Perspective Cite This: ACS Catal. 2018, 8, 328−341
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Chiral Catalysis at the Water/Oil Interface Wengang Guo, Xianghui Liu, Yan Liu,* and Can Li* State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People’s Republic of China ABSTRACT: The unique physicochemical properties of water as a solvent have attracted great interest from synthetic chemists for many years, and tremendous research progress on chemical reactions under aqueous conditions has been reported. Among them, catalytic asymmetric reactions have also been demonstrated and water turns out to not only be a unique solvent but also participate in the reactions. In this Perspective, we summarize and discuss recent advances in chiral catalysis at the water/oil interface. Emphasis is placed on the concepts/approaches used in chiral organocatalysis and metal catalysis. KEYWORDS: chiral catalysis, organocatalysis, metal catalysis, on water, in water an organic solvent.10 Thereafter, a tremendous number of chemical reactions under aqueous conditions were reported. Theoretical models mainly focus on an explanation of how the rates of chemical reactions “on water” or “in water” are accelerated by water, which have been discussed in previous excellent reviews11 and articles.12 Among them, the driving force accounting for such rate acceleration in water/oil biphasic system was mainly ascribed to hydrogen-bonding interactions at the interface and hydrophobic effects. Selectivity, especially enantioselectivity, is the most important and intrinsic parameter in chiral catalysis. Enantioselectivity is mainly determined by the transition state, which is involved with the interactions among substrate, reagent, catalyst, and even environment. Water was thought to be imcompatible with many organic reactions. Actually, in some enzyme catalyses, water plays an important role in stereocontrol through hydrogen-bonding interactions. For example, a [3,3]sigmatropic rearrangement, which is catalyzed by chorismate mutase for the conversion of chorismate to prephenate, involves a water-bridged hydrogen-bonding interaction in the transition state (Scheme 1).13 Thus, water as the reaction medium has become an important topic in the field of chiral catalysis. Considerable efforts have been made in developing water-compatible catalytic asymmetric reactions, and a variety of C−C and C−heteroatom bond forming reactions have been reported.2 This Perspective briefly summarizes the recent advances in chiral catalysis at the water/oil interface through asymmetric organocatalysis and metal catalysis. Among them, chiral organocatalysis at the water/oil interface are discussed in three subsections: “emulsion organocatalysis”, “hydrophobic hydration in noncovalent organocatalysis under water/oil biphasic conditions”,
1. INTRODUCTION Driven by the ever-increasing demand for optically pure chemicals in the fields of the pharmaceuticals industry, materials science, and agriculture, the development of efficient catalytic methods for the synthesis of enantioenriched products is highly desirable. Heterogeneous chiral catalysis has been attracting significant interest because of its practical advantages, including the recovery and reuse of the costly chiral catalyst/ ligand and reduction of contaminations by catalyst residues in the products.1 Typically, heterogeneous chiral catalysis involves the use of immobilized solid chiral catalysts in the liquid phase. Recently, liquid/liquid biphasic chiral catalysis which represents a distinct type of heterogeneous chiral catalysis was reported. In this case, some nonconventional reaction media such as aqueous phase,2 fluorous phase,3 ionic liquid,4 and supercritical carbon dioxide5 are regarded as “mobile carriers” to immobilize chiral catalysts through the interaction of noncovalent bonding. Among various liquid/liquid biphasic systems, water/oil biphasic catalysis has attracted much attention, because water as a reaction medium brings the advantages of low cost, safety, and environmental friendliness. However, it is often more difficult to achieve high catalytic performance in water. Several approaches have been invoked to achieve asymmetric catalysis using water as the solvent, including hydrophilic modification of the chiral catalysts by sulfonation or quaternary cation salt formation,6 the use of amphiphilic additives such as surfactants7 or phase-transfer catalysts,8 and so on. On the other hand, encouraged by the vital role of water in biological reactions catalyzed by enzymes for the construction of various chemicals with accurate chiral centers in nature, water has been recognized as a key promoter in some organic reactions. In this regard, in the 1980s, Breslow reported a pioneering work on acceleration of the achiral Diels−Alder reactions performed in water.9 After that, Sharpless defined some “on water” reactions, which exhibit a remarkable reaction rate acceleration in comparison to that of the same reaction in © 2017 American Chemical Society
Received: June 28, 2017 Revised: November 20, 2017 Published: November 26, 2017 328
DOI: 10.1021/acscatal.7b02118 ACS Catal. 2018, 8, 328−341
Perspective
ACS Catalysis
proven by several elegant reaction systems, which have been discussed in prior articles.16 Our group found that tunable emulsion droplets as nanoreactors could supply a different interfacial microenvironment, which might exhibit some peculiar function to control selectivity. Our group reported that the reactivity and stereoselectivity of the direct asymmetric aldol reaction between cyclohexanone and aryl aldehydes were remarkably enhanced when a chiral catalyst was used in an emulsion (Scheme 2).17 It was found that an amphiphilic catalyst possessing a shorter alkyl chain and lower hydrophilic/lipophilic balance value could form metastable emulsions, which could be characterized by optical microscopy, and show higher reactivity (Figure 1a,b). Dynamic
Scheme 1. [3,3]-Sigmatropic Rearrangement Catalyzed by Chorismate Mutase Involving Water-Bridged Hydrogen Bonding
and “water-bridged hydrogen-bonding interactions in organocatalysis”. Two subsections, “chiral metal catalysis in a micellar system” and “nonmicellar chiral metal catalysis”, are discussed in the section on metal catalysis at the water/oil interface. Among these, emphasis is placed on the concepts/approaches used in each sections.
Figure 1. Optical micrographs of emulsions: (a) mixture of 0.019 mmol of catalyst 3a, 400 μL of water, and 1 mL of cyclohexanone (metastable water in oil emulsions); (b) mixture of 0.019 mmol of catalyst 3b, 400 μL of water, and 1 mL of cyclohexanone (metastable water in oil emulsions); (c) mixture of 0.019 mmol of catalyst 3c, 400 μL of water, and 1 mL of cyclohexanone (unstable emulsions); (d) mixture of 0.019 mmol of catalyst 3b, 500 μL of cyclohexanone, and 3.5 mL of water (metastable oil in water emulsions). Adapted with permission from ref 17. Copyright 2007 Elsevier.
2. ORGANOCATALYSIS AT THE WATER/OIL INTERFACE 2.1. Emulsion Organocatalysis. When water is used as the solvent, the incompatibility between water and organic compounds is a frequently encountered problem, which can be solved in various ways. The most efficient approach is to add a surfactant to the reaction system, which solubilizes the reactants to form a colloidal dispersion in the reaction system. According to the type of surfactant, different reaction states can be categorized as phase transfer, micelle, microemulsion, and emulsion.14 Among these, emulsion droplets with diameters of 0.1−10 μm are thermodynamically metastable. Therefore, an amphiphilic catalyst in an emulsion catalytic system could settle between the water and oil phases after demulsification, which could provide a simple method to separate and recycle the catalyst.15 Emulsion catalysis has been used for some water-compatible catalytic asymmetric reactions. Usually, organocatalysis using emulsions as media is regarded as one of the efficient ways to overcome compatibility between water and organic compounds and enable the concentration of reactants, thus leading to considerable rate enhancement. These advantages have been
light scattering showed that the sizes of the spherical emulsion droplets formed from 3a,b were about 0.1−0.2 μm. The amphiphilic catalyst acts as a “bifunctional” surfactant to maintain metastable emulsion droplets and provide high interfacial surface areas, thus resulting in high reactivity. The catalyst in an emulsion can be organized as a well-ordered three-dimensional chiral surface, which may be responsible for the high stereoselectivity. This work and reports by other research group16 indicate that chiral catalysts in an emulsion could act effectively to perform catalytic asymmetric reactions in water. A series of proline-derived imidazoles were applied to catalytic asymmetric cascade reactions of α-keto acids with aldehydes for the synthesis of chiral isotetronic acid.18 It was found that catalysts 5c−g bearing hydrophobic alkyl chains with C8−12 lengths exhibited higher reactivities and good to
Scheme 2. 3b-Catalyzed Aldol Reaction of Cyclohexanone and Aldehydes in Water/Oil Interface
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DOI: 10.1021/acscatal.7b02118 ACS Catal. 2018, 8, 328−341
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ACS Catalysis excellent enantioselectivities (Scheme 3).18c Moreover, the reaction systems catalyzed by 5c−g are in metastable emulsion
Scheme 4. Cascade Reaction of 6 and 7 Catalyzed by 5g in Different Solvents
Scheme 3. Cascade Reaction of 6 and 7 for the Synthesis of Isotetronic Acids 8 Catalyzed by 5
most of the reported examples are natively promoted by water. In this context, water participates in the catalytic cycle and changes the energy of the transition state. (2) The chiral surface of an emulsion droplet may govern the approach of substrates, thus cooperating with the individual catalyst to control the stereoselectivity. 2.2. Hydrophobic Hydration in Noncovalent Organocatalysis under Water/Oil Biphasic Condition. 2.2.1. Hydrophobic Hydration. The terminology “hydrophobic hydration” denotes the rearrangement of the structure of local water molecules by the incoming apolar solutes. When a nonpolar compound is transferred into water, the extended network of hydrogen bonding of water must be disrupted for the insertion of the apolar solute. However, each water molecule is reluctant to lose its hydrogen bond, thus leading to reorientation of the water molecule around the apolar solutes and a loss of entropy. Gaseous methane has been selected by chemists as a simple molecular model to interpret the hydrophobicity of apolar compounds in various organic solvents and water at 25 °C.19 This model shows that the dissolution process of apolar methane in polar solvents, especially in water, is predominantly promoted by enthalpy, in comparison with the small changes in enthalpy for the solvation in organic solvents. The model also shows that the poor solubility of apolar solute is completely dominated by the large loss of entropy. Water avoids this unfavorable factor to squeeze the organic solutes together to decrease the solute/water interfacial area, therefore leading to
states, while catalysts 5a,b which cannot form emulsions in the reaction systems display poor reactivities and enantioselectivities. The obviously different enantioselectivities achieved by 5c−g implied that catalysts bearing different lengths of hydrophobic tails might supply different microenvironments on the surface of emulsion droplets in the reactions and thus strongly affect the stereoselectivities (Figure 2). The reaction most possibly occurs on the surface of the emulsion droplets, as determined through a direct fluorescence image of the reaction system (Figure 2). The control experiments (Scheme 4) were also performed for the reactions of 6 and 7 with catalyst 5g using different solvents to prove the importance of water. Overall, the following factors could be responsible for the enhancement of enantioselectivities in some certain reactions using chiral catalysis in emulsion. (1) It is not a surprise that
Figure 2. Fluorescence microscope images of (a) reaction mixtures of 6 (0.75 mmol) and 7a (0.25 mmol) in 2 mL of H2O with 0.025 mmol of 5a, (b) 5g (0.025 mmol) combined with α-keto butyric acid 6 (0.25 mmol) dispersed in water, and (c) 7 (0.75 mmol) added to system (b). (d) Enlarged images of emulsion droplets and the emulsion reaction model. Adapted with permission from ref 18c. Copyright 2012 John Wiley and Sons. 330
DOI: 10.1021/acscatal.7b02118 ACS Catal. 2018, 8, 328−341
Perspective
ACS Catalysis an increase in solute concentration which can be utilized for rate acceleration in chemical reactions. 2.2.2. Noncovalent Asymmetric Organocatalysis on Water. In living organisms, biosynthetic reactions are carried out in an aqueous environment to sustain life. In this process, the hydrophobic effect plays a pivotal role in the interaction between enzymes and substrates. Although the key ideas of organocatalysis are derived from enzyme catalysis, organocatalytic reactions have mostly been carried out in organic solvents since their renaissance as a “third pillar” of asymmetric catalysis, except for some chiral amino derivative catalyzed reactions, which proceed via enamine or iminium intermediates. Hydrogen-bonding interactions build on the foundation of noncovalent organocatalysis, in which the substrates are activated synergistically by acid/base bifunctional catalysts including phosphoric acid catalysts and Lewis base catalysts with (thio)urea, squaramide, and even hydroxyl group moieties. It was proposed that such noncovalent, hydrogen-bondingpromoted organocatalysis is a priori incompatible with aqueous conditions, because water itself is an excellent hydrogenbonding donor/acceptor to break the hydrogen-bonding interaction between the catalyst and substrate. Nonetheless, were hydrophobic hydration to play a key role, the respective noncovalent organocatalyzed reactions should be accelerated. In this regard, Schreiner and co-workers reported that activation of epoxide via hydrogen-bond formation on water is possible on the basis of an analysis of the work model of epoxide hydrolases (Scheme 5), thus leading to excellent yields of the ring-opening products with various nucleophiles under on-water conditions (Table 1).20
Notably, the relative accelerations are nearly as large as 200fold (entry 1, Table 1). DFT computations reveal that the hydrogen-bonding interactions are indeed amplified on water and the corresponding activation energy is the lowest overall. This phenomenon is termed as “hydrophobic amplification” by the authors. Recently, Song and co-workers reported Michael addition of 1,3-dicarbonyl derivatives to nitroalkenes “on water” by using Rawal’s bifunctional squaramide organocatalysts.21 They found that water is an exceptionally efficient solvent for these noncovalent hydrogen-bonding-promoted asymmetric reactions. Interestingly, the observed “hydrophobic amplification” can be easily enhanced by improving the hydrophobicity of the catalyst by just hydrogenation of its C3-vinyl group on the quinuclidine scaffold. As indicated in Scheme 6, the calculated log P values of HQN-SQA (2.68) and HQD-SQA (5.29) are higher than those of QN-SQA (2.41) and QD-SQA (5.02), respectively, therefore furnishing higher catalytic reactivity on water, and vice versa. Moreover, the rate acceleration imposed by the hydrophobic effect is dramatically decreased by using an antihydrophobic reagent, such as LiClO4, and deuterated water, thus ruling out the possibility of a polarity effect on this rate acceleration. However, it is still undeniable that the power of “on water” chemistry has not been well demonstrated in the field of catalytic asymmetric reactions at this moment, because the aforementioned examples also work well in organic solvents in terms of stereoselectivity and isolated yield. In this regard, developing new reactions “on water” for otherwise unreactive substrates is highly desirable and challenging. Very recently, an elegant contribution was reported by Song and co-workers wherein unactivated β,β-disubstituted nitroalkenes are competent for Michael addition reactions with dithiomalonates “on water”, affording valuable precursors for the synthesis of γ-aminobutyric acid (GABA) derivatives with chiral quaternary carbon centers.22 The reactivities of these reactions “on water” are also strongly dependent on the log P values of catalysts (Scheme 7). In contrast, when the reactions are carried out in toluene, DCM, or THF, the reactants are completely intact. As a good leaving group, arylsulfone derivatives, such as αamido sulfones and sulfonyl indoles, have been regarded as versatile precursors for the in situ generation of imine derivatives under mildly basic conditions, therefore becoming the most suitable substrates to date for studies on asymmetric Mannich reactions “on water”.23 The specific examples of using these types of substrates on water are presented as follows. In this respect, Deng’s group reported that the issue of instability of carbamate-protected alkyl imines could be addressed by using a stable α-amido sulfone as the precursor of the alkyl imine in the Mannich reaction of dibenzyl malonate catalyzed by a quinidine-derived thiourea organic catalyst under biphasic conditions, thus providing a concise and highly enantioselective route for the synthesis of optically active aryl and alkyl β-amino acids (Scheme 8).24 Interestingly, the reaction rate is remarkably accelerated by using an aqueous solution of an inorganic base in comparison to that of directly employing a solid inorganic base, and the cinchona alkaloid derived thiourea is completely compatible with strongly basic conditions. Water molecules may participate in the activation of these substrates via hydrogen-bonding interactions, thus facilitating the elimination of the Ts group. Taking into account the mechanism for the in situ generation of N-protected imines, work by Schaus and co-workers is of
Scheme 5. Epoxide Recognition for Epoxide Hydrolase and Schreiner’s Thiourea 9
Table 1. Selected Examples of Organocatalytic Nucleophilic Ring Opening of Epoxides on Water
yield (%) entry epoxide 1 2 3 4 5 6
10 10 10 11 11 11
NuH
DCM (no cat.)
DCM (cat.)
H2O (no cat.)
H2O (cat.)
t-BuNH2 n-Pr2NH morpholine t-BuNH2 n-Bu2NH morpholine
