Evolution of Solvents in Organic Chemistry - ACS Sustainable

Perspective pubs.acs.org/journal/ascecg

Evolution of Solvents in Organic Chemistry Bruce H. Lipshutz,*,† Fabrice Gallou,*,‡ and Sachin Handa*,§ †

Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States Novartis Pharma AG, CH-4057 Basel, Switzerland § Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States ‡

ABSTRACT: An overview is presented on the unfortunate use of organic solvents as the traditional medium in which organic synthesis has been, and continues to be, practiced. An argument is made, from the environmental perspective, for a long overdue switch to alternative reaction media, and water in particular, following Nature’s lead. KEYWORDS: Organic solvents, Micellar catalysis, Cross-couplings, Palladium, Alternative media, Designer surfactants, Nitro group reductions, Amide bond formation

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INTRODUCTION

How did we chemists get ourselves into this situation? Why do we so willingly pay for solvents up front, and then pay far more at the back end to have a costly service cart them away? The answer that most likely comes to mind is that “we have no choice; most organic substrates and catalysts are only soluble in organic solvents.” Well, if that is true, then how can it be that Nature so readily does chemistry in water, with both watersoluble and water-insoluble materials, and has been doing so for millions, if not billions, of years in the absence of organic solvents? The harsh reality is that as a result of the path chosen many decades ago by the brilliant minds of those times, organic chemistry was developed in organic solvents. And so we now find ourselves, on the one hand, with an impressive, sophisticated science, while on the other hand it is also a discipline that produces amounts of waste each year that are so large they are beyond both our willingness to accept and our ability to comprehend. It is all the proof needed to conclude that organic chemistry, as currently practiced, is not sustainable. From the perspective of the academician, where small-scale chemistry is the norm, oftentimes the attitude is that organic waste is more of an industry-created problem. After all, it is

What was the first organic solvent? It should be a very simple, innocent question. But ask around, and the response may be surprising: no one seems to know. Even an authority on chemistry matters of historical significance, Jeff Seeman (University of Richmond), went quiet when this inquiry came his way. Ultimately, his response was “That’s a good question.” One can only imagine the possibilities: was it benzene, a contribution from Faraday back in 1825, that eventually became an industrial solvent showing good dissolution properties?1 Or, perhaps, it was ethanol, another discovery by Faraday, although dating its use as a solvent is apparently unknown. Whatever the history, whichever the solvent, what is abundantly clear is that modern organic chemistry has embraced organic solvents as the reaction media of choice. How unfortunate! Indeed, from the environmental perspective, the world is now paying dearly for these decisions made well over a century ago. That is, over 80% of the organic waste produced by the practice of synthetic chemistry worldwide is attributable to a single reaction variable: organic solvent. Several are taken, in large measure, from our petroleum reserves, purified, used to do chemistry, and then what?2,3 Where does all of that waste go each time it is removed from the lab, to be disposed of “properly”? Is it burned? Recycled? Or, is it, contaminated with water, salts, and organics, simply buried in locations that today are “approved”? Few among us likely know the answers; even fewer seem to care. © 2016 American Chemical Society

Special Issue: Building on 25 Years of Green Chemistry and Engineering for a Sustainable Future Received: August 1, 2016 Revised: September 13, 2016 Published: September 16, 2016 5838

DOI: 10.1021/acssuschemeng.6b01810 ACS Sustainable Chem. Eng. 2016, 4, 5838−5849

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ACS Sustainable Chemistry & Engineering argued, reactions run with milligrams of a metal catalyst in milliliters of an organic solvent cannot be major contributors to the creation of organic waste. In fact, research groups in academia are among the worst of fenders in this regard. Those small-scale reactions in organic solvents usually get worked up by transferring each into a 50 or 100 mL separatory funnel containing several volumes of water. Then more organic solvent is added to carry out multiple extractions, each with fresh organic solvent, after which the combined extracts are dried with brine, concentrated, and then removed in vacuo and collected, instantly becoming waste. So if the volumes for all solvents and contaminated water are added up and their total weight is divided by the weight of the eventually isolated product, the resulting E Factor4−9 for the reaction (based on just solvent and/or water usage) will be in the hundreds!!6 And that is for just about every reaction run in academia at the graduate/postdoctoral level, every day, worldwide. What about the waste generated in the undergraduate organic teaching laboratories? Of course, this scenario is played out as well in industrial laboratories, especially in medicinal chemistry, where the accent is not even on yield, which means more byproducts and hence, waste per reaction. At the process level, on almost any scale, the waste streams can be enormous. And yet, there are many options for totally avoiding, or at least, recycling, organic solvents as reaction media, and although several are of recent vintage (e.g., ionic liquids, scCO2, fluorous media, ball milling, etc., vide infra),5−9 Nature again provides time-honored guidelines for doing synthetic chemistry. Could there be a more perfect model? Even though these guidelines were available to chemists then, as they are now, they continue to be ignored. Outlined below (Table 1) is a summary of the state of affairs between organic chemistry today versus chemistry as performed in Nature.

Extensive effort has been made to develop ionic liquids (ILs), as featured in numerous reviews on this subject,13−17 These now include progress made with respect to biodegradability,18,19 in addition to their uses in various types of chemical processes. The fate of ILs postreaction, as with organic solvents eventually released into the environment, must not be ignored. As Jordan and Gathergood noted in their review,18 “The parameters of biodegradability, toxicityand recently mutagenicityare becoming more significant.” Such is already the case with DMF, widely known for its health issues.20 Positive attributes associated with ILs include their low volatility, relatively inert nature, thermal and chemical stability, and overall robustness. Supercritical CO2 is another alternative solvent.21−26 It is nontoxic, nonflammable, nonpolluting, and easily separated from the desired product. Reviews have appeared based on its use over the past two decades.22−26 A variety of reactions in synthesis have been studied in this medium, including important “name” reactions involving Pd catalysis (e.g., Heck reactions)27−30 and those based on catalytic amounts of Rh (e.g., hydroformylation).29−31 By definition, however, high pressure is required to maintain CO2 in its compressed state. Yet another alternative reaction medium is based on fluorinated solvents,13,32−34 originally represented by perfluorinated hydrocarbons, now obtainable as fluorous amines and ethers. They tend to be immiscible with most traditional organic solvents and water, although solubility properties are typically temperature-dependent. The mixing of a fluorousbound catalyst with a nonfluorous solvent with heating leads to homogeneity, and thus, catalysis, after which cooling provides the separation of phases and ease of product separation from the organic solvent layer. A wealth of organic chemistry: new fluorous solvents, catalysts, and reagents now exists, and the drop in costs associated with this fascinating approach to bond constructions makes it an attractive alternative to traditional media. There are other approaches also helping organic chemists to move away from using organic solvents.4−9 For example, the clever use of “switchable” solvents is one such technology, widely recognized for its practical applications to wastewater treatment, CO2 capturing, and solvent recovery.35 But what about water??

Table 1. Comparison between Nature and Synthetic Chemistry synthetic chemistry historical span reaction medium energy invested amount of catalyst (e.g., transition metals)

ca. 150 years organic solvent high; heating or cooling 1−10 mol %

Nature billions of years water zero; mild temperatures trace (ppm)

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NATURE VS THE ORGANIC CHEMIST: WHO WINS? It is another simple question, perhaps suggesting an adversarial relationship between the two. If we choose not to ignore the first of the 12 Principles of Green Chemistry (“Waste prevention”, instead of remediation), how do we begin to make the switch? As important to this goal as these alternatives (above) are in documenting the possibilities, the choice of medium of broadest applicability is most likely going to follow Nature’s lead: water. An aqueous environment is where most enzymatic processes take place, and here, several known transformations can be effectively conducted for synthetic gain.36−38 Nonetheless, there are many valued reactions that, at least to date, are unknown within the domain of naturally occurring enzymes. Protein engineers, however, are changing that.39−41 Enzymatic properties are now being tuned through iterative mutagenesis such that, for example, atypical educts can be recognized.38 Biocatalysts can now be fashioned that perform useful synthetic chemistry, in water, and with the remarkable enantioselectivities characteristic of enzymatic processes. In a Perspective on “the

Clearly, there is not a single overlapping reaction parameter; not the medium, not the temperature, and not the amounts of metal catalysts, precious or otherwise, being used at the same ppm levels, even though several are endangered (e.g., the platinoids).10 What’s wrong with this picture?

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ALTERNATIVE REACTION MEDIA Many groups throughout the world have recognized that there must be alternatives; new ways of running organic reactions in media that do not lead to the same waste streams; that begin the process of shifting the paradigm away from organic solvents. Fortunately, there are choices insofar as selecting greener solvents, e.g., 2-Me-THF rather than water-soluble THF, and while the selection guides now routinely line the hallways of most pharmaceutical companies,11 at the end of the day, they are still organic solvents, many still being derived from petroleum reserves and other natural sources.12 5839


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ACS Sustainable Chemistry & Engineering

copper catalyst is miscible with water, and yet, the reactions take place at room temperature. Use of organic solvents (e.g., DCM, THF, DMSO, etc.) or alcohols (MeOH, EtOH) gave inferior results in both yield and ee’s. The presence of higher aggregation states associated with the insoluble catalyst, formed only in a purely aqueous medium, may be crucial for the success of this new chemistry. Using water as the “solvent”, where it is actually the medium forcing neat, hydrophobic interactions that lead to the selectivities observed, is rather unusual, and in fact is rarely the experimentalist’s first choice. This is understandable, as the outcomes of reactions under such irregular heterogeneous conditions are almost impossible to predict given the lack of solubility of most educts in water at ambient temperatures. On the other hand, the approach that does allow for water to function in this capacity (as the exclusive medium) and does lead to both substrate and catalyst solubilization and subsequent reaction under mild temperatures is micellar catalysis.47−51 Given the history and wealth of information on micelles,52 their use in transition metal-catalyzed synthetic chemistry has been surprisingly quite limited. The explanations for the paucity of applications may lie in (a) the only recent increase in attention paid to environmental issues associated with organic synthesis; (b) the apparent lack of interest in studying such chemistry in water, where a systematic investigation that matches this technique to the intended synthetic goals had yet to be carried out; and (c) the limited training that organic chemists receive in this area; indeed, avoidance of water, in general, is the norm in synthesis. So the gap between modern organic synthesis and Nature clearly exists, but it need not widen. Today, there is every reason to believe that synthetic chemists can achieve the desired outcomes in critical bond constructions by altering the methodology, where water is the medium and micellar catalysis provides the crucial “solvent” that enables chemistry to occur.53 But there is even more to be gained from the switch to greener chemistry than removal of organic solvents, minimizing energy input into reactions, and solving the metal shortages that exist by devising equivalent or better chemistry that only requires ppm levels of usage. That is, there are surprises associated with chemistry in this new environment, where concentrations can be ten times those found in traditional organic reactions, and where the “rules” so well established in organic media may not only be different, they are only now coming to light. Hence, exciting opportunities in this “new world”, positioned between the existing world of organic chemistry and the world of alternative media, while borrowing from both, are extensive and ripe for discovery (Figure 1).

nature of chemical innovation: new enzymes by evolution”, Arnold discusses several “non-natural” reactions that can be carried out by modifications of cytochrome P450-derived enzymes.39−41 Representative conversions using this “directed evolution” approach include cyclopropanations,42 aziridinations,41 and regio-divergent aminations.36 From the industrial perspective, outstanding work in this area at Codexis has led to development of a modified enzyme (HHDH; Scheme 1), Scheme 1. Codexis Enzymatic Process to an Intermediate for the Synthesis of Lipitor

significantly improving access to large amounts (i.e., greater “volumetric activity”) of the side chain of atorvastatin (Lipitor).43 These examples are likely to be the “tip of the iceberg” insofar as potential for chemists to make similar modifications to numerous families of enzymes, which by definition, should lead to reactions that occur under mild conditions, with high levels of efficiency and stereocontrol, and with terrific prospects for “cascade” (i.e., sequential, one-pot) processes. Notwithstanding these remarkable and exciting achievements in expanding enzyme-mediated transformations in water, there are simpler alternatives to enzymes that are earmarked for specific synthetic transformations. One conceptually attractive approach, as with enzymes, is to use water itself as the reaction medium, thereby completely avoiding organic solvents. The history of reactions performed “on water”44 suggests that there is much yet to be learned regarding the interactions between substrates, catalysts, and water.45 Nonetheless, there are recent studies, e.g., from Kobayashi and co-workers, further attesting to the synthetic potential of such heterogeneous catalysis.46 In this case, a new Cu(II) catalyst (see nonracemic ligand L, Scheme 2) leads to asymmetric conjugate additions of the Fleming PhMe2Si residue to enones, enoates, as well as unsaturated nitriles and nitro olefins, with ee’s typically 80− 98%. Most intriguing is that none of the starting materials or

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CONTINUING EVOLUTION OF SUZUKI−MIYAURA (SM) REACTIONS According to Colacot, Snieckus, and co-workers,54 the Suzuki− Miyaura reaction is the most heavily utilized among Pdcatalyzed cross-couplings over the past decade (i.e., 2000− 2010). But during that time frame, green chemistry was in its infancy, with the 12 Principles first appearing in 1996.55,56 Thus, the traditional reaction conditions involving moist organic solvents (e.g., THF, DMF, NMP, etc.), were originally chosen to accommodate both educts and base, as the role of hydroxide is usually crucial in the catalytic cycle, while the organic solvent played an obvious part in bringing the reactants and catalyst into solution. But times have changed. Today, such

Scheme 2. Asymmetric 1,4-Additions of SiPhMe2 on Water at Room Temperature

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spontaneously in water above their critical micelle concentrations (which are quite low; ca. 10−4 M).64 The physical phenomena that surround use of micellar catalysis are unlike those of traditional organic solvent-based chemistry. All components of a micellar medium; the individual molecules of a surfactant, the catalyst and starting materials present, additives, and the products formed, are all in a constant state of flux.64 These components exchange between micelles in water, through the water. Thus, the key to using micelles for synthetic purposes is to design these nanoreactors such that enough “grease”, or lipophilicity within each micelle, serving as the reaction solvent, remains available in which to house the educts and catalyst for a reaction to take place at a reasonable rate (Figure 4). With smaller particles as exist with common surfactants such as Triton X-100, cremophor, and solutol, these form ca. 15 nm micelles and do not retain enough individual molecules of surfactant, under exchange conditions, to allow for reactions to go to completion at reasonable rates. Hence, they are simply, in most cases, unsatisfactory. Larger micelle-forming surfactants (>100 nm), such as Brij-30, are oftentimes equally nonfunctional due to the heterogeneous nature of their particles. Early publications in this area demonstrated the potential for SM couplings to be run in nanomicelles composed of first generation surfactant PTS, which forms ca. 22−25 nm micelles.65,66 No organic solvent is needed, and couplings go at room temperature with occasional heating to 45 °C when highly crystalline substrates are involved. Both aromatics and heteroaromatics are amenable. More recently, MIDA boronates have been studied as they are stable, slow release forms of the corresponding boronic acids, thereby avoiding competitive protodeborylation.67−69 Given that many products of SM reactions are solids, it has been shown that by simple filtration of the aqueous reaction mixtures from which the (mainly) biaryls precipitate, these reactions involve no organic solvent from start to finish (Scheme 3); i.e., an environmental or “E” Factor of zero based on use of organic solvents. The water retains both the surfactant and Pd catalyst and can be recycled with equal efficiencies.71 More challenging has been application of the same concepts to the 2-pyridyl array, notorious for its enhanced rate of deborylation. The current literature on this topic also relies on MIDA boronate derivatives,69,70 but uses them in the presence of undesirable additives such as a Cu(I) salt (50 mol %) in DMF at elevated temperatures. A far greener solution that allows for such couplings to take place in water under mild conditions, and in the complete absence of copper, involves use of 6-fluoro or 6-chloro analogs.71 Here, the halogen in the product can be either removed, or utilized for a second-stage conversion to new products via an SNAr or SM coupling, all in one pot (Figure 5).72 Notwithstanding the promise of nanomicellar technology for using water as the reaction medium, left unaddressed is the issue of the catalyst. That is, SM reactions still rely, in general, on amounts of precious metal in the 1−5 mol % range, an unsustainable level of use. This key issue has now been addressed in two distinct ways: (1) development of the new ligand HandaPhos73 (Scheme 4) and (2) discovery of new nanoparticles (NPs) that contain trace levels of palladium, formed upon treatment of FeCl3 with MeMgCl in THF at room temperature (Scheme 5).74 The former, HandaPhos, which upon treatment with Pd(OAc)2 forms a 1:1 complex and contains a highly lipophilic triisopropylbenzyl residue on the

Figure 1. New world of chemistry within aqueous nanomicelles.

chemistry should also be considered within the context of waste creation, most notably, when using especially egregious dipolar aprotic solvents leading to large wastewater streams, which thereby begs the question: The reaction may work according to the script, but at what cost to the environment (Figure 2)?

Figure 2. Suzuki−Miyaura couplings: broad scope vs waste generation.

Technologies that take advantage of micellar catalysis have begun to make significant advances over the past decade. These advances not only allow for the elimination of organic solvent as the reaction medium, but also do away with heating above room temperature for most couplings. These virtues are ascribed to the lipophilic interiors of nanomicelles (being used at low concentrations; e.g., 2 wt % TPGS-750-M (Figure 3; MW = 1264; 20 mg/mL water = 0.016 M) that are typically highly populated; indeed, concentrations on the order of 2 + M are the norm. This explains the only occasional need for applying heat, and even then, reaction temperatures rarely exceed 45 °C, thus leading to very clean, high-yielding reactions. The micellar-forming species (Figure 3) engineered for these purposes are derived from not only environmentally benign compounds, they are simple diester derivatives of dietary supplements: e.g., vitamin E, and β-sitosterol (a cholesterol mimic).57 They differ from existing nonionic surfactants, used on a occasional basis previously in the literature.47,58−63 They vary not only in their constitution, but more importantly, based on the size and shape of their nanomicelles formed 5841


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Figure 3. Designer surfactants used for micellar catalysis-enabled reactions in water.

Figure 4. High concentrations of reaction mixture occupants, all in a state of flux.

Scheme 3. Couplings of MIDA Boronates: No Organic Solvents

Figure 5. Cu-free strategy for couplings of 2-pyridyl-MIDA boronates.

precious Pd (Fe/ppm Pd NPs) and mediates SM under mild conditions (Scheme 5, bottom). For both, their aqueous reaction mixtures are recyclable, and hence, E Factors associated with their use are reduced significantly (i.e., by an order of magnitude) relative to the typical values seen with such couplings used in the pharmaceutical arena.5−8 Both reagents, however, use ligands (HandaPhos in the former, SPhos in the latter) that take several steps to prepare. Nonetheless, with presumed increasing demand, use at the ppm level, and recyclability, this may not be a significant hurdle to widespread future use. While these advances are suggestive of the possibilities now available to the community, they take on added significance once applied on scale. Indeed, with proper process chemistry,

BI-DIME skeleton, leads to catalysis of SM couplings in water at rt at the parts per million (ppm) level (e.g., using 1000 ppm or 0.1 mol %). The latter reagent, generated and used in situ or isolated and stored as a solid, also contains ppm amounts of 5842


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ACS Sustainable Chemistry & Engineering Scheme 4. HandaPhos-Enabled SM Couplings with Pd at the ppm Level

Scheme 5. Fe/ppm Pd NPs for Sustainable SM Couplings

full advantage can be taken leading to improved efficiency and selectivity, as well as substantially streamlined processes that bring about productivity savings and much improved mass utilization. As illustrated in Scheme 6, a process consisting of consecutive Suzuki−Miyaura cross-couplings was developed at Novartis (unpublished) starting from the challenging dichloropyrimidine core. Its selective monocross-coupling with (3formylphenyl)-boronic acid was achieved under very mild conditions utilizing micellar catalysis technology. An almost perfect stoichiometry of halide to boronic acid (1:1.05) is responsible for the essentially complete lack of observed product of disubstitution (the 5% excess was used to account for decomposition of the boronic acid). The high quality of the first crude product enabled a subsequent cross-coupling with a 2-pyridyl MIDA boronate in the same pot, without further addition of catalyst, thereby recycling the aqueous medium. This tandem sequence was also made possible thanks to the presence of a cosolvent. Thus, the use of THF (5% by volume) allowed for slow addition of the boronic acid and then the MIDA boronate in a controlled manner, thus avoiding accumulation of these two reaction partners of limited stability. In this way, a nonoptimized process utilizing 1 mol % catalyst could be developed and scaled up. It proceeded smoothly in 75% yield after extraction with isopropyl acetate, simple filtration through a plug of charcoal to deplete the content of residual palladium to below 10 ppm, and crystallization to a high quality product (purity >98%).

a

Conditions: ArX (0.5 mmol), Ar′Y (0.6 mmol), SPhos (3 mol %), FeCl3 (5 mol %), MeMgBr in THF (10 mol %), K3PO4·H2O (1.5 equiv), 2 wt % TPGS-750-M, 0.5 M, rt or 45 °C.

Scheme 6. Sequential, One-Pot Suzuki−Miyaura CrossCouplings in Water at Room Temperature

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removal and trituration with pentane to obtain a free-flowing powder (see Scheme 5, above), although they are best made in situ and used directly.74 However, by simply leaving the ligand out of this recipe, the resulting NPs, while unsuitable for SM couplings, have been found to reduce functionalized aromatic and heteroaromatic nitro-containing compounds in water at room temperature in high yields (Scheme 7).75,76 Even less palladium is required in these reductions, with amounts on the

NITRO GROUP REDUCTIONS IN WATER AT ROOM TEMPERATURE The Fe/ppm Pd NPs that mediate SM couplings in water at temperatures between rt and 45 °C require a ligand (SPhos) to be present within their fundamental architecture. They are made by treatment of FeCl3-containing, or doped with, ca. 400 ppm Pd(OAc)2, with MeMgCl in THF, followed by solvent 5843


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ACS Sustainable Chemistry & Engineering Scheme 7. Nitro Group Reductions with Ligand-Free Fe/ ppm Pd Nanoparticles at Room Temperature

Scheme 8. Peptide Coupling in Water at Room Temperature Using COMU

Scheme 9. Amide Bond Formation Followed by an SNAr Reaction in Water order of 80−100 ppm or so found to be sufficient. NaBH4 was identified as the best choice as the source of hydride. Once a reaction is complete, simple in-flask extraction using minimal amounts of a single organic solvent (e.g., EtOAc) leads to product isolation, leaving the aqueous reaction mixture behind for recycling.

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AMIDE AND PEPTIDE BOND CONSTRUCTIONS As recently illustrated and discussed by Brown and Boström, amide bond formation is the most heavily utilized reaction in organic synthesis over the past 30 years.77,78 As with the vast majority of traditional organic synthesis, amide/peptide bonds have been, and continue to be, made in organic solvents. Typical conditions involve either DMF or DCM, both of which are environmentally egregious.79,80 Recently, studies applying micellar catalysis based on the designer surfactant TPGS-750-M have illustrated the potential for such bonds to be formed in water at ambient temperatures.81,82 The key to success was in the use of the all-in-one coupling agent COMU (1.1 equiv; a uronium salt derivative of the safe reagent Oxyma), and the choice of base, in these cases, 2,6-lutidine (Scheme 8). Reaction times tended to be between 30 min and 4 h at a global concentration of 0.5 M. No racemization was observed, while yields tended to be high (82−99%). Cbz, Boc, and Fmoc protecting groups on nitrogen showed excellent tolerance to these reaction conditions. By contrast, a coupling run “on water” (i.e., a coupling in the absence of surfactant), afforded the desired peptide in low (53%) yield relative to that obtained in the presence of nanomicelles (96%). For the example shown in Scheme 9, the selectivity and efficiency of this micellar technology could be applied initially to generation of an amide via activation with EDCI and HOBt at room temperature in the presence of a substituted benzylic amine. The newly generated amide could then be treated with morpholine, which smoothly leads to a nucleophilic aromatic substitution on the 2-chloropyridine intermediate, under gentle warming to 40 °C, ultimately affording the adduct in high yield. The mild conditions, together with the use of essentially no excess of reagents, are presumably responsible for the essentially perfect chemoselectivity. This dramatically reduced

the challenges of product purification, as impurities related to the desired product were absent, thus contributing to a practical, scalable process. Additional studies along these lines at Novartis in Basel have further focused on amide bond constructions, where amino alcohols are the coupling partners (Scheme 10). At issue is potential initial competitive ester formation, or esterification following generation of the initially desired amide bond. Surfactant screening identified TPGS-750-M as the preferred micelle-forming amphiphile, while N-methylmorpholine appeared to be the best choice of base. The coupling agent needed to be changed here as well, from COMU to EDCI/ HOBt, notwithstanding the required care in handling HOBt, in an aqueous medium at 0.25 M at 40 °C. Under these conditions, side-by-side comparisons between micellar conditions and both CH3CN and DMF as sole solvents led to comparable results in several model systems.83 That the products tend to be water-insoluble solids adds yet another bonus to this chemistry, as simple filtration expedites workup and handling and thus, may add yet another economic advantage. Clearly, on the basis of these early reports,78,80,84 the prognosis for eliminating DMF from the reaction medium for peptide and amide couplings looks very encouraging. With an already powerful but growing toolbox, a scaffold (as in 4; Scheme 10) was targeted that combined an SNAr85 5844


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as previously described using EDCI/HOBt. Again, high selectivity was observed when a minimum amount of coupling acid was used (1.05 equiv). The end product 4 was isolated in 94% yield from this overall very practical and streamlined process. Interestingly as well, a much-improved mass utilization was now observed, along with reduced catalyst usage. Insofar as the solvent strategy is concerned, a toolbox of chemistry compatible with TPGS-750-M in water was in hand, with only minor variations being the small amounts of THF and acetone used as cosolvents, and the organic solvent (i-PrOAc) for extraction. With respect to the quality of the final compound, this was carefully monitored, clearly a top priority when it comes to implementation of the technology on-scale in a pharmaceutical portfolio. The mild conditions associated with this technology not only led to increased yields but also to high selectivities. The intermediates could easily be isolated to ensure the necessary control points, or submitted as such to subsequent steps in most cases. Such a streamlined sequence opens up numerous opportunities both at the development stage (50−200 g), as discussed above, or in basic research given the fast and facile derivatization of highly complex compounds as is oftentimes found in the pharmaceutical industry.

Scheme 10. Sequential Reactions: SNAr/Suzuki−Miyaura/ Nitro Group Reduction/Amidation

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EVOLUTIONARY SEQUENCE: WHAT’S NEXT? Is there another reaction medium coming along that can be better than just H2O? Probably not. And so, now that many technologies enabled by micellar catalysis in water are available (Figure 6), it seems obvious that on one level, many additional reactions in organic synthesis can be converted to greener processes using this medium. As a result, reliance on organic solvents, and the energy input associated with many trans-

Suzuki−Miyaura cross-coupling, a nitro group reduction, and last, amide bond formation in a 4-step sequence. While the route had been worked out in traditional organic solvents, it suffered from several unattractive features, including (1) modest yield; (2) a complex overall process; (3) the need for protecting group chemistry to minimize or reduce the extent of competing isomer formation (C vs O selectivity in amide bond formation); (4) decomposition (protodeborylation) requiring a protecting group on the pyrazole; (5) an overall involved purification strategy (several crystallizations involved); (6) a misaligned solvent strategy. Micellar technology was anticipated to increase selectivity, and allow for a more direct approach, bypassing the need for protecting groups. Indeed, after an initial SNAr addition proceeding smoothly to 1 in quantitative yield, subsequent cross-coupling with the moderately stable pyrazole MIDA boronate to afford 2 also proved to be high yielding (86% isolated). While the two steps could be carried out in the same pot, the optimal process required precipitation of the SNAr product 1 from a TPGS-750-M/H2O + THF solvent mixture, filtration of the solid, and resubmission to Suzuki− Miyaura cross-coupling in a TPGS-750-M in water/acetone solvent mixture. Upon completion, precipitation led to the desired product in high purity. Recycling of this catalytic system could be achieved at least one more time without a noticeable decrease in overall efficiency. Our recent results have also demonstrated the practicality of Fe/ppm Pd nanoparticles (NPs) as a catalyst for selective reductions of nitro groups in the presence of a variety of other functionality.75,76 Here, too, the same high efficiency was observed (conversion of 2 to 3, Scheme 10). This process is all the more remarkable as it takes place without requiring a high pressure vessel, after careful design of the process and using KBH4 (rather than NaBH4 in this case) as the optimum hydride source.83 Aminopyridine 3 could be isolated in 95% yield after a single extraction with isopropyl acetate and filtration through charcoal. Further purification could be effected by recrystallization from the resulting solution in i-PrOAc, if desired. Alternatively, precipitation with heptanes led to material that could be submitted as such to the final amide bond formation,

Figure 6. Micellar catalysis applied to numerous transformations. 5845


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formations, will become less common, and the impact in terms of organic waste created by the chemical enterprise should decrease significantly. But what about the use, and release into the environment, of transition metals, especially those recognized as endangered; how can this chemistry in water be used to greater advantage? One idea is to devise new platforms for nanoparticles that position trace amounts of highly active metal atoms on a surface, thereby avoiding deactivation via aggregation. Such NPs containing ppm levels of ligated (or not) metals could then take advantage of the “nano-to-nano” concept, where the substrate(s) is delivered to the NP catalyst by the PEG contained within the nanomicelles, driven by PEG-induced chelation and stabilization.74,86 This delivery mechanism operates in water, with or without the presence of small amounts (1−10% by volume) of a cosolvent, as nanomicelles are typically not formed in organic solvents alone. It also avoids the usual elevated reaction temperatures characteristic of heterogeneous catalysis. This concept has been applied to both Lindlar reductions using palladium NPs,86 and Suzuki− Miyaura reactions74 using recyclable NPs containing iron in which very low (essentially nondetectable) levels of Pd are sufficient to effect cross-couplings in water under mild conditions. Other areas ripe for development include the synthesis of nonracemic micelles capable of inducing asymmetry without reliance on ligands; where the nanomicelle is the solvent and the ligand. Further inroads to new ligand types matched to micellar catalysis offer tremendous opportunities in synthesis, as those the community today has come to embrace are not necessarily those that will best serve synthesis under micellar catalysis conditions in water going forward. Potentially exciting applications to continuous flow also seem like a natural fit but have yet to be documented in the literature.

The authors declare no competing financial interest. Biographies

Bruce Lipshutz (Ph.D., Yale 1977, Harry Wasserman; postdoc with E. J. Corey, Harvard) began his academic career at UC Santa Barbara (UCSB) in 1979 and continues there today as Professor of Chemistry. His current research program focuses on developing new technologies for use in organic synthesis that are environmentally responsible. Thus, his group is determined to (1) get organic solvents out of organic chemistry; (2) eliminate the need for investing energy into reactions; and (3) provide new reagents that enable transition metal catalysis

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using either precious or base metals at ppm levels.

PERSPECTIVE. NATURE VS THE ORGANIC CHEMIST: WHO WINS? AND THE ANSWER IS... ...BOTH!! Is there any other possible outcome? Imagine the state of technology today had we followed Nature’s lead 100+ years ago. Making the change is long overdue. Yes, it will take considerable time and effort in research for sure. But in this overview it should now be clear that we already have a strong indication that the tools are there to be had; that organic chemists can solve environmental problems created by both those who came before us, and by those who refuse to acknowledge the environmental implications of the work that goes on along traditional lines. How much longer can we continue to pollute our planet? It is only a matter of time before the wave of change comes; whether based on health/ toxicological issues, an environmental disaster, an energy shortage, geographical limitations, economic restrictions, public relations, or political pressures; or maybe we just no longer have access to palladium! Sooner or later, we are going to make the change. Where will your chemistry be when it happens?

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Fabrice Gallou received his Ph.D. from The Ohio State University (2001) in the field of natural products total synthesis. He then joined Chemical Development at Boehringer Ingelheim, USA. He sub-

AUTHOR INFORMATION

sequently moved in 2006 to the Chemical Development group at

Corresponding Authors

*E-mail: [email protected]. Tel.: 805-893-2521. Fax: 805-893-8265 (B.H.L.). *E-mail: [email protected]. Tel.: 41 61-324-9911. Fax: 41 61 324-9536 (F.G.) *E-mail: [email protected]. Tel.: 502-852-5977. Fax: 502-852-8149 (S.H.).

Novartis, Switzerland, where he now is responsible for global scientific activities worldwide, overseeing development and implementation of practical and economical chemical processes for large scale production of APIs. 5846


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Sachin Handa was born in Patti-Amritsar, India. He received M.S. degree in applied pharmaceutical chemistry from Guru Nanak Dev University, after which he worked as a research chemist in drug discovery at Panacea Biotec. He came to the U.S in the Fall of 2009 for graduate studies and received a Ph.D. in chemistry from Oklahoma State University in 2013, after which he did postdoctoral work in the Lipshutz group at UCSB. He began his independent career as an Assistant Professor in the fall of 2016 in the Department of Chemistry at the University of Louisville, in Kentucky.

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ACKNOWLEDGMENTS

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REFERENCES

Financial support (B.H.L.) provided by the NSF (GOALI SusChEM 1566212) and Novartis is warmly acknowledged. S.H. thanks the University of Louisville for financial support.

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