Green Chemistry SelectionIndustry Challenges
Problem 1: Full Lifecycle Approach to Chemical Transformations in Aqueous Media
Chemical transformations in or on water represent a greener alternative to the use of organic solvents, which have associated carbon footprint in the manufacture and waste disposal, as well as other harmful environmental effects. However, in order for this approach to be truly sustainable, two issues need to be addressed. Firstly, viable methods for purification of the reaction products from water are required. Secondly, the water waste needs to be suitable for disposal via the general sewerage system (e.g. following biotreatment), as aqueous waste streams requiring incineration are not sustainably viable.
Exemplification of Problem
Significant advances in recent years have developed chemical reactions in or on water, addressing problems of insolubility of reagents and products, long reaction times and low yields. A range of examples are highlighted in a recent review.1 As an illustration, pioneering work by Lipshutz and coworkers has developed chemistries where water can be used as the reaction solvent, in combination with small quanities of surfactants to increase solubility.2, 3 Suzuki̠−Miyaura cross couplings of MIDAboronates and aryl halides have been demonstrated without the use of organic solvents.4This process also allowed reuse of the aqueous media in the next reaction, which should realise improved sustainability for these processes.
For many chemistries performed in or on water, purification is an issue. For example, extraction into organic solvents followed by crystallisation may be required. Another issue which is not generally considered is the ultimate fate of the aqueous waste stream. In many cases, the aqueous waste must be incinerated, due to being unsuitable for return to the sewerage system. Generic methods for treatment of these waste streams to allow for green waste disposal would make these processes much more sustainable, e.g. through the development of biotreatment methods.
Expected Output of Research
The expected output of the research would be to address issues associated with using water as solvent for organic chemistry transformations, in place of organic solvents. Expanding the range of chemical transformations which may be carried out in or on water is one part of addressing the problem. However, solutions to the problem should take a full lifecycle approach to sustainability, considering how the products may be extracted and purified, and how the aqueous waste may be treated and disposed of.
1Gawande, M. B.; Bonifácio, V. D.; Luque, R.; Branco, P. S.; Varma, R. S. Chem. Soc. Rev.2013, 42, 5522
2Lipshutz, B. H.; Ghorai, S. Green Chem.2014, 16, 3660.
3Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovkiy, A. J. Org. Chem.2011, 76, 4379
4Isley, N. A.; Gallou, F.; Lipshutz, B. H. J. Am. Chem. Soc.2013, 135, 17707.
Problem 2: C-H oxidative transformations
Remote C-H functionalization is a transformation of great synthetic utility that has gained a lot of attention in past several decades.[1] Various methods have been developed including (i) transition metal catalysis,[2] (ii) concerted C-H oxidation with metal carbenes or nitrenes[3] and (iii) remote H-radical shift with oxygen and nitrogen radicals.[4] Allylic oxidations is a more classical example of C-H functionalization but synthetic methods, even today, rely on selenium based reagents for regioselective C-H oxidation.
Exemplification of Problem
Many transition metals have been screened in the oxidation of C-H bonds including ironbased catalysts.[5] However, the ligandsrequired to impart the desired reactivity to the active systems, are often too complex/expensive to enable widespread use of these methods. Further work is needed to understand and tune the activity of these systems so that better predictive models for regio- and chemo-selectivity are generated and with less over-oxidation by-products.Figure 1.
Figure 1.
Ruthenium and rhodium systems have been employed with success in the inter and intramolecular C-H amination of various molecules.[6] In some cases, excellent diasteoselectivity is also accomplished.[7] However, in these examples, benzylic, allylic or tertiary3a systems tend to predominate. See Figure 2 and 3.
Figure 2.
Figure 3.
While not a new concept, it is anticipated that modern free radical strategies such as aliphatic sp3 C-H bond oxidation by remote H- radical abstraction will provide access to highly functionalized molecules. However, challenges remain for further development in terms of reaction efficiency and practicality. Figure 3.
Figure 3.
In the examples above it is evident that absolute reagent control over chemoselective and regioselective C-H bond oxidation is still not solved and further work remains to be done.
Expected Output of Research
Research in this area should identify and develop suitable catalysts which will enable the scalable, oxidative transformation of remote C-H bonds. The functionalization of C-H bonds to introduce halogen, oxygen and nitrogen can be considered as a formal oxidation process. Greener alternatives and renewable solvents should be considered for these reactions. The use of fixed bed systems and continuous systems would be within scope. If oxygen or hydrogen peroxide is used, safe use in a Pharmaceutical environment should be considered. A view towards broader application and industrialization should also be provided
Problem 3: Green Oxidations
Oxidations are frequently used in the pharmaceutical manufacturing and synthesis of fine chemicals. Yet there is still a lack of satisfactory solution in many cases.Recent development in use of sub-stoichiometric amounts of metal catalysts in concert with environmentally friendlier oxidizing reagents such as low level of oxygen, bleach and hydrogen peroxide has led the way towards greener approaches to oxidations.Organocatalysis, in particular with TEMPO and analogs, looks particularly promising with ongoing work in both industry and academia for alcohol oxidationas well as -oxidation of aldehydes.
Exemplification of Problem,
Use of oxygen or an organic oxidant as the stoichiometric oxidant would be the preferred green and sustainable solution to the problem.[8] However, the catalyst loading and the volume of organic solvents used were too high in the example shown. Water and other non-flammable solvents would be preferred. The efficient mass transfer of gaseous reagents into a continuous process stream also remains a challenge. Examples of recent advances include the use of palladium in alkenedihydroxylation[9] and copper complexes in primary alcohol oxidation.[10] Another approach has been the development of organocatalysts such as iminium salts in the (asymmetric) epoxidation of alkenes[11] as well as combinations of metal and organocatalysts. TEMPO and analogs mediated oxidations have been reviewed and widely used but further research on novel and stable analogs such as nitroxides with -hydrogens are ongoing.[12] Chemistry using continuous flow ozonolysis on lab scale exemplifies the sort of approach which may be employed.[13]
A) J. Org. Chem. 2013, 78, 11680; B) Nat. Commun.2015, 6:6070
Expected Output of Research
Research in this area should establish oxidation reactions in pharmaceutical syntheses through the use of a cheap, safe and atom economical oxidant and catalytic amounts of metals and/or organic mediators. Engineering solutions such flow techniques should enable aerial oxidations to be performed in a safe and efficient manner. A view towards broader application and industrialization should also be provided.
Problem 4: An efficient synthesis of oligonucleotides
Synthetic oligonucleotides have become a new class of therapeutic agents in recent years. Currently oligonucleotides are synthesized by the phosphoramidite-based solid phase synthesis. Although this process provides high quality oligonucleotides at quantities required for clinical development, it requires excess reagents and extremely large volumes of solvents, hence it is not considered to be sustainable, and not suitable for the large scale commercial production.
Exemplification of Problem
The current phosphoramidite method had become the “method of choice” to synthesize oligonucleotide since late 1990’s as a group from ISIS pharmaceuticals established the automated process. Since then, numerous modifications/improvements have been made to make this process more efficient, as a result, it becomes the standard method for the oligonucleotide synthesis.[14]
Phosphoramidite based solid phase oligonucleotide synthesis
Besides the phosphoramidite method, on the other hand, there are numerous reports utilizing different modes of coupling methods, such as H-phosphonate approach, phosphate trimester approach, and phosphotriester approach. Because the majority of the focus has been devoted to phosphoramidite chemistry for the past decade, these alternative approaches are still underdeveloped.[15]
The phase of synthetic process is another consideration. The solid phase synthesis is currently employed in all practical oligonucleotide syntheses. Whilst the solid phase synthesis has clear advantages over solution phase syntheses, such as easy removal of excess reagents, it normally requires large excess reagents/solvents to achieve high chemical conversion. Other media have been explored (ionic liquid, solution phase, PEG, Fluorous), but all approaches are still considered to be primitive.[16],[17]
Expected Output of Research
Development of a synthetic process which uses significantly fewer volumes of solvents than the current solid phase synthesis. Demonstration of the process which enables production of 15-20-mer oligonucleotides with comparable quality to the current state of the solid phase synthesis. Ideally, the new process would be capable of scaling up to >10 kg scale.
Problem 5: Hydride-free Reduction of Amides
Amide reduction can be a preferred approach to amine synthesis. Common methods for reduction of amide bonds, however, involve the use of metal hydrides (LiAlH4, DIBAL, RedAl, etc.), diborane, Et3SiH or polymethylhydrosiloxane (PMHS). Many of these methods can lead to product isolation issues (slow filtrations, product occlusion, etc.) and waste disposal problems (e.g. aluminum waste).
Exemplification of Problem
One of the steps in the synthesis of Paroxetine involves the reduction of a piperidinedione to the corresponding piperidine using LiAlH4.[18] While LiAlH4 has a favorable hydride density, aluminum waste disposal (aluminum hydroxide salts) is an issue for high-volume products.
Hydrogen gas is the ideal reducing agent as the only by-product is water. Whilst there has been progress in area of metal-catalyzed reduction of amides using hydrogen gas,[19] current methods require high temperatures and pressures (e.g. 160 °C, 100 bar H2). Pressures of these magnitudes are not routinely available in a typical pharmaceutical manufacturing plant and many functional groups are not compatible with the reaction conditions.
Expected Output of Research
Identification and development of suitable catalysts which would enable direct amide bond reduction with the use of hydrogen gas as the hydride souce, under mild temperatures and pressures. Renewable solvents should be considered as media for these reactions, and they should demonstrate improved ‘green’ metrics versus the transformation they are replacing. A view towards broader application and industrialization should also be provided. Electrochemical methods may be considered.
Problem 6: To Increase the Efficiency of Continuous Hydrogenations by Monitoring and Minimizing Catalyst Deactivation and Facilitating Catalyst Regeneration.
Catalytic hydrogenations are the most efficient and green type of reduction in that the reducing agent is inexpensive and readily available, the metal catalyst can be used in substoichiometric quantities, and there are no stoichiometric byproducts. Continuous hydrogenations offer the added advantages that (1) high pressures and temperatures can be achieved safely in low volume flow reactors, (2) the local catalyst loading in the flow reactor is extremely high yet the overall catalyst loading for an extended period of flow is very low, and (3) the effluent stream is just product in solvent, ready for isolation or the next synthetic step without work up. These first two factors provide a very powerful reducing environment for clean and fast reactions, and the third factor lowers the number of unit operations in the process. These advantages are predicated upon stable, long lived catalysts. Thus we are seeking:
- Noninvasive analytical methods to observe catalyst deactivation before it affects the product stream by detecting changes in the properties of the pressurized catalyst bed during partial catalyst deactivation while the catalyst is still active enough to give complete conversion.
- More robust heterogeneous hydrogenation catalysts or hydrogenation conditions which are resistant to catalyst poisoning (e.g. from nitrogen compounds, sulfur compounds, or tars), coking from the dehydrogenation of substrates, or leaching of the metal catalyst.
- Well defined and efficient methods for catalyst regeneration within the flow reactor such that two beds can be used for prolonged periods with alternating reduction and regeneration cycles.
Exemplification of the Proposal
The continuous hydrogenation of substituted pyridine 1 to transpiperidine2 proceeds with greater diastereoselectivity and higher catalyst turnover than the corresponding batch hydrogenation.[20] Piperidine2 is a component of JAK inhibitor tofacitinib.
Expected Output of the Research
Increased use of more efficient and green continuous hydrogenations.
Problem 7: Replacements for Dipolar Aprotic and Halogenated Solvents
Chemical transformations are typically conducted in solvents that have significant environmental, health, safety, or a combination of these, issues. Work-up of reactions frequently leads to contaminated aqueous waste streams that can not be sent for bio treatment. Additional solvents may also be required leading to mixed solvent waste which may not be easily separated. A limited range of chemistries may be run in water, however, many API intermediates are not readily water soluble and do not mix well in pure water. Putative “green” alternatives (e.g. ionic liquids, critical solvents, fluorous solvents) frequently have unknown EHS properties, or limited solubilising capability (e.g. sc CO2); work-up and separation often requires organic solvents. Furthermore, recycle and reuse are typically not built into solvent selection processes.
Exemplification of Problem
In particular, solutions are required for replacing current dipolar aprotic solvents such as dimethylformamide, n-methyl pyrollidone, and acetonitrile. All of these solvents are synthetically useful and are often essential for certain transformations (e.g., alkylations using NaH/DMF, substitution reactions using dipolar aprotics). For these systems and others which utilize dipolar aprotics, more benign solutions are sought. Alternative suggestions might include ionic solvents with favorable environmental profiles (including recycle and reuse), or aqueous solvents modified with more benign organic solvents and ionic components.
Another area of concern is the use of methylene chloride (Dichloromethane). Methylene chloride has significant environmental impacts from its low boiling point (e.g., it can require refrigerated storage and can be difficult to fully condense), its environmental persistence, and its relative toxicity. Friedel Crafts chemistry, for instance, is typically run in halogenated solvents which are typically carcinogenic or suspected carcinogens. Substitutes for halogenated solvents are sought which can facilitate these chemistries while offering a better environmental profile.
Expected Output of Research
Through experimental research, physical properties measurement and estimation, and theoretical modeling, determine effective substitutes for dipolar aprotic solvents and halogenated solvents. These solutions may involve expansion of chemistries that can be performed in water, the use of more benign solvents in mixtures, the use of benign and recycleable ionic solvents, and the use of materials which are commonly considered solvents but which could potentially be developed as solvent sources.
Solutions should consider the full life cycle of the solvent being utilized, ensuring recycle and reuse and impacts to downstream processing are included. For instance, the efficient separation of product from the solvent should be demonstrated. An evaluation of EHS properties relative to alternatives should be prepared. Special consideration should be given to solvents which can be derived from renewable resources.
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[20] Hawkins, J. M., et al., manuscript in preparation.