Chemistry Takes a Bath: Reactions in Aqueous Media - The Journal of

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Chemistry Takes a Bath: Reactions in Aqueous Media

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hemical reactions in water underpin the very existence of life. But to synthetic chemists, water is usually considered an enemy, lurking in the shadows, waiting to reduce yields and destroy reproducibility. Indeed, chemists often take great pains to exclude even traces of water from their reaction media, and if water does make an appearance in a synthetic procedure, it is only in the course of workup. Instead, fine-chemical syntheses tend to use petroleum-derived solvents, which contribute to a vast pool of toxic waste,1,2 and water-sensitive reactions, which complicate process development and oftentimes create safety hazards.3 Thus, there has been an increasing push in industry and academia to replace reactions run in traditional organic solvents with alternatives that function in aqueous media. Aqueous reactions also provide a crucial interface between chemistry and biology. On the fundamental side, attachment of non-natural moieties to biomolecules, as in the fluorescent tagging of proteins, allows for observation of the underlying mechanisms of biological systems from single cells to complex organisms.4 On the applied side, chemical modification of biomolecules enables the development of therapeutics, including antibody−drug conjugates, bioactive peptides, and derivatives of small-molecule natural products. Since most biomolecules are at best insoluble and at worst unstable in organic solvents, none of these endeavors would be possible without water-based reaction methodology. Despite the potential utility of aqueous reactions, organic solvents still dominate methods development. What then are the obstacles that hinder the widespread adoption of aqueous media? Perhaps the most obvious complaint is that, unlike biomolecules, most reactants and catalysts employed in organic synthesis are simply not very soluble in water. However, as shown herein, this problem seems overstated, since reactions need not be homogeneous to occur efficiently. On the contrary, heterogeneity can greatly facilitate both catalyst separation and product recovery; as such, solid-phase catalysts are commonplace in industrial processes and are widely considered advantageous.5−7 A trickier problem is that many reactive species, particularly organometallic compounds, are unstable in water, sometimes violently so. While this may seem like an insurmountable limitation, recent breakthroughs have upended our preconceptions about what is and is not water-compatible. The “on-water” reaction is one of the simplest strategies to unite synthetic chemistry with aqueous media, but also among the most mysterious. In this paradigm, reactants are dispersed in water, usually with vigorous agitation, but are not themselves miscible or soluble in water.8 Despite being heterogeneous, these reactions can proceed rapidly and quantitatively, with water exerting a critical effect on the reaction rate and selectivity. The precise role of water is difficult to know, but one hypothesis is that the water surface presents hydrogenbonding donors and acceptors that can activate substrates and facilitate proton transfer (Figure 1a). On-water acceleration has mainly been demonstrated for nucleophilic additions and pericyclic reactions,8 but chemists are continually seeking new ways to harness this phenomenon. This has led to surprising © 2018 American Chemical Society

Figure 1. Reactions on water. (a) Activation of reactants by Hbonding at the aqueous interface. (b) On-water addition of organolithium and organomagnesium reagents to imines and nitriles.10

discoveries, like the observation that organolithium and organomagnesium reagents, which are normally kept as far from water as possible, can be deployed for on-water alkylation reactions that occur in high yield with reaction times as short as five seconds (Figure 1b)!9,10 But as amazing as it is, chemistry on water will not fulfill all of our synthesis needs. Thus, additional strategies are needed for synthetic chemistry to move into water. To gain inspiration, chemists have looked to nature, the unrivalled master of aqueous synthesis. Of its many talents, one approach that nature uses to great effect is encapsulation; that is, using membranes to create microenvironments that differ from the surroundings. Chemists, in turn, have developed synthetic surfactants that spontaneously assemble in water to create contained hydrophobic regions, or micelles (Figure 2a).11 With just a low weight percent of the additive, even typically hydrophobic reactions like Pd-catalyzed biaryl couplings can occur in water. Once a burden, the hydrophobicity of the reactants now becomes a benefit since the substrates and catalysts are driven into areas of high local concentration, while the product can be removed simply by extraction or precipitation. As a result, reactions in micellar media are often higher yielding and require lower temperatures than their fully homogeneous counterparts. In yet another blow to conventional wisdom regarding water sensitivity, micellar media have even been shown to accommodate organozinc reagents, formed in situ, leading to highly efficient Negishi-like couplings (Figure 2b).12 Another way chemists have sought inspiration from nature is to replace workhorse synthetic reactions, like metal-catalyzed asymmetric hydrogenation, with alternatives that use nature’s catalysts, enzymes. Indeed, esterases, aldolases, transaminases, and keto- and imine reductases have found application to finechemical synthesis (Figure 3),13 supplanting not only organic solvents but often expensive transition metals as well. Yet misconceptions about how enzymes work, and how to work with them, have made chemists hesitant to employ enzymes with the same zeal with which they might use, say, a phosphine ligand. One belief is that enzymes require specialized techniques that are inaccessible to synthesis laboratories. It is Special Issue: Organic and Biocompatible Transformations in Aqueous Media Published: July 20, 2018 7319

DOI: 10.1021/acs.joc.8b01412 J. Org. Chem. 2018, 83, 7319−7322

The Journal of Organic Chemistry

Editorial

Figure 2. Moving organic reactions into water. (a) Hydrophobic species can react in the micelle interior. (b) Negishi-like couplings in micellar media.

Figure 3. Common enzymatic transformations used in synthesis.

true that old-school biocatalytic reactions may have resembled a witch’s cauldron, with catalysts being added in the form of ground-up snails,14 but this view is outdated. Nowadays, enzymes can be overexpressed in organisms like E. coli and prepared as solutions or powders that are used just like any other catalyst. Protein expression may be uncommon in synthetic chemistry laboratories, but advances in biotechnology have made this procedure accessible even to those lacking expertise in molecular biology. Thus, the preparation of an enzymatic catalyst is considerably less arduous than the preparation of many small-molecule catalysts, especially since E. coli does most of the work! Another misconception is that enzymes are specific to a single substrate and, therefore, are useful solely in process chemistryand only after extensive engineering. But biocatalysis studies have repeatedly shown that enzymes will accept more than just their native substrates. Furthermore, hypothesis-guided engineering, such as active-site mutagenesis, can create focused catalyst panels to convert a broad range of substrates. Chemists are already happy to test dozens of ligands for metal-catalyzed reactions, so testing a few enzymes should not appear arduous. It is true that without rigorous optimization, the activity with non-native substrates will likely not match the fastest known enzyme kinetics, but even a “bad” enzyme can provide hundreds to thousands of turnovers, plenty for the purposes of laboratory synthesis. One might think, however, that the most intractable difficulty with enzymes is their limitation to nature’s repertoire of reaction types, which excludes a large swath of synthetic chemistry. But even this barrier is beginning to break down as chemists are discovering that enzymes, when exposed to unnatural reagents or conditions, will perform reactions that are completely new to nature, such as carbene and nitrene transfer (Figure 4a)15 and radical hydrodehalogenation (Figure 4b).16,17 Such mechanistic promiscuity should not be surprising, since after all, enzyme cofactors are reactive species just like smallmolecule catalysts, and nature has faced no selective pressure against these reaction types. Thus, it is reasonable to expect that the extent to which genetically encoded catalysts can be adapted to new-to-nature reactions has only begun to be uncovered. In this special issue of The Journal of Organic Chemistry, there are 30 articles describing research that reflects a variety of modern advancements, all realized in aqueous media. Synthesis

Figure 4. Repurposing native cofactors for new reactions. (a) Carbene and nitrene transfer by heme proteins and (b) radical hydrodehalogenation by NADPH- and FAD-dependent reductases.

is the aim of most of the papers, which include sustainable methodology,18−20 asymmetric catalysis,21 “on-water” chemistry,22,23 micelle-enabled reactions,24−29 heterogeneous catalysis,30−33 electro-34 and photochemistry,28,35 and reactions mediated by enzymes.36−41 These reports also highlight how aqueous reactions facilitate the synthesis and modification of highly hydrophilic compounds, such as amino acids, 40 peptides,42 and carbohydrates.43 But in addition to synthesis, we also find papers focused on biology, including bioorthogonal reactions44−47 and characterization of therapeutic compounds,48 thus attesting to the diversity of topics in this compendium dedicated to “Chemistry in Water”, as illustrated on the cover of this thematic issue.

David K. Romney, Guest Editor Division of Chemistry and Chemical Engineering, California Institute of Technology

Frances H. Arnold, Guest Editor Division of Chemistry and Chemical Engineering, California Institute of Technology

Bruce H. Lipshutz, Guest Editor Department of Chemistry & Biochemistry, University of California, Santa Barbara 7320

DOI: 10.1021/acs.joc.8b01412 J. Org. Chem. 2018, 83, 7319−7322

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(15) Brandenberg, O. F.; Fasan, R.; Arnold, F. H. Exploiting and Engineering Hemoproteins for Abiological Carbene and Nitrene Transfer Reactions. Curr. Opin. Biotechnol. 2017, 47, 102−111. (16) Emmanuel, M. A.; Greenberg, N. R.; Oblinsky, D. G.; Hyster, T. K. Accessing Non-Natural Reactivity by Irradiating NicotinamideDependent Enzymes with Light. Nature 2016, 540 (7633), 414−417. (17) Sandoval, B. A.; Meichan, A. J.; Hyster, T. K. Enantioselective Hydrogen Atom Transfer: Discovery of Catalytic Promiscuity in Flavin-Dependent ‘Ene’-Reductases. J. Am. Chem. Soc. 2017, 139 (33), 11313−11316. (18) Huang, X.; Chen, Y.; Zhen, S.; Song, L.; Gao, M.; Zhang, P.; Li, H.; Yuan, B.; Yang, G. Cobalt-Catalyzed Aerobic Cross-Dehydrogenative Coupling of C−H and Thiols in Water for C−S Formation. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b02718. (19) Jin, X.-Y.; Xie, L.-J.; Cheng, H.-P.; Liu, A.-D.; Li, X.-D.; Wang, D.; Cheng, L.; Liu, L. Ruthenium-Catalyzed Decarboxylative C-H Alkenylation in Aqueous Media: An Expedient Synthesis of Tetrahydropyridoindoles. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00229. (20) Chatterjee, T.; Kim, D. I.; Cho, E. J. Base-Promoted Synthesis of 2-Aryl Quinazolines from 2-Aminobenzylamines in Water. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00327. (21) Yan, J.; Sun, R.; Shi, K.; Li, K.; Yang, L.; Zhong, G. NHCCatalyzed Asymmetric Benzoin Reaction in Water. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00481. (22) Nam, T. K.; Jang, D. O. Radical “On Water” Addition to the CN Bond of Hydrazones: A Synthesis of Isoindolinone Derivatives. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b03193. (23) Chakraborti, G.; Paladhi, S.; Mandal, T.; Dash, J. “On Water’’ Promoted Ullmann-Type C−N Bond-Forming Reactions: Application to Carbazole Alkaloids by Selective N-Arylation of Aminophenols. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b03020. (24) Feng, Q.; Chen, D.; Hong, M.; Wang, F.; Huang, S. Phenyliodine(III) Bis(Trifluoroacetate) (PIFA)-Mediated Synthesis of Aryl Sulfides in Water. J. Org. Chem. 2018, DOI: 10.1021/ acs.joc.8b00435. (25) La Sorella, G.; Sperni, L.; Canton, P.; Coletti, L.; Fabris, F.; Strukul, G.; Scarso, A. Selective Hydrogenations and Dechlorinations in Water Mediated by Anionic Surfactant Stabilized Pd Nanoparticles. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00314. (26) Zhou, F.; Hu, X.; Zhang, W.; Li, C.-J. Copper-Catalyzed Radical Reductive Arylation of Styrenes with Aryl Iodides Mediated by Zinc in Water. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00278. (27) Guo, P.; Zhang, H.; Zhou, J.; Gallou, F.; Parmentier, M.; Wang, H. Micelle-Enabled Suzuki-Miyaura Cross-Coupling of Heteroaryl Boronate Esters. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00257. (28) Finck, L.; Brals, J.; Pavuluri, B.; Gallou, F.; Handa, S. MicelleEnabled Photoassisted Selective Oxyhalogenation of Alkynes in Water under Mild Conditions. J. Org. Chem. 2018, DOI: 10.1021/ acs.joc.7b03143. (29) Schmidt, M.; Deckwerth, J.; Schomäcker, R.; Schwarze, M. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00247. (30) Tadrent, S.; Luart, D.; Bals, O.; Khelfa, A.; Luque, R.; Len, C. Metal-Free Reduction of Nitrobenzene to Aniline in Subcritical Water. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00406. (31) Li, D.; Zhang, J.; Cai, C. Pd Nanoparticles Supported on Cellulose as a Catalyst for Vanillin Conversion in Aqueous Media. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00246. (32) Ghorpade, P. V.; Pethsangave, D. A.; Some, S.; Shankarling, G. S. Graphene Oxide Promoted Oxidative Bromination of Anilines and Phenols in Water. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00188. (33) Shen, G.; Osako, T.; Nagaosa, M.; Uozumi, Y. Aqueous Asymmetric 1,4-Addition of Arylboronic Acids to Enones Catalyzed by an Amphiphilic Resin-Supported Chiral Diene Rhodium Complex under Batch and Continuous-Flow Conditions. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00178. (34) Gerken, J. B.; Pang, Y. Q.; Lauber, M. B.; Stahl, S. S. Structural Effects on the PH-Dependent Redox Properties of Organic Nitroxyls:

Chao-Jun Li, Guest Editor

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Department of Chemistry, McGill University

AUTHOR INFORMATION

ORCID

David K. Romney: 0000-0003-0498-7597 Frances H. Arnold: 0000-0002-4027-364X Bruce H. Lipshutz: 0000-0001-9116-7049 Chao-Jun Li: 0000-0002-3859-8824 Notes

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

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DOI: 10.1021/acs.joc.8b01412 J. Org. Chem. 2018, 83, 7319−7322