When Does Organic Chemistry Follow Nature's Lead and “Make the

Perspective pubs.acs.org/joc

When Does Organic Chemistry Follow Nature’s Lead and “Make the Switch”? Bruce H. Lipshutz* Department of Chemistry & Biochemistry University of California, Santa Barbara, California 93106, United States ABSTRACT: The case is made for transitioning organic chemistry from a developed discipline that remains highly dependent upon organic solvents to one that will be sustainable, based on water as the reaction medium. Processes in hand that today achieve the same bond constructions characteristic of traditional organic synthesis, but can be accomplished under environmentally responsible conditions, are discussed as representative of the potential that lies ahead.

■

“MAKE THE SWITCH”? WHAT SWITCH? Most organic chemists, and especially those who are cardcarrying synthetic chemists, have been taught from day one that the vast majority of reactions in organic chemistry have been, and presumably will always be, conducted in organic solvents. Having a Ph.D. from the Wasserman group at Yale and then finding myself as a postdoc collaborating on the challenging and worldwide competitive goal of synthesizing the antitumor agent maytansine (1)1 surrounded by incredibly talented students in the Corey group at Harvard, well, I was about as traditional a synthetic chemist as one gets. But after leaving New England for southern California in 1979, and spending more than the next quarter of a century contributing new reagents, processes, and syntheses to further the field, something struck me in 2007 as not quite “right”. I started to realize that my group was generating large amounts of organic waste from our ongoing research. In fact, we were informed by the Environmental Health & Safety Office on campus that our group was the largest polluter in the entire county of Santa Barbara! Wow. At that time I was actually quite proud of this reputation, since the implication was that we were working hard and making great progress. How ironic that just a decade later I now look back at that status with considerable remorse. Indeed, this distinction was not going to make it onto my CV.

In that decade before our group made the switch, the 12 Principles of Green Chemistry by Anastas and Warner2 had only recently been scribed (1998), while Trost’s “atom economy” (1991) was already a buzzword of the times.3 While these early guidelines ushered in the beginnings of the broad new era of environmental awareness, synthetic organic chemists had yet to embrace these seemingly fundamental concepts. To many, however, the notion that the manner in which modern organic chemistry is practiced is not sustainable seemed obvious; too much organic waste, and huge wastewater streams being created by the chemical enterprise worldwide every day. And the vast majority of the organic waste: organic solvents.4 While there was considerable talk about how to address this situation at various levels of government, industry, and academia, and especially at the ACS Green Chemistry Institute,5 making significant and lasting changes to “green-up” the practice of organic chemistry in any kind of a broader context seemed like a pipe dream.

■

JUMPING IN Back in 2007, with, quite frankly, a very modest appreciation of green chemistry to my credit, I nonetheless realized that we had an opportunity to do much of the same organic synthesis we were performing, but under aqueous conditions. The history behind this “sense” came about from our work in the coenzyme Q10 (2; CoQ10; Figure 1) arena,6 where years earlier we had developed an especially efficient (one-step) synthesis of this crucial dietary supplement, the majority of which derived from solanesol, isolated from tobacco waste.7a,b Although we had gained access to CoQ10, its highly lipophilic properties derived from its 50carbon polyprenoidal side chain accounted for its total water insolubility and, hence, very low in vivo bioavailability.7c As Received: January 3, 2017 Published: March 17, 2017

© 2017 American Chemical Society

2806

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry

sizes in water14 and cryo-transmission electron microscopy (cryo-TEM) analyses to reveal particle shapes and sizes.15 The former technique documented that while many of these commercial surfactants led to fairly small, 10−15 nm, micelles in water, PTS formed somewhat larger nanomicelles with an average in the 22−25 nm range. More revealing from the latter technique was that this average value reflected individual PTS nanoparticles ranging from 10 to 80+ nm and, hence, contained micelles of varying lengths and even shapes (spheres and worms; Figure 3). Invariably, after showing such data at each talk given

Figure 1. Retrosynthetic analysis of CoQ10.

important as this vitamin-like substance remains today to human health (e.g., it is responsible for energy production in our mitochondria),8 sprinkling grams of it onto our Wheaties in the morning leads to essentially zero absorption in the gut. The secret to its cellular uptake is its dissolution within aqueous nanoparticles, and for this purpose we found that “PTS”, a vitamin E-based surfactant, had already been developed.9 Admix CoQ10 with PTS (Figure 2) in water and, after appropriate heating and cooling, a clear red-orange solution results containing nanoparticles of CoQ10, with the bioavailability essentially doubling.

Figure 3. Cryo-TEM of PTS revealing both spherical and worm-like nanoparticles in water.

Figure 2. Structure of PTS.

Based solely on this early observation, I wondered whether such nanomicelles were actually “matched” to what was inside their lipophilic cores, or, more likely, that they are unconcerned with the nature of their payload. So if a molecule such as CoQ10 weighing 863 fits easily within these cores, why not chop it up into three molecules weighing about 300 each, consisting of two reaction partners and a catalyst? This rather naive question was presented to a few students in the group, each being asked to try a variety of synthetically useful reactions in transition-metal catalysis. And so, starting with Dr. Subir Ghorai and Karl Voigtritter, olefin metathesis was examined,10 while Ben Taft pursued Heck reactions.11 Soon thereafter, Alex Abela delved into Suzuki−Miyaura cross-couplings,12 each reaction type being pursued in water at room temperature (rt). Everything worked...and worked well. No organic solvents were anywhere in the equation, and no energy other than that provided at ambient temperatures (i.e., ca. 22 °C in southern California) was apparently needed. We were beginning to feel like we were on to something here....

on this subject, someone would ask the obvious question: Which size and shape of these nanoparticles is the one in which the chemistry takes place? It was a great question, and I was always a bit embarrassed to volunteer the same answer: I do not know. Although to this day I still do not have the answer, the fact that PTS contains such a variety of particle shapes and sizes was an important hint as to how to make this chemistry in water “faster, better, cheaper”. If this surfactant, unlike the others examined to date, had larger nanomicelles, could it be that the chemistry favored these over the smaller sized particles, and hence, could we make a new surfactant engineered to form only larger particles? From a retrosynthetic perspective, PTS is nothing more than a simple, unsymmetrical diester (Figure 4). Its synthesis is made complicated and low yielding by the use of PEG-600 that can react at either or both terminal hydroxyl groups, thereby creating tough to separate, undesired diester byproducts. If a monomethylated PEG, or “MPEG” is used, this problem disappears. Second, use of sebacic acid, a 10-carbon diacid, meant that, again, both ends could participate in symmetrical diester formation, so even more byproducts could result from this approach to PTS. By using succinic acid in the form of its anhydride, however, this problem is also solved. From a synthetic viewpoint the synthesis is reduced to two steps,16 with the remaining variable being the length of the hydrophilic MPEG attached to the succinic acid linker. We were limited here as only a few are available as items of commerce: MPEG-350; see Figure 2, bottom (n = 8), −550 (n = 13), −750 (n = 17), and −1000 (n = 23). Which one affords the “right” particle size best enabling the desired synthetic chemistry? No one, not even the world’s top theorists in nanomicelles (including those at UCSB), could predict the outcome. So, we

■

HOOKED ON EARLY SUCCESS During the course of these studies, it was only natural to make comparisons between surfactants; after all, this could surely be a reaction parameter that might need to be varied. Opening the Aldrich catalog revealed that several alternative nonionic surfactants can be purchased, and these are typically much less costly than it would be to make PTS.13 An obvious question would be “Why use ours?” The answer eluded us for some time, but eventually, after showing in side-by-side reactions that other surfactants, such as Triton X-100, cremophore, and solutol typically afforded inferior results, we “discovered” dynamic light scattering (DLS) as a technique for measuring average particle 2807

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry

Figure 4. Components of PTS and problems with its synthesis.

diameter. As a “rule of thumb”, therefore, the larger the PEG chain (and presumably, MPEG) for a given lipophilic section, the smaller the micelles formed in water. The MPEG-750 used to make 3 appeared to be the best compromise: smaller particles rarely lead to useful levels of reaction conversion, while larger micelles (e.g., >150 nm) can be heterogeneous and typically give even less useful results. Why? In time, we came to appreciate that micelles are not like golf balls; they do not retain the specific components from which each micelle derives, nor do they house their reactants and catalysts until the desired chemistry is over. Rather, micellar arrays are dynamic; they are continuously undergoing exchange phenomena between their occupants that are roaming from micelle to micelle through the surrounding water and exchanging the very surfactant molecules that have combined to form them.18 Hence, if a significant fraction of surfactant molecules that make up any micelle is “exchanging”, that leaves little of the hydrophobic portion of the amphiphile (i.e., the vitamin E portion of each surfactant) available to function as reaction solvent, which in turn results in slow, incomplete reactions. If this analysis is correct, it explains why the already well-established and very much related “vitamin E TPGS” does not normally function as an acceptable nanomicelle-forming surfactant: it forms ca. 15 nm micelles17 that do not provide the needed levels of “solvent” in which the chemistry takes place. Perhaps this accounts for why use of micellar catalysis for Pd-catalyzed crosscouplings had not been studied to any significant degree when we entered this field.19 As we increased our familiarity with using micellar catalysis for synthetic gain, we broadened our survey of reactions to include several different types of C−C, C−H, and C−heteroatomforming constructions; representative examples are summarized in Figure 6. What this single graphic hopefully conveys is that two of the three key reaction parameters associated with running such a variety of organic reactions have been standardized: (1) the choice of solvent, and (2) the reaction conditions. That is, the choice was no longer about which organic solvent, and whether to heat or cool a reaction. TPGS-750-M in water leads to nanoreactors that function as the solvent in which to run homogeneous catalysis, and most need only ambient temperatures. Only 2 weight % of 3 need be present, which means for a molecule with an average weight of 1262, use of 20 mg surfactant/mL of water leads to a concentration of 0.016 M!

had no choice: we made them all, four of them, and tested each in a series of side-by-side reactions against our original standard, PTS. The “winner” was clearly “TPGS-750-M” (3), a “designer” surfactant incorporating MPEG-750 (Figure 5).17 But it was not

Figure 5. Structural comparison between designer surfactant TPGS0750-M and vitamin E TPGS.

until we took the DLS on this new nonionic surfactant that we realized it was forming nanoparticles averaging ca. 50−60 nm, confirmed by cryo-TEM, showing solely spherical micellar arrays. Hence, in all regards we had made a giant leap forward; we had identified a new surfactant that led to greater rates and extents of conversion in a number of important transition-metalcatalyzed reactions; we had greatly simplified the preparation of the new surfactant TPGS-750-M, and we had identified a new aqueous medium that led to an indication as to the required nanoparticle size for obtaining the yields of products that are oftentimes as good or better than those seen in traditional organic solvents...and this aqueous medium was recyclable! But why does TPGS-750-M, and not the very closely related and common amphiphile “vitamin E TPGS” (4), lead to far better synthetic chemistry in water? The only difference between these is the PEG/MPEG. With increasing PEG length (i.e., more ethyleneoxy units), the greater its internal coiling (e.g., due to hydrogen bonding with the surrounding water), and thus, the greater 3-D space occupied by this portion of the surfactant. With greater space demands per molecule of surfactant, fewer molecules can be accommodated per nanomicelle. This is driven by the micellar interior, reflecting the attraction and interactions between the vitamin E subsections (thereby pulling the individual molecules together), thus arriving at a nanoparticle that has fewer molecules of amphiphile, and hence, a smaller 2808

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry

than simply providing an aqueous medium in which to do synthesis. Nature, in fact, had other plans, and proceeded to make it very clear that exciting times lied ahead, that we had gotten into this area of research for the long haul. The first realization along these lines came in the form of our discovery that Negishi-like couplings could be done in water.22 When first presented to me, I did what any advisor would do faced with such seemingly nonsensical claims: I chastised both postdocs Christoph Duplais and Arkady Krasovskiy and told them to come back to reality. But part of the beauty to chemistry is that, as Louie Fieser put it, “facts is facts”, and soon I had no choice but to accept their outstanding observations as part of this new reality. Clearly, we were operating under new rules that allowed us to do, experimentally, what seemed at the time “impossible”; to do what today falls under the blanket of “reductive couplings”,23 starting with two halides/pseudohalides and proceeding through very water-sensitive organozinc reagents...in water (Scheme 1). The in situ generated organozinc halide, protected from the surrounding water by a micelle, makes its way into the hydrophobic inner micellar core fully prepared for cross-coupling. A crucial element associated with these crosscouplings is use of the Amphos ligand, a commercially available ligand provided by Johnson Matthey in the form of the palladium catalyst PdCl2(AmPhos)2. Take away the p-Me2N- residues, and the level of success drops markedly. This advance alone convinced us that just about any chemistry might be possible in this medium. Another example of valuable synthetic chemistry that comes about by different rules concerns our discovery of the “nano-tonano” effect. This is one of those occurrences that was destined to happen in spite of our lack of knowledge in the materials arena. Little did we know that nanoparticles (NPs), functioning as ppm level transition-metal-containing catalysts (e.g., Pd, and Cu) are stabilized by PEG.24 This polyether is likely acting as a ligand, thereby bringing the substrate(s) housed within the micelles directly to the catalyst. In other words, we had found an internal delivery system: nano..micelles to nano...NPs...BOOM! cryoTEM analyses (Figure 7) confirm this “nano-to-nano” effect, which is presumably the explanation behind why this heterogeneous catalysis takes place under such mild reaction conditions: at the ppm level of metal and, yet, within the rt to 45 °C temperature range. This phenomenon, nonexistent in organic solvents, led (1) graduate students Eric Slack and Chris Gabriel to generate NPs of Pd that in the presence of NaBH4 selectively reduce alkynes to cis-olefins (i.e., Lindlar reductions) in water at ambient temperatures (eq 1);25 (2) postdoctoral students Sachin Handa and Ye Wang to develop and apply new Fe-based catalysts containing ppm amounts of Pd for Suzuki−Miyaura reactions in water (eq 2);26 and (3) Aurelien Adenot, a student

Figure 6. Representative, and yet several dissimilar, types of reactions all run in aqueous TPGS-750-M.

Perhaps even more exciting is the notion that sequential reactions could be run in a single pot, since the medium for each is the same (vide infra). Along the way, we realized that the “rules” governing micellar catalysis (i.e., chemistry within a dynamic system),18 can oftentimes be different from those associated with traditional synthesis in organic solvents.19 As examples: (1) solvent effects take on a new meaning, as concentrations within a nanomicelle are ca. 10 times those commonly used in organic media;20 (2) sophisticated and cleverly engineered ligands chelating transition metals leading to highly effective catalysts that perform under a given set of traditional conditions may not be effective in aqueous nanoreactors. In essence, our perspective on this new frontier was evolving; we were forging into totally unknown territory by tailoring a new, highly effective reaction medium for organic chemistry. That notion alone gave us pause; how many among us can make such a claim to have designed a new “solvent”? We began to realize that we are creating a newly designed world apart from not only the traditional world of chemistry in organic solvents but also quite distant from other “alternative media” (e.g., ionic liquids, fluorous media, supercritical CO2, and even water alone).21 We began to appreciate the potential future of synthetic organic chemistry that, armed with new rules, started to look environmentally responsible and a lot greener. And, quite frankly, we began to really worry about from where funding might originate, given that government agencies had no programs offering grants at the time earmarked for green chemistry.

■

THINKING WAY OUTSIDE THE BOX Having made the switch from using organic solvents to nanomicelles in water as reaction media, we simply had to accept that there are new rules under which we were going to be operating from this point onward. Surely this meant much more

Scheme 1. Representative Example of Ground-Breaking “New Rules” for Synthetic Chemistry: Net Negishi-like Couplings...in Water

2809

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry

Scheme 3. AbbVie’s Comparison of Conditions for a Sonogashira Coupling

Figure 7. Cryo-TEM images for (A) PTS (see Figure 2) in water; (B) TPGS-750-M (3) in water; (C) metal nanoparticles in an aqueous solution of 3, showing aggregation.

in DMSO using 5% of a Pd catalyst and 10% CuI led to none of the desired arylated alkyne. However, in water at ambient temperature, with less catalyst (1%) and in the absence of copper, the unsymmetrical acetylene could be obtained in 48% yield.29 These are just a few examples documenting that this green technology can be very useful at the medicinal chemistry level.

■

OK, BUT DOES THIS CHEMISTRY WORK AT SCALE? Perhaps the first and most commonly asked question after every talk I have given on this chemistry is can it be used in more than the academic lab? I am quick to point out that we have certainly not discovered “micellar catalysis.” This type of chemistry has been around for decades and is used every day by industries that need to mix oil and water, such as the cleaning, textiles, petroleum, cosmetics, carpet, and pharmaceutical industries, at multikilo scales. Our contribution is the identification of environmentally benign surfactants that enable synthetic chemistry to be run in water under very mild conditions. While dismissal of the question about scale was one that could not be made on the basis of work done at UCSB, we were most fortunate to attract the attention of scientists at Novartis, in particular Dr. Laurence Hamann at the Cambridge site (now at Celgene), and ultimately in collaboration with Dr. Fabrice Gallou in Basel, who never doubted the potential of this green technology regardless of scale. Moreover, although we had begun to demonstrate that tandem reactions could be done under these aqueous conditions in a single pot, it was quite a challenge for us to compete with the assets that this big pharma company could direct toward evaluating the potential. And so while Novartis has already applied our micellar catalysis in their laboratories in China at the tens of kilos scale,30 their specific sequence of reactions involved remains proprietary.31 Nonetheless, another sequence that impressively adapts this technology, involving some of the most consistently used reactions in the pharma industry over the past 30 years,32 is shown in Scheme 4. This model study accomplished several goals: it documented (1) operational simplicity using nanomicelles; (2) improved yields and increased selectivity, leading to enhanced throughput; (3) reduced costs; (4) reliance on limited amounts of excess boronic acid (≤20% excess), and importantly; (5) eliminated dependence on dipolar aprotic solvents, and DMF in particular, that avoids its reported effects on human health.33 Especially noteworthy is the role that an added cosolvent can have on larger scale reactions, a key observation made by Fabrice Gallou, Michael Parmentier, and co-workers at Novartis. That is, depending upon the individual solubility properties of the substrates and the resulting product in any given reaction, there may be practical limitations (e.g., stirring issues, undesired aggregation, etc.) that could be overcome by the presence of an organic, usually water-miscible, cosolvent. Those that have been

“on loan” from Paris Tech, to successfully investigate a ppm-level copper(I)-doped Fe-based catalyst that mediates click reactions in water at room temperature (eq 3).27There are other examples of chemistry operating under new rules, such as the unprecedented impact of micellar catalysis on levels of enantioselectivity in several important asymmetric reactions, but these are still under study in our group and will be reported in due course. It is rewarding to see that other researchers, especially those in industrial laboratories, have benefited from this technology. For example, medicinal chemists led by Wilfried Braje at AbbVie in Ludwigshafen have used micellar catalysis to either obtain better yields than those seen using traditional conditions or, in some cases, isolate the desired product where none could otherwise be generated in organic media.28 As a representative case, dihydroquinolinones can now be easily prepared via an initial Rh-catalyzed 1,4-addition of a boronic acid, followed by cyclization of the intermediate ester (Scheme 2). Scheme 2. AbbVie’s Tandem 1,4-Addition/Cyclization: Traditional Approach vs Micellar Catalysis

While the product with R = Me resulted from use of aqueous dioxane/KOH at reflux in moderate yield (47%), the same reaction in aqueous nanoreactors derived from TPGS-750-M afforded this product at room temperature (95%). The corresponding case of R = Ph, however, afforded no product under these same traditional conditions, while in water, a 78% yield was obtained. Likewise, Sonogashira coupling (Scheme 3) 2810

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry Scheme 4. Model Sequence Used by Novartis (ca. 10 g Scale)

experimentally determined to have the greatest impact include THF, acetone, and PEG, although others can, on occasion, find favor (e.g., CH3CN and toluene). Note that in Scheme 4, THF was present to the extent of 20% of the reaction volume. Given their water-miscible properties, these solvents do not significantly compete with educts for space within the micelles that might otherwise slow reaction rates. In addition, since they remain predominantly in the aqueous layer, they are recycled along with the reaction mixture, or they can be distilled off once the reaction is complete and then recycled. Used mainly at the 5−15% (v/v) level, they may offer several advantages beyond impacting the physical nature of the process itself. For example, rates of reactions may be enhanced by initially “softening” the lattice of an otherwise highly crystalline material, prior to addition of the aqueous surfactant solution, allowing it to more easily gain entry into a micellar core. This “trick”, initially discovered on a small scale by Dr. Sachin Handa, can make a significant difference in cases where “brick dust” might be viewed as an inappropriate match for this type of chemistry. An initial communication describing this technological breakthrough resulting from an ongoing, extensive collaborative study in both Basel and Santa Barbara is now available.34 Representative examples associated with this work are illustrated in Figure 8.

Figure 8. Representative examples illustrating the impact of a cosolvent on reactions run under micellar catalysis conditions.

Warner list principle no. 5 as use “benign solvents”. But in the course of developing this chemistry, substrates and catalysts must compete for space within the limited numbers of nanoreactors present in the water, given that only 2 weight % surfactant is used. This leads to high internal concentrations (ca. 2−2.5 M)20 and, hence, reactions that can take place at ambient temperature. Thus, principle no. 6 is also addressed by definition: “design for energy efficiency”. But what about the third and, arguably, most costly of the three key reaction parameters: the catalyst, especially when a precious metal is involved? Here, our technology might meet the standard of catalysis, using 1−5 molar % amounts that are characteristic of most “catalytic” processes. And while catalysis is technically

■

NEXT HURDLE: CATALYSIS AT THE PPM LEVEL OF METAL USAGE, á la Nature With good options now available to the synthetic community, and a low barrier to making the switch to a greener alternative to traditional chemistry in organic solvents (i.e., water, with TPGS750-M being commercially available from Sigma-Aldrich; catalog no. 733857), a major reaction parameter had been addressed. Indeed, among the 12 Principles of Green Chemistry,2 Anastas and 2811

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry

Figure 9. Using lipophilicity as a tool to increase the presence of catalyst inside the micellar core.

Figure 10. Evolution of ligand design; origins of the new ligand HandaPhos.

associated with principle no. 9 (“Catalysis vs. Stoichiometric Reactions”), we knew that such levels of precious metal usage are not sustainable, that Nature had long ago figured out how to effect catalysis with trace levels regardless of which metal. Why could synthetic chemists not do the same, thereby mimicking Nature on all counts: chemistry in water under mild conditions using trace metal catalysis? Sure, there are many isolated cases in traditional organic synthesis where ppm35 or even ppb36 levels of a metal effect a particular transformation. But do such green processes exist of sufficient generality that offer transition-metal catalysis involving “real” (i.e., highly functionalized) molecules? What about Suzuki−Miyaura cross couplings under such circumstances using ppm levels of Pd? Are there multiple types of gold-catalyzed reactions reported at the ppm level?37 I would argue the answer to questions along these lines is “no”. Aside from the obvious cost associated with catalysis by precious metals, what’s to be done about the warnings from the ACS Green Chemistry Institute alerting us to the endangered status of several commonly used metals?38 For example, how many synthetic chemists think that zinc is endangered? It is! Imagine a world 100 years from now...without palladium catalysts available from our favorite vendors!39 Clearly, we had come to realize that there was room for years full of important contributions to be made not only to green chemistry, but for the well being of society that today depends heavily on endangered metalcatalyzed processes that produce, as examples, many drugs for human health and agrochemicals essential for food production. How do we make the switch to chemistry at the ppm level,

thereby extending the lifetime of these metals by a factor of 10 to 100? For this challenge, at least we had an idea. We thought about how others in the field of catalysis devise new ligands; what parameters does one today have at one’s disposal? We could list them: (1) steric effects: groups on the heteroatom, usually phosphorus, could be adjusted in size to control the extent of binding to the metal; (2) stereoelectronic effects: more or less electron density going to the phosphorus that impacts its binding to a metal; (3) conformational rigidity: to control the threedimensionality surrounding chelation, especially to establish the nature of a chiral, nonracemic environment around the metal; and (4) donicity: controlling the number of ligands accommodated by a metal, potentially impacting catalyst reactivity due to open or occupied coordination sites. But all of this thinking falls “inside the box”; it leads to predictions borne out by experiments taking place in solution; in organic solvents. Micellar catalysis follows different rules; Pd catalysts added to water are not in solution. So what dictates greater dissolution of a catalyst inside a micelle? What makes any water-insoluble catalyst want to spend more time inside those hydrophobic inner cores doing catalysis at high concentrations, and less time participating in the exchange processes that are taking place with all species present in the flask? Answer: lipophilicity. Yes, lipophilicity, which means essentially nothing to traditional organic chemists, as long as the desired compounds are in solution using organic solvents. But just as more lipophilic and 2812

DOI: 10.1021/acs.joc.7b00010 J. Org. Chem. 2017, 82, 2806−2816

Perspective

The Journal of Organic Chemistry less water-soluble educts are better choices for micellar catalysis, so should a more lipophilic catalyst have a greater binding constant to the micellar core (Figure 9). In looking at many ligands, the BI-DIME oxaphosphole platform (5), reported by Boehringer-Ingelheim, appeared to be quite effective in asymmetric Suzuki−Miyaura cross-couplings.40 This architectural array takes an existing biaryl nucleus (e.g., 6) and builds a ring that includes the phosphine (e.g., 7), thereby eliminating conformational flexibility at phosphorus and creating a defined trans-stereochemical relationship by virtue of substitution at the adjacent carbon (Figure 10). This substituent, R* (in 7 and 9), inserted via alkylation of a precursor phosphine oxide anion 8, was envisioned by Sachin Handa to be key to controlling lipophilicity, and indeed, by alkylating with 2,4,6-triisopropylbenzyl bromide a new ligand was created, eventually called HandaPhos (10).20 This species was found to offer many of the desired properties upon complexation with palladium: (a) it allowed for use of inexpensive Pd(OAc)241 as the source of palladium; (b) it formed a 1:1 complex with Pd(OAc)2,20 thereby suggesting high activity due to its coordinatively unsaturated nature; and (c) as a Pd(II) catalyst precursor, it catalyzed Suzuki−Miyaura crosscouplings in water at room temperature using ≤1000 ppm levels of palladium (i.e.,