schemes, such approaches excel because of their bio-orthogonality, which thereby overcomes the frequently observed challenge of over-reduction by “contaminating” alcohol dehydrogenases (Scheme 15). Thus, by way of the classi-

essing (DSP) and “postpones” this task to further up-scaling. Particularly in environmental considerations, DSP is mostly not included. In fact, the majority of publications only qualitatively comment on product isolation (and purification), and E factor analyses are difficult to perform on the basis of the published data. Table 4 summarizes the E factors of some industrial-scale biotransformations, including DSP.

Table 4. E factors for selected industrial-scale biocatalytic reductions. Product

Ereaction[a]

EDSP

(S)-ethyl-4-chloro-3-hydroxybutyrate 18 (5.8) 2.9 (R)-tetrahydrothiophene-3-ol 8.8 (2.5) 18 (E)-methyl 2-(3-{3-[2-(7-chloroquinolin-2-yl)- 7.8 (4.8) 25 vinyl]phenyl}-3(S)-hydroxypropyl)benzoate

Reference [b]

[6e] [31a] [31b]

[a] Values in parentheses show the E factor excluding water. [b] 85 % recycling efficiency of the solvents used was assumed.

Scheme 15. Schematic representation of the “over-reduction challenge” of using crude preparations (or whole cells) of OYEs together with an NAD(P)H regeneration system. Next to the OYE production enzyme, “contaminating” ADHs are also regenerated, which leads to additional reduction of the carbonyl group.

cal NAD(P)H-dependent reaction schemes, ADHs present in the reaction mixture can also perform NAD(P)H-dependent ketoreduction of the substrates and products, which often leads to complex product mixtures. The use of artificial electron donors circumvents this issue, as ADHs present in the reaction mixture will not be regenerated, and they, therefore, stay inactive; this results in higher chemoselectivity of the reaction together with higher yields and facilitated downstream processing. Overall, it can be concluded that two decades of intensive research on efficient cofactor regeneration systems have resulted in a broad range of efficient systems. Green chemistry aspects have, so far, not played a prominent role in the selection of the regeneration system.

Table 4 is insightful in several aspects. First, it demonstrates that substrate loadings tend to be high on the industrial scale,[35, 97] which results in low E factors. Second, the contribution of DSP to the overall E factor is significant and in the order of magnitude or even higher than the E factor of the actual transformation. One conclusion from Table 4 surely is that academic researchers should also spare some thoughts about the consequences of the reaction system chosen on possible preparative applications, including DSP. Many if not most chemical products are produced from bulk chemicals in several steps. Having in mind that prechains are important and that DSP can contribute to the overall environmental impact significantly, the recent trend of cascade and domino reactions appears attractive, also from an environmental point of view.[98] Exemplary for the many enzyme cascades reported recently,[91b, 93a, 99] a four-step, one-pot cascade generating valuable sugar derivatives from starting materials is shown in Scheme 16.

Downstream Processing—Just a Matter for Future Scale-up? “It is no product unless it is in a bottle!” (C. Wandrey). Even a highly efficient catalytic system with optimized yields and catalyst performance (and E factors) will be incomplete unless a scalable and efficient method for the isolation (and purification) of the product is available. Unfortunately, the catalysis community notoriously underestimates the importance of downstream proc-

Scheme 16. 4-Enzyme-cascade involving acid phosphatase (PhoN-Sf), glycerol phosphate oxidase (GPO)/catalase, and rabbit muscle aldolase (RAMA) for the conversion of simple starting materials (glycerol, aldehydes) into chiral sugar building blocks.[99f, 100]


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ologies developed (especially in academic laboratories) and a self-critical comparison with other methods is highly desirable. Of course, a holistic evaluation as in case of full LCAs goes beyond the scope of most research projects, but fast, massbased evaluations such as the E factor will give valuable insight and help to de-bottleneck reaction schemes (not only from an environmental point of view). Despite all of its shortcomings (missing energy contributions Scheme 17. Four-step, one-pot chemoenzymatic synthesis of (S)-tembamide. KJ = potassium iodide. and the question of waste quality) the E factor is a valuable tool for researchers to substantiate (or disprove) green claims in a fast and efficient manner. We Also, chemoenzymatic cascades are gaining interest, as hope to see more of these analyses in the future. these open up new possibilities to combine “the best of both worlds” (i.e., exploit the complementary reaction scope of chemical and enzyme catalysis).[58a, 90b, 91, 101] For example, Acknowledgements Schrittwieser et al. reported a chemoenzymatic one-pot, fourstep cascade for the synthesis of tembamide from simple startFinancial support by the Deutsche Bundesstiftung Umwelt, Cheming materials (Scheme 17).[102] The authors also compared their BioTec (AZ 13253) is gratefully acknowledged. one-pot sequence with reported multistep syntheses. As shown in Table 5, the EDSP factor correlates almost linearly with Keywords: biocatalysis · E factor · green chemistry · sustainable chemistry · water chemistry Table 5. Comparison of various multistep syntheses of tembamide. Number of individual steps[a]

Ereaction(s)[b]

EDSP

Reference

1 (4) 2 (3) 2 (3) 3 (3) 4 (5) 5 (5)

79 155 457 88 180 74

227 814 367 397 1554 2068

[102] [103] [104] [105] [106] [107]

(18) (147) (143) (88) (180) (62)

[a] Numbers in parentheses indicate the number of individual transformations. [b] Numbers in parentheses exclude water.

the number of individual steps and (especially in case of multistep syntheses) overcompensates the contributions of the reactions.

Outlook Biocatalysis surely bears an enormous potential to make chemical synthesis environmentally more benign. We should, however, be aware of the fact that no chemical process can ever be really green. All chemical transformations consume resources in the form of energy and materials and generate wastes. With that in mind, the term “greener chemistry” appears to be more applicable than just “green chemistry”. It is clear that fulfilling one or a few of the famous 12 Principles of Green Chemistry is not sufficient to be green(er). In our mind, a more quantitative evaluation of the catalytic method 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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