Water in N-heterocyclic carbene-assisted catalysis.

Review pubs.acs.org/CR

Water in N‑Heterocyclic Carbene-Assisted Catalysis Efrat Levin,† Elisa Ivry,† Charles E. Diesendruck,‡ and N. Gabriel Lemcoff*,† †

Chemistry Department, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel

‡

CONTENTS 1. Introduction 2. Palladium 2.1. Homogeneous Suzuki−Miyaura Reaction 2.1.1. Palladium NHC Complexes with Group 15 Ligands 2.1.2. DNHC (Di-N-Heterocyclic Carbenes) Palladium Complexes 2.1.3. CNC Pincer Dicarbene Palladium Complexes 2.1.4. NNC Pincer Palladium Complexes 2.1.5. NCN Pincer Palladium Complexes 2.1.6. Sulfonated NHC−Pd Complexes 2.1.7. Abnormal NHC Palladium Complexes 2.2. Heterogeneous Suzuki−Miyaura Reaction 2.2.1. Silica-Supported Catalysts 2.2.2. Resin-Supported Catalysts 2.2.3. Dendritic Catalysts 2.2.4. Self-Supported Polymers 2.3. Heck Reaction 2.4. Sonogashira Reaction 2.5. Hiyama Reaction 2.6. Miscellaneous Reactions 2.6.1. Arylation of Benzoic Anhydride, Enones, Allylic Alcohols, and N-Tosylarylimines with Arylboronic Acids 2.6.2. Dioxygenation of Alkenes 2.6.3. Hydroxycarbonylation of Aryl Halides 2.6.4. Tsuji−Trost Reaction 2.6.5. Reduction of α,β-Unsaturated Carbonyls, Direct Reductive Amination of Carbonyls, and Aminocarbonylation of Aryl Iodides 2.6.6. Telomerization of Butadiene 2.6.7. C−H Bond Activation 3. Ruthenium © XXXX American Chemical Society

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3.1. Olefin Metathesis Reactions 3.1.1. Aqueous Olefin Metathesis Based on Grubbs-Type Catalysts 3.1.2. Ruthenium Complexes Bearing PEGContaining Ligands 3.1.3. Solid-Supported Catalysts 3.1.4. Ruthenium Catalysts with Ammonium Tags 3.1.5. Metathesis in Biological Systems 3.2. Miscellaneous Reactions 3.2.1. Cyclization 3.2.2. Hydrogenation 3.2.3. Isomerization of Allylic Alcohols 3.2.4. Carbon Dioxide Reduction 3.2.5. Atom Transfer Radical Polymerization 3.2.6. Hydrosilylation Gold 4.1. Alkyne Hydration 4.1.1. NHC−Au(I)X Complexes 4.1.2. Sulfonated NHC−Au(I) Complexes 4.1.3. Gold Complexes Bearing Atypical NHC Ligands 4.1.4. NHC−Au(III)X3 Complexes 4.2. Nitrile Hydration 4.3. Allene Hydration 4.4. Enone Formation 4.4.1. Rearrangement of Propargylic Acetates 4.4.2. Meyer−Schuster Rearrangement 4.5. Cyclization Reactions 4.6. Miscellaneous Reactions Rhodium 5.1. Addition of Boronic Acids to Aldehydes 5.2. 1,4-Conjugate Addition of Arylboronic Acids to Enones 5.3. Hydroformylation 5.4. Hydroamination 5.5. Dehydrogenation of Primary Alcohols 5.6. Ketone Hydrogenation Copper 6.1. Copper-Catalyzed Huisgen Cycloaddition 6.2. A3-Coupling (Aldehyde−Alkyne−Amine) 6.3. Borylation Reactions of Alkynes 6.4. Addition of Terminal Alkynes to Nitrones Iridium 7.1. Hydroamination 7.2. Hydrogenation 7.3. C−H Bond Activation 7.4. Water Oxidation

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Received: November 5, 2013

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DOI: 10.1021/cr400640e Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 7.5. Addition of Boronic Acids to Aldehydes 8. Silver 8.1. Alkynylation of Isatins 8.2. A3-Coupling (Aldehyde−Alkyne−Amine) 9. Platinum 10. Nickel 11. NHCs as Organocatalysts 12. Conclusions Author Information Corresponding Author Author Contributions Notes Biographies Acknowledgments Dedication References

Review

environment, an organocatalytic reaction that predated the modern excitement surrounding this type of reactions. Even so, organometallic chemists have been reticent to use water as the solvent for metal-catalyzed reactions with (or without) NHC ligands, and only recently an increasing amount of reports dealing with the topic of this review can be found.18−20 The reasons for the historical restricted use of water as the reaction medium may be traced to two main reasons: the first is the aforementioned lability of organometallic complexes in aqueous surroundings, and the second is the hydrophobic effect which severely limits the solubility of nonpolar organic materials. This important drawback is also the main reason why most of the reactions that are carried out with water include also a cosolvent to improve solubility. In addition, the removal of water from a reaction mixture is made more difficult owing to its high boiling point and enthalpy of vaporization. On the other hand, the motivations for the use of water in organic reactions are quite obvious in a world with dwindling petroleum resources, severe environmental challenges, and continuous financial woes. Reactions in water or aqueous media may bring about many benefits, among them, easy product separation due to lower solubility of the products in water, safer reaction media, reduced costs (not always), recyclability, and even the possibility to develop bioorthogonal coupling reactions. As testament to the increasing number of studies on NHCtransition metal catalysis in water, two recent reviews have briefly summarized the most important recent developments in this young field.19,20 Herein, we extensively summarize the chemistry of NHC catalysis of organic reactions in aqueous media during the past few years. This review does not discuss reports that present water-soluble NHC complexes which were not studied for catalysis. In addition, early transition metals are more generally oxophilic, and their NHC complexes are relatively scarce. Moreover, they are not found in the literature in water surroundings, and this is why they are missing in this review. For reasons of commodity we have chosen to organize the reactions by the metals used, starting with the most prolific metals, and the type of reaction catalyzed; finally, the last section deals with (metal-free) organocatalytic NHC reactions.

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1. INTRODUCTION Water is one of the most abundant molecules on earth. It is inexpensive, especially when compared to organic solvents, nonflammable, and nontoxic, it has a large heat capacity, and its use as a solvent may bring about many environmental benefits if used properly. Life most likely emerged in an aqueous surrounding, and it is obviously a natural solvent for organic chemistry transformations given that a plethora of biochemical reactions occur in this medium. Nonetheless, a very small percentage of synthetic organic reactions are carried out in the presence of water and of these most using mixtures of water and a miscible organic cosolvent. For the past three decades the field of organic reactions in aqueous media has steadily grown, commencing from the seminal discovery by Ron Breslow1,2 on the acceleration of pericyclic reactions in water, followed by the “click” reactions presented by Fokin and Sharpless,3,4 and the “in-water”−“on-water” controversy found in the literature.5−7 In parallel, N-heterocyclic carbenes (NHCs) have also found remarkable use, especially in the field of organometallic chemistry, acting as stable electron-donating ligands for numerous transition metals.8 Since the first report of a metal coordinated by an NHC by Ö fele and Wanzlick in 19689 and the discovery and isolation of the first stable nitrogen heterocyclic carbene by Arduengo in 1991,10 NHCs have become quite ubiquitous in the chemical literature, especially as ligands for metal complexes. In addition to the classical NHC, derived from substituted imidazole rings, abnormal NHCs have been explored and proved useful in organic catalysis.11−14 Instigated by the work of Bertrand, Grubbs, Herrmann, Nolan, Organ, and others, NHC ligands have become much more than simple phosphane surrogates and have been used to catalyze a multitude of organometallic reactions with almost every metal employed for catalysis in the periodic table. Of these, it is worth mentioning ruthenium as the catalytic center for olefin metathesis and palladium for cross-coupling reactions as the two most influential examples where NHCs have made their mark.15,16 However, with water often considered the “natural enemy” of organometallic species, the lion’s share of these reactions has been carried out in dry organic solvents. Once again, Breslow was the pioneer who first proposed NHC catalysis in water.17 The discovery of the ability of NHCs to catalyze reactions in water may be traced to his discovery of thiamine reactivity in 1958. Here, a thiazolium moiety was proposed to go through a carbene intermediate in a biological

2. PALLADIUM Palladium has a very rich organometallic repertoire, and its high functional group tolerance makes it an attractive metal to study catalysis in water.21−23 Consequently, it is no surprise that out of all metals covered in this review, palladium spans the widest reaction scope. Reactions covered here include Suzuki− Miyaura, Mizoroki−Heck, and Hiyama couplings, as well as other miscellaneous addition, reduction, and C−H activation processes in aqueous environments. 2.1. Homogeneous Suzuki−Miyaura Reaction

The Suzuki−Miyaura reaction is probably the most prevalent C−C coupling reaction catalyzed by palladium complexes (Scheme 1).24,25 Countless ligands are widely used to catalyze this Nobel accolade reaction, but only since 1995 Herrmann et al. pioneered N-heterocyclic carbenes as spectator ligands for Scheme 1. Representative Suzuki−Miyaura Aryl Coupling

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Figure 1. Palladium NHC complexes with group 15 ligands.


1),which form five-membered chelate rings, were explored in Suzuki−Miyaura reactions in pure water.33 Complex Pd-3b, with the bulky 2,6-diisopropylphenyl (Dipp) substituent on the NHC, was found to be the most active catalyst among them and gave good conversions with 1 mol % of catalyst loadings in the reaction of various aryl chlorides and arylboronic acids with KOH at 100 °C. In a slightly different approach which did not involve chelation of the N-ligand, the research group of Shao reported NHC−palladium−1-methylimidazole, Pd-4a-b (Figure 1).34,35 Pd-4a (IPr) was found to be more active than Pd-4b (IMes) and catalyzed Suzuki−Miyaura reactions of arylboronic acids with several aryl or heteroaryl chlorides with high yields. The reactions were carried out in pure water at 80 °C with catalyst loadings of 2 mol % and KOtBu as the base. Moreover, reactions at room temperature succeeded in a water/THF (2:1) mixture with 1 mol % catalyst loading and K3PO4·H2O. Reducing the catalyst loadings to 0.01 mol % also gave good conversions but at 50 °C. In addition, Pd-4a showed effective catalytic activity for couplings of benzyl chlorides with phenylboronic acids or potassium phenyltrifluoroborate.36 The greater efficiency of Pd-4a over Pd-4b could be explained by the bulkier NHC ligand in Pd-4a, especially for coupling of difficult substrates such as aryl chlorides, probably due to more efficient stabilization of the active Pd(0) species in the aqueous environment. Another room-temperature Suzuki coupling setup was carried out with low catalyst loadings (0.02−0.05 mol %) using a racemic mixture of Pd-5 (Figure 1) by Rajabi et al.37,38 A variety of activated and deactivated aryl bromides or chlorides and arylboronic acid were tested in H2O/iPrOH mixture to give excellent isolated yields. The authors state that the enantiomerically pure version of the ligand is soon to be prepared and analyzed for its catalytic potential.

Heck couplings and 3 years later for Suzuki and Sonogashira couplings as well, immediately demonstrating the enhanced activity these ligands have to offer to this popular reaction.26−28 2.1.1. Palladium NHC Complexes with Group 15 Ligands. Given the solubility and catalytic activity of enzymes in water, amino acid derivatives are good starting points to develop ligands for reactions in/on water. The bidentate NHC−palladium complex Pd-1 derived from rac-proline (Figure 1) was prepared by Shao and co-workers and found to be a good catalyst for the Suzuki−Miyaura reaction.29 KOtBu was chosen as the base, and the reaction was conducted in pure water at room temperature. Several arylboronic acids and aryl iodides/bromides were investigated, including substrates with electron-donating and electron-withdrawing groups. All produced good to excellent yields at catalyst loadings of 0.2−1.0 mol %. Aryl chlorides were also examined at catalyst loadings of 5 mol % but delivered poor yields, even at high temperatures. In addition, heteroaromatic systems were also positively tested. Unfortunately, asymmetric Suzuki couplings30 could not be studied because the proline-based ligand was curiously prepared from a racemic mixture. A similar complex, Pd-2 (Figure 1) reported by Hor and co-workers, was able to catalyze Suzuki− Miyaura couplings at room temperature.31 A wide range of substrates were tested with catalyst loadings of just 0.2 mol %. When water was added to the organic solvent (MeOH/DMF) the conversion was significantly improved (more than 90% in almost all cases), perhaps due to improved solubility of the carbonate base leading to faster reduction of the palladium or solubility of the substrate itself. In accordance to this explanation, in pure water the conversion slightly decreased. Also, only one activated aryl chloride was reported giving low yields (43%), which could be somewhat improved (61%) by addition of TBAB (tetrabutylammonium bromide) as a phase transfer agent.32 Other N-chelating complexes Pd-3a−c (Figure C


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Figure 4. Palladium complexes bearing two carbene ligands.

Recently, another example of nonchelated nitrogen ligands was disclosed in a cationic cis-NHC−Pd(II) complex Pd-6 (Figure 1) with two acetonitrile ligands by Kühn and coworkers.39 This complex was found to be a good catalyst for the Suzuki−Miyaura coupling of several aryl bromides in water/ DMF (4:1) solution, although temperatures of 80−100 °C were needed. Türkmen et al.40 reported the use of pyridine carboxylic acids and benzimidazolylidene ligands, affording sturdy palladium complexes that successfully catalyzed Suzuki−Miyaura crosscoupling reactions in aqueous media. The reactions were conducted at 100 °C in the presence of KOH. Good to excellent yields were obtained with a series of aryl chlorides and phenylboronic acids using as low as 1 mol % catalyst loading. Complexes Pd-7 and Pd-10, which have a carboxylic acid group in the ortho position, provided slightly better yields than Pd-8 and Pd-9, substituted in the para and meta positions, suggesting that the carboxy group might be positively interacting with the metal (Figure 2). Furthermore, complex Pd-10c was tested for recyclability. The coupling between 4-chloroacetophenone and phenylboronic acid gave satisfactory conversion for two cycles; however, in the fourth cycle the yield decreased to about 50%. With 4-bromoacetophenone the recyclability was much better, displaying 90% yield after 3 cycles. Using a hydrophilic phosphane ligand, additional watersoluble NHC complexes Pd-11a−d were studied (Figure 2).41

Conversion rates for Suzuki−Miyaura reactions catalyzed by Pd-11a−c were higher than those obtained with Pd-10a−c, revealing the higher efficiency of the TPPTS (tris(3sulfophenyl)phosphine trisodium salt) ligand relative to pyridine carboxylate. In recyclability studies with Pd-11c, 4chloroacetophenone and phenylboronic acids showed high catalytic capacity for at least 4 runs. These studies revealed the curious fact that the NHCs with ortho-methyl substituents on the aromatic benzyl ring performed better with the more challenging aryl chloride substrates, while complex Pd-11d (that lacks the ortho-methyl groups) was a bit less efficient. Having said this, the differences found in the catalytic activities of Pd-10a−d were quite small, not surprising taking into account the similar substitution patterns on the aromatic rings. Cazin and co-workers reported a series of mixed tertiary phosphine−NHC−Pd complexes, Pd-12a−g Pd(II) and Pd-13 Pd(0) (Figure 3).42 The reaction between phenylboronic acid and 4-chlorotoluene was tested with all complexes in water/ isopropanol 9:1 mixture and compared with other commercially available complexes: Pd-14,43 Pd-15,44 and PEPPSI-IPr catalyst.45,46 All biphenyl phosphine-based complexes (Pd12e−g and Pd-13) gave excellent conversions with barely 0.1 mol % catalyst loadings, while the commercially available catalysts and Pd-12a−d provided moderate results. Pd-12-f, which delivered the best results, was able to efficiently catalyze many couplings with only 0.03 mol % catalyst loadings. Once D


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Scheme 2. pH-Responsive N-Heterocyclic Dicarbene−Pd(II) Complexes

active species in water. The reaction conditions were set at 100 °C with NaOMe and water. NaOMe was the most effective base due to the formation of beneficial MeOH, which probably aids in solvation issues. A control reaction with sodium hydroxide and methanol gave comparable results, supporting this theory; unfortunately other organic bases, such as sodium ethoxide or potassium tert-butoxide, were not tested to support this theory. The reaction with a variety of aryl bromides provided excellent yields, but with aryl chlorides the efficiency slightly dropped. However, addition of TBAB to the reaction mixture as a phase transfer agent increased the reaction conversion dramatically. Additionally, the catalyst could be efficiently recycled three times without significant loss in yields. The use of biorenewable and readily available chemicals as precursors for NHC ligands is certainly an important concept that should be expanded in the field of aqueous NHC-assisted catalysis to promote environmentally friendly processes. Luo et al. explored this idea to prepare the DNHC palladium catalyst, Pd-18 (Figure 4).50 The dicaffeine palladium complex provided good yields in the Suzuki−Miyaura cross-coupling between phenylboronic acid and p- or m-bromotoluene. The reactions were conducted with KOH or NaOtBu at 25−65 °C and 2 mol % catalyst loadings in pure water. The Wang group explored the pH responsiveness of DNHC palladium complexes containing carboxylic groups.51 Complexes Pd-19−23 (Scheme 2) were used to catalyze a benchmark Suzuki−Miyaura reaction between 4-bromoacetophenone and phenylboronic acid. Optimized conditions were found to be 100 °C, K2CO3, with 0.001−0.1 mol % catalyst loadings in pure water. The yields were excellent for all complexes; however, in the case of complex Pd-19 a small amount of homocoupling byproduct was observed. A comparison between hydrophilic complex Pd-22 and its hydrophobic analogue Pd-19 revealed that, at the beginning of the reaction, Pd-22 had higher catalytic activity than Pd-19, probably due to poor solubility of the latter in water. In later stages of the reaction, complex Pd-19 showed pronounced rate enhancement, rationalized by hydrolysis of the ester group. For inactive aryl bromides, such as 4-bromoanisole, TBAB was added in order to improve yields. On the other hand, when aryl chlorides were reacted with boronic acids the yields were disappointing. The pyridine ligands of complex Pd-22 could be

again, these results show the importance of steric shielding by tuning ancillary ligands in order to provide high turnover numbers and promote difficult reactions. 2.1.2. DNHC (Di-N-Heterocyclic Carbenes) Palladium Complexes. A number of DNHC−Pd complexes have been prepared and tested in Suzuki−Miyaura cross-couplings. Luo and co-workers synthesized the DNHC−palladium-chelated metallacrown ether complex Pd-16 (Figure 4) as one of the first examples of a metallacrown DNHC.47 The complex catalyzed cross-couplings for a wide range of aryl bromides and phenylboronic acids; the optimum conditions were 100 °C, t BuOH, neat water, and catalyst loadings of 0.1−0.001 mol %. The yields were acceptable, and TONs up to 84 000 were obtained. Even though the precatalyst Pd-16 possesses an interesting crown ether structure, this was not apparently used to influence the reaction. Moreover, it is most likely that in this case and in the following DNHC examples that for the reaction to follow the accepted mechanism the neutral ligands in the catalytic cycle must isomerize to a cis conformation to allow the reductive elimination step, and it is not clear how the crown ether structure would accommodate this. An alternative explanation may be that even though NHC ligands strongly ligate metals, one of them may dissociate freeing up a coordination site for the reaction. Another metallacrown ether NHC generated in situ from silver−NHC (Ag-1) (Figure 4) and PdCl2(CH3CN)2 was investigated in Suzuki−Miyaura couplings.48 Control experiments without Ag-1 or palladium source provided moderate or no activity at all for the coupling reaction. The scope of the reactions was studied with the addition of TBAB in water and resulted in good isolated yields for a variety of aryl halides and arylboronic acids. The Lin group synthesized water-soluble glucopyranoside DNHC palladium complexes Pd-17a−c (Figure 4).49 These complexes, in loadings of 0.05−0.1 mol %, efficiently catalyzed Suzuki−Miyaura reactions between phenylboronic acid and aromatic substrates (2-chloro/bromobenzoic acid and 1-chloro3-nitrobenzene). The catalytic activity was benefited by longer alkyl chain substituents on the imidazolinylidene; consequently, Pd-17c performed with the highest efficiency. This finding could be related to the observations made above regarding the positive influence of bulkier NHC ligands on the stability of the E


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activity in the cross-coupling of 4-chlorotoluene and phenylboronic acid in 1,4-dioxane/water mixtures at 80 °C with Cs2CO3 as base and 3 mol % catalyst loading. The best results were achieved either in pure 1,4-dioxane or in a 1:1 1,4dioxane/water mixture. Sadly, in systems with more water than 1,4-dioxane, the efficiency of the Suzuki reaction dropped dramatically. Other in-situ-generated palladium complexes synthesized by Ö zdemir, Yiğit, and Ç etinkaya were screened in the Suzuki− Miyaura reaction. Benzimidazolium salts 1a−c, 2a−c, and imidazolinium salts 3a−f (Figure 5) were reacted with 0.5 equiv of Pd(OAc)2 in the presence of Cs2CO3 in DMF/water 1:1 media at 80 °C under air.55,56 A variety of para-substituted aryl chlorides (chloroanisole, chlorobenzaldehyde, chlorotoluene, chloroacetophenone, and chlorobenzene) were reacted with phenylboronic acid for 6 h and provided impressive yields for all salt precursors with palladium loadings of 1.5 mol %. Salts 1b and 2b, possessing (likely) coordinating methoxyethyl substituents, provided superior results. Similar in-situ complexes were prepared with benzimidazolium salts 4a−g (Figure 5).57 The catalytic reaction conditions were similar, differing only in the base used (KOtBu), palladium loadings (1 mol %), and reaction time (up to 2 h). Reaction using ligand 4a provided the best results and overall isolated yields. In 2009, Yiğit further expanded this study using other in-situ-formed complexes with 1,3-alkyl perhydrobenzimidazolinium salts 5a− e (Figure 5).58 This time K2CO3 was chosen as the base and the reaction time was set to 1 h. Palladium complexes with salts 5a−e produced excellent isolated yields in the Suzuki−Miyaura reaction of para-substituted aryl chlorides and phenylboronic acid. A different palladium source, PdCl2, was tested with benzimidazolium salts 6a−e (Figure 5) for an in-situ catalytic system by the Zou group.59 Salt 6b in DMF with only 5% water supplied good conversions for a selection of aryl halides. Another interesting family of NHCs is the flexible bioxazoline derivative. This NHC was first made by Glorius and co-

removed by acidification with HCl to pH = 4, forming complex Pd-23, which crashes out of solution as a white precipitate. Raising the pH resolubilizes the complex. This reversible reaction is useful for catalyst recycling. After one cycle of crosscoupling, HCl was added to the reaction mixture, causing catalyst precipitation, which could be easily separated. The addition of base allowed reuse of the catalyst. Up to 4 cycles could be carried out with good conversions; however, upon more careful examination the formation of Pd(0) nanoparticles was revealed by TEM analysis. This phenomenon, which is not always tested but probably more pervasive than realized in many catalytic palladium studies (including those presented in this review!),52 downgrades the intricate NHC complexes to precatalyst species or just metal reservoirs. Schatz and co-workers reported a dicarbene palladium complex derived from calixarene-based imidazolium salts.53 Calixarenes54 bearing imidazolium groups are water soluble and provide a hydrophobic cavity. In-situ mixing of calix[4]arenebased imidazolium salt with Pd(OAc)2 produced NHC−Pd complexes (Scheme 3). These complexes showed catalytic Scheme 3. Generation of Calix[4]arene−DNHC−Pd Complexes

Figure 5. NHC ligand precursors for in-situ-prepared Suzuki−Miyaura catalysts. F


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Figure 6. Benzimidazolium−DNHC−Pd cis and trans complexes.

Figure 7. Complexes containing two carbene ligands and two palladium centers.

workers.60,61 In-situ mixing Pd(OAc)2 and 7 (Figure 5) in a 10:1 ratio of THF/water with KOtBu at room temperature handed over the synthesis of di- and tri-ortho-substituted biaryl compounds from sterically hindered aryl chlorides and arylboronic acid. Huynh et al. used a thiophene benzimidazolylidene ligand to prepare the DNHC−Pd(II) complex Pd-24 (Figure 6).62 This complex was isolated and crystallized in the cis-anti configuration, revealing that the thiophene group did not chelate the metal (probably expected because 2 equiv of the NHC precursor was added). However, in solution, a nonseparable mixture of both rotamers cis-anti and cis-syn was observed in a 3.5:1 ratio, respectively. The catalytic activity of this mixture was preliminarily examined in the Suzuki−Miyaura reaction between aryl bromides and phenylboronic acid in water with K2CO3 as base and 1 mol % catalyst loading. For activated aryl bromides the temperature was set to 25 °C, while deactivated aryl bromides required 85 °C and the addition of TBAB. Cross-couplings with aryl chlorides gave yields below 15%. However, the facile synthesis and encouraging first results certainly deserve further research efforts with this family of complexes. Additional benzimidazolylidene-based palladium complexes with symmetrical and nonsymmetrical substitutions on the nitrogens were reported by Sarkar and co-workers: mononuclear dicarbene Pd-25a-b (Figure 6) and halide-bridged

dinuclear Pd-26a−d (Figure 7).63 The coupling reaction between phenylboronic acid and bromoanisole was tested in water. While symmetrical complexes cis-Pd-25a and Pd-26a afforded high conversions only when heated to 90 °C, the nonsymmetrical Pd-26b−d, Pd-25b, and trans-Pd-25a provided excellent conversions also at room temperature. Another NHC-based catalyst for Suzuki−Miyaura reactions in water investigated by Huynh and his research group was a dimeric Pd(II) benzimidazolin-2-ylidene complex Pd-27 (Figure 7).64 The reactions were run at 0.5 mol % catalyst loading (1 mol % of Pd) with K2CO3 as base in pure water. Activated aryl bromides gave excellent yields at room temperature; however, for deactivated aryl bromides, heating to 85 °C and adding TBAB was necessary to increase the conversions. Under the same forcing reaction conditions, aryl chlorides were cross-coupled in moderate yields. It is worth noting that Pd-27 is probably cleaved to a monomeric complex (the actual active species), as the authors showed how different nucleophiles may cleave the complex generating monomeric compounds. Recently, Liu et al. developed bis[NHC−Pd(II)] complexes Pd-28a with a 1,6-hexylene bridge65 and ethylene glycol-based linker Pd-28b (Figure 7).66 The activity of these catalysts was examined in Suzuki−Miyaura couplings between 4-bromotoluene and phenylboronic acid. The reactions with Pd-28b were carried out with 0.1 mol % catalyst loadings and K3PO4·3H2O G


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Figure 8. Cationic CNC pincer palladium complexes.

at 50 °C. Moderate yields were obtained with methanol as solvent, and even poorer results were obtained in pure water. Curiously, when changing the solvent system to 1:1 methanol/ water mixture, the conversions increased significantly. Moreover, the addition of TBAB or PPh3 was found to be essential for further improving the conversions. Control experiments, conducted with PdCl2(CH3CN)2, provided poor yields, demonstrating the positive effect of the NHC ligand. The same reaction was carried out with 0.2 mol % of Pd-28a at 40 °C while varying base and solvent. The optimal results were obtained with K3PO4·3H2O and water/TBAB (10 mol %), providing 98% conversion. These optimized conditions were used to screen a variety of phenylboronic acids and aryl halides affording good results. However, in many of these cases it is not clear at all whether the original complex is actually participating in the catalytic cycle or if it breaks up during the reaction to produce undefined catalytic species. 2.1.3. CNC Pincer Dicarbene Palladium Complexes. Additional strategies for the synthesis of stable NHC complexes for catalysis in water involve the construction of tridentate ́ pincer-type complexes. For example, SanMartin, Dominguez, and co-workers synthesized hydrophilic CNC pincer complexes, constructed with a dicarbene ligand bridged by a pcarboxylate-pyridine (Figure 8).67 A wide range of aryl bromides and arylboronic acids were coupled using catalyst Pd-29 to provide the Suzuki−Miyaura products. Excellent yields were obtained with just 0.1 mol % of catalyst and K2CO3 at 100 °C in neat water for both electron-rich and electronpoor bromoarenes and arylboronic acids. The authors claimed the catalyst loadings could be reduced to 10−7 mol % to achieve an exceptional TON of 107 for the coupling of phenylboronic acid and bromobenzene; however, the report did not fully disclose the details of the procedures when working at these very low levels of catalyst loading. In any case, some control experiments (reaction without catalyst) were carried out, and these results seemed to highlight the importance of stabilizing the metal center when working in the aggressive aqueous environment. The stability of the complex under forcing conditions (boiling in water for several hours) and the fact that the reaction could be recycled up to 5 times without any significant loss in performance afforded circumstantial evidence that the stable complex was indeed the catalytic species. However, no experiments were carried out to test for the presence of palladium nanoparticles in this first study. More thorough studies on this subject with this type of catalyst (Pd30a-b in Figure 8) finally provided strong evidence for nanoparticle formation.68 Several control studies such as stability and kinetic studies, mercury drop test to distinguish between homogeneous and heterogeneous catalysis, selective chemical poisoning with triphenyl phosphine, pyridines, CS2, and Hg, and clear TEM images supported the catalytic

participation of Pd(0) nanoparticles. Therefore, these pincerNHC−Pd complexes seem also to act only as precatalysts and can be regarded as excellent reservoirs for metallic palladium. Tu et al. recently synthesized a similar CNC pincer complex with a dibenzimidazolylidene ligand, Pd-31 (Figure 8).69 Reactions of 4-bromoacetophenone with a variety of arylboronic acids were carried out at 100 °C with K2CO3 in pure water and produced excellent isolated yields. Other aryl bromides were also successfully cross-coupled; however, due to the low solubility of these substrates in pure water, a mixture of MeOH/water 1:1 was used to increase conversions. All experiments were carried out with very low catalyst loadings (0.005 mol %, 50 ppm). A model system of 4-bromoacetophenone and phenylboronic acid was chosen to examine recyclability of the complex under low catalyst loadings. Even when the catalyst loading was reduced to just 8 ppm, quantitative yields were obtained, and even at 8 ppb loadings a decent 62% yield was obtained, reaching almost TON = 107. Curiously, this very active catalyst was not tested in Suzuki couplings with the more sluggish (but economical) aryl chlorides. Unlike the previous case, mercury drop and poly(4-vinylpyridine) poisoning tests did not suggest nanoparticle formation, and a molecular species was proposed as the active catalyst. The stark difference with the SanMartin and ́ Dominguez outcome may be due to better stabilization of the Pd−pincer complex through stronger σ donation of the benzimidazolylidenes, according to the authors. 2.1.4. NNC Pincer Palladium Complexes. In 2006, NNC-type pincer palladium complexes bearing tridentate pyridyl-pyrazolyl-NHC ligands were synthesized and probed for catalytic activity in aqueous media.70 This study was one of the first reports on the use of NHC−Pd catalysis in aqueous mixtures, and it demonstrated the feasibility of this catalytic process. The strong σ donation of the chelating pyridyl-NHC fragment and the lability of the pyrazolyl group probably play an important role in the catalytic activity of the pincer complexes. Pd-32 and Pd-33 (Figure 9) were screened in

Figure 9. Pyridyl-bridged pyrazolyl-NHC palladium complexes. H


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(Figure 11) toward the Suzuki−Miyaura coupling of phenylboronic acid with 4-bromoacetophenone or 4-chloroacetophe-

coupling reactions of a large variety of aryl iodides and bromides with arylboronic acids. Isolated yields were excellent, although somewhat heavy catalyst loadings of 0.5−5.0 mol % and temperatures in the vicinity of 80−120 °C had to be employed. Reaction optimization determined that the best solvent for the reaction was a mixture of DMF/water (10:1) with Cs2CO3 as base. Notably, the reaction without water was much less efficient; however, the authors did not further study the reasons behind the enhancement of the reaction when water was added. 2.1.5. NCN Pincer Palladium Complexes. Chen’s group used the fashionable click chemistry to synthesize an NCN-type pincer ligand (Figure 10).71 The ligand was used to make

Figure 11. Dicarbene palladium complexes with sulfonate groups.

none was tested with K2CO3 at 110 °C in neat water. Complexes Pd-36 and Pd-38 provided the best catalytic results and were further tested at 10−3 mol % catalyst loadings, showing high yields for 4-bromoacetophenone couplings. As usual, when using 4-chloroacetophenone as the coupling partner, reduced catalyst loadings afforded lower yields. Diverse substrates were also tested in a solvent mixture of 1:1 H2O:iPrOH in order to increase reagents’ solubility and broaden the reaction scope. Again, complexes Pd-36 and Pd38 produced high conversions with aryl bromides, while with aryl chlorides the results were less satisfying. It was emphasized that complex Pd-36, a cis-DNHC−Pd complex, showed overall better results than its robust counterpart, pincer complex Pd38. The Plenio group reported the synthesis of a series of sulfonated NHC ligands in 2007.74 An attractive synthetic aspect of this work is that all disulfonated imidazolylidene and imidazolinylidene NHC−Pd complexes could be synthesized in situ by mixing Na2PdCl4 and the NHC precursors in the presence of KOH in water. A variety of aryl chlorides with arylboronic acids were examined with precursors 8−10 (Figure 12) in boiling water. Me-substituted salt 8 showed excellent activity at loadings of 1 mol %, but when catalyst loading was reduced to 0.5 mol %, the activity slightly dropped. Due to the well-known fact that Dipp-substituted NHC ligands are more active in cross-coupling reactions than their methyl counterparts,45 it was expected that complexes obtained from 9 and 10 would show better activity. However, the complex with 9 as a ligand was found to be less efficient when compared to the complex prepared using 8. Complex made with preligand 10 presented more promising results. Activated aryl chlorides produced full conversions even at 0.1 mol % catalyst loadings, and deactivated aryl chlorides afforded high conversions (∼80%) with 0.5 mol % of 10 and palladium salt. Even difficult heterocyclic substrates, like 2-chloropyridine and 2chloro-4-methyl-quinoline, gave excellent results. Additional improvements were further introduced by adding a cinnamyl ligand to obtain complex Pd-40 (Figure 12).75 Complex Pd-40 was tested in a solvent mixture of 1:1 water/n-butanol at loadings of 0.1 mol %. With this catalyst, couplings between several boronic acids and aryl chlorides or 2-chloropyridines gave very good results but not as good as the best nonaqueous

Figure 10. NCN pincer NHC palladium complexes.

palladium and platinum complexes, and the palladium complex, Pd-34, was used to catalyze a double Suzuki−Miyaura coupling between phenylboronic acid and a large variety of 1,1dibromoalkenes (Scheme 4). Trisubstituted alkenes were Scheme 4. Double Suzuki−Miyaura Coupling between Phenylboronic Acids and a Variety of 1,1-Dibromo-1alkenes

obtained in moderate to excellent yields when the reactions were run under air atmosphere in pure water at 100 °C. The usual tests to check for formation of palladium nanoparticles were not carried out in this study; thus, their formation cannot be ruled out. Another NCN chelating palladium complex was recently used to catalyze a biphasic Suzuki−Miyaura coupling.72 At first, Pd-35 (Figure 10) was tested in the coupling between bromobenzene and phenylboronic acid with catalyst loadings of 0.2 mol % and KOH and at 60 °C. A variety of organic solvents were tested and provided poor results; however, methanol gave excellent conversions. In the case of pure water, only traces of product were obtained. Nevertheless, when using water/methanol mixtures the yields increased dramatically and the best results were achieved with a 5:1 methanol/water mixture. The improved results were explained by the authors as a base and catalyst solubility effect, leading to a faster reduction of the Pd(II) species to Pd(0), as previously reported by Hor.31 These reaction conditions were examined for reactions between different aryl halides (including aryl chlorides) and phenylboronic acid and provided moderate to high conversions. 2.1.6. Sulfonated NHC−Pd Complexes. Increased complex solubility in water may be achieved by attaching charged groups to the NHC ligand. Peris and co-workers recently synthesized mono-, di-, and tridentate ligands with sulfonate appendages.73 The reactivity of complexes Pd-36−39 I


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Figure 12. Water-soluble NHC-precursors 8−10, (NHC)PdCl(cinnamyl) Pd-40, and poly(ethylene glycol) NHC precursors 11.

reports in the literature.76−78 Still, this is one of the best results obtained for aqueous NHC−Pd Suzuki−Miyaura reactions involving aryl chlorides. Moreover, water-soluble imidazolium salts bearing poly(ethylene glycol), 11a−c (Figure 12), were reported to catalyze the Suzuki−Miyaura reaction when mixed with Pd(OAc)2 and Et3N in water.79 The most active precursor 11c was tested with several arylboronic acids and aryl bromides to give excellent yields. 2.1.7. Abnormal NHC Palladium Complexes. Abnormal NHC ligands11−14 have also been used to prepare catalysts for palladium-catalyzed Suzuki−Miyaura reactions in water. Among these catalysts we find the air- and moisture-stable complexes Pd-41−43 (Figure 13).80 Pd-41−43 were tested in the

reactions of this type, the bulkier catalysts were found to be more efficient. In addition to the catalytic studies, a detailed investigation on the isomerization of these complexes was also presented in this work, revealing that trans-Pd-44f is the dominant species, as expected from the strong trans influence exerted by the NHC ligand (Figure 14). 2.2. Heterogeneous Suzuki−Miyaura Reaction

Heterogeneous metal catalysis offers important environmental advantages, such as lowering of metal content in products, prevention of catalyst decomposition, and recyclability. NHCs, presenting strong σ donation and stabilizing effects, can be efficient components as linkers of catalytic metal centers to different solid supports. The compatibility of NHCs to a variety of transition metals and their synthetic versatility make supported NHCs a growing field in heterogeneous catalysis.83−85 Within this framework, heterogeneous palladium catalysis has emerged as a useful tool for many palladium catalyzed transformations in general and for Suzuki crosscoupling in particular.86,87 Throughout the years, a great variety of solid supports have been developed and used as platforms and linkers for palladium Suzuki cross-coupling catalysis. 2.2.1. Silica-Supported Catalysts. Tetradentate imidazolium compounds, as precursors for NHC ligands, were synthesized by the Zhang group (Figure 15) in 2003 with the prospect of promoting Suzuki couplings in benign solvents.88 Reactions with Pd(OAc)2 and ligands 12 or 13 were efficient only in Suzuki−Miyaura couplings of aryl bromides and phenylbororonic acid in aqueous ethanol (70−95%) or nbutanol. Seemingly, solubility problems of NHC precursor 12 in pure water led to formation of palladium black and prevented reaction progress. The use of a solid support such as silica addressed the solubility problem and allowed efficient coupling of different aryl bromides with phenylboronic acid (50−98% yields) in water and with low catalyst loadings (10−4−0.1 mol %). The high polarity of the tetradentate salt made this precursor ideal for silica gel immobilization. Even though the characterization of the supported complex was unavailable (probably consisting of various species), control reactions showed that the use of the ligand benefits reaction yields (although the authors state that even without the ligand reactions proceeded, albeit in a less effective manner). In work done by Sen and co-workers, an organosilane alkyl spacer was used to link imidazolium precursors to colloidal silica. The grafted silica was further reacted with Pd(OAc)2 to obtain NHC−Pd nanoparticles Pd-46a-b (Figure 16).89 The palladium content of the nanoparticles was measured by ICPAES to be about 0.24 mmol/g. Pd-46a was also characterized

Figure 13. Expanded (NHC)PdCl(cinnamyl).

coupling reaction of 3-chloropyridine and 4-tolylboronic acid with NaHCO3 and TBAB in refluxing water. Complexes with bulky Dipp substituted on the NHC provided better activity (except for Pd-43a-b, which was very low with both substituents). Further studies using numerous heteroaryl chlorides and bromides with arylboronic acids were carried out successfully with the most active complex Pd-42b. Novel pyrazolin-4-ylidene ligands were introduced in abnormal NHC−Pd(II) by Huyn and co-workers (Figure 14).81,82 Reactions were carried out in water with K2CO3, with 1 mol % catalyst loadings under air. First, phenylboronic was reacted with a variety of para-substituted aryl bromides. Reactions with bromobenzaldehyde or bromoacetophenone produced moderate to excellent conversions with precatalysts Pd-44a-f and Pd-45b; yet, with complex Pd-45a poor results were obtained in both cases. For bromoanisole, all precatalysts gave excellent results; however, higher temperatures and addition of TBAB was needed. In the case of p-chlorobenzaldehyde, poor conversions (14−52%) were obtained even after addition of TBAB. Overall, as pointed out above for many J


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Figure 14. Neutral and ionic abnormal NHC−Pd(II) complexes.

recyclability of this system was greatly hampered by avoiding the use of the NHC component. In the case of Pd-47 (Figure 16), EDX spectroscopy showed palladium loadings of up to 86 μmol per gram of silica.90 Pd-47 was used as a catalyst in the Suzuki coupling of phenylboronic acid with a variety of aryl halides. Reactions were conducted in the presence of 0.5 mol % of Pd-47 and K2CO3 in DMF/H2O 1:1 at room temperature for 2 h. All aryl iodides and aryl bromides tested, regardless of their substituents, gave excellent results; however, 4-chloroanisole produced only 7% yield. An example of iodobenzene coupling performed in neat water gave a promising result of 87%. Pd-47 was reused in the Suzuki coupling of bromobenzene and phenylboronic acid under the same conditions for 4 runs without compromising the high yields of >95%. Lower catalyst loadings were also examined using iodobenzene as substrate. Lowering loadings from 0.5 mol % to 0.05 mol % and 0.005 mol %, raised TONs from 198 to 1560 and 6400, respectively; yet the yields dropped from 99% to 78% and 32% accordingly. In later work carried out by Jin and co-workers, the same alkyl spacer was used as a tether to a silica support.91 Two methods of preparation were taken into consideration. As shown in Scheme 5, either the imidazolium was first attached to the silica and then mixed with Pd(OAc)2 to yield Pd-48 or, alternatively, the DNHC−Pd complex Pd-49 was first isolated and then bound to the solid support. Due to the poor solubility of Pd-49 in most solvents, the former synthesis was chosen as the preferred route toward Pd-48. ICP of immobilized Pd-48 showed 36 mg of palladium content per gram of silica support, meaning about 2.6 imidazolium units per palladium atom. The characterization of the hybrid material included IR analysis that showed the characteristic absorption band of the imidazolium’s double bond. Suzuki couplings of aryl iodide and phenylboronic acid were used to find the optimum reaction conditions: 0.1 mol % catalyst loadings of Pd-48, Na2CO3 (2 equiv) as base, in DMF/ H2O 1:1 at 65 °C. When screening coupling reactions under the optimized conditions, excellent results were obtained for aryl iodides and both activated and deactivated aryl bromides with a variety of functionalized aryl boronic acids. Only slightly longer reaction times were required for deactivated aryl iodides and aryl bromides. Couplings of aryl chlorides with phenyl-

Figure 15. Tetradentate NHC precursors.

Figure 16. Idealized illustration of silica nanoparticles bearing NHC− Pd complexes.

by TEM images which showed that no aggregation occurred upon palladium addition. The catalytic activities of the two systems were tested with the Suzuki coupling of 4-iodotoluene and 4-iodoanisole with phenylboronic acid with 2 mol % of either Pd-46a or Pd-46b in isopropanol/water 1:1. Both substrates produced high yields with slightly better results in favor of Pd-46a. Therefore, Pd-46a was chosen as the catalytic system to probe the scope of this method. Despite good to excellent yields obtained with aryl iodides and a variety of aryl bromides, reaction with reluctant chlorobenzene gave only 29% yield. Pd-46a was also able to catalyze the coupling of 4iodotoluene and phenylboronic acid under the same conditions for 5 successive cycles without noticeable decrease in yields and with high catalyst recovery. It is important to note that besides a somewhat vague characterization of the metal complexes, control experiments run with n-octyl-functionalized silica nanoparticles (RP-8) in the presence of Pd(OAc)2 afforded 82% in the model reaction coupling. That being said, the K


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Scheme 5. Alternative Approaches for Immobilization of NHC−Pd Complexes on Silica Gel

deductions about catalytic activity were inconclusive. Alternatively, di(N-(trimethoxysilylpropyl)-N′-aryl)imidazolylidene palladium complexes were synthesized, isolated, and immobilized on silica support to obtain Pd-51 (Scheme 7). In this case

boronic acid were conducted in the presence of 1 mol % of Pd48 at elevated temperature of 85 °C and longer reaction times, but only chlorobenzene provided good conversion (92%), while both activated and deactivated aryl chlorides amounted to low yields of products and a high amount of biphenyls as homocoupling byproducts. The Pd-48 system could be recycled 3 times in the coupling of iodobenzene and 1bromo-4-nitrobenzene with 0.2 mol % catalyst loadings without any meaningful loss in activity. No leaching of palladium into the solution media was observed by atomic absorption spectroscopy, and so good catalytic features and robustness of the system were attributed to the strong ligation of the NHC to the palladium and the prevention of interactions between catalytic centers. In a more recent paper by Tyrrell et al.92 both methods of immobilization were compared once again. Thus, (N(trimethoxysilylpropyl)-N′-aryl)imidazolium was first attached to the silica surface and then reacted with Pd(OAc)2 to supposedly yield NHC−Pd complexes Pd-50 (Scheme 6).

Scheme 7. Synthesis of Palladium Complexes and Immobilization on a Silica Surface

the likelihood of having a supported NHC−Pd species is reasonably much higher, and several simple Suzuki−Miyaura couplings were carried out with satisfactory results, even after 4 recycling sequences. In contrast to the work of Jin et al. the comparison between both methodologies revealed that complexes synthesized prior to attachment onto the silica provided better catalytic results than analogous complexes prepared from grafted imidazolium salts. Mesoporous silica could also be utilized in the immobilization of NHC−Pd complexes. Materials such MCM-41, SBA-15, and SBA-16 were used as solid supports, taking advantage of the well-structured porous and high surface area which may provide good anchoring points for imidazolylidene ligands. The porous framework further assists in catalysis due to the prevention of metal aggregation and positioning of well-defined catalytic centers. This is especially true in the case of palladium catalysis, in which palladium complexes tend to aggregate into bulk metal by leaching of Pd(0) into the reaction mixture. The first elegant example by Yang et al. explored commercially available SBA-16.93 The outer silanol groups of SBA-16 were capped with Ph2SiCl2 to enforce linkage of imidazolium precursor 14 and complex Pd-52 (Figure 17) on the inner surface of the silica cavities. The system was tested in the Suzuki reaction of functionalized aryl bromides at 50 °C in

Scheme 6. Immobilization of Imidazolium Salts and Possible Complexation with Palladium

Even though elemental analysis of the silica indicated the presence of palladium in the material, there was no further characterization of Pd-50 and the actual nature of the palladium species was undetermined. When 0.2 mol % palladium loadings were employed into a DMF/H2O 1:1 mixture at 80 °C, Suzuki−Miyaura couplings of aryl bromides gave satisfactory yields. Aryl chloride, however, gave very poor results even at 100 °C. Due to the heterogeneous nature of the catalyst composition, meaning the probable presence of mono-NHC as well as DNHC species and even uncoordinated palladium, L


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ligand.95 Under optimized conditions in DMF/H2O 1:2, different aryl iodides and aryl bromides were successfully coupled with arylboronic acids in excellent yields. The catalytic SPIONs were then easily removed from the reaction mixture using a simple magnet. After washing with ethanol and acetone Pd-54 was then reused in 7 successive cycles of Suzuki− Miyaura coupling under the optimized conditions, maintaining high activity of up to 93% yields and a minimal amount of Pd leaching after the first run. 2.2.2. Resin-Supported Catalysts. Lee’s group began investigating polymer-supported Pd−NHC complexes and their catalytic properties in the aqueous phase in 2004.96 In their first report, methylimidazole was covalently attached to a chloromethyl polystyrene resin (CM PS, 2.3 mmol Cl/g polymeric support, cross-linked with 1% DVB 100−200 mesh) as shown in Scheme 8. As expected, higher imidazolium loadings led to increased swelling volumes in polar solvents. The addition of Pd(OAc)2 and Na2CO3 to the imidazolium polymer afforded the groundwork to achieve a Pd−NHCsupported complex Pd-55 (Scheme 8). Coupling between iodobenzene and phenylboronic acid was used as the benchmark reaction to test the efficiency of the supported catalyst. The reaction produced better results when a DMF/ H2O 1:1 mixture was used as the solvent at 50 °C, due to better solubility of the reagents and improved swelling of the resin. Under the optimized reaction conditions, other aryl halide substrates gave good to excellent yields naturally, with better results for aryl iodides than aryl bromides. The study above revealed that only about one-third of the initial palladium content was actually attached to the polymer, a result explained by the difficulty of the palladium to penetrate the inner layers of the polymer. As typical when using these types of resins, it could be concluded that it is difficult for reagents (both palladium and substrates) to diffuse into catalytic sites located within the buried structure of the polymer and polymer swelling (which is solvent dependent) is of paramount importance. With this in mind, Lee et al. developed a surface-grafted NHC polystyrene support with catalytic active sites located solely on the surface of the polymer to make catalyst Pd-56 (Scheme 9).97,98 The coupling of iodobenzene and phenylboronic acid with this catalyst (1 mol % of palladium) was examined. Better yields were still obtained for water−organic solvent mixtures; however, the DMF/H2O ratio could be lowered to 1:7 while maintaining excellent yields and high rate conversions for a wide scope of substrates. In order to improve catalysis in neat water, two NHC precursors were synthesized by attaching imidazole rings to PEG 200 and PEG 600.99 These precursors were reacted with Merrifield resin to obtain amphiphilic polymer 15, which when treated with palladium and base afforded the supported catalysts Pd-57, as indicated in Scheme 10. Coupling between iodobenzene and phenylboronic acid in neat water, PS-PEG 600-NHC−Pd afforded 91% yield and efficient recyclability, compared to 57% with PS-PEG 200-NHC−Pd, suggesting that the PEG length affects the reaction in water. Unfortunately, even though the catalytic system showed improved results in water, it appears that an organic cosolvent was still needed in some of the reactions in order to increase substrate solubility. In 2008, Lee explored another polymeric support for heterogeneous Suzuki coupling.100 Macroporous chloromethyl polystyrene (MPS, 0.7 mmol Cl/g polymeric support) was chosen as a support for NHC−Pd complexes (Scheme 11) due to its large surface area and high porosity, two features that

Figure 17. Precursor and NHC−Pd complexes used for functionalization of SBA-16.

ethanol/water 1:1 and low 0.01 mol % catalyst loadings. All substrates gave excellent results regardless of the electronic nature of the substituent, although deactivated aryl bromides required somewhat longer reaction times. Recycling for the Suzuki coupling of bromobenzene and phenylboronic acid was carried out for 4 cycles without loss in yield. Even after 10 cycles the reaction still afforded nearly quantitative yields, although prolonged reaction times of up to 49 h were needed providing a calculated TON of 45 400. The effect of the SBA16 mesoporous architecture was determined by the comparison to SBA-15 and regular silica, each impregnated in the same manner with 14 and Pd-52. Even though both the SBA-15 and the silica compounds produced 99% and 95% yield, respectively, in the first run of Suzuki coupling, the catalytic abilities of these two systems dramatically dropped after the second cycle. XPS and TEM analysis of fresh SBA-16 and 3 times reused SBA-16 showed that Pd(0) particles of 95% yield and a remarkable TOF = 5200 h−1.103 In addition, these polymers catalyzed Heck reactions with similar results.

NHC precursors.104 The rationale behind this strategy was to utilize the amino acid residue as a peptide linkage to a solid support. Thus, the ligand precursors were attached to commercially available amino-functionalized PEGA-NH2 resin (Rink amide resin)105 through a Val-Phe dipeptide by solidphase peptide synthesis techniques to obtain Pd-61 (probably including coordinating solvent) and Pd-62 (Figure 21) after deprotonation of the imidazole and addition of a PdCl2(COD) complex. The catalytic ability of solid-supported complex Pd61 was examined in both Sonogashira and Suzuki−Miyaura reactions. Ten different phenylboronic acids were reacted with iodo- and bromobenzene in neat water and 2.5 mol % catalysts loading. With one exception (pentafluorophenyl boronic acid), all substrates gave good yields with better results for the more reactive iodobenzene. The recyclability of Pd-61 was tested in eight successful cycles of coupling between tolylboronic acid and iodobenzene in neat water. In an important drawback to this method, complex Pd-62 had to be released from its solid support (using TFA) in order to be active. Under homogeneous conditions, catalyst Pd-62 afforded slightly better Suzuki coupling results than those obtained with supported Pd-61 (0.05% catalyst loading, microwave heating at high temperatures in water). At the interface between homogeneous and heterogeneous systems, Lipshutz et al. found that the use of micellar catalysis can improve Suzuki−Miyaura couplings in water.106 PEG 600yl-α-tochopheryl sebacate (PTS) was used as the micelleforming amphiphile and commercially available Neolyst CX31 as the NHC ligand. Notably, only the use of the Neolyst ligand led to efficient cross-couplings between aryl chlorides (but not aryl bromides) and aryl boronic acids, while the use of a phosphane ligand was unproductive. 2.2.3. Dendritic Catalysts. Due to their special properties, i.e., well-defined globular structures and uniform size, dendritic catalysts can enjoy the best of both worlds: Catalytic reactions of a homogeneous nature on one hand and easy separation from a reaction mixture by ultrafiltration on the other.107−109 O


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Figure 21. Peptide-tethered NHC−Pd complexes.

An important advantage of dendrimers over polymers is chemically equivalent dendrimer termini, a very useful feature when studying novel properties, especially in catalysis. The Haag group designed an elegant dendritic-like system, constructed from a polyglycerol framework and NHC−Pd complexes as end groups (Figure 22).110 The NHC ligands

Figure 23. Pd−NHC−MCOPs.

(Pd-65 is synthesized in DMSO which probably acts as the capping agent for the end groups). Notably, not only did the more reluctant aryl chlorides give good results but also the authors showed one special example of coupling of an “inert” aryl fluoride. Despite these obvious advantages the system still required relatively high temperatures, and the catalytic activity was reduced after each cycle, supposedly due to the filtration technique used to separate the polymer from the reaction mixture. In order to improve the system, NHC−Pd−MCOP Pd-65b was synthesized113 with the intent that a triethylene glycol moiety would increase the solubility of the polymer in water and facilitate better separation. Indeed, NHC−Pd− MCOP Pd-65b showed good solubility in aprotic polar organic solvents such as DMF and DMSO and excellent solubility in water. The catalytic activity of NHC−Pd−MCOP Pd-65b was tested in a series of Suzuki−Miyaura reactions including various aryl bromides and aryl chlorides in water. Especially noteworthy is the successful coupling of electron-rich aryl chlorides with phenylboronic acid at room temperature and the coupling of a sterically hindered substrate, albeit with higher catalyst loading and higher temperatures. Furthermore, separation difficulties were solved by using a simple dialysis technique, and the catalyst was used in the staggering number of 17 additional cycles without losing its performance abilities. Following this, further structure−activity studies were carried out. Specifically, NHC−Pd−MCOPs Pd-65c and Pd-65d were synthesized in order to examine the effect of the N-substituted alkyl chain on the catalytic activity.114 The best result was the coupling of challenging aryl chlorides by Pd-65d, with much shorter reaction periods than those of Pd-65a. Also, poisoning control experiments indicated that the active species was soluble, discarding heterogeneous pathways by palladium black. The consistently higher yields and advanced activity in neat water led the authors to the assumption that an increase of hydrophobicity next to the catalytic center due to the long alkyl chain was the explanation for this behavior. Pd-65d could be used up to 7 cycles without significant loss of activity, although the reaction time had to be increased after the fourth cycle.

Figure 22. Proposed structures for hyperbranched polyglycerol NHC−Pd complex and monomer analogue.

were attached to the dendrimer using click chemistry on alkyne N-substituted imidazolium groups (with an additional PEG chain on the other imidazolium nitrogen atom) and vicinal bisazide termini on the hyperbranched polyglycerol. The triazole connections granted additional stability and afforded bisNHC−Pd entities when treated with palladium acetate. The NHC was further substituted with methoxypoly(ethylene glycol) to increase the solubility of the construct in polar solvent systems, including neat water (complex Pd-63). When the catalytic activity of Pd-63 in neat water was compared to a monomeric analogue (Pd-64, not isolated) in the coupling of 2tolylboronic acid and aryl bromides, both showed similar TONs. The clear advantage of the hyperbranched polymer was evident by the easy separation of the products from the catalyst using dialysis. The separation enabled reuse of the system in four additional cycles while maintaining high conversions. This method of separation, however, led to a total loss of up to 20% of the polymer. Nonetheless, the dendritic system gave reasonable yields and even better performance than the monomeric analogue in some cases, a welcome unexpected result with this type of catalyst. The authors proposed that the dendritic system presents improved stability due to the high density of the carbene ligands near the palladium metal atoms. 2.2.4. Self-Supported Polymers. Under the category of NHC−Pd polymers, a striking example is the work of Karimi and Akhavan and their use of NHC main chain organometallic polymers (NHC−Pd−MCOPs) for Suzuki coupling reactions in water. Inspired by the work of Bielawski,111 they tested the NHC−Pd−MCOP complex Pd-65a (Figure 23)112 as a recyclable catalyst for the Suzuki−Miyaura coupling of a wide variety of aryl halides with phenyl or tolyl boronic acid in water P


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will focus naturally on Heck couplings that are catalyzed by Nheterocyclic carbene palladium complexes28 in water or aqueous mixtures. As mentioned above, amphiphilic polymers Pd-60a−c (Figure 20) functionalized with NHC−Pd complexes promoted cross-coupling between iodobenzene and styrene in water.102 Reactions with all three systems gave high yields (over 93%) within 1.5−2 h. A TOF of 570 h−1 for Pd-60b was the highest obtained, while a TOF of 150 h−1 for Pd-60a was the lowest, probably because the spacer was too short to efficiently separate the active NHC−Pd complex from the polymer surface, preventing accessibility of the substrates. Separation of Pd60c from the mixture could be easily achieved by extraction of the products. Three cycles of catalysis were performed by this fashion with minimum decrease in activity. Acetal-functionalized imidazolium NHC−Pd complexes, Pd67−69, were reported by Hwang and co-workers (Figure 25).119 These complexes, in 0.5−1 mol % catalyst loadings, were tested in Heck coupling reactions of styrene with bromobenzene in the presence of potassium carbonate and TBAB for 2 h. However, low yields were obtained when using water as the solvent, especially when compared to DMF. It is possible that aqueous conditions at high temperatures led to partial hydrolysis of the acetal function (notwithstanding the basic surroundings), decomposing the ligands and catalysts. The NHC salts 4a−g57 and 5a−e58 (Figure 5), previously used as ligands for Suzuki couplings, tridentate salts 17 and 18,120 and bidentate salts 19 and 20121 (Figure 26) were utilized to catalyze the Heck coupling between styrene and aryl bromides. All reactions were heated in DMF/water solutions at 1:1 ratio and the catalysts were generated from in-situ mixing of Pd(OAc)2 with the NHC salts. Control experiments in the absence of NHC salts provided no conversion. A variety of para-substituted aryl bromides (bromoanisole, bromobenzaldehyde, bromotoluene, bromoacetophenone, and bromobenzene) were tested and provided excellent isolated yields (67−98%) when coupled with styrene. However, aryl chlorides did not afford coupled products. Remarkably, it was noted that the nature of the N-alkyl group had a stronger influence on the outcome of the reaction than whether an o- or p-xylyl bridge was used. Moreover, cyclobutyl derivative salts 21 and 22 (Figure 26) were explored at similar conditions, though in pure water, and afforded similar results.122 In 2009, Gülcemal et al. reported a series of benzimidazolium oligoether NHC−Pd(II) complexes (Figure 27).123 Catalytic activity studies of the complexes were carried out for a Heck cross-coupling between styrene and p-bromoacetophenone with Cs2CO3 at 100 °C in pure water. For the in-situ-generated complexes using ligands 23−33, the authors noticed that longer ethylene oxide groups (n = 3), pentamethylphenyl substituents (25−27, 31−33), and methyl groups on the benzimidazole ring (b) produced slightly better results. Mixed NHC-phosphine palladium complexes Pd-71c-d showed better conversions than DNHC complexes Pd-70c-d; however, the in-situ-generated catalysts using ligands 23−33 delivered the best overall conversions. Recyclability of the complex generated from ligand 26b was examined in 3 cycles, giving good yields (95% in the first run, 92% in the second, and 90% in the third). A proline NHC bidentate complex Pd-72 (Figure 28) was found to catalyze the Heck−Mizoroki reaction in neat water (note the similarity to Pd-1 used by the same group for Suzuki, both complexes derived from rac-proline).124 The scope of the reaction between aryl halides and acrylic acid and acrylate esters

The phenylethynyl spacer in Pd-66 (Figure 24) was introduced not only to increase the rigidity and stability of

Figure 24. Insoluble bidentate palladium complex for heterogeneous Suzuki−Miyaura coupling.

the complex but also to bestow hydrophobicity and ensure complete insolubility in water, providing a heterogeneous nature to the catalytic process.115 A 0.1 mol % amount of Pd-66 was efficient in the Suzuki−Miyaura coupling in the presence of K2CO3 in neat water at 100 °C. Coupling of substituted bromoand iodobenzene with phenylboronic acid produced moderate to high yields. Typically, the use of chlorobenzenes was unsuccessful. When larger aromatic substrates, 1-bromonapthalene and 1-naphthalenylboronic acid, were used, a higher loading of the catalyst, 2 mol %, was needed to obtain 55% yield. One disadvantage of using neat water in this case is the deterioration of Pd-66 to form small amounts of palladium black. This however could be prevented by degassing the water with nitrogen. Since the catalyst is also insoluble in diethyl ether, separation of the catalytic system was conducted as if Pd66 was a solid support by removal of the aqueous reaction mixture with a syringe followed by extraction and decantation of the organic solvent. Thus, 10 successive couplings of pbromoacetophenone and phenylboronic acid were performed, producing quantitative yields at each cycle. Several experiments such as a mercury drop test and poisoning by substoichiometric amounts of CS2 and PPh3 further confirmed that the true catalytic nature of Pd-66 is heterogeneous. Nevertheless, poisoning by pyridine and poly(4-vinylpyridine) excluded the option of soluble metal nanoparticles leaching from the Pd-66 as the active species. This is contrary to previously reported Pd30 (Figure 8)68 for which strong evidence of catalytic participation by Pd(0) nanoparticles was obtained. Thus, while water-soluble Pd-30 were postulated to act as reservoirs for metallic palladium, the insoluble Pd-66 itself is believed to promote heterogeneous catalysis. 2.3. Heck Reaction

The Heck−Mizoroki−Fujiwara reaction (Scheme 13) is undoubtedly one of the most versatile palladium coupling Scheme 13. Heck Reaction

reactions.116 The simple starting materials involved, together with facile conditions and the enormous reaction scope, certainly swayed the Swedish committee to honor Richard Heck with the 2010 Nobel Prize in Chemistry for his contributions to the reaction that bears his name.117,118 While Heck coupling reactions have been carried out with almost all available solvents and innumerable ligands, in this review we Q


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Figure 25. Acetal-substituted imidazolium NHC−Pd complexes.

bromoacetophenone and methyl acrylate in water could be improved by adding detergent Brij 30 (polyoxyethylene(4)lauryl ether) to the mixture in a ratio of 2:1 water/Brij 30. The coupling reactions with iodobenzene were effective also in pure water. Hwang and co-workers studied two homoleptic NHC−Pd complexes with pyridinium termini, Pd-74−75 (Figure 29).126 These complexes gave excellent yields in the coupling between phenyl bromide and styrene in water with Cs2CO3/NaOAc at 140 °C. In 2014, Huynh et al. disclosed three water-soluble sulfonateNHC−Pd(II) complexes, Pd-76−78 (Figure 29), that were found to be active in the Mizoroki−Heck reaction of tert-butyl acrylate and aryl bromides in water with the addition of triethylamine and TBAB.127 The best catalytic activity was achieved with complex Pd-78, yet aryl chloride couplings were still out of reach. 2.4. Sonogashira Reaction

The Sonogashira cross-coupling reaction is one of the best organometallic examples for metal cooperation in catalysis.128 The use of both palladium and copper metals to couple alkynes to aryl and alkenyl halides is a powerful synthetic method that relies on the generation of a copper−acetylide species, followed by the traditional palladium mechanistic cycle to create the new carbon−carbon bond.129 Nonetheless, efforts to achieve “copperless” methods combined with benign reaction conditions continue to stimulate the development of novel palladium ligands (Scheme 14). In this section we will summarize a few of the recent NHC−Pd catalysts used for Sonogashira coupling reactions in water. Two robust DNHC−Pd complexes Pd-79 and Pd-80 were developed by the Ghosh group, and their activity was evaluated against PEPPSI (pyridine-enhanced precatalyst preparation stabilization and initiation, a lengthy but descriptive acronym)45,46 type catalysts Pd-81a-b (Figure 30).130 Complex Pd79 was obtained with the more typical trans-isomer configuration, yet complex Pd-80 embraced the cis configuration as a result of hydrogen bonding between the amide functionalities of the NHCs. Notably, complex Pd-80 is the first example of a cis-NHC complex in which the NHC units are not covalently bridged. Both complexes provided high yields in short periods of time in a DMF/water 3:1 mixture for the Sonogashira cross-coupling between substituted aryl halides and a variety of alkynes. The reaction took place in the presence of 10 mol % of CuBr and Cs2CO3 as a base. Furthermore, these complexes showed low yields of the homocoupled byproduct, and for dihalide (bromo-iodo)substituted aryls, coupling took place chemoselectively at the iodo site, while the bromo remained unscathed. In summary, the DNHC complexes showed improved activity compared to

Figure 26. NHC precursor salts for palladium Heck catalysts.

was probed with KOtBu at 100 °C and 1 mol % of catalyst. When KOH was used, addition of tBuOH was essential to the progress of the reaction, suggesting that KOtBu actually hydrolyzes to KOH and tBuOH (probably expected in aqueous environment). General yields for the Heck reaction with acrylic acid and acrylate esters were good to excellent with aryl iodides. Aryl chlorides were unreactive. Furthermore, a homodinuclear Pd−NHC complex Pd-73 derived from proline (Figure 28) was also found to be a good catalyst toward the Heck− Mizoroki reaction in similar conditions.125 In this case, NaOtBu was found to be a better base (85% conversion compared to 50% with KOtBu; seemingly in this case the base is not just the hydroxide obtained from hydrolysis). Acrylic acid and a variety of aryl iodides and bromides supplied moderate to excellent isolated yields. The caffeine-derived DNHC palladium catalyst (Pd-18, Figure 4), previously mentioned as an effective catalyst for the Suzuki−Miyaura cross-coupling, was also investigated for Heck cross-couplings.50 Reactions were carried out with 2 mol % of catalyst Pd-18 at 90 °C. The coupling between 4R


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Figure 27. Benzimidazole-based ligands.

Scheme 14. Sonogashira Reaction

hints that the required isomerization is not a rate-determining step. The study with PEPPSI-themed catalysts was extended to complexes Pd-82a−d, Pd-83a-b,131 and N-fused derived abnormal Pd-84a−d132 (Figure 30). Activity for the Sonogashira reaction was tested once again in DMF/water mixtures and Cs2CO3 as the base in the absence of the cuprous additive. All complexes gave reasonable to high yields. When the reaction was compared to a control containing PdCl2 as catalyst, the impact of the NHC was evident. This control seems to suggest that copper is not inadvertently being added

Figure 28. Proline-functionalized NHC−Pd complexes.

the PEPPSI analogues. The authors explained this by a more efficient oxidative addition of the aryl halide to the metal during the reaction’s catalytic cycle due to the presence of two strongly electron-donating NHCs. To note, even though a cis configuration needs to be in place for the oxidative addition step to take place, no significant differences in reaction rates could be found between Pd-79 and Pd-80, which probably

Figure 29. Homoleptic and sulfonate-NHC−Pd(II) complexes. S


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under these conditions. Comparison to a control reaction with PdCl2 as catalyst demonstrated the superiority of the PEPPSI complexes. When probing the scope of the reaction, each of the complexes gave good to excellent yields for the coupling of aryl bromides functionalized in the para and ortho positions with trimethoxy(phenyl)silane and poor results with trimethoxy(vinyl)silane. Other complexes that catalyzed fluoride-free Hiyama reactions were the diastereomeric mixture of Pd-85,135 prepared by direct metalation of racemic hydroxyl-functionalized imidazolium salt 34 with Pd(OAc)2 (Scheme 16). Initial Scheme 16. Preparation of DNHC Complex Pd-85 Using Imidazolium Salt 34

Figure 30. NHC Pd complexes for Sonogashira couplings.

with the carbonate base, as found to be the case in many other copperless Sonogashira couplings. In the previous section, sulfonated NHC−Pd complexes, developed by the Plenio group, were shown to be effective catalysts for Suzuki−Miyaura reactions in water.74 The sulfonated NHC precursor 10 (Figure 12) was also investigated in Sonogashira cross-couplings. Thus, the NHC−palladium complex was generated in situ from 1 equiv of Na2PdCl4 and 2 equiv of 10 in a water/isopropyl alcohol 1:1 media (the alcohol was added to improve the substrate’s solubility). Phenylacetylene and a variety of aryl bromides were reacted with 0.5 mol % catalyst loadings to produce conversions of about 80%. All of the reactions were carried out at temperatures of 90−95 °C for 12 h and using KOH as base. Halide-substituted pyridines or thiophenes were also reacted with three different phenylacetylenes, with catalyst loadings of 0.25 mol %. N/SHeterocyclic bromides afforded excellent yields, and also pyridine chlorides provided good to excellent conversions. Remarkably, the typical suppressive effect of the N/Sheterocyclic group on the reaction was hardly noticeable in water. Finally, less reactive alkylacetylenes were also tested with a variety of N/S-heterocyclic halides, resulting in outstanding conversions. The caffeine-based DNHC palladium catalyst Pd-18 developed by Luo (Figure 4) was also tested in the Sonogashira reaction.50 4-Bromonitrobenzene and phenylacetylene were mixed with 1 mol % catalyst loading at 90 °C in water; KOH or NaOtBu was used as base, and CuI was added. In this case, the addition of detergent Brij 30 to the reaction mixture was essential to obtain suitable yields.

studies were conducted in three sets: (a) in the presence of 0.1 mol % of complex Pd-85, (b) in-situ complex formation using 34 and Pd(OAc)2, and (c) with Pd(OAc)2 as a control reaction. The results obtained in the absence of NHC precursor 34 were significantly lower. In addition, the use of water as solvent substantially improved the results. The scope of the reaction was explored using 34 and Pd(OAc)2 in the ratio of 2:1 in 50% aqueous NaOH at 120 °C microwave heating. Both activated and deactivated aryl bromides gave satisfactory yields; however, coupling of the more sluggish aryl bromides and aryl chlorides required the use of TBAB as a phase transfer agent. The effect of the relative ratio between Pd(OAc)2 and 34 was tested recently to observe how this would affect the reaction.136 After evaluating reaction parameters it was determined that the optimal conditions were 0.1 mol % of Pd(OAc)2 loadings and around 5 equiv of 34. The scope of the Hiyama reaction was reevaluated using the new optimal ratio in 50% aqueous NaOH at 120 °C with greatly improved results. 2.6. Miscellaneous Reactions

2.6.1. Arylation of Benzoic Anhydride, Enones, Allylic Alcohols, and N-Tosylarylimines with Arylboronic Acids. Complex Pd-86 (Scheme 17a) is yet another example from the Shao group of a palladium catalyst bearing an NHC ligand substituted with an L-proline moiety.137 This complex catalyzed coupling reactions between benzoic anhydride and various phenylboronic acids (and also β-naphtyl boronic acid) in water in the presence of NaHCO3 (Scheme 17a). Phenylboronic acids bearing electron-donating groups gave lower yields compared to substrates with electron-withdrawing groups. The authors concluded that the different coordination behavior (nonchelated in this case), compared to Pd-1 (Figure 1) and Pd-72 (Figure 28), was due to the presence of the N-phenyl substituent on the pyrrolidine ring. However, it is not clear if the existence of N-methyl imidazole in the reaction mixture (produced by the decomposition of the precursor ligand) could complicate the chelating binding mode observed in the other cases. In addition, Pd-4a (Figure 1), previously mentioned as a catalyst for the Suzuki reaction, was also examined in this

2.5. Hiyama Reaction

Complexes Pd-82−83 (Figure 30) catalyzed the Hiyama reaction133,134 (Scheme 15) as well as the Sonogashira reaction.131 Activity tests were performed in a 1,4-dioxane/ water 2:1 mixture and using NaOH as base. Most importantly, the reaction advanced in the absence of fluoride, usually needed to increase the nucleophilicity of the organosilicon reagent; this is one of very few examples for the Hiyama reaction preformed Scheme 15. Hiyama Reaction

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Scheme 17. Arylation with Aryl Boronic Acids

Figure 31. Chiral bidentate DNHC−Pd(II) complexes.

transformation.138 The reaction between benzoic anhydride and phenylboronic acid with Pd-4a gave better yields than the commercially available PEPPSI-IPr catalyst (99% compared to 60%, respectively) and also better than Pd-86 (94% with higher catalyst loadings and longer reaction times). Pd-4a catalyzed couplings with several phenylboronic acids and with a number of carboxylic acid anhydrides with moderate to high isolated yields. Allyl−aryl coupling of allylic alcohols with arylboronic acids was also tested with Pd-4a in neat water (Scheme 17b).139 Primary and secondary allylic alcohols generated the same coupling product (linear) in moderate to high yields regardless of the substituents on the aromatic rings. Shi and co-workers reported axially chiral cis-chelated DNHC−Pd(II) complexes Pd-87a−c (Figure 31).140 Complexes Pd-87a−c were tested for asymmetric conjugate addition of arylboronic acids to cyclic enones under the optimal reaction conditions: THF/water 10:1 with catalyst loadings of 3 mol % and KOH (Scheme 18). The reaction between 2-cyclohexenone and phenylboronic acid catalyzed by Pd-87b-c produced isolated yields of 95% and 97%, respectively, and enantiomeric excesses of 93% and 94% correspondingly.

Scheme 18. Conjugate Addition of Arylboronic Acids to Cyclic Enones

Complex Pd-87a failed to deliver the expected product, indicating that the two weakly coordinating carboxylate groups have a critical role in the catalytic cycle of the reaction. Other arylboronic acids were also investigated with 2-cyclohexenone and provided good to excellent yields and very good enantioselectivity; however, for electron-poor arylboronic acids, yields and enantiomeric excess slightly dropped. Pd87b-c were actually the first chiral NHC−Pd(II) complexes that catalyzed an asymmetric conjugate addition of arylboronic acids to cyclic enones, and this feat was accomplished in a water-containing system.141 U


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Additionally, the Shi group used these chiral complexes to study enantioselective arylations of N-tosylarylimines with arylboronic acids using chiral cationic NHC−Pd hydrated complexes Pd-88a−e (Figure 31).142 Reactions were carried out in THF with 1 equiv of K3PO4·3H2O and the addition of 4 Å molecular sieves, most likely to eliminate coordinated water molecules and activate the catalytic cycle. Obviously, water was not used as part of the solvent system in this study, but the important role of coordinated water in the complex persuaded us to include the work in this review. 2.6.2. Dioxygenation of Alkenes. In 2010, the dioxygenation of alkenes was explored with Pd-87a−d and Pd-88f, demonstrating the versatility of this system (Scheme 19).143 In

Scheme 21. Hydroxycarbonylation Reaction of Aryl Halides

Scheme 19. Dioxygenation of Alkenes

the reaction with trans-stilbene, Pd-88f was found to be the most active catalyst and provided the hydroxyacetate product with 63% isolated yields and with good syn-diastereoselectivity (90%), along with 8% isolated yield of the diacetate product. Control experiments under anhydrous conditions demonstrated that water addition was essential for hydroxyacetate product formation. Other alkenes afforded good to excellent yields with acceptable diastereomeric ratios in most cases. 2.6.3. Hydroxycarbonylation of Aryl Halides. The Reiser group reported an ingenious system of graphene-coated cobalt nanoparticles grafted with NHC−Pd complexes through π−π stacking interactions (Scheme 20).144 The reversible weak interactions can be disrupted at high temperatures, activating the complex for hydroxycarbonylation reactions. Thus, when treating complex Pd-89 with cobalt nanoparticles in water, supported complex Pd-90 was established, and when boiling the water solution, complex Pd-89 could be freed. Using this system, aryl halides were carboxylated under 1 atm of CO at 100 °C in water with K2CO3 as base (Scheme 21a). In addition, this catalyst could be recycled up to 16 times consecutively. Furthermore, due to the magnetic cobalt ligand, complex Pd-90 could be easily separated from the products by magnetic decantation and used for the next run. This same transformation was also reported by Huynh and co-workers with Pd-91 (Figure 32).145 The hydroxycarbonylation reaction to produce benzoic acids was carried out with low catalyst loadings in THF/water mixtures (1:5 ratio) (Scheme 21b). High yields (86−96% isolated yields) were obtained for three different iodobenzenes, notwithstanding the electron-donating or -withdrawing properties of the substituents.

Figure 32. NHC−Pd complex Pd-91.

2.6.4. Tsuji−Trost Reaction.146 In 2007 Roland and coworkers reported a series of in-situ-generated NHC−Pd− phosphine complexes that catalyzed allylic alkylation and amination reactions in a biphasic system (1 M KOH or K2CO3 and CH2Cl2) (Scheme 22).147 These allylations were Scheme 22. Allylation of Dimethyl Malonate

run by mixing a palladium source [Pd(η3-C3H5)Cl]2, an NHC− Ag complex, and PPh3 (except for complex Pd-92, which was directly mixed with PPh3) (Figure 33). The conversions were moderate to excellent, depending on the bulkiness of the substrate or the complex. In control experiments without PPh3 or without the NHC−Ag complex, the conversions were either low or null. Complexes Ag-3a and Ag-3b, being less bulky, produced the highest conversions. Moreover, bulky complex Ag-3g produced low conversions with bulky substrates 35 and 36 but with less hindered substrates like 37, affording quantitative conversions. However, chiral NHCs Ag-2 and Pd-92 afforded low enantioselectivities, especially when

Scheme 20. Reversible Preparation of Complexes Pd-89 and Pd-90

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Figure 33. NHC−Ag/Pd complexes.

organic solvents. For all three reactions, yields obtained in pure water ranged from good to excellent for a wide variety of substrates. Furthermore, the system could be recycled by simple filtration 4−6 times without significant yield or selectivity loss. One of the reasons for the enhanced activity in water could be that in water the polymer folds within itself leaving the more polar catalytic moiety exposed to the water interface (even though the polymer is cross-linked there is still significant swelling of the pores, even in water). 2.6.6. Telomerization of Butadiene. The intriguing telomerization reaction of butadiene with ethylene glycol was conducted in a biphasic system in the presence of an NHC−Pd complex generated in situ from Pd(acac)2 and imidazolium salt 39 (Scheme 26).151 A mixture of monotelomers, ditelomers, and butadiene dimer products was obtained, ditelomers being the major products. When the reaction was conducted in pure water, lower yields were obtained when compared to the biphasic system. More recent work evaluated a series of NHC−Pd complexes for the telomerization reaction of butadiene with methanol in the presence of water (Scheme 27).152 Phospine-NHC mixed complexes Pd-93 and Pd-94 as well as in-situ-generated palladium complexes using imidazolium salts 39 and 40 were tested. Curiously, the water-soluble complexes that possessed a sulfonate appendage were not active in the presence of water, while only the complex prepared from 39 and palladium acetate displayed decent activity (50% conversion), improved regioselectivity, and high TON (10 000) for the synthesis of the linear telomer in water. 2.6.7. C−H Bond Activation. Activation of an otherwise inactive C−H bond is one of the most valued synthetic transformations in modern organometallic chemistry. C−H bond activation can be a powerful tool for the creation of new functionalized substrates; thus, much creativity is being put to use in the development of novel methodologies to advance this conversion.153−156 Naturally, the C−H activation in water adds an additional challenge due to the conceivable pernicious participation of water in the reaction and catalyst decomposition. In H/D exchange, water can be used both as the solvent and as a source of deuterium.157 Terdentate complex Pd-95, upon addition of the silver salt, was found to exist as a mixture of dimer complex Pd-96 and complex Pd-97 (Scheme 28). Entropic factors determine that at elevated temperatures the amount of complex Pd-97 increases, leading the authors to

triphenylphosphine was added. The amination reaction of allyl acetate 35 with benzylamine was also investigated in the presence of complex Ag-3a. Full conversion was achieved after changing the base from KOH to K2CO3. Control experiments and NMR studies showed that the NHC−Pd−PPh3 complexes are generated in situ and act as catalysts, although their actual structures were not fully characterized. 2.6.5. Reduction of α,β-Unsaturated Carbonyls, Direct Reductive Amination of Carbonyls, and Aminocarbonylation of Aryl Iodides. One of the polymer-supported Pd− NHC systems described earlier by Lee (Pd-55 in Scheme 8)96 was found to be efficient not only for catalysis of the Suzuki reaction but also in three additional useful organic transformations. These reactions, depicted in Schemes 23, 24, and Scheme 23. Selective Reduction of α,β-Unsaturated Carbonyls

Scheme 24. Reductive Amination of Carbonyls

25 include the chemoselective reduction of α,β-unsaturated carbonyls,148 direct reductive amination of carbonyls,149 and aminocarbonylation of aryl iodides.150 In the optimization of these reactions, the Bhanage group clearly demonstrated the superior activity of the system in water when compared to Scheme 25. Aminocarbonylation of Aryl Iodides

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Scheme 26. Telomerization Catalyzed by Pd−NHC

improved activity and stability. Naturally, the beneficial effects of NHCs on organic solvent-based olefin metathesis were translated to reactions in water,169,170 where the enhanced stability of the catalysts is of paramount importance. 3.1.1. Aqueous Olefin Metathesis Based on GrubbsType Catalysts. The Blechert group investigated RCM (ringclosing metathesis) and CM (cross-metathesis) with Grubbs second-generation catalyst and Ru-1 (Figure 35) in mixtures of water and organic solvents under air.171 RCM of diallyl tosylamine 41 (Figure 36) was investigated with catalyst loadings of 3 mol % in mixtures of MeOH or DMF with water. Curiously, while the Grubbs second-generation catalyst achieved almost quantitative conversion in pure MeOH and at a MeOH/H2O 3:1 ratio, the yields precipitously dropped to 29%; the addition of more water to the mixture actually improved the yields to 54% (1:1) and 77% (3:1). In DMF the results were very similar, pure solvent gave very high yields, a low ratio of water strongly decreased yields, but high percentage of water reclaims the efficient conversions. In both cases, this was probably due to an on-water effect3 when the solvent mixture is polar enough so that the substrate was insoluble. For catalyst Ru-1 the results were similar but with improved conversions. In the RCM of dienes 42 and 43 (Figure 36), catalyst Ru-1 produced excellent conversions of over 98% in a solvent mixture of 4:1 MeOH/H2O. However, in the more difficult CM reaction of alcohol 44 (Figure 36) with 5 mol % of catalyst Ru-1 in a 4:1 ratio of MeOH/H2O, the conversions were very low, including 35% of dimerization product. In any case, it would seem that once enough water is present in the system there is a shift from poor (in water) to satisfying (on water) catalytic activity. In addition, this pioneering work opened the way for the myriad aqueous olefin metathesis studies that followed. In the work of Raines and co-workers, the catalytic activity of Grubbs second generation was examined in RCM of diallyl tosylamine 41 in aqueous solutions.172 Results of over 95% conversions were obtained using three different mixtures:

Scheme 27. Telomerization Reaction of Butadiene

propose that this was the active form responsible for the H/D exchange. To further probe the C−H activation and avoid the dimerization of the active species, complexes Pd-98a, Pd-98b, and Pd-99 were synthesized. When tested for H/D exchange of benzene on D2O, all complexes showed good activity; yet complex Pd-98a provided the best results with 95% yield (Scheme 29). Once dimerization was prevented, the temperature dependence disappeared and the reaction could be carried out at 55 °C. H/D exchange of various organic substrates was examined in heavy water with Pd-98a. Good yields were obtained for ethers, ketones, and even saturated hydrocarbons such as cyclohexane. Altogether, in this case it was definitely shown that the NHC ligand played an important role by weakening the coordination of the solvent to the metal.

3. RUTHENIUM Ruthenium stands out as the metal that benefited the most from the strong sigma donation of NHCs.158−162 Among the ruthenium-catalyzed reactions that were carried out in water we find olefin metathesis15,163 as the most prevalent in addition to isomerization, hydrogenation, hydrosilylation, and atom transfer radical polymerization reactions. This section will dwell on all the ruthenium−NHC-catalyzed reactions in aqueous systems. 3.1. Olefin Metathesis Reactions

The advent of N-heterocyclic carbene ligands has had a tremendous impact in organometallic chemistry and catalysis, none the more so in ruthenium olefin metathesis.164−167 Arduengo’s carbene was first adopted in the Grubbs secondgeneration catalyst (Figure 35)168 leading to significantly

Figure 34. Telomerization catalysts and precursors. X


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Scheme 28. Palladium Complexes Used as Precatalysts for C−H Activation

Scheme 29. H/D Exchange Promoted by Pd-98a with Benzene as an Example

acetone/H2O 4:1, DME (dimethoxyethane)/H2O 4:1, and PEG-500 dimethyl ether/H2O 3:1. These cosolvents outperformed aqueous mixtures of THF, 1,4-dioxane, and DMF. The activities of Grubbs first generation, Grubbs second generation, Hoveyda−Grubbs first generation, and Hoveyda− Grubbs second generation (Figure 35) were compared for the RCM of 41 in 2:1 DME/H2O at room temperature with 1 mol % catalyst loading. The second-generation catalysts, bearing the NHC ligand produced better results than their phosphanebearing analogues. The authors proposed that the strong σ donation by the carbene ligand stabilizes the ruthenium center and protects it from water coordination and subsequent decomposition. After determining that Hoveyda−Grubbs second generation was the prime catalyst for aqueous reactions, kinetics were monitored by NMR (with deuterated solvents) to

Figure 36. RCM and CM substrates for aqueous metathesis.

establish an optimal reaction time of 90 min. Thus, the scope of RCM reactions of various dienes (Figure 36) was probed in DME/H2O and (CD3)2CO/D2O solutions. Most of the substrates produced high conversions to yield 5-, 6- and 7-

Figure 35. Ruthenium olefin metathesis NHC catalysts. Y


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61, and enyne 66 (Figure 39) were screened, affording products in good to excellent yields. However, diene 62 failed

membered rings. Even the difficult homo-CM of allyl alcohol 54 was achieved with 10 mol % of Hoveyda−Grubbs second generation in acetone/water solution. Surprisingly, watersoluble substrates, such as 45 and 52, required high catalyst loadings of 10 and up to 40 mol %, respectively, to yield reasonable conversions. Notably, two substrates, 46 and 47, did not undergo metathesis whatsoever. In addition, RCM of 41 was readily achieved with Hoveyda−Grubbs second generation in a 3:2 DME/PBS (phosphate buffer saline) aqueous solution in the presence of ribonuclease A, opening a new window of possibilities for the incorporation of commercial catalysts for olefin metathesis reactions in biological systems (vide infra). Polshettiwar and Varma explored the reactivity of Grubbs second-generation catalyst in pure water, without any additional solvents or additives.173 A wide range of RCM substrates were examined at 45 °C with 4 mol % catalyst loading and provided moderate to excellent conversions in most cases (Figure 37).

Figure 39. Substrates for “emulsion” metathesis.

to form the desired 16-membered ring, a precursor to Exaltolide. CM reactions were also successfully carried out with other substrates (olefins 63−65 in Figure 39). For example, the self-metathesis of 65 provided good conversions; it was also possible to separate the product by simple decantation, obviating environmentally unfriendly extraction procedures. The preparation of ROMP (ring-opening metathesis polymerization) resins designed for solid-phase organic synthesis was investigated by Janda and co-workers.176 A variety of norbornene dimers 67−70 (Figure 40) were reacted with

Figure 37. RCM substrates.

Another interesting study, conducted by Grela and coworkers, examined metathesis reactions catalyzed by Grubbs second-generation catalyst and indenylidene catalyst Ru-2 (Figure 38) occurring inside emulsion drops.174 The general

Figure 40. Norbornene ROMP cross-linkers.

Scheme 30. Cross-Linked Polymer Synthesis in a Biphasic System Figure 38. Catalysts Ru-2 and Ru-3.

procedure was to ultrasonicate water-insoluble substrates and 5 mol % of catalysts on water at 40 °C for 5 h. Thus, the benchmark 175 RCM reaction of diethyl diallylmalonate (DEDAM, 48) was tested, affording quantitative conversions of RCM product with both catalysts. A control experiment was conducted in neat conditions in order to explore whether the reaction occurs inside the emulsions drops. The reaction (without sonication) produced 18% oligomeric ADMET (acyclic diene metathesis polymerization) products in addition to the RCM product. This somewhat different behavior supports the hypothesis that the reactions occur inside oily droplets of the substrate/product and shows that the surrounding water does play a role in the outcome of the reaction. To probe substrate scope, RCM of dienes 41, 48, 60,

norbornene 71 and norborn-2-ene-5-methanol 72 (Scheme 30) with Grubbs second generation. First, the ROMP monomers and cross-linkers were stirred in a biphasic system, 1,2dichloroethane (DCE) as the organic phase and water with surfactant (acacia gum) and NaCl as the aqueous phase. Then a colloidal suspension of the catalyst in methanol was added to the mixture and stirred for 3 h at 45 °C. ROMP cross-linked polymers were obtained in 33−80% yields. After further modifications, the polymers were used as solid supports for several reactions, such as electrophilic aromatic substitutions. Z


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In the attempt to explore processes for the production of novel biorenewable materials under environmentally bening conditions, Hoveyda−Grubbs second-generation catalyst was in employed for ADMET of jojoba oil.177 The two products of this oligomerization, hydrocarbons (mainly 9-octadecene) and polyesters are of great practical interest and could be obtained with high atom economy. During metathesis the hydrocarbon products were distilled out under reduced pressure to advance the ADMET reaction. Steam distillation was also attempted to remove the hydrocarbons without the need for extreme temperatures (up to 100 °C) and vacuum. Although the metathesis of jojoba oil progressed in neat water in the presence of 0.2 mol % of precatalyst, this method produced low conversions compared to the reaction in neat oil. In summary, commercially available NHC ruthenium alkylidenes in pure water can catalyze a wide scope of olefin metathesis reactions, highlighting the great functional group and environmental tolerance of this type of catalysts and the versatility of the many forms of the metathesis reactions. An attempt to improve the performance of the catalysts by the use of bulky NHC ligands, such as the one in NHC−Ru− indenylidene complex Ru-3 (Figure 38), failed to give good results with water as solvent.178 For example, RCM of diene 60 provided just 17% conversion in pure water, while in CH2Cl2, 97% conversion was achieved within 30 min. In 2011, Grubbs’ group synthesized the first example of a ruthenium complex in which the adamantyl substituent of the NHC ligand underwent C−H activation by the ruthenium metal center (Ru-4, Figure 41).179 Ru-4 was intended to sway

Figure 42. Catalysts and monomer used by Mingotaud for micellar ROMP.

acceleration in the case of catalyst Ru-6 may be explained by the probable exchange of perfluorocarboxylate groups with chloride ions, producing an active Hoveyda−Grubbs second generation that may reside within the micelle in the hydrophobic environment. The ROMP reaction in micellar solution of nondegassed water was also examined. Watersoluble norbornene derivative 75 and the poorly soluble parent norbonene (0.136−0.049 M) were screened with catalysts Ru-5 and Ru-6, producing excellent conversions. In addition, Mingotaud et al. studied the activity of Hoveyda−Grubbs second generation on ROMP reactions in micelles.182 The concentration of the catalyst was kept low in order to achieve miscibility of the catalyst in the micelle solution. Different measurements indicated that dodecyltrimethylammonium chloride (DTAC) or cetyltrimethylammonium chloride (CTAC) micelles were able to dissolve the hydrophobic catalyst well and provided excellent conversions for ROMP of 75. The molecular weights of the polymers were even closer to the expected theoretical values than those obtained in CH2Cl2 solution, suggesting a more controlled polymerization process inside the micelles. The work realized by Lipshutz and co-workers in metal catalysis in combination with micelles certainly deserves a special mention for its simplicity and efficiency. In order to advance olefin metathesis in water, Lipshutz et al. examined the contribution of surfactants 76−81 (Figure 43) for CM reactions catalyzed by Grubbs second generation in water.183 Thus, allylbenzene and tert-butyl acrylate were mixed in the presence of 2.5% (by weight) surfactants 76−81, 2 mol % of

Figure 41. Ru complex for Z-selective metathesis.

metathesis toward the highly desired Z product of crossmetathesis.180 Surprisingly, when tested in the cross-metathesis between Z-2-butene-1,4-diactetate 73 and allyl benzene 74 (Scheme 31) under different conditions, the equivalent addition of water to the THF mixture raised the conversion to 64% and raised the Z/E ratio to 7, thus improving selectivity. Scheme 31. Z-Selective Cross-Metathesis

Mingotaud et al. described two Grubbs catalyst analogues with long alkyl and perfluoroalkyl chains (Figure 42).181 Catalysts Ru-5 and Ru-6 are surface-active molecules, forming stable monolayers at the water−air interface (studied by Langmuir−Blodgett through methods and Brewster angle microscopy). Reactivity of the catalysts was examined by RCM reaction of DEDAM 48 at room temperature in D2O with the addition of DTAC (dodecyltrimethylammonium chloride). In the case of Ru-5 the conversions were disappointing; however, with Ru-6, 91% conversion was accomplished (TON of 186 and TOF of 0.9 min−1). The

Figure 43. Surfactants tested for metathesis catalysis in neat water. AA


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catalyst in neat water at room temperature. Surfactants 77−81 afforded results similar to the control reaction conducted without added surfactant (on-water reaction conditions), producing only reasonable yields. The results for PTS 76 however were quite noteworthy, providing 97% yield. Results obtained with Grubbs first generation were poor, indicating the importance of the NHC in the stabilization of the complex in this environment. The authors demonstrated that a solution of PTS and Grubbs second generation in water forms a stable colloidal suspension, and upon addition of various alkene reactants, products readily formed within hours. Furthermore, the system was able to catalyze the ring-opening/crossmetathesis of cyclohexene in the presence of tert-butyl acrylate or methyl vinyl ketone. The RCM of several dienes184 was also surveyed under the same conditions, producing 5-, 6-, and 7membered rings in high yields. Decreasing the PTS amount to a mere 0.8% did not compromise the 99% yield obtained in the RCM reactions of diallyl tosylamine 41 and mono- and disubstituted internal alkenes 82 (Figure 44). This system was

Scheme 33. CM of Type II Alkenes with OTBS-Protected 2Allylphenol

Figure 44. Diene substrates for micellar RCM.

Figure 45. Commercially available ruthenium catalysts used for micellar metathesis.

so efficient that it achieved quantitative yields in the synthesis of trisubstituted alkenes starting from 83 and 84, and even RCM of 85 produced 66% yield, a quite impressive result taking into consideration that RCM to form tetrasubstituted alkenes is extremely difficult and would give very low yields without the micellar system. A more thorough study on the effects of salt addition and pH influence on olefin metathesis reactions in PTS/water systems was recently published.185 Significantly, CM of sterically encumbered trisubstituted alkenes (of the isopropylidene type) as substrates with 3 mol % of Grubbs second generation in the presence of 2.5% PTS in water proceeded smoothly (see, for example, Scheme 32), and the addition of 3 M NaCl to the reaction media shortened the reaction time from 12 to 6 h. However, when using type II olefins186 as substrates, the addition of KHSO4 was found to be much more beneficial, raising the yield to 95% (Scheme 33). When the reaction was run in 95% ethanol (instead of water) in the presence of the same acid, the reaction was completely arrested. Many other NHC ruthenium catalysts (Figure 45) and substrates (Figure 46) were also studied in micellar conditions, giving very satisfactory results. Recycling studies on the PTS system were carried out for three reactions using 2 mol % of Grubbs second generation. All reactions showed good

Figure 46. Olefin substrates reacted by micellar olefin metathesis.

recyclability, and no significant decrease in yield was observed even after 8 cycles. In order to further examine possible applications for the acidic (0.02 M KHSO4) PTS/water system, CM of 86 and ethyl vinyl ketone was performed. This substrate is a good model for a key step in the synthesis of (+)-epicalyxin F.187 The CM step in the known synthesis of this substance yielded 42% and required harsh conditions of 20 mol % of catalyst in benzene at 60 °C for 24 h. The aqueous/micellar system afforded 75% yield within just 8 h at 22 °C and using only 4 mol % catalyst loadings. Finally, the addition of copper(I) salt (designed to remove the phosphane ligand) also proved beneficial in the PTS/water CM reaction of tetrazole and tert-butyl acrylate, significantly improving the yield from 55% to 80%. The commercially available Neolyst M2 initiator

Scheme 32. CM of TBS-Protected Citronellol with Ethyl or Butyl Acrylate

AB


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Figure 47. Cyclodextrin, salts, and calix[n]arene additives examined in aqueous metathesis.

(Figure 45) was also recently exploited by Slugovc and coworkers for the polymerization of dicyclopentadiene in water to produce a polyHIPE (high internal phase emulsion) material with important physical properties.188 In another type of compartamentalization study, Schatz and co-workers investigated the influence of soluble calix[n]arenes and imidazolium salts on metathesis reactions catalyzed by ruthenium in pure water (vide supra for a study of this ligand with palladium on Suzuki reaction).189 The RCM reaction of diene 41 with Grubbs second generation in CH3OH/H2O 1:1 solution (4 h, room temperature, 5 mol % of catalyst) gave low yields (36%), but in pure water, the conversion improved to 75%. The same reaction was examined in pure water in the presence of various additives 89−97 including a few calixarenes (Figure 47) at a stirring rate of 1000−1400 min−1 (a serendipitous discovery led to the finding that fast stirring promotes the reaction more efficiently). The best outcome was obtained by the addition of sulfonated calixarenes 93a−c, which provided 99% conversions. However, the self-metathesis of allyl alcohol 54 and RCM of water-soluble substrates 46, 98, and 99 (Figure 48) with the calixarenes failed to deliver satisfactory yields. Continuing with the exploration of surfactant catalysts (catsurfs), Grela and co-workers reported a ruthenium carboxylate complex with a long lipophilic chain and a polar headgroup Ru-7 (Figure 49).190 This catalyst was investigated

Figure 49. Surfactant catalyst Ru-7.

in metathesis reactions of insoluble substrates in pure water. In a general procedure, catalyst Ru-7 (2−5 mol %) was stirred in nondegassed distilled water for 1 h at 30 °C. Addition of substrates 41, 48, 60, and 100 (Figure 50) (0.2 M) provided

Figure 50. Olefin metathesis substrates.

excellent isolated yields (94−96%), and even the intricate diene 101 delivered 72% yield. CM reactions also provided good yields, albeit expectedly lower than those obtained by the RCM reactions. For example, olefins 102 and 103, each with 2 equiv of 67, provided a 9:1 E/Z ratio in 76% and 68% isolated yields of the cross-metathesis products, respectively. Other examples such as substrate 104 also afforded satisfactory results.

Figure 48. Water-soluble RCM substrates. AC


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Figure 51. PEG−NHC−Ru catalysts. 1

3.1.2. Ruthenium Complexes Bearing PEG-Containing Ligands. An important subclass of NHC−Ru alkylidenes bears poly(ethylene glycol) (PEG) groups in order to facilitate water solubility. Such catalysts were first reported by the Grubbs group in 2005 (Figure 51).191,192 The catalytic activity of Ru-8 was examined in ROMP reactions in water at 45 °C. HCl was added in order to facilitate the dissociation of the phosphane ligand and thus accelerate the reaction rate. The polymerization of the exo-norbornene monomer 105 provided 95% conversions in 15 min, and even for the hindered endo-monomer 106, the conversions were similar after 24 h (Figure 52).

H NMR was not observed in D2O, even though after extraction with methylene chloride the signal reappeared. The authors proposed a micelle-type arrangement in water due to the hydrophilic character of the PEG group and hydrophobicity of the ruthenium region to explain this phenomenon. Perhaps more important in the context of NHC catalysis in water is the fact that attempts to synthesize an active phosphane version of complex Ru-5 (Figure 42) failed. Another pegylated NHC−Ru complex, Ru-10 (Figure 51), in this case bound through the benzylidene moiety, was introduced by Zaman et al.193 Complex Ru-10, at 5 mol % loadings, was used in the benchmark RCM of DEDAM (48) in three different solvent mixtures: ethanol, methanol, or acetone combined with water in 2:1 ratios. The acetone/water system provided the best results (95% conversion in 16 h) and was chosen for further investigation. Several nitrogen-containing dienes were tested and provided moderate to excellent results in RCM reactions (Figure 53). It is important to point out that the pegylated benzylidene is a “throw-away” ligand in the precatalyst, and according to the accepted mechanism, it should not be attached to the catalyst after the first cycle.

Figure 52. Water-soluble metathesis substrates for catalysis.

Catalyst Ru-9, with a more strongly sigma-donating saturated NHC ligand, showed improved reactivity even without the addition of HCl. Another difference that arose from the use of different NHC ligands was that while catalyst Ru-8 failed in the RCM of α,ω-dienes and CM in water, catalyst Ru-9 provided excellent results. However, more difficult dienes, such as 107 and 46, gave substandard yields. The CM reaction in water with catalyst Ru-9 was also examined. Homodimerization of 54 and isomerization of 108 provided excellent conversions in aqueous media but also failed with other similar substrates derived from ammonium salts and carboxylic acids. A curious observation was that the distinctive benzylidene proton signal observed in

Figure 53. RCM conversions analyzed by 1H NMR after catalysis with Ru-10. AD


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Figure 54. Hoveyda−Grubbs-type catalyst supported to PEGA−NH2 resin.

facilitate catalysis in water by the formation of a stable colloidal suspension with the insoluble precatalyst. Precatalyst Ru-14 may be water- soluble, yet its amphiphilic benzylidene detaches from the ruthenium at the initiation step, leaving an identical propagating species to that of Grubbs second-generation complex and a free micellar-forming PQS-2 ligand. Thus, it is likely to assume that both catalytic systems are promoted by a similar mechanism. RCM of substrate 83 (Figure 44) could be repeated 8 successive times without dropping below 90% yield, just by using the aqueous phase containing remaining Ru-14 (starting from just 2 mol % of ruthenium). Recycling of Ru-14 in the cross-metathesis of 1-OTBS-10-undecene (OTBS = tertbutyldimethylsilyl ether) and tert-butyl acrylate was less efficient, dropping to 65% yield in the seventh cycle. 3.1.3. Solid-Supported Catalysts. The first work on olefin metathesis reactions in water catalyzed by an NHC− ruthenium complex was reported by Blechert’s group in 2002.199A substituted Grubbs-type catalyst was covalently linked to PEGA−NH2 resin (a hydrophilic solid support) to produce complex Ru-15 (Figure 54). RCM and CM reactions were carried out using 5 mol % of catalyst loading and exposed to air for 12 h. Two different α,ω-heptadienes were tested for RCM. Diallylammonium 45 provided only a small amount of product in water and moderate conversions in methanol; however, for insoluble 114 (Figure 55), the conversion in pure

In a variation of the fast initiating Grubbs third-generation catalyst194 (Figure 35) Emrick prepared complex Ru-11195 (Figure 51), bearing two pegylated pyridine ligands which enabled solubility and increased stability in water. The catalytic activity of complex Ru-11 was tested in the ROMP of watersoluble monomer 111 (Figure 52) in neat water and aqueous HCl solution (pH = 1.5). Under neutral conditions, complex Ru-11 failed to initiate; however, under acidic conditions, polymers could be obtained. Despite the successful polymerization in acid solution, the polymers obtained had molecular weights higher than the expected theoretical values as well as rather high PDI values (1.3−2.4). These results most likely indicate slow and incomplete initiation of the catalyst. Notably, the same initiator Ru-11 in methylene chloride afforded excellent results with a typical norbornene monomer. The separation of complex Ru-11 from excess PEG-pyridine ligands during its synthesis was quite convoluted; thus, Emrick and co-workers explored alternative pegylation methods in the synthesis of complex Ru-12 (Figure 51),196 synthesized by click methods.197 Complex Ru-12 was evaluated in aqueous ROMP of monomer 111 at different pH environments; pH = 1.5 gave quantitative conversion of the monomer, while ROMP at pH = 4 and 7 with monomer−catalyst ratios of 20:1 gave low conversions and low molecular weight polymers. As before, the efficiency at lower pH could be explained by labilization of the ligand by protonation. To avoid limiting ROMP to acid-stable monomers, copper salts were added to neutral solutions to bind the pyridine ligands. Addition of CuSO4 and CuBr2 at neutral pH raised polymer molecular weights and afforded conversions of 70%. The polymers obtained by this method were similar to those obtained at pH = 1.5. Complex Ru-13 (Figure 51), bearing a phosphoryl choline functionality instead of the PEG chain, was also put forth by the Emrick group. The motivation behind this study was its biological relevance, especially related to membrane and micelle formation. The catalyst was tested in the ROMP of monomer 111, and optimal results were obtained in the presence of CuSO4, producing polymers with Mw = 28 000 (g/mol) and PDI of 1.6 at a monomer−catalyst ratio of 50:1. Complex Ru-14 (Figure 51) is ligated by a PQS-2functionalized benzylidene.198 PQS-2 is comprised of three water-soluble moieties: reduced ubiquinol, sebacic acid, and polyethylene glycol 2000, thus bestowing the entire complex with enhanced aqueous solubility. The long lipophilic hydrocarbon of the ubiquinol also helps to solubilize organic substrates in the reaction media. RCM and CM promoted by Ru-14 in neat water under ambient conditions produced high yields of various products. The abilities of Ru-14 are comparable to those obtained by Grubbs second-generation complex in the presence of 76 (Figure 43). PTS is said to

Figure 55. Water-soluble metathesis substrates.

water was 96%. Several CM substrates were also investigated in pure water. While olefins 54 and 115 provided 79−83% conversions of the homodimer products, substrates 102 and 116 gave very low yields. In addition, α-C-glycoside 117 was also investigated; nonetheless, this case also provided almost no conversion in water. The main conclusion from this work was that the reaction actually proceeds not surrounded by the bulk water solvent but in the less polar region inside the pores of the resin; thus, the more hydrophobic substrates afforded much better conversions, whereas water-soluble substrates could not reach the catalytic active site and gave poor or insignificant yields. The respective activities of catalysts Ru-16 and Ru-17 in the cyclopolymerization of DEDPM (diethyl dipropargyl malonate) (Scheme 34) in aqueous media were tested in the presence of SDS (sodium dodecyl sulfate) or copolymer Me30Non6(PenOH)2Pip.200 The guiding notion was that catalysis would benefit from the micelles created by the AE


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the required catalytic cycles; lately this mechanism has been questioned by Plenio in Hoveyda−Grubbs systems204,205 and brought again to the limelight by the excellent work of Fogg et al.206 The water-soluble polymer contained on average three units of grafted isopropoxy−styrene ligand, yet only about onethird chelated the ruthenium complex. The unoccupied ligands presumably functioned as ruthenium alkylidene “fishhooks”, meant to promote the return of the ruthenium complex to the polymer. The catalytic activity of the system was assessed by RCM of DEDAM 48. When 1 mol % catalyst loading was tested in different solvents, water outperformed all other solvents (including CH2Cl2, the first-choice solvent for RCM reactions), providing 90% conversion within 1 h. This enhanced activity was explained once again by the micellar arrangement of the amphiphilic polymer. Loadings of just 0.1 mol % catalyst gave 39% conversion in 20 h and a TON of 390. In recycling experiments the system was used for five successive cycles, albeit with decreasing conversion in each cycle and apparent decomposition of the catalytic system. Another example where the powerful hydrophobic effect was used to induce efficient catalysis involves the occlusion of Grubbs second-generation catalyst on a PDMS (polydimethylsiloxane) matrix.207 In a sense this work can be compared with the efficient catalysis observed in the Lipshutz micellar studies, a nonpolar organic haven surrounded by the “narcissistic” water molecules. Exposing PDMS blocks to a concentrated CH2Cl2 solution of Grubbs second generation occluded catalyst molecules inside the PDMS; subsequent evaporation of the solvent provided a catalyst-loaded polymer. This catalyst− polymer hybrid was used to catalyze RCM and CM reactions of various metathesis substrates in aqueous mixtures to give good isolated yields. The hydrophobicity of the PDMS−Grubbs blocks allowed selective RCM reactions of 118 and 119 performed at different pH solutions (Scheme 35). An acidic environment in the first experiment prevented the formation of the ionic form of 118; thus, both substrates reacted as expected; however, when the pH was changed to basic, substrate 118 was deprotonated and did not infiltrate the hydrophobic blocks, promoting the RCM of 119 exclusively. For some substrates it was found that the PDMS−Grubbs second-generation catalytic blocks catalyzed isomerization rather than cross-metathesis in hot aqueous methanol.208 Notably, when using the free Grubbs second-generation catalyst in CH2Cl2, the homo-CM reaction was preferred. Naturally, in order for the Grubbs second-generation catalyst to catalyze isomerization, it must first generate a hydrido species,209 quite plausible in the presence of methanol,

Scheme 34. Cyclopolymerization of DEDPM by NHC−Ru Complex Bearing a Trifluoro Acetic Acid Group

surfactant. However, initial experiments produced only short oligomeric precipitates instead of the desired polymer products. In order to solve this problem, the catalyst was covalently linked to a polymer support in order to perform the aqueous cyclopolymerization. This strategy was meant to keep the catalytic site within the hydrophobic interior of the micelles, where the concentration of substrates should be higher. Indeed, cyclopolymerization of DEDPM by ruthenium-bound polymers Ru-18 and Ru-19 (Figure 56) in water outperformed free

Figure 56. NHC−Ru-supported complex.

complexes Ru-16−17 in CH2Cl2 and reduced the reaction time from 2 h to merely 30 min, producing well-defined polymers without compromising the molecular weights and PDIs of the products. Due to the efficient characteristics of this system, the authors fondly referred to the micelles formed as “nanoreactors”. Citing the “boomerang” effect,201,202 Weberskirch and coworkers linked a ruthenium catalyst to a macroligand polymer through the benzylidene moiety Ru-20 (Figure 57).203 The release/return mechanism is expressed by the return of the benzylidene ligand to the catalytic ruthenium after performing

Figure 57. Hoveyda−Grubbs second-generation-type catalyst bound to an amphiphilic block copolymer. AF


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Scheme 35. pH Dependency of RCM Reactions Catalyzed by PDMS−Ru Catalysts

Figure 59. RCM and CM substrates catalyzed by complexes Ru-21.

counterion in the catalyst activity. Surprisingly, catalysts Ru21a and Ru-21c provided very low to moderate conversions, indicating the counterion has a significant influence on the precatalyst. An additional Hoveyda−Grubbs-type catalyst with an electron-withdrawing pyridinium group Ru-22 is shown in Figure 60.214 The ionic tag improved the catalytic activity,

revealing yet another potential use for NHC−Ru catalysts in aqueous environments. 3.1.4. Ruthenium Catalysts with Ammonium Tags. A quaternary ammonium-tagged catalyst (Ru-21a, Figure 58) was

Figure 60. Pyridinium-functionalized Ru catalysts.

enhanced solubility of the complex in polar solvent systems, including water, and allowed easier separation of products from ruthenium impurities. RCM reactions of 41 and 42 provided low conversions in a water/ethanol 2:5 mixture. However, enyne cyclomerization of 66 delivered full conversion in the same solvent system in just 30 min. Additionally, the product after purification contained only 28 ppm contamination of ruthenium. RCM of 41 in the same solvent system with catalyst Ru-23 (Figure 60)215 provided acceptable conversions, an improvement over catalyst Ru-21. CM of olefin 54 was investigated in pure water and catalysts Ru-23 and Ru-22 as well as Grubbs second generation, Hoveyda−Grubbs second generation, and Grela−Hoveyda−Grubbs second generation all presented no conversion. Addition of NH4Cl to the reaction with Ru-23 (to promote anion exchange) somewhat improved conversions. In any case, catalysts Ru-21 and PEG-functionalized Ru-9192 (Figure 51) gave the best results for this reaction. In 2007, Grubbs examined the activity of catalysts Ru-24 and Ru-25 (Figure 61) in ROMP, RCM, and CM reactions in aqueous surroundings.216 Catalyst Ru-25 was soluble in water, while catalyst Ru-24 was found to be only slightly soluble. The performance of catalysts Ru-24 and Ru-25 in ROMP of endomonomer 106 in water provided good polymer yields, similar to PEG-functionalized Ru-9. RCM reactions of dienes 45, 46, 107, 109, and 110 afforded dissimilar results. For dienes 109 and 110 the conversions were excellent; for substrate 45, catalyst Ru-24 presented excellent conversion while catalyst Ru-25 provided significant amounts of the cycloisomerization product. In the case of diene 107 the conversions were poor, and with 46, no RCM product was observed. Both Ru-24 and Ru-25 displayed poor to slightly moderate performance with

Figure 58. Quaternary ammonium complexes Ru-21.

synthesized and explored by Grela and co-workers.210,211 The ammonium group plays a double role; on one hand, it acts as an electron-withdrawing group that was shown to provide enhanced catalyst initiation; on the other hand, it also raises the aqueous solubility of the complex. As an added benefit, the charged group increases the catalyst’s affinity to silica gel, thus facilitating its separation from reaction products. Catalyst Ru21a was tested with several substrates with catalyst loadings of 5 mol % in solvent mixtures of methanol or ethanol with water or in pure water. For example, the RCM of diene 42 provided 99% conversion in a methanol−water 5:2 solvent mixture in 30 min. In the case of diene 41 in a homogeneous 5:2 ethanol− water mixture, an 83% conversion was obtained; however, in pure water (a heterogeneous mixture) the conversion was raised to 99% in 1 h. This phenomenon was observed also with dienes 109, 50, and 120 (Figure 59) in pure water and contributed to excellent conversions. The on-water effect was evident also in CM of olefin 65. In the homogeneous 5:2 methanol−water experiment, no CM was observed; however, when the ratio was changed to 2:5, a heterogeneous mixture was obtained and practically quantitative conversions were obtained. In addition, homo-CM of allyl alcohol 54 was examined with a variety of catalysts. No reaction was observed with various Grubbs second-generation catalysts (Figure 35);212,213 however, with catalyst Ru-21a excellent conversions were obtained. Catalysts Ru-21b and Ru-21c were also investigated in order to explore the significance of the AG


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that was completely unreactive under the conditions used. Moreover, executing the reactions in buffer solutions, like MES/HEPES, reduced catalytic efficiency. Importantly, the addition of KNO3 to pure water provided conversions similar to the ones in pure water, supporting the assumption that the chloride anions stabilize the catalytic species. In addition, a UV−vis study showed enhanced stability of Ru-25 in aqueous media in the presence of KCl. Protonation of the amino functional groups in complexes Ru-26 and Ru-27 (Scheme 36)225 by Brønsted acids should naturally increase their water solubility. Furthermore, it allows for exquisite control and fine tuning of the reaction’s mechanism by simple pH dependency. Protonation of complex Ru-26 by DCl addition led to dissociation of the phosphine ligand, creating a complex mixture of ruthenium complexes but not Ru-26′. On the other hand, phosphane-free complex Ru-27 was smoothly converted into its ammonium salt Ru-27′. Nonetheless, both complexes failed in the attempted ROMP of cationic exo-7-oxanorbornene 128 (Figure 63) and the RCM of

Figure 61. Ammonium-tagged catalysts Ru-24 and Ru-25.

the more challenging CM reactions. These disparate results evidently reveal that whenever possible tailoring a specific NHC catalyst for a specific reaction is the most appropriate approach for olefin metathesis in water. In general, we can see that as is prevalent in organic solvents, the tuning of the ruthenium alkylidenes for specific metathesis reactions is of utmost importance to achieve optimal results.217 In ruthenium metathesis complexes the importance of the chloride ligands has been widely recognized.218−220 Thus, one of the reasons for deactivation of metathesis catalysts in water or other protic solvents may be due to dissociation of these ligands.221−223 Supporting this, Grubbs showed (vide supra) that addition of hydrochloric acid improved catalytic activity in water.216 In order to avoid the use of acid, Matsuo et al. explored the effect of KCl salt on the catalytic activity of watersoluble complex Ru-25 (Figure 61).224 Ring-closing metathesis of dienes 45, 46, 110, and 127 (Figure 62) was examined in

Figure 63. Substrate for ROMP in acidic aqueous media.

DAM 118 (Scheme 35) at 50 °C and 4 mol % catalyst loading. It was suggested that the reversal in the electronic character of the NHC substituent from amino (EDG) to ammonium (EWG) could be one of the reasons for the unsatisfactory results. Raines and co-workers226 improved the synthesis of known catalysts Ru-28a-b227 and designed water-soluble Ru-28c (Figure 64) based upon the two former complexes. Ru-28c displayed surprisingly high tolerance toward water and air, unlike other complexes bearing cationic moieties. According to NMR analysis, 40% of the complex was still intact in a CD3OD:D2O 3:1 mixture for 2 days open to air. The activity of complex Ru-28c in RCM of various dienes was tested in different solvents and conditions. The complex showed reduced activity in nonpolar solvents, e.g., 40 h of reaction in benzene was needed to obtain good results. In contrast, the activity of Ru-28b and Ru-28c was shown to increase when reactions

Figure 62. RCM substrates for aqueous metathesis with Ru-25.

pure water, buffer, and KCl solutions. Due to a large difference in the substrate concentration, the results obtained in pure water do not coincide with the results previously reported by Grubbs (Grubbs 200 mM vs Matsuo 8.4 mM). In any case, the addition of KCl to the reaction mixture improved the activity of all reactions, with the exception of RCM of reluctant diene 46

Scheme 36. Dimethylamino-Substituted NHC−Ru Complexes and Their Protonated Derivatives

AH


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Figure 66. Substrate for enyne metathesis.

3.1.5. Metathesis in Biological Systems. The development of the olefin metathesis reaction for chemical modifications in protein scaffolds is quickly becoming a goal of interest for biological chemistry. Without a doubt, the progress of NHC-based catalysts in water alongside its tolerance to many functional groups has much to contribute to this relatively new field.230 Davis and co-workers investigated the reactivity of Hoveyda−Grubbs second-generation catalyst in CM reactions of amino acid derivatives and allyl alcohol as a model for site-selective bioorthogonal protein modifications (Scheme 37).231 No reaction was observed with homoallyl glycine derivative 130. On the other hand, cysteine derivatives 131−132 and 133a provided cross-products in isolated yields of 56−68%. However, when the length between the alkene and the sulfur atom was expanded (133b-c), no CM product was detected, possibly due to sulfur chelating to the ruthenium center (creating five/six-membered rings with the ruthenium).232−235 Supporting these results, substrates 134a-b also showed similar behavior. Allyl sulfide 134b afforded 52% isolated yield of the CM product, while the others substrates did not react. In the series provided by 135−137 the allyl sulfide (135) was the most successful and thus used for incorporation into proteins. Allyl sulfide-modified protein SBL156Sac was reacted with allyl alcohols 54 and 138−141 in aqueous tBuOH with Hoveyda−Grubbs second-generation catalyst (Figure 67). A significantly enhanced reactivity was found by adding MgCl2, probably due to the documented ability of the Mg ion to prevent binding of certain amino acids to the ruthenium center. Other allyl alcohols 138−141 were reacted with the same protein under the same conditions (excess MgCl2, excess allyl substrate, 37 °C, 30% tBuOH in water, pH = 8) and provided 50−60% conversions of CM products hinting at the scope of the reaction. Importantly, his method allows for post-translational modifications of proteins by olefin metathesis using commercially available NHC-based catalysts.230 The synthesis and study of Ru-4 (vide supra) eventually led to a series of nitrato cyclometalated ruthenium complexes, among them are Ru-33−34 (Figure 68).236 This type of

Figure 64. Ruthenium complexes Ru-28.

were conducted in a polar solvent like methanol. When 5 or 10 mol % of Ru-28c was evaluated in a CD3OD/D2O 2:1 mixture, RCM of 45 and 53 afforded outstanding results, over 95% conversion. For 45 this was the highest reported conversion in aqueous solutions, even compared to the robust PEG Grubbs catalyst Ru-9 (Figure 51).192 Complex Ru-28c was also able to promote the RCM of reluctant substrate 46. Furthermore, enyne RCM of substrate 66 in CD3OD/D2O 5:2 mixture with 10 mol % catalyst loading provided over 95% conversion within 6 h, similar to the result obtained by Grela et al. with catalyst Ru-21a (Figure 58).210 More recently, four additional quaternary ammonium chloride complexes Ru-29-32 were synthesized and their olefin metathesis catalytic activity examined in pure water (Figure 65).228,229 Complexes Ru-29, Ru-30, and Ru-32 showed limited solubility in water (2−3 mg/mL), while complex Ru31 with two ammonium chloride groups was quite water soluble (35 mg/mL). The isomerization of olefin (Z)-108 to (E)-108 (Figure 52) in deuterated water was achieved with catalyst Ru-30 in moderate conversion; however, catalysts Ru29, Ru-31, and Ru-32 gave 94% conversions. CM of alcohol 54 (Figure 36) with catalyst Ru-31 provided very low conversions and an E/Z ratio of 12.5:1, and with complexes Ru-29 and Ru30 the conversions improved and reached a 16.7:1 E/Z ratio. RCM reaction of diene 109 (Figure 52) with catalyst Ru-29 was unsatsisfactory, but using Ru-31, Ru-30, or Ru-32 as catalysts the conversions were raised to 88%, 96%, and 99%, respectively. Enyne metathesis of substrate 129 (Figure 66) with Ru-29, Ru-30, and Ru-31 catalysts produced low to moderate conversions. Additionally, after RCM reaction of 48 (DEDAM) with catalyst Ru-31, water was added to the mixture and the leftover ruthenium catalyst migrated to the water phase in just one wash. To prove that the catalyst was still active, olefin (Z)-108 was added to this aqueous phase and after 1 h 94% yield of the (E)-isomer was obtained.

Figure 65. Ruthenium complexes bearing positively charged nitrogen atoms. AI


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Scheme 37. Cross-Metathesis of Different Substrates with Allyl Alcohol

heteroatom-containing amino acids giving the better yields. The use of either aqueous solvent or salt addition was not advantageous, contrary to the results obtained using the Hoveyda−Grubbs second-generation catalyst.231 This inhibiting effect emphasizes the inherent differences found for different catalysts, in this case, chelated vs nonchelated ruthenium complexes. A creative approach to Ru−NHC-based olefin metathesis in water has been the incorporation of protein scaffolds to the catalytic site. Enzymes are without a doubt nature’s catalytic masters with massive TONs and substrate specificity, enticing chemists to try to emulate their efficiency. Three examples of metalloenzymes incorporating a Ru−NHC moiety were recently presented. Complex Ru-35 (Figure 69), developed by the Hilvert group,238 was linked to the M. jannaschii small heat shock protein 16.5 (MjHSP)239 through a covalent bond formed by a bromoacetamide linker and the protein’s single cysteine moiety. MjHSP was chosen for its robustness and its 3 nm pores, which enable the entry of small molecules from the solution media into the protein’s inner layers. The novel metalloprotein complex was tested in an RCM reaction of diallyl tosylamine 41, with 4% catalyst loading at 45 °C in aqueous solutions and compared to the activity of free complex Ru-35, with 2% catalyst loading and 20% added tert-butanol. Poor results were obtained at neutral pH; however, when the reactions were run at low pH, the TONs of both ruthenium complexes were slightly increased. Thus, at this time, it seems that the main role of the enzyme in this study is to impart water solubility to the catalytic ruthenium. In a similar approach Ward and co-workers chose to use modified Hoveyda−Grubbs second-generation complex (Biot1 and Biot-m-ABA, Figure 69) and tethered it to streptavidin and its genetically optimized version avidin.240 Biot-1 ring closed 41 in 74% conversion; however, conversions dropped when streptavidin was added. The authors explained this result by the inhibition of the catalyst due to the numerous functional groups present on the protein. Activity of complexes in the presence of streptavidin could be improved by lowering the pH to 4.0 and addition of 0.5 M MgCl2. The catalytic performance was also tested in the presence of avidin. Once again,

Figure 67. Cross-metathesis partners for a protein allyl−sulfide substrate.

Figure 68. Adamantyl-chelated NHC−Ru complexes for Z-selective metathesis.

complexes displayed high selectivity toward the usually less favorable Z product by preferential substrate coordination trans to the adamantyl ligand. The geometry of double bonds in peptides and peptidomimetics is an important structural motif vital for the correct folding of the protein; thus, stereoselectivity is highly desired. In 2014, the Z-selective Ru-33−34 were used to probe reactivity in peptides.237 As a model reaction, homodimerization of modified Boc-protected alanine with homoallyl end groups was probed under different conditions. In all solvents tested, all of which are commonly used in peptide synthesis, the Z selectivity was high; however, yields were somewhat low. Homocoupling of modified amino acids containing heteroatoms (serine and cysteine) in THF produced higher yields than the aliphatic modified substrates (allylglycine and homoallylglycine), implying participation of the heteroatom in the metathesis cycle. Cross-metathesis of these 4 amino acids with allyl acetate promoted by Ru-33−34 was probed also under conditions more compatible to peptide synthesis using tBuOH/H2O 1:1 with or without added LiCl or MgCl2 (as previously mentioned, known beneficial additives for metathesis in proteins). Not surprinsingly, the results showed the same trends as the homocoupling experiments, with the AJ


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in the absence of α-chymotrypsin. The RCM trials with substrates 41, 45, and 127 did not afford very impressive results, reaching a maximum of 20 turnovers for the RCM of 127. Nonetheless, this is an important starting point for the development of unnatural metalloenzymes with the help of NHC ligands. In addition to the obvious advantages of developing biologically compatible organometallic complexes, these systems may also promote stereoselective catalysis by taking advantage of the protein’s chiral environment. Certainly, this area will see further growth and progress in future studies. To summarize the metathesis section, it can certainly be observed that the huge success of ruthenium olefin metathesis and its documented relative stability toward water has attracted many groups to invent new methods and new catalysts for olefin metathesis in water. Different applications and different substrates required design and optimization of new catalysts able to rise to the diverse challenges. Undoubtedly, the development of aqueous olefin metathesis will continue to occupy many journal pages in the years to come. 3.2. Miscellaneous Reactions

3.2.1. Cyclization. Complex Ru-37 (Scheme 38) bearing ammonium chloride substituents is water soluble and could be

Figure 69. NHC−Ru metathesis metalloenzyme precursors.

Scheme 38. Intramolecular Cyclization of cis-3-Methylpent2-en-4-yn-1-ol

conversions could be significantly improved by the addition of 0.5 M MgCl2 and lowering the pH to 4.0. Under these conditions Biot-1 gave 95% conversion with or without the presence of avidin. As in the previous example, the role of the protein is not quite defined here, other than enhancing water solubility. The structure of Ru-36 (Figure 69) was designed by Matsuo et al. to fit into the catalytic pocket of α-chymotrypsin.241 αChymotrypsin is a serine protease recognizing the residues of hydrophobic amino acids, thus possessing the ability to incorporate organic molecules of this type. Covalent association of the Hoveyda−Grubbs second generation through the NHCs handle to the catalytic pocket was carried out by linking the ruthenium catalyst to an L-phenylalanyl choloromethylketone terminus. The L-phenylalanyl choloromethylketone is a known inhibitor of α-chymotrypsin and was expected to guide the organometallic catalyst to the hydrophobic pocket of the enzyme. A subsequent nucleophilic attack by His57 (part of the hydrolase catalytic triad) ensures the covalent insertion of Ru36 into the pocket. This careful planning placed the ruthenium catalytic center in the natural position for catalytic activity, supposedly allowing facile diffusion of metathesis substrates and products from and to the solvent surrounding. Other than characterization by CD, UV−vis, ES-MS, and MALDI-TOFMS, an elegant control experiment was designed to verify the covalent association of Ru-36 to the protein. The hydrolysis of N-succinyl-L-Phe-p-nitroanilide (a standard protease substrate) by α-chymotrypsin was evaluated in the presence of Ru-36, an epimer of Ru-36 bearing D-phenylalanine and without additives. Indeed, the activity of α-chymotrypsin was inhibited only in the presence of Ru-36, suggesting that the original catalytic pocket of the protein was now occupied by the Hoveyda−Grubbs second-generation catalyst, and thus, hydrolysis could not proceed. The catalytic activity of the new system was tested on RCM of substrates 41 (Figure 36) and 45 and 127 (Figure 62) in 100 mM KCl solution and compared to the activity of Ru-36

utilized to catalyze the cyclization of cis-3-methylpent-2-en-4yn-1-ol under biphasic conditions (water:toluene 1:1) as indicated.242 This expedient catalyst was readily reused and promoted the formation of 2,3-dimethylfuran in five consecutive cycles without decrease in conversion. 3.2.2. Hydrogenation. An in-depth study on the fate of complex Ru-38 in aqueous solution and its catalytic activity was performed by the Joó group (Scheme 39).243 When dissolved in pure water, complex Ru-38 was found to exist in equilibrium with two hydrated ruthenium species, monohydrate Ru-39a and dihydrate Ru-39b. Upon addition of 0.1 M KCl solution, Ru-39a became the main species. Furthermore, raising the pH tilted the scale toward hydroxo complexes Ru-40a and Ru-40b depending on the amount of base added. Phosphine 1,3,5triaza-7-phosphaadamantane may also promote ligand exchange when mixed with Ru-38, generating two new complexes in water: Ru-41 and Ru-42 (Scheme 39). Complexes Ru-38 and Ru-41 were tested for hydrogenation reactions of various substrates (cinnamaldehyde, benzylideneacetone, acetone, acetophenone, propanal, allyl alcohol, 4-styrenesulfonic acid Na salt) under 10 bar of H2 in phosphate buffer. Both complexes competently catalyzed the hydrogenation of ketones, unprecedented with phosphane complexes. Additionally, both complexes could chemoselectively catalyze the carbon−carbon double-bond hydrogenation of cinnamaldehyde and benzylideneacetone. Continuing with this study, an immobilized Ru-38/ AK


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Scheme 39. Water-Soluble Ru−NHC Complex and Its Water-Ligated Derivatives

Figure 70. Catalysts for hydrogenation of acetophenone.

Al2O3 system was also examined.244 This heterogenized system was able to catalyze hydrogenation of olefins and ketones, yet with lower activity compared to homogeneous Ru-38. The hydrogenation of styrene to ethylbenzene was tested with water-soluble Ru-43 by Dyson and co-workers.245 The reaction was carried out in a 1:2 ratio of water:cyclohexane and gave low conversions, although it was able to keep its activity for three runs. Kühn and co-workers also recently developed a series of metal−NHC complexes, Ru-44−46, designed to catalyze hydrogenations (Figure 70).246 The sulfonated-NHC ligands designed successfully coordinated three different metals, ruthenium, rhodium, and iridium, affording complexes that produced good to excellent yields in the hydrogenation of acetophenone in water under a hydrogen atmosphere. 3.2.3. Isomerization of Allylic Alcohols. Ru-38 (Scheme 39) was also shown to competently catalyze isomerization of allylic alcohols 142 and 143 (Scheme 40). Due to the dynamic behavior of Ru-38, the isomerization was tested as a function of pH and chloride concentration.247 Reactions were conducted in salted aqueous phosphate buffers (pH = 6.10, 6.90, 7.50, 8.20) under 1 bar of H2 at 80 °C. Optimal results (isomerization of the double bond and production of the carbonyl compound) were obtained around pH = 7 and 0.2 M NaCl. The catalyst was shown to catalyze four additional cycles without significant loss of activity.

Scheme 40. Catalytic Redox Isomerization and Hydrogenation of Allyl Alcohols

Chiral complex Ru-47 (Figure 71) also catalyzed the isomerization of allylic alcohols to carbonyl compounds.248 The catalyst (0.2 mol %) was dissolved in H2O with 3 equiv of AgOTf as halide scavenger, activating the catalyst and improving its solubility in water. Under these conditions, Ru47 afforded excellent yields in the isomerization of allylic alcohols 142b−e; yet, for allylic alcohol 144 (a nonterminal alkene) (Scheme 40), poor results were obtained. Other NHC-based water-soluble catalysts for isomerization of allyl acohols were studied in the Peris group.249 Complexes AL


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hence, slight background corrections to the TONs obtained had to be made. 3.2.5. Atom Transfer Radical Polymerization. Ruthenium complexes Ru-54−56 (Figure 74) and Ru-28a-b (Figure

Figure 71. Chiral Cp-NHC-ligated Ru complex.

Ru-48 and Ru-49 (Figure 72) bearing a sulfonate-functionalized NHC ligand were prepared. The polar complexes were

Figure 74. Ru−alkylidene ATRP catalysts bearing Schiff base ligands.

64) are chelated by both oxygen and nitrogen atoms and are also active in metathesis reactions (vide supra).227,252 In these complexes, the Ru−N bond supposedly dissociates first to create an empty coordination site. Many metathesis complexes are known to catalyze also other types of reactions;253 thus, these complexes were tested for atom transfer radical polymerization (ATRP) of acrylates and methacrylates (Scheme 41) under different conditions, including with

Figure 72. Sulfonated NHC−Ru complexes.

insoluble in organic solvents, while their solubility in water was measured to be a whopping >300 g/L. Catalysis was tested in neat water with 0.2 mol % catalysts loadings at 100 °C. Complex Ru-50 as well as [RuCl2(p-cymene)]2 and RuCl3·H2O were used in control reactions. Complex Ru-48 provided the best results, with over 98% conversions for allylic alcohols 142a and 142c−e. Ru-49 could only isomerize the less reluctant parent allyl alcohol (142a), presumably because the decoordination of the arene ligand is easier with p-cymene than with hexamethylbenzene.250 The requirement for the NHC ligand was highlighted by the fact that no conversion was observed with RuCl3. In addition, complex Ru-48 could be easily separated from the reaction mixture by extraction of the products. For the allylic isomerization of 142e and 142d with 1 mol % catalysts loading in neat water at 100 °C, complex Ru-48 was successfully used for 8 cycles. 3.2.4. Carbon Dioxide Reduction. In a world where global warming due to CO2 emissions is a challenge that we must confront, reactions that can capture CO2 and transform it into usable materials or fuels (CO2 cycle) are highly desirable. Complexes Ru-51−53 were prepared to test their activity in the catalytic reduction of CO2 to formate (Figure 73).251 Ru-51

Scheme 41. ATRP Catalyzed by Ru-54−56 and Ru-28a-b

addition of AgBF4 in a toluene/water (1:1) biphase. The AgBF4 salt was added to remove the chloride ligand and create a cationic 14-electron complex (potentially more reactive). Of interest for the topic of this review, better conversions and higher Mw values were obtained with the cationic form in the water mixture. Notably, while water had a positive effect on the activity of Ru-54a−d and Ru-28a-b, their phosphine analogues displayed the opposite effect.254 Complexes Ru-55 and Ru-56 were evaluated in the ATRP of methyl methacrylate. Both produced better results, i.e., higher conversions (>95%) and lower PDI values (5 possess wider N−C−N angles that bring the N-substituents closer to the metal center, effectively creating a catalytic environment with increased steric tension. The effect of this geometric constrain was tested by an NHC−Au(I)Cl bearing a seven-membered N,N′-diamidocarbene ligand Au-22 (Figure 82) prepared by Bielawski and coworkers.276 The novel ligand used for this complex provided enhanced electron-donating abilities, which probably arise from the wider N−C−N angle. Nonetheless, the reactivity was quite typical, affording 36% yield in 3 h and 78% after 12 h for the hydration of phenylacetylene using 2 mol % of Au-22 in MeOH/H2O 1:1 at 80 °C. Complexes Au-23−24 were also tested in alkyne hydration reactions to assess the effect of the larger rings on catalysis.277 Hydration of phenylacetylene and diphenylacetylene in 1,4dioxane/H2O 2:1 at 80 °C and 0.1 mol % catalyst loading and

44). Complexes Au-15a−e were tested in the hydration of terminal alkynes using 2 mol % catalyst loading in MeOH/H2O 1:1 ratio. Au-15c and Au-15e proved to be the most efficient, with 92% and 94% yields, respectively, for the hydration of phenylacetylene; however, reactions in neat water afforded low conversions (just 17% conversion after 3 h in refluxing water). Generating a more electrophilic cationic gold species by removing the anionic ligand can improve catalysis, and this could be achieved by the introduction of cocatalysts H2SO4 and AgOTf. In the hydration of phenylacetylene promoted by 2 mol % of Au-15a in MeOH/H2O 5:1 it was observed that the addition of 10 mol % of H2SO4 significantly increased the reaction rate. Lowering Au-15a loading to 0.1 mol % and increasing the reaction time to 48 h in the presence of 10 mol % of H2SO4 afforded 93.5% yield (TOF 19.5 h−1, TON ≈ 900). Terminal alkynes bearing electron-donating substituents such as 1-hexyne and 4-ethynylanisole gave low conversions (around 50% with 2 mol % of catalyst). Curiously, the addition of AgBF4 or AgOTf significantly hindered reaction progress, probably leading to decomposition of the resulting cationic complexes (some evidence for the formation of purple gold particles after adding silver was obtained). The study of sulfonated NHC−Au(I) complexes was expanded to the hydration of terminal alkynes also with complexes Au-17−18 (Figure 81).274 Although these catalysts were able to promote the reaction of water-soluble propargyl

Figure 81. Sulfonated NHC−Au(I) and their analogue complexes. AQ


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gold complexes bearing atypical and abnormal NHCs demonstrate that catalysis utilizing these complexes is possible and certainly opens a window for further research in this area. 4.1.4. NHC−Au(III)X3 Complexes. Given the rich catalytic chemistry of inorganic gold(III), Nolan and co-workers targeted NHC−Au(III)X3 complexes, and synthesized Au30−33 (Figure 84) starting from their NHC−Au(I)Br precursors.280 While the NHC−Au(I)Br complexes decomposed to colloidal gold(0) upon water addition, the NHC− Au(III)Br3 complexes were stable to air and water. Hydration of phenylacetylene was examined with 10 mol % of Au(III) catalyst loadings in a 1:1 MeOH/H2O mixture. Complex Au-30 provided the best results, 95% conversion in 24 h under optimal conditions. When conducting the reaction with 10 mol % catalyst loadings in 1:1 solvent/water mixtures, MeOH was by far the preferred choice, yielding better results than neat water and other polar solvent mixtures. It is important to highlight that no enol ether or acetal was observed, i.e., MeOH does not seem to be actively participating in the reaction mechanism and only aids in solvation of the substrate. The addition of 1 equiv of AgPF6 as a cocatalyst enabled the reduction of catalyst loading (2 mol %) and reaction time (from 24 to 1 h) and afforded quantitative yields. The scope of the reaction (Scheme 45) was examined under the optimal conditions, yielding satisfactory results for all terminal alkynes (except for 1,1-diphenyl-prop-2-yn-1-ol). However, no product was obtained for the internal alkynes tested, even at higher catalyst loadings of 20 mol %. The NHC−Au(III)Br3 (Figure 84) complexes were the first of their kind to be reported, and the enhanced catalytic abilities of Au-30 promoted further gold catalysts development. Having said this, it is important to note that a control reaction of the hydration of phenylacetylene performed with AuCl3 produced a 94% yield of benzaldehyde, challenging the requirement of the NHC ligand in this case.

Figure 82. Au(I) complex bearing six- and seven-membered NHCs.

AgBF4 was not successful, even after 17 h of reaction, a surprising result when compared to the observed reactivity of Au-22 under similar conditions. Hydration of aliphatic alkynes was more successful, and here a small difference could be observed with the most sterically hindered complex Au-24b that gave slightly lower yields, in contrast to Nolan’s observation where diisopropylphenyl substituents on the NHC gave better yields than mesityl substituents.263 Hydration of 2-hexyne also did not afford any significant regiochemical preference with the different complexes. Abnormal NHC ligands, where the C5 of the imidazole ring is bound to the metal center (instead of the classic C2 carbene), are said to possess more efficient σ donation, increasing the stability of the complex and improving its catalytic abilities on the one hand. On the other they are somewhat less stable than “normal” NHCs; thus, it was of interest to probe their abilities in aqueous surroundings.11,12 Complexes Au-25−26278 (Figure 83) were tested as catalysts for the hydration of phenylacetylene with silver salts and varying amounts of water. Optimal results were obtained using 5 mol % of Au-25 in the presence of 5 mol % of AgSbF6 and 4 equiv of water. In order to determine the contribution of the abnormal NHC ligand, the catalytic efficiency was compared to NHC complexes Au-27− 28 (Figure 83). Hydration of phenylacetylene in the presence of 5 mol % of gold catalyst and AgSbF6 in MeOH and 4 equiv of water showed that the abnormal NHC−Au complexes were outperformed by the standard NHC−Au complexes Au-27− 28. Contrary to expectations, single-crystal X-ray analysis and DFT calculations of complexes Au-25−26 showed longer Au− carbene bond lengths than those in Au-27−28. Thus, this study concluded that traditional NHCs are more efficient as promoters in gold-catalyzed hydration of phenylacetylene than abnormal NHCs. Another abnormal NHC gold complex probed for alkyne hydration was complex Au-29, highly stable at ambient conditions (Figure 83).279 Hydration of 1-phenylpropargyl ester catalyzed by 3 mol % of Au-29/AgSbF4 was found to proceed best in a solvent mixture of CH3CN/H2O 40:1, affording the product in 95% yield. The scope of the reaction was probed using a variety of propargyl esters, all giving good to excellent results (83−99%), including demanding substrates bearing electron-withdrawing groups. The above examples of

4.2. Nitrile Hydration

In 2009, Nolan added the hydration of nitriles to afford amides (Scheme 46) to the repertoire of hydration reactions catalyzed by gold complexes.281 The scope of the reaction was investigated under optimized conditions (determined using benzonitrile as substrate), 2 mol % of complex Au-34 (Figure 85), THF/H2O 1:1 mixture, and 140 °C microwave heating for 2 h. The study surveyed a wide variety of nitriles, starting with functionalized benzonitriles and moving to heteroaromatic and aliphatic nitriles. Electron-poor benzonitriles showed good to excellent results, yet electron-rich benzonitriles gave lower yields. Ortho-functionalized benzonitriles also proved to be difficult substrates (longer reaction time and higher catalyst loadings). In an extension of the study on the fate of the active gold species presented previously by Nolan,265 the counterion effect of dinuclear complexes Au-7, i.e., [{Au(IPr)}2(μ-OH)][X], on catalysis was investigated.282 The activity of Au-7a−e was

Figure 83. Abnormal and classical NHC gold complexes. AR


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Figure 84. NHC−Au(III)Br3 complexes.

Once it was demonstrated that dinuclear gold complexes requires no acid or silver activation in hydration of alkynes269 and complex Au-7a was able to successfully catalyze the hydration of demanding substrates hydrocinnamonitrile and 4cyanopyridine,282 complexes Au-7a and Au-9−12 (Figure 77) were also probed in the hydration of 4-methoxybenzonitrile.269 Using 0.5 mol % catalyst loadings in THF/H2O 1:1 at 140 °C microwave heat for 2 h, all complexes performed well (86%− 92% conversion) except for the complex bearing the bulkiest NHC Au-11 which gave only 53% conversion. Lowering the catalyst loadings to 0.25 mol % revealed Au-9 as a most effective catalyst, filling the gap for hydration of electron-rich aromatic nitriles.

Scheme 45. Water Addition to Alkynes Promoted by Au-30

4.3. Allene Hydration

In 2009, the hydration of allenes (Scheme 47) catalyzed by Au3 (Figure 75) was investigated by Widenhoefer and co-

Scheme 46. Hydration of Nitriles to Amides

Scheme 47. Hydration of Allenes to Allylic Alcohols Promoted by Au-3

Figure 85. NHC−Au(I)X complexes for the hydration of nitriles.

compared to the activity of complexes Au-6 (Figure 76) and Au-34 and Au-35 (Figure 85) in the hydration of benzonitrile in a THF/H2O 1:1 mixture. All complexes gave very good conversions for the reaction tested without any noticeable dependence on the anion involved for the Au-7 series. As mentioned before, Au-6 required the addition of acid to be active; however, dinuclear complexes have shown activity without the assistance of acid or silver. Dinuclear Au-7a outperformed Au-34 in the hydration of substituted benzonitriles, giving good to excellent results with these substrates, including 3-phenylpropanenitrile and isonicotinonitrile, which afforded only 30% conversion with Au-34. An important observation was the decrease in reactivity as the reaction progressed; thus, it was suggested that the amide products could be inhibiting the reaction. Mixing Au-6 and benzamide led to the expected amide complex. Indeed, very poor conversions in nitrile hydration were observed with this new complex, supporting the inhibition hypothesis. On the other hand, the replacement of the labile ligand in complex Au-6 by nitriles to obtain [Au(IPr)(NCR)][X] (viable intermediates in the hydration of nitriles) led to complexes with good catalytic activity. Moreover, the different nitrile ligands (mostly benzonitriles) did not seem to influence the reactivity of the complexes, providing further clues on the mechanism of the reaction.

workers.283 Water being more a reagent than a solvent for this reaction, the hydration of 2,3-pentadienyl allene with 2 equiv of water was shown to improve with water-miscible solvents. Best results were obtained in 1,4-dioxane, where products 145 and 146 (2:1) provided a 77% combined yield (Scheme 47). Hydrations of different allenes were explored in 1,4-dioxane with 5 mol % of Au-3/AgOTf at 23 °C. All substrates gave modest yields. To note, an enantiomerically enriched substrate AS


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the desired product, making Au-5 the catalyst of choice for this reaction. The scope of the reaction was screened using four sets of functionalized substrates (Scheme 49). Aryl-functionalized propargylic acetates gave good isolated yields for all substrates regardless of substituents. The second set of substrates included acetylenic-substituted propargylic phenyl acetates. Both conjugated aldehyde and trans-chalcone were obtained in excellent yields; however, TMS and tBu-substituted alkynes were unreactive, even under harsher reaction conditions, as a consequence of the steric hindrance presented by the substrates. Of great synthetic value, aryl-substituted terminal alkynes were also probed, providing enals in good yields. In order to examine whether π conjugation with the carbonyl was the driving force behind the reaction, alkyl- and benzylsubstituted propargylic acetates were also checked. Results showed that various enones could be obtained in high yields, even those hailing from typically reluctant substrates. Finally, the use of microwave heating at 80 °C shortened the reaction period to merely 12 min. All enone products were obtained in excellent yields, and most of the syntheses did not require product purification. Additionally, Au-5 remained apparently intact under these conditions, demonstrating its durability. In 2012, this reaction was re-examined by Shi to test the effect the silver salt has on the course of catalysis.267 A 2 mol % mixture of Au-3/AgBF4 in THF/H2O 10:1 at 65 °C for 24 h was consistent with Nolan’s results, yielding 92% yield. Catalysis only by gold species (removal of silver with Celite) proved to be less successful under the same conditions, producing just 19% yield of the enone. Shi concluded that enone formation under these conditions follows a silver-assisted gold catalysis pathway. In a valuable application of this method, the highly desirable α-ionone (Scheme 50) was targeted for synthesis through a rearrangement of a propargylic acetate catalyzed by NHC− Au(I) complexes Au-6 and Au-7a-b (Figure 76) and Au-34 and Au-35 (Figure 85).286 In all three solvent systems tested, acetone, MeOH/water 10:1, and 2-butanone/water 100:1, a substantial amount of byproduct was formed. The best result (52% yield of α-ionone) was obtained starting with catalyst Au7a in the solvent system with the highest amount of water, methanol/water 10:1. In order to increase chemoselectivity and reduce byproduct formation, three propargylic benzoates (158b−d) were tested in the same reaction. In this case, 2butanone/water 100:1 gave the highest yield, slightly surpassing the results obtained with the acetate. The documented beneficial effects of bulky NHCs in catalytic complexes together with the disposal of the need for silver additives when using NTf2− anions derived in the synthesis of gold complexes bearing exceptionally large NHCs and the aforementioned anionic ligand, such as Au-38 (Figure 87). The activity of this series of complexes in the catalytic rearrangement of propargylic acetates was directly compared to similar complexes with less sterically hindered NHCs.287 Thus, isomerization of 155 was tested in the presence of 2 mol % loadings of complexes Au-34 and Au-37−43 in THF/H2O 10:1 at 80 °C microwave heating for a short period of 6 min. The best result was obtained by Au-39, giving 89% product and only 7% of allene byproduct. The rest of the complexes gave acceptable to good yields (from 38% to 79%), apart from Au38 which provided merely 8% yield of the desired product accompanied by 18% of the allene byproduct. Since Au-38 was the only one to provide such poor results, it was tested once again in different solvent systems to check for a solvent effect.

(R = Me, R1 = Ph, 78% ee) afforded 147 as a racemate under the noted reaction conditions. 4.4. Enone Formation

4.4.1. Rearrangement of Propargylic Acetates. After obtaining α,β-unsaturated carbonyl 157 as a byproduct in the 1,5-enyne cycloisomerization of 155 (Scheme 48) in the Scheme 48. Reaction of Propargylic Acetate as a Function of Reaction Media

presence of Au-3,284 two plausible mechanisms for byproduct formation were first put forth by Nolan: a [3,3] rearrangement followed by hydrolysis of the acetate and an SN2′ addition of water with the acetate acting as a leaving group.285 Both proposals emphasized the necessity of water in order to obtain enone 157 as a byproduct. In experiments carried out using either dry or aqueous CH2Cl2 (Scheme 48) it became evident that the absence or presence of water dictated the selectivity of the reaction. However, reactions in neat water (as with toluene, DMF, ether, or pentane) did not yield any product. The authors attributed this to insolubility of the gold catalyst. Mechanistic studies were conducted in order to establish the role of water in the reaction. Experimental data ruled out a Meyer−Schuster-type rearrangement, and DFT calculations excluded SN2′ mechanisms. In the alternative mechanism proposed, the active gold species was assumed to be of a cationic nature, triggering the alkyne reaction. Backing the mechanistic proposal is the fact that after removal of the chloride ion by the silver salt, many cationic NHC−Au(I) complexes can be obtained with noncoordinating ligands. Even though the mechanism has still not been completely confirmed, [(NHC)Au(I)OH] and [(NHC)Au(I)L] (L = noncoordinating ligand) are believed by the authors to be the true active species in the synthesis of enones and indenes, respectively. In addition to complex Au-3, complexes Au-4−5 (Figure 75) and Au-36 (Figure 86) were also tested in this transformation. It was found that greater steric hindrance of the NHC ligands increased selectivity and yields of the reaction. Thus, Au-36 gave 63% conversion to the enone accompanied by 6% indene and 7% allene as byproducts, and Au-5 gave 98% conversion to

Figure 86. NHC−Au(I)Cl complex used in enone formation from propargylic acetates. AT


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Scheme 49. Substrate Scope in the Formation of Enones from Propargylic Acetates Using Catalyst Au-5

Scheme 50. Isolated Yields in the Synthesis of α-Ionone

Using benzene/H2O 10:1 increased the overall conversion to 90% however the byproduct was found to be actually the main product, with 67% yield. Using DCE/H2O 10:1 however produced 78% yield of the desired product with no allene formation but with 22% yield of indene 156. The difference in selectivity between benzene and DCE was rationalized through stabilization of the cationic gold species by a benzene molecule performing as a readily available yet labile ligand. This theory was supported by previous work288 in which complexes of the type [(NHC)Au(L)] (where L is a labile nitrogen-based ligand) were employed in nonaqueous solvents and also showed selectivity toward the allene product. The versatility of gold complexes in Au(I)/Au(III) states can be fully appreciated in the work by Nevado from 2011, where Au-28 (as Au(I)) is first used for the rearrangement of propargylic acetates to form enones and then its oxidation to

Figure 87. [(NHC)Au(NTf2)] complexes for the rearrangement of propargylic acetates. AU


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Au(III) with Selectfluor facilitates fluorination at the α (vinyl) position by reductive elimination (Scheme 51). 289 In

must be an equilibrium taking place during the reaction where thermodynamics dictate the fate of the final product. The third set was constructed by propargylic alcohols with seemingly random varied functional group modifications at both the acetylenic and the phenyl moieties. Alkyl substituents at both positions gave poor to reasonable results. Substrates with at least one aryl group gave very good results. Finally, a set of substrates that included terminal alkynes (or TMS protected alkynes) and primary alcohols failed to give good yields. The proposed mechanism features a gold cationic complex activating a molecule of water rather than the triple bond. Such mechanism involves the formation of an [(NHC)Au(I)OH] complex, like Au-6, and the participation of water molecules in the process of the rearrangement, illustrating the active role of water in the mechanism rather than a traditional “innocent” solvation role. Another piece of the mechanism puzzle was provided by Shi and co-workers and their extensive study of the silver effect (vide supra).267 The Meyer−Schuster rearrangement of 1phenylhept-2-yn-1-ol was re-evaluated in MeOH/H2O 10:1. The reaction promoted by 2 mol % of Celite filtrate from Au3/AgSbF6 mixture (without silver) produced 26% yield; however, the addition of 2 mol % of AgSbF6 to the filtrate extremely improved catalysis, giving 94% yield of the desired enone. Once again, this behavior classifies this Meyer−Schuster rearrangement as silver-assisted gold catalysis, alongside the related enone formation from propargylic acetates. In another Meyer−Schuster rearrangement of 1-phenylhept2-yn-1-ol, Au-6 did not show activity even after a prolonged reaction time of 48 h at 60 °C.291 In the presence of HBF4 the yield increased to 98% within 0.5 h. The extreme difference in reactivity of Au-6 with and without acid reinforced to the assumption that Au-6 performs as a precatalyst to create the dinuclear complex Au-7a in acidic aqueous media. Au-7a by itself produced full conversions (99%) in 1 h. For means of comparison, Au-34 (Figure 85) also gave 99% conversion under the same conditions, albeit in 3 h. In order to examine the fate of Au-34 in the Meyer−Schuster rearrangement, dinuclear complex Au-7b (a rare example in which NTf2− acts as a spectator anion rather than a ligand despite its strong ligating abilities) was also surveyed. Thus, complexes Au-6, Au7a, Au-34, and Au-7b were examined in the Meyer−Schuster rearrangement of four propargylic alcohols (Scheme 53).

Scheme 51. Sequential Rearrangement and Fluorination of Propargylic Acetates by Au-28.

optimization studies, which included 5 mol % of catalyst, 2 equiv of Selectfluor, and 20:1 MeCN/H2O as solvent, it was determined that only the NHC-bearing complex, Au-28, gave complete conversion of the substrate and excellent selectivity, in contrast to the use of a phosphine ligand which did not afford the fluorinated product. All propargylic acetates gave good isolated yields. One exception is the p-methoxyphenylsubstituted propargyl acetate (R2 = H, R3 = nBu), which produced a substantial amount of bisfluorinated side product, formed by nucleophilic attack of water on the double bond causing a second fluorination. 4.4.2. Meyer−Schuster Rearrangement. As shown above, α,β-unsaturated ketones can be obtained from propargylic acetates; however, the use of propargylic alcohols is cheaper and allows a more straightforward synthesis of the desired carbonyls. Therefore, the catalytic abilities of complexes Au-3−5 (Figure 75) were examined in the Meyer−Schuster rearrangement (Scheme 52) in water.290 In the rearrangement Scheme 52. Meyer−Schuster Rearrangement of Propargylic Alcohols to α,β-Unsaturated Ketones

of 1-phenylhept-2-yn-1-ol in MeOH/H2O 7:1 and AgSbF6, complex Au-3 outperformed complexes Au-4 and Au-5, yielding 99% ketone in 4 h at room temperature. Four different sets of substrates were surveyed with Au-3/AgSbF6 in MeOH/ H2O 6:1 (molar ratio) at 60 °C overnight to guarantee maximum conversion of the more demanding substrates. The first set, consisting of aryl-functionalized 1-arylhept-2-yn-1-ols, gave good to excellent yields and E selectivity for all substrates. In the second set of substrates, benzyl alcohols with an alkyne at the benzyl position and different substituents at the acetylenic group (the R3 substituent in Scheme 52) were probed. This set gave good results as well, yet showed a lower E/Z selectivity of 1.5:1 for an ethoxy-functionalized substrate, which also led to a final product that underwent transesterification with MeOH. Curiously, carrying out the reaction in 1,4-dioxane not only circumvented the transesterification but also raised the E/Z ratio to 5. Notably, a propionate alkyne produced a cyclic furanone product in good yields. This example is quite revealing because in order for the cyclic furanone to be formed the double bond must be in the Z configuration, and the opposite configuration was observed with all other substrates. The logical conclusion is that there

Scheme 53. Meyer−Schuster Rearrangement of Propargylic Alcohols

Reactions were conducted in MeOH/H2O 10:1 mixture with 2 mol % loadings of Au-6, Au-7a-b, and Au-34 at room temperature with 1.5 equiv of HBF4 added only for reactions with Au-6. All substrates and complexes provided similar results, supporting the precatalyst hypothesis. The remarkable stability and capacity of Au-7a were fiercely tested by the continuous addition of substrate to a reaction mixture AV


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Scheme 54. Synthesis of Prostaglandins PGF2α Using Dinuclear Complexes Au-7a-b

Scheme 55. Tandem Synthesis of β-Disubstituted Ketones Using Au-34 and Rhodium Complex

formation of an inactive cationic species [NHCAuBINAP]+. Orthogonal tandem catalysis was achieved by using a diene ligand that binds and activates only the Rh ion. Scheme 55 details the enantioselective two-step pathway to produce the desired ketone with an enantiomeric excess of 96%. Optimization of the base (50 mol % of KOH) reduced sideproduct formation, allowing excellent yields and enantioselectivities using a wide variety of propargylic alcohols and boronic acids.

containing just 0.03 mol % of catalyst during a period of 3 weeks, yielding a final TON of 3330. Complexes Au-7a-b were also applicable to one of the steps in the synthesis of PGF2α prostaglandins, in which unsaturated ketone 160 was obtained in 86% and 84% yield, respectively, under mild conditions and 2 mol % catalyst loadings in MeOH/H2O 10:1 (Scheme 54), thus improving on a previously reported synthesis292 of this unsaturated biological active fatty acid. After this demonstration of strength by Au-7a in the Meyer− Schuster rearrangement of 1-phenylhept-2-yn-1-ol in MeOH/ H2O 10:1 at 60 °C without any additives, complexes Au-9−12 were tested with just 0.5 mol % loadings.269 Au-9 was the only one of these who performed well under these conditions, providing 85% conversion. Complexes Au-10−12 could not produce conversions higher than 27%. This clearly shows that successful catalysis can be obtained by dinuclear systems without silver assistance, classifying the rearrangement of 1phenylhept-2-yn-1-ol in an aqueous system as genuine gold catalysis. This complements Shi’s findings,267 (vide supra) who reported that Au-3 performed well only after AgSbF6 addition and shows that the type of precatalyst used can influence the activation method required to achieve efficient gold catalysis. In particular, the Au-3/silver salts and dinuclear complexes are essentially different species; therefore, it could be expected that in one case silver was needed to activate the reaction and in the other it was not. Nonetheless, even though silver salts play a major role in this type of reactions, the mechanism proposal could still benefit from further study. In an ingenious example of the great potential of gold catalysis, Hashmi et al. developed a one-pot process which included tandem reactions catalyzed by gold and rhodium.293 The initial study included a sequential addition of Au-34 (Figure 85), [Rh(cod)OH]2, and rac-BINAP to a 5:1 MeOH/ H2O solution of propargylic alcohols. The first stage catalyzed a Meyer−Schuster rearrangement, and the second step promoted the 1,4-addition of p-Tol-B(OH)2 to obtain β-disubstituted ketones. The MeOH/H2O-specific solvent system had a great impact on the propargylic alcohol rearrangement and produced high selectivity (>30:1) toward the E α,β-unsaturated ketone. Although these mild conditions were able to promote both transformations, the sequential addition was mandatory due to coordination of the BINAP ligand to gold and the consequent

4.5. Cyclization Reactions

As evident from the above, the literature on aqueous gold catalysis is mainly devoted to alkyne hydrations and related reactions. However, the stability and Lewis acidity of gold complexes also allow for other reactions to be pursued, for example, intramolecular cyclization reactions. Following a successful report on a phosphine-bearing gold catalyst for intramolecular hydroaminations of different olefin substrates,294 Widenhoefer proposed NHC complex Au-3 (Figure 75) for the same reaction (Scheme 56).295 Indeed, Scheme 56. Intramolecular Alkene Hydroamination

complex Au-3 efficiently catalyzed the intramolecular hydroamination of the urea substrate with 5 mol % catalyst loading and 5 mol % of AgOTf as cocatalyst at room temperature in 95% aqueous methanol, producing nearly quantitative yields. Wang and co-workers subsequently used the multitalented Au-3 to catalyze a cascade insertion−cyclization reaction (Scheme 57).296 Simple salts of copper, silver, and gold afforded the water insertion product 163 solely, while phosphine−gold complexes gave only traces of desired products 161 (6-endo-dig cyclization) and 162 (5-exo-dig cyclization). On the other hand, Au-3 afforded 95% yield of 1:1 161 and 162 in a 1:1 MeCN/H2O mixture, highlighting the importance of the NHC ligand in this reaction. Other solvent systems, including neat water and neat MeCN, gave lower conversions; however, using a 1:1 DMF/H2O mixture AW


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Scheme 57. Insertion−Cyclization of Water with Phenyldiazoacetates Promoted by Au-3

In a great example of the power of gold(III) NHC catalysts in water, complexes Au-45 were thoughtfully designed for the selective cycloisomerization γ-alkynoic acids (Scheme 59).299,300 In water, precursor complexes Au-44 were found to decompose and form gold nanoparticles (as evident by purple coloration of the solution). Complexes Au-45 displayed higher stability, showing first signs of decomposition only after 4 days. 4-Pentynoic acid was chosen as the model substrate for screening the solvent systems using 2.5 mol % catalyst loadings of Au-45b in 1:1 aqueous/organic mixtures. The use of MeCN, Et2O, toluene, and CH2Cl2 mixtures all provided >99% conversion, yet best results were obtained with the heterogeneous toluene mixture, which provided 81% isolated yields within 1 h (TOF = 40 h−1) and no hydration byproduct. In aqueous media, zwitterionic complexes Au-45b-c exist mostly as Au-46b-c. The labile nature of the pyridine ligand in aqueous solutions is assumed to facilitate the coordination of the substrate. In nonaqueous solutions the solubility of the polar catalyst is reduced, and also the abstraction of the chloride ligand, needed to enable coordination of substrates, is more difficult. Therefore, reactions catalyzed by Au-45b in pure organic solvents yielded only traces of the product, except for the reaction in MeOH, due to the relatively facile dissociation of the chloride ligand in this solvent. Interestingly, the reaction in pure water resulted in only 50% yield of the desired lactone and also 3-acetylpropanoic acid as a byproduct. This byproduct was shown to be generated by posterior hydrolysis of the product, facilitated by the presence of the liberated HCl. 3Acetylpropanoic acid was not observed in the biphasic systems, which could be rationalized by the existence of the lactone and HCl in different phases of the reaction. Once again, the solvent system is accountable not only for improving conversions but also for high selectivity. Control experiments in the presence of solely HCl (2.5 mol %) provided very poor yields, refuting Brønsted acid participation. Also, the addition of KOH to Au45b did not retard reaction progress. Together with 0% conversion by the corresponding imidazolium salt, it could be concluded that the mechanism probably relies entirely on gold complex activity. Experiments carried out with 2.5 mol % of AuCl and AuCl3 in toluene/H2O 1:1 independently gave good conversions, yet a significant amount of byproduct was also obtained, thus demonstrating the importance of the NHC ligand as well. Under the optimal conditions, complexes Au-

produced 90% yield and significantly raised the selectivity of 161 versus 162 to 4:1. In 2011, the Nolan group reported the synthesis of substituted furans from diynes (Scheme 58).297 The catalysts Scheme 58. Synthesis of 2,5-Disubstituted Furans

chosen for the task were Au-3 and the successful combination of Au-6 and acid. Surveying different reaction conditions using 1,4-diphenylbuta-1,3-diyne as substrate and Au-3 or Au-6 as catalysts, led to optimized conditions of 1 mol % of Au-6 and 1.5 mol % of HNTf2 at 80 °C in 1,4-dioxane/H2O 2:1. Even though activation of the precatalyst by HNTf2 supposedly led to in-situ formation of Au-34, the reaction performed under the same conditions using isolated Au-34 provided lower yields. All diynes tested, including symmetrical and unsymmetrical substrates, afforded moderate to good yields. Most surprisingly, both p-phenyl- and sterically hindered o-phenyl-substituted diynes afforded the desired furan products; however, a mphenyl-substituted substrate failed to do so. Although the authors did not dwell on this result, it is reasonable that a methoxy substituent in the meta position resulted actually in an electron-poor substrate, and this prevented the reaction (the σ Hammett value for methoxy at the meta position is 0.12 compared to −0.27 in the para position).298 In addition, reactions of diynes substituted with two aliphatic groups were also unproductive.

Scheme 59. NHC−Au(III)Cl3 Complexes and Their Chelated Forms in Aqueous Media

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Figure 88. Dendritic NHC gold complexes bearing PEGs as end groups.

ether was added in order to increase solubility of Au-3 in reaction media. Hence, it would seem that the amphiphilic NHC ligands are the main contributors to the complexes solubility in water and to the success of the catalysis. Au-47PEG slightly outperformed the other complexes and produced 82% yield at 1 mol % catalyst loadings. The scope of the reaction was then screened with 1 mol % of Au-47-PEG in neat H2O to give acceptable yields in a series of transformations, albeit in prolonged reaction times. In the cyclization of Nmethyl-3-phenylprop-2-yn-1-amine the catalyst was reused for 3 runs by successive addition of substrate to the reaction mixture over 3 days, achieving a TON of 210 (compared to 82 when the reaction was run for 24 h). Au-34 (Figure 85) successfully catalyzed the 5-endo-dig cycloisomerization of o-alkynyl N-methylaniline in neat water, producing an 85% isolated yield of the substituted indole (Scheme 61).302 This transformation was then utilized as one

44a−c and Au-45c all gave >99% conversion and TOF = 40 h−1. It is noteworthy that the Au(I)Cl complexes Au-44a−c performed well without any additives for chloride abstraction, a success that can only be attributed to better chloride discharge in these complexes. At lower catalyst loadings of 0.1 mol % good isolated yields (81%−85%) were obtained for all complexes tested in maximum reaction times of 3 h. Au-44c and Au-45c with longer ligand “arms” provided higher TOFs than the other complexes, perhaps thanks to lower steric hindrance introduced by the pyridine during the catalytic cycle. When the scope of the reaction was probed with 2.5 mol % of Au-45b and various γ-alkynoic acids in toluene/H2O 1:1 at room temperature, all terminal alkynes produced good to excellent isolated yields. Remarkably, under the same conditions, Au-45b was able to selectively promote cycloisomerization of just one of the triple bonds in terminal bispropargylic acids. Internal alkynes and bispropargylic acids containing two internal alkynes required harsher conditions and produced 6-membered ring lactones as a result of endo cyclization. Terminal alkynes proved to be more reactive in unsymmetric bispropargylic acids (containing both terminal and internal alkynes). The same trends were observed with complexes Au-44a−c and Au-45c at 0.1 mol % in toluene/H2O 1:1. Au-44c was determined as the best catalyst providing highest TOF in the cycloisomerization of all substrate types. The biphasic system also enabled the easy separation of the water-soluble catalysts from the organic product, allowing recovery and reuse of the catalyst. In the cycloisomerization of 2-(2-propynyl)-4-pentynoic acid, the aqueous phase containing 2.5 mol % of Au-45b was reused in 10 successive catalytic cycles without apparent loss in the activity or selectivity. Most recently, Fujita et al. utilized Fréchet-type dendritic NHCs with poly(ethylene glycol) end groups as amphiphilic ligands (Figure 88) for the gold-catalyzed cyclization of propargylic amines with CO2 in aqueous media (Scheme 60).301 N-Methyl-3-phenylprop-2-yn-1-amine was cyclized with Au-47 or Au-48-TEG in MeOH or neat H2O. All complexes produced significantly better yields (up to 85%) than Au-3 in neat water, even when 8 mol % of tri(ethylene glycol) dimethyl

Scheme 61. 5-Endo-dig Cycloisomerization of o-Alkynyl Aniline

of the steps in a concurrent synthesis in which Au-34 is also used as catalyst in oxidative additions of ynamides to indoles. For detailed discussion on this protocol see section 4.6. 4.6. Miscellaneous Reactions

Cui et al. tested complex Au-4 for the catalytic oxidation of pbutylphenylallene (Scheme 62) with 2 mol % of catalyst, alongside 8 mol % of AgBF4, 0.5 mol % of H2SO4, and 20 equiv of water in 1,4-dioxane.303 A combined yield of 60% was achieved for the α-diketone and aldehyde mixture, notably lower than the performance achieved by phosphine-bearing Scheme 62. Oxidation of p-Butylphenylallene to α-Diketone and Aldehyde by Au-4

Scheme 60. Carboxylative Cyclization of Propargylic Amines

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reduction of p-nitrotoluene and p-bromonitrobenzene gave reasonable results. Even though Au-51 has a larger surface area, which should have enabled better catalysis, in all three cases Au-50 outperformed Au-51. Alongside evident decomposition of the MOMPs into gold nanoparticles during catalysis, it seems that the catalytic species might not be the defined MOMPs. When the complexes were tested in a threecomponent Strecker reaction in DCM, no traces of gold nanoparticles were found in the solution leading to the assumption that the aforesaid decomposition could be due to the reductive reagent sodium borohydride. In an extensive screening of the reaction conditions between N-methylindole and ynamide (Scheme 65) using different gold complexes and DCE/H2O mixtures, the profound influence of water on the selectivity of the reaction was revealed.307 In DCE, all gold precatalysts, including Au-34, Au-40, and a variety of phosphine-bearing complexes, afforded the diketone compound as the major product. When a syringe pump technique was used to introduce the oxidant into the reaction mixture to prevent overoxidation, the enamine was obtained as the major product. Interestingly, selectivity could be improved simply by adding water to the reaction mixture. When the reaction was conducted in neat water, Au-34 outperformed phosphinebearing gold complexes by providing both high yields and selectivity, thus making NHC and water a winning combination for the synthesis of indole−amide products. Mechanistic studies seem to imply that water does not participate directly in the formation of key intermediates. Due to the solubility of the oxidant in water and insolubility of the other reagents, it is plausible that water in this case aids the reaction by a hydrophobic effect which controls the amount of oxidant near the substrates, preventing overoxidation. Proving its utility, the conditions were also applied to the synthesis of Pfizer’s chiral endothelin antagonist UK-350,926, yielding 65% yield of the desired precursor (Scheme 66). The reaction was further extended to the use of tertiary aniline derivatives as substrate instead of indoles (Scheme 67). When N,N-dimethyl aniline

gold complexes. Thus, in this reaction the NHC used was bested by phosphane ligands. In 2007, a Au-3/AgBF4 mixture was tested for the catalysis of 1,3-acetate shift in allyl acetates.304 Although the reactions were nearly quantitative in 1,2-dichloroethane as solvent, reactions in neat water produced less than 5% of the desired product. Further investigations with aqueous mixtures were not conducted. This example highlights the complexity of catalytic reactions in water; while in many cases Au-3 proved as an excellent catalyst in water, in this specific reaction the results were much better in apolar organic solvents. In the hydrophenoxylation of diphenylacetylene (Scheme 63) in anhydrous toluene, Au-35 gave poor conversion.305 Scheme 63. Hydrophenoxylation of Diphenylacetylene

When the reaction was repeated in the presence of 3 drops of water, conversion was dramatically improved to 81%. Since this reaction was successful in toluene when Au-7a was used, the observed improvement by water could be rationalized by the insitu generation of active Au-7a from Au-35, a transformation which is possible only with water. By reacting Au-49 with 1,4-diethynylbenzene or 1,3,5triethynylbenzene under basic conditions, two main-chain organometallic microporous polymers (MOMPs) Au-50 and Au-51 can be easily obtained (Scheme 64).306 Both materials are spherical in shape and differ in size. While Au-50 has faces of 19.7 Å and a size of 100−600 nm, Au-51 has smaller faces of 13.7 Å and size distribution of 50−100 nm. The abilities of the MOMPs were tested as heterogeneous catalysts in the reduction of nitroarenes with sodium borohydride in a 1:1 H2O/MeOH mixture. For the reduction of p-methoxynitrobenzene both complexes gave excellent results and the

Scheme 64. Synthesis of MOMPs Containing Triphenylene-Tris(NHC) Gold Complexes

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Scheme 65. Synthesis of Substituted Indoles Using Au-34

Scheme 66. Proposed Synthesis of Pfizer’s Chiral Endothelin Antagonist Using Au-34 In Neat Water

Au-34 successfully catalyzed the 5-endo-dig cycloisomerization of o-alkynyl aniline in neat water, producing 85% isolated yield of the substituted indole. As shown, this product can be easily coupled with ynamide in the presence of oxidant. Notably, a model system showed that a concurrent synthesis of the two reactions (Scheme 69) in which all of the reagents were

Scheme 67. Coupling of Tertiary Aniline Derivatives and Ynamides

Scheme 69. Concurrent Catalysis by Au-34

was used as a model reaction, the same effect of selectivity was observed with the use of water. Increasing the amount of aniline to 3 equivalents further minimized the hydration byproduct. Thus, a variety of substituted anilines were oxidatively coupled with ynamides, yielding 63−97% of the desired product. When a secondary amine, N-methyl aniline, was used no aromatic substitution was observed, and along the diketone and enamide byproducts, an N−H insertion product was obtained (Scheme 68). In this case, although water

introduced together produced higher yields in shorter reaction times than the tandem synthesis where the ynamide and the oxidant are introduced to an already running cycloisomerization. A study of the scope of this reaction produced 43−70% yields of substituted indoles, widening the utility of Au-34.

Scheme 68. Coupling of Secondary and Primary Aniline Derivatives and Ynamides

5. RHODIUM Rhodium is one of the most active transition metals for catalysis and participates in numerous catalytic processes, for example, formation of C−C bonds,308 hydroformylations,309 hydrogenations,310 C−H activation, and others. In the following section we will present several Rh−NHC complexes and their catalytic activities in aqueous or wet media. 5.1. Addition of Boronic Acids to Aldehydes

Fürstner et al. were the first to report the arylation of aldehydes with phenylboronic acid (Scheme 70) catalyzed by in-situgenerated NHC−Rh complexes in an aqueous biphasic system.311 A model reaction between p-methoxybenzaldehyde and phenylboronic acid was explored with several imidazolium

prevented the formation of the diketone, it also increased the production of the enamide byproduct. In order to obtain the N−H insertion product as the major one, a DCE/H2O 1:1 solvent system was used. The scope of this reaction provided a variety of α-amino amides in 76−99% yields starting from electron-rich and electron-poor anilines. The above examples nicely illustrate the versatility of Au-34 in neat water. In order to achieve a new level of synthetic sophistication, these mild conditions were utilized to perform a concurrent catalysis.302

Scheme 70. Addition of Boronic Acids to Aldehydes

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performed in a solution of 3:1 DME/H2O at 60 °C with KOtBu, 1 mol % of rhodium salt, and 2 mol % of imidazolinium salts under argon atmosphere. Moderate to high yields were obtained with phenylboronic acid and a variety of aldehydes bearing electron-donating or -withdrawing groups (Figure 90). In the absence of NHC salts (control experiment), 4chlorobenzaldehyde and phenylboronic acid did not react at all. A series of Rh(I) tetrahydropyrimidin-2-ylidene COD complexes was prepared by the Buchmeiser group (Figure 91)316 and tested as catalysts for the addition of arylboronic acids to aldehydes and α,β-unsaturated ketones in DME/H2O (3.6:1) (Scheme 73). All reactions were conducted in the presence of NaOH at 80 °C. Complex Rh-1 was investigated at 0.3−0.7 mol % catalyst loadings and provided TONs of 23− 140 for the desired alcohol product. Similarly, Rh-2, at 0.5−2.4 mol % catalyst loadings, provided TONs of 40−200. The simple exchange of the halide ligand by trifluoroacetate (Rh-3) induced a great enhancement in the catalytic reactivity, and TONs in the range of 340−1230 at 0.08−0.13 mol % catalyst loadings were obtained. Complex Rh-4 proved somewhat more efficient than Rh-1, indicating some influence of the NHC ligand; however, all attempts to exchange the chloride by a trifluoroacetate anion in Rh-4 failed. This series of studies asserted the robustness of NHC−Rh(I) complexes in water and their ability to catalyze typical organometallic reactions in aqueous media. More recently, other Rh(I)Cl(NHC)(COD)-type complexes Rh-5−8317−319 and Rh(I)Cl(NHC)(NBD) (2,5-norbornadiene) complexes Rh-9320 (Figure 92) were tested for their catalytic activity in the addition of phenylboronic acid to several aromatic aldehydes (4-methoxy, 4-chloro, 3,4,5-trimethoxy, and more) in 3:1 DME/H2O solution with 1 mol % catalyst loadings. Reactions with COD-based complexes provided higher isolated yields (73−99%) compared to the NBD-based complexes (29− 87%). Also, planar chiral imidazolium salts based on [2.2]paracyclophane (Figure 93) were studied in the asymmetric addition reaction between phenylboronic acid and 1naphthaldehyde in biphasic solvents mixtures.321,322 Reactions were conducted by mixing rhodium(II) acetate dimer and salts 172a-b in situ. A solvent mixture of water with organic solvents (like DME, tBuOH) provided poor to moderate yields with enantiomeric excesses of 36−47%. In addition, isolated complex Rh-10 (Figure 93)323 was also tested in the same reaction. In both cases, organic solvents without water afforded better results for this transformation.

salts (Scheme 71) and Rh(I)(acac)(COE)2 as the rhodium source at loadings of 3 mol %. All reactions were run in DME/ Scheme 71. Imidazolium-Based Ligands for Aqueous Rhodium-Catalyzed Phenylboronic Acid Addition to pAnisaldehyde

H2O 4:1 solution at 80 °C with NaOMe as base. In order to test the in-situ formation of the carbene ligand in the reaction process, the isolated carbene 164′ (IPr; 1,3-bis(2,6diisopropylphenyl)imidazol-2-ylidene) was reacted under the same reaction conditions and provided the desired product in a reasonable 55% isolated yield. This result supported the theory that the carbene ligand indeed takes part in the catalytic process, albeit the in-situ procedure provided better results. Several rhodium sources were investigated, and the simple RhCl3·3H2O delivered the best results, affording 93% isolated yields of the addition product by employing the imidazolium salt 164 at just 1 mol % catalyst loading. This optimized system was used to screen the addition reactions of a wide range of boronic acids and aldehydes and produced moderate to high isolated yields while displaying a high chemoselectivity for aldehydes. Thus, many aldehydes could be effectively arylated by this method, including electron-rich and -poor aromatic aldehydes as well as aliphatic aldehydes. Also, the chiral Garner aldehyde 169312 was tested and afforded the antidiastereomer with high diastereoselectivity (Scheme 72). Scheme 72. Addition of Boronic Acids to Garner Aldehyde

5.2. 1,4-Conjugate Addition of Arylboronic Acids to Enones

The rac-proline-derived NHC ligand previously mentioned in the palladium section was also used in rhodium complexes by Shao and co-workers.324 Complexes Rh-11a-b (Figure 94) were tested as catalysts for a 1,4-conjugate addition of arylboronic acids to enones in neat water at 40 °C (Scheme 74). Initially, the reaction between a 1 M solution of phenylboronic acid and cyclohex-2-enone was conducted for 24 h with catalyst loadings of 1 mol %, KOH as base, and water as the solvent. Catalysts Rh-11a and Rh-11b provided excellent isolated yields of 98% and 90%, respectively. Even when the reaction was diluted 3-fold, the yield was still a decent 87%. A variety of arylboronic acids were reacted with enones and provided high yields (77−99%) for the 1,4-conjugate addition products. It is important to note that the authors did not specify whether at these high concentrations in pure water the

Concomitant with Fürstner’s study, Frost and co-workers reported the reaction between 1-naphthaldehyde and 4methoxyphenylboronic acid with 1 mol % of RhCl3·3H2O salt and ligand 165 (Scheme 71) at 80 °C in DME/H2O 1:1 solution.313 This reaction afforded a respectable 88% yield of the desired product. Other in-situ catalytic combinations for the addition of phenylboronic acid to aldehyde were further investigated by Ö zdemir and co-workers.314,315 Nine different air- and moisture-stable imidazolinium chloride salts 170a−e and 171a−d were synthesized, and each was mixed with the [RhCl(COD)]2 complex (Figure 89). All reactions were BB


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Figure 89. Imidazolinium chloride salts used as Rh(I)−NHC ligand precursors.

Figure 90. Reaction products and yields for phenylboronic acid addition to aldehydes.

Rhodium hydroxide species were recognized to be the actual active catalyst generated from rhodium complexes in situ at aqueous media.326 Thus, well-defined rhodium hydroxide complexes were prepared by Nolan and co-workers with strongly electron-donating NHCs.327 These Rh(I)−COD− hydroxide complexes (Rh-13, Figure 94) were also explored as catalysts in the 1,4-addition arylation of enones. Under microwave heating at 100 °C in a 10:1 THF/H2O mixture and KOH as base the reactions were over in just 30 min with a series of cyclohexenones and aromatic boronic acids with high yields and using just 0.2 mol % of catalyst. Furthermore, Peris and co-workers studied the monorhodium complex Rh-14 and trirhodium complex Rh-15 (Figure 94) in the reaction between cyclohexen-2-one and arylboronic acids under similar reaction conditions to give moderate conversions (which could be improved in toluene solution).328

Figure 91. Rh(I) tetrahydropyrimidin-2-ylidene-COD complexes.

reactions were heterogeneous or not. The 1,4-conjugate addition was also studied with chiral imidazolylidene phenoxyimine-based rhodium complex Rh-12 (Figure 94) by Douthwaite and co-workers under different reaction conditions (10:1 1,4-dioxane/water, 3 mol % catalyst loadings, triethylamine, and reflux for 3 h).325 Also in this case high conversions were obtained for different enones and arylboronic acids, although it was made clear in this case that all components are completely solubilized.

Scheme 73. Addition of Arylboronic Acids to Aldehydes and α,β-Unsaturated Ketones

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Figure 92. Rh(I)Cl−NHC−COD and Rh(I)Cl−NHC−NBD complexes.

Figure 93. [2.2]Paracyclophane-based NHCs.

Scheme 74. 1,4-Conjugate Addition of Arylboronic Acids to Enones

An amphiphilic polymer-supported NHC−Rh(I) catalyst system was first explored by Weberskirch and co-workers.331 Complex Rh-16 was immobilized on a poly(2-oxazoline) block copolymer to create Rh-17 (Scheme 75), with an average of two metal ions per polymer chain. This metallopolymer was utilized to promote the hydroformylation of 1-octene in an aqueous biphasic system. The reaction conditions were 0.01 mol % of catalyst in degassed water at 100 °C for 2 h under 50 bar of 1:1 CO/H2. At the end of the reaction, the organic phase was easily removed and the catalyst recycled. Hydroformylation of 1-octene provided the “normal” and “iso” aldehyde products, although isomerization products of 1-octene were also obtained. Recyclability of the system was tested for 4 runs

Figure 94. Rh(I)−NHC−COD complexes.

5.3. Hydroformylation

The hydroformylation of alkenes to produce aldehydes is an important industrial reaction which is usually catalyzed by rhodium.329,330 The use of NHC−Rh(I) complexes as catalysts for this reaction was also studied in aqueous media. BD


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Scheme 75. Synthesis of Amphiphilic Polymer-Supported NHC−Rh-17

with TOF up to 2360 h−1 and a normal:iso selectivity of 72:28 for the first cycle and 57:43 for the fourth cycle.

The Grützmacher group reported the oxidation of primary alcohols (Scheme 77) with NHC−Rh(I) complexes Rh-19 and

5.4. Hydroamination

Scheme 77. Oxidation of Primary Alcohols

The formation of carbon−heteroatom bonds is a standard procedure that synthetic organic chemists are frequently reliant upon for their molecular endeavors. Thus, it is not surprising that many important methodologies are still being developed to advance this fundamental transformation.332 Relevant to this discussion, CCC-pincer complex Rh-18 (Figure 95), reported by Hollis and co-workers, was found to

Figure 96. Tropamine-based NHC−Rh(I) complexes. Figure 95. CCC-NHC-Pincer Rh(III) complex Rh-18.

Rh-20 (Figure 96).334 First, the reactions were tested in DMSO/H2O 2:1, DMSO acting both as a solvent and as an oxygen acceptor. Precatalyst Rh-19 afforded poor activity, while Rh-20 provided good conversions but poor selectivity toward the acid products when octanol was used as substrate. Adding THF to the solvent mixture significantly improved activity and selectivity toward the acid product. A variety of different primary alcohols were mixed in DMSO/H2O/THF mixtures in the presence of Rh-20. Low to good isolated yields (27−81%) were obtained. This example highlights how aqueous NHCcatalyzed chemistry can be relevant in developing chemically green processes, where alcohols can be oxidized to aldehydes or acids using dioxygen as the oxidant and water as both solvent and reagent.

be an efficient catalyst in the intramolecular hydroamination− cyclization reaction of secondary amines with alkenes in the presence of air and water.333 Secondary aminoalkene 173, in the presence of Rh-18, provided almost quantitative yields of the desired pyrrolidine 174 in hot water and traces of the internal alkene isomers 175 (Scheme 76). When performing Scheme 76. Intramolecular Hydroamination−Cyclization of 173

5.6. Ketone Hydrogenation

The sulfoalkyl-NHC complexes previously described in the ruthenium section were also used for the preparation of watersoluble rhodium complexes with the same goal to catalyze the hydrogenation of acetophenones.246 Complexes Rh-21, Rh-22, and Rh-23 (prepared in situ from Rh(III)acetate) were tested under a hydrogen pressure of 40 atm at room temperature in water, providing very good conversions for all catalysts tested (Figure 97).

this reaction in benzene, toluene, or THF, similar results were obtained. A control experiment without catalyst provided no reaction. Scope studies were carried out in benzene with several alkene−amines affording satisfactory results. 5.5. Dehydrogenation of Primary Alcohols

Oxidation of primary alcohols with O2 to afford the corresponding carboxylic acids is classified as a useful “green” reaction. In water, the environmental benefits are even more substantial, especially when compared to the traditional chromate oxidations in chlorinated solvents.

6. COPPER As mentioned in the Introduction, one of the first modern attempts to endorse water as a preferred solvent for metalBE


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Figure 97. Sulfoalkyl-NHC rhodium complexes.

efficient as those obtained under neat conditions if competing pathways do not decompose the substrates or catalysts (e.g., hydrolysis). The Odobel group synthesized a variety of zinc and nickel azidoporphyrins (Figure 98) and reported their CuAAC reactions catalyzed by Cu-4 (Scheme 78) in a 3:1 THF/H2O mixture.347 For all reactions tested, improved results were obtained with the NHC-ligated catalyst compared to other copper salts or organocopper complexes. Obvious drawbacks of this method were the very high catalyst loadings used (a staggering 50 mol % for the general procedure) and the long reaction times required (3 days). Following this initial study, a variety of different [(NHC)2Cu]X complexes Cu-5−11(a,b) were examined (Figure 99).348 The main target of this research was to lower the catalyst loadings for this powerful reaction (2 mol % catalyst loadings). Complex Cu-5a (with hexafluorophosphate as the counterion) provided 71% conversion in 18 h, while Cu5b (with tetrafluoroborate) provided full conversion in 8 h according to 1H NMR. Cu-6, Cu-7, and Cu-10 produced full conversions in 5−6 h, independently of the counterion used. Also, complex Cu-11a provided similar results to Cu-5a; however, Cu-11b gave poor results. As seen from these results, no systematic reactivity pattern could be determined for these complexes; however, complex Cu-9a, which provided 99% conversion in 90 min, was selected for further investigation under neat conditions, affording excellent results. The puzzling fact from this very important work is that reactions catalyzed by Cu-9a in organic solvents such as THF, acetone, or acetonitrile (most efficient) were more efficient than in water, as opposed to the author’s previous observation with Cu-3. Recently, Huynh and co-workers prepared a series of NHC− Cu heteroleptic complexes (Cu-12−18, Figure 100).349 All were tested in a practical one-pot sequential CuAAC reaction in water: starting from aromatic amines, preparing the corresponding azide by diazotization and azidation, followed by addition of phenylacetylene and copper precatalyst. Complex Cu-1 (Scheme 78), Cu-5a (Figure 99), and Cu-12−18 (Figure 100) provided low to moderate conversions with aniline as starting material. Precatalyst Cu-12, which afforded the best results, was tested with additional aromatic amines to probe the reaction scope and generally gave good isolated yields (Scheme 79). These results highlight the recent trend toward expanding the use of water as a solvent for several NHC-catalyzed reactions by judicious ligand screening. Latent catalysts have recently shown many practical uses, especially in olefin metathesis and where polymerizations are involved.167,350−352 A dormant NHC−Cu(I) catalyst was reported by Nolan and co-workers in 2008.353 Due to its low activity, complex Cu-19 (Figure 101) was explored in the benchmark reaction of benzyl azide and phenylacetylene with 2 mol % catalyst loading in different solvents. After testing many solvents it was found that the sluggish reaction in DMSO could

catalyzed organic synthesis was the use of copper(I) to promote the azide−alkyne cycloaddition (CuAAC), i.e., the most widespread of the click reactions.197 NHC−Cu(I) complexes are stable toward oxygen, moisture, and heat; thus, they are ideally suited to promote catalysis335−338 in water. However, while there is a vast amount of work carried out for the CuAAC in aqueous environments (including in vivo examples),339,340 the use of N-heterocyclic carbene ligands significantly lags behind and is quite ripe for further development. 6.1. Copper-Catalyzed Huisgen Cycloaddition

Five decades ago Huisgen discovered the azide−alkyne 1,3dipolar cycloaddition reaction,341 which, under thermal conditions, produces a mixture of 1,4- and 1,5-substituted1,2,3-triazoles as dictated by the Woodward−Hoffmann rules.342 The use of Cu(I) alters the mechanism of the reaction to produce the 1,4-product selectively343,344 under mild conditions, benign solvent, and perfect atom economy.345 This reaction became the paradigm for click chemistry.197 In 2006, the first [(NHC)CuX] complexes that catalyzed Huisgen cycloadditions in water were examined by Nolan and co-workers (Scheme 78).346 The model reaction between Scheme 78. Alkyne−Azide Cycloaddtion Reaction Catalyzed by Complexes Cu-1−4 (Dipp = 2,6-diisopropylphenyl)

benzyl azide and phenylacetylene was tested in the presence of complexes Cu-1−4 in 5 mol % at room temperature. Organic solvents (THF, CH2Cl2, tBuOH) produced poor conversions, while solvent mixtures of water/tBuOH provided improved results (with the exception of catalyst Cu-1). Cu-2 was able to produce 65% yields, while the saturated analogues Cu-3 and Cu-4 afforded excellent 93% and 95% isolated yields, respectively. Catalyst Cu-4 was also tested in pure water and provided 98% yield in 30 min, although reactions carried out neat also gave quantitative results in less time and with lower catalyst loadings. Control experiments with CuBr (without NHC ligand) did not result in product formation, indicating the necessity of the NHC ligand to achieve good results. The authors did not try in this paper to explain the cause for the high benefit of aqueous solvents, although as previously observed the fact that the reactants are insoluble in very polar mixtures (including water) can lead to reactions as BF


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Figure 98. Zinc and nickel azido and ethynyl porphyrins.

conversion. In addition, microwave heating displayed an acceleration effect in comparison to conventional heating. Control experiments showed that in the absence of the copper catalyst poor conversions and low regioselectivity were observed. However, a simple Cu(0)/CuSO4 mixture was found to be even a better copper source than Cu-20, indicating that NHC ligands are not always beneficial for catalysis in water. Building on previous similar studies, the Li group recently developed a set of ammonium-tagged NHC−Cu complexes Cu-21−22 (Figure 102).355 These water-soluble complexes were tested in a one-pot click reaction between benzyl bromide, NaN3, and phenylacetylene in pure water. Complex Cu-21a provided the best results, 98% isolated yield in 3 h, using 5 mol % catalyst loadings. Reducing the amount of the catalyst to 0.5−2 mol % delivered 88−95% isolated yields with longer reaction times but higher turnover numbers. Complexes Cu22a and Cu-21c produced 92−94% isolated yields, while Cu22c gave only moderate result. Curiously, changing the counterion from chloride to bromide completely shut down the main reaction due to the formation of unidentified products. Over 20 different substrates were explored and provided excellent results with complex Cu-21a, and even a double click reaction of diyne gave very good yields (84%). In addition, recyclability tests of complex Cu-21a (2 mol % of catalyst) provided good yields in up to four cycles. The addition of aromatic N-donor ligands to NHC−copper complexes in order to improve the catalytic activity in CuAAC reaction was investigated by Gautier and co-workers356,357 in a model reaction between benzyl azide and phenylacetylene in a 2:1 tBuOH/H2O solvent mixture. Copper complexes (Cu-1, Cu-2, Cu-3, and Cu-19) at 1 mol % catalyst loadings provided low yields (0−15%). However, the addition of 1 equiv of 1,10phenanthroline (Phen) led to 78% isolated yield when using Cu-3 as catalyst. Other aromatic nitrogen ligands were also tested, and many improved reaction yields to 70−90%. In the case of the pyridine family of ligands, it was shown that electron-poor members (like 2/4-acetylpyridine and 4-

Figure 99. DNHC copper catalysts for azide−alkyne 1,3-dipolar cycloadditions.

be “turned on” by both heating and adding water to the reaction mixture; by following this procedure quantitative conversion was achieved within 1 h. Thus, substrates could be mixed with Cu-19 in DMSO at room temperature, and even after more than 1 week no product was observed. Then the catalyst could be activated by the addition of water and heating to 60 °C. A variety of azides and alkynes were investigated, and as depicted in Scheme 80, the use of the latent protocol provided moderate to excellent yields for several CuAAC reactions. Nolan et al. continued their scope studies of aqueous catalysis with simple NHC−halide complexes by exploring the synthesis of 1,2,3-triazolyl-carbanucleosides (Figure 101).354 First, a model reaction between azidocarbocycle (±)-176 and phenylacetylene was conducted with 5 mol % of Cu-20 loadings at 125 °C in microwave (Scheme 81). Pure water, as the solvent, provided only 20% conversion, while changing the media to a mixture of 1:1 tBuOH/H2O afforded 100% BG


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Figure 100. Heteroleptic NHC copper complexes for aqueous CuAAC reaction.

Scheme 79. Isolated Yields of Sequential One-Pot CuAAC Reactions Catalyzed by Cu-12

cyanopyridine) could not activate the copper catalyst; on the other hand, pyridines with electron-donating groups (like 4methoxypyridine, 4-methylpyridine, and 4-dimethylaminopyridine) promoted high yields. A wide scope of alkynes and azides were probed with 2 equiv of 4-DMAP or 1 equiv of phenanthroline as additives to the copper complex (Figure 103). The authors proposed that complex Cu-23 (Figure 104) plays an important role in the catalytic cycle of the reaction.

Figure 101. NHC−halide copper complexes.

Scheme 80. Reactions between Azides and Alkynes Catalyzed by Cu-19 at 60 °C in DMSO/Water

BH


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Scheme 81. Synthesis of 1,2,3-Triazolyl-Carbanucleosides Using Complex Cu-20

In 2012, Gautier’s group further explored CuAAC in water by synthesizing a water-soluble NHC−copper complex (Cu24) with two peculiar triazolyl choline arms (Figure 104).358 First, a reaction between N3TyrOH 177 and propargyl alcohol 178 was conducted with a variety of buffers (Scheme 82). Only reactions conducted in buffers HEPES pH 7.6 and MES pH 6.2 provided full conversions. The addition of different solvents, salts, or amino acids to the reaction mixture with 0.2 M HEPES was also investigated. When adding 25% v/v MeOH, DMSO, NMP, or HFIP, the reaction was not affected; however, adding MeCN reduced conversion to 50%, while NaCl addition slightly decreased the conversion to 80%. Addition of amino acids provided interesting results; for example, alanine, cysteine, or glutathione caused a strong inhibition, while N-acetyl alanine/cysteine/methionine had no effect at all. Even more puzzling, N-acetyl histidine caused a dramatic drop in conversions, but if the reaction was run in MES buffer with 5 mol % catalyst loadings, the conversions were quantitative. Eventually this catalytic system was used for the CuAAC of three different alkyne-functionalized peptides 179a−d with azides 178/180 (Scheme 83). The reactions were successful, although very high catalyst loadings (sometimes even stoichiometric amounts) were needed. On the other hand, the authors highlighted the fact that the substrates and catalysts used for the reactions carried out here were completely soluble in water, avoiding the generation of on-water conditions usually seen when pure water is used and the lack of the need for protective additives. Recently, Chen and co-workers prepared Cu-25 (Figure 105) with a bidentate naphthyridine-based triazolium salt ligand.359 This complex was investigated in the CuAAC of 4(propargoxy)-TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy) and benzyl azide in several solvents (Scheme 84). When the reaction was tested in water, only 11% yield was obtained, possibly due to poor solubility of the catalyst. However, methanol provided promising results and therefore was chosen for further scope experiments with a variety of azides and alkynes. An abnormal NHC−Cu, Cu-26 (Figure 106), was also studied in the CuAAC reaction.360 The benchmark reaction between benzyl azide and phenylacetylene was tested with 3

Figure 103. Variety of products for Huisgen cycloaddition reaction catalyzed by Cu-3 with 4-DMAP or phenanthroline.

Figure 104. NHC-phenantroline copper complex (Cu-23) and ionictagged NHC−Cu complex with triazolyl choline arms (Cu-24).

Scheme 82. Cycloaddition Reaction Catalyzed by Cu-24

mol % of Cu-26. A solvent mixture of 1:1 tBuOH/H2O gave 62% isolated yield in 24 h, while in pure water 80% yields were readily obtained in 40 min. However, the best result was achieved in neat conditions (95% in 20 min) as seen in previous cases; nonetheless, reactions in water may still be needed in larger scales due to the exothermic nature of the click reaction and the high heat capacity of water, one of its main attributes as a solvent for chemical reactions. Silica-supported NHC−Cu complex Cu-27 (Figure 107) was reported by Wang and co-workers and investigated in the cycloaddition of benzyl azide and phenylacetylene at room temperature.361 Solvent effects were explored with a variety of solvents; with water delivering 71% isolated yields some organic solvents (like DMF, CH2Cl2 and MeOH) provided better results. Neat conditions also gave the best results in this case, 93% yield; therefore, the scope and recyclability of this system were only investigated under neat conditions.

Figure 102. Ionic tagged NHC−copper complexes. BI


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Scheme 83. Cycloaddition Reaction of Peptides 179a−d with Azides 177/180, Catalyzed by Cu-24

mesityl-3-(3-trimethoxysilypropyl)imidazole-2-yildene copper(I) with silica gel to give silica-immobilized NHC−Cu(I). A 0.096 mmol amount of metal copper per gram of mixture was measured by ICP analysis. A model reaction between benzyl chloride, phenylacetylene and sodium azide was tested with 0.5 mol % loading of the silica-immobilized NHC−Cu(I) catalyst at diverse reaction conditions. The best outcome was achieved with water at 80 °C, although quite comparable to organic solvents and neat conditions so that the effect of running the reaction in water was not very clear. After running the reaction, the complex was separated by filtration and reused in the next cycle to assess the recyclability of the system. Up to 6 cycles could be performed without any meaningful loss in activity. Scope experiments with terminal aryl alkynes and diverse benzyl halides (and one example of cyclohexyl bromide) also gave good results (Scheme 85). Other heterogeneous systems for the CuAAC reaction were ́ reported by Diez-Gonzá lez and co-workers by mixing azolium salts with three diverse silica support materials: silica flakes, silica nanoparticles, and magnetite/silica nanoparticles together with CuI to give Cu-29Si‑FK, Cu-29Si‑NP, and Cu-29M/Si‑NP, respectively (Figure 107). All were characterized by TEM, EDS, and ICP.363 The activity and recyclability of 1 mol % loadings of supported NHC−Cu systems were tested with benzyl azide and phenylacetylene at room temperature on water. The first cycle provided full conversions for all systems. However, only catalyst Cu-29M/Si‑NP retained its activity even after 9 cycles, probably due to its easy separation by the help of a magnet (this catalyst contains magnetite cores which render it ferromagnetic). Scope experiments were done with Cu29M/Si‑NP with a diversity of azides and alkynes. Moreover, conversions were good and improved dramatically when heating the mixture to 40 °C. In addition, an experiment with silica flakes and CuI was conducted in the absence of

Figure 105. Bidentate-NHC−copper complex Cu-25.

Scheme 84. Cycloaddition Reaction Catalyzed by Cu-25

Figure 106. Abnormal NHC complex.

Another silica-supported NHC−Cu complex, Cu-28 (Figure 107), was reported and studied in a one-pot CuAAC reaction.362 This complex was prepared by mixing iodo-1-

Figure 107. Silica-supported NHC−copper complexes. BJ


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Scheme 85. Isolated Yields of One-Pot CuAAC Reactions Catalyzed by Silica-Supported Cu-28

6.3. Borylation Reactions of Alkynes

NHC and gave only 56% yield under the same conditions, which emphasizes the significance of the NHC for the activity. Cu-29M/Si‑NP was also compared to a homogeneous NHC−Cu analogue Cu-29, providing similar catalytic activity. However, ICP analysis of the reaction products revealed a large difference in copper contamination, the main feature of the heterogeneous system.

The borylation reaction of alkynes catalyzed by copper is an efficient method in preparing useful organoborane compounds.367−369 Moreover, copper−NHC complexes were also reported as efficient catalysts for this transformation in organic solvents.370−372 To date only a single work was reported in the literature by Ong and co-workers describing borylation of alkynes with NHC−Cu and the addition of water as a hydrogen source in organic solvents.373 Guanidine-based NHC−Cu complex Cu-31 (Figure 108) was found to be an efficient

6.2. A3-Coupling (Aldehyde−Alkyne−Amine)

Propargylamines and derived compounds may be typically produced by the three-component coupling reaction of aldehydes, alkynes, and amines. While the use of copper catalysis in this reaction is well documented,364 only a few studies have been carried out with NHCs in water. In the first example of this type the Wang group ran A3-coupling reactions in aqueous media using a silica-supported NHC−Cu complex.365 Complex Cu-30 (Figure 107) was synthesized and tested using phenylacetylene, paraformaldehyde, and piperidine as substrates and 2 mol % catalyst loadings for 24 h (Scheme 86). In this study, several different solvents were

Figure 108. Guanidine-based NHC−Cu complex.

Scheme 86. A3-Coupling Reaction between Phenylacetylene, Paraformaldehyde, and Piperidine

catalyst in the hydroboration and semihydrogenation of alkynes. Thus, hydroboration of symmetrical diarylacetylenes, unsymmetrical alkyne or terminal alkyne with 10 mol % catalyst loadings delivered Z-selective products (Scheme 87a) with Scheme 87. Borylation Reactions Catalyzed by Cu-31

checked: water and ethanol provided only 24−30% isolated yields, DMF and DMSO slightly improved the conversions to 52−62%, and toluene, THF, MeCN, CH2Cl2, and acetone provided excellent yields. Finally, coinciding with many observations for the CuAAC reaction, neat conditions provided the best results. The second example for preparation of propargylamines was recently reported by the Navarro group.366 Navarro used SIPr− CuCl (complex Cu-19 Figure 101) as the catalyst for an A3coupling reaction of phenylacetylene, cyclohexanecarbaldehyde, and piperidine with different solvents (0.5 mol % catalyst loadings, 3 h, room temperature). Also here poor conversions were obtained with water, and only MeOH provided satisfying results. As can be seen from these two pioneering examples, NHC−Cu catalysis of A3-coupling reactions in water is still in need of further research.

excellent yields. The typical addition of a base was not required, perhaps due to the guanidine side chain on the catalyst ligand. Moreover, a semihydrogenation reaction (Scheme 87b) was tested with this system as well by adding LiOtBu in DMF and raising the temperature to 80 °C, affording Z-olefins in good conversions. 6.4. Addition of Terminal Alkynes to Nitrones

The addition of terminal alkynes to enantiomerically pure nitrones was studied with NHC−copper complexes in neat water by Michalak and co-workers (Scheme 88).374 Complexes BK


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Scheme 88. Addition of Terminal Alkynes to Nitrones and NHC−Cu Complexes

carried out in benzene (other solvents tested were toluene and THF).

Cu-1−3 (Scheme 78), Cu-5a (Figure 99), Cu-19−20 (Figure 101), and Cu-32−36 (Scheme 88) were studied in this transformation to give good yields. The best complex was Cu36, which provided 97% isolated yield with only 1 mol % catalyst loadings. In addition, a variety of terminal alkynes and nitrones were screened with Cu-36 to give moderate to excellent yields and very high diastereoselectivities. As a proof of scope, this transformation was applied in an important step in the synthesis of (−)-lentiginosine.

7.2. Hydrogenation

Carbon dioxide reduction to formate by transfer hydrogenation is a well-known and important reaction, first reported in 1976.379 Naturally, the use of carbon dioxide as a starting material to obtain more complex structures is particularly appealing, and iridium complexes have been widely used to catalyze this reaction. Peris and co-workers reported numerous NHC−Ir(III) complexes (Figure 110) and their catalytic activity in the

7. IRIDIUM NHC−Ir complexes have been frequently presented in the literature as catalysts for a wide array of reactions, mainly performed in organic solvents.375−378 As could be expected, the NHC−iridium catalysts are quite related to their Rh counterparts; however, the water-splitting ability of NHC−Ir complexes is worth special mention. To date, just a few examples can be found for NHC−Ir catalysis in water, and this section surveys several studies where water was used either as the solvent or as the reagent in this area. 7.1. Hydroamination

It is common practice to test the usefulness of certain ligands by creating complexes with different metals to assess their catalytic properties. Hollis and co-workers used the same pincer NHC ligand used in the CCC−Rh complex (vide supra)333 to prepare iridium complex Ir-1 (Figure 109). Ir-1 was found to

Figure 110. NHC−Ir complexes Ir-2−7.

reduction of carbon dioxide.251,380,381 First, this reaction was tested using Cp*NHC−Ir complexes Ir-2−4 under 40−60 atm of a 1:1 CO2/H2 at 80 °C in 1 M KOH (Scheme 89a). All experiments presented a similar trendTON could be improved by reducing the concentration of the complex, increasing the temperature and reaction times, or increasing the KOH concentration. Complex Ir-3 afforded better results Figure 109. Pincer CCC−Ir(III) complex.

Scheme 89. Reduction Reactions of Carbon Dioxide

be an efficient catalyst in intramolecular hydroamination− cyclization reactions in water and afforded results quite comparable to its rhodium counterpart, with the iridium catalyst being slightly more effective under the same conditions. Even though the authors state that other solvents provided similar results, most of the reactions reported in the paper were BL


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Figure 111. COD-alkyl-sulfonate-NHC iridium complexes.

studied in aqueous solution at 60 °C with 0.8 bar partial pressure of H2. The best outcome was achieved using Ir-10a with itaconic acid as the substrate (TOF of 86 h−1). The redox isomerization of allylic alcohols to keto compounds in water was also studied with Ir-9a-b giving conversions over 90% in less than 1 h. When this reaction was carried out under hydrogen with oct-1-en-3-ol, about one-half of the product was the reduced alcohol (octan-3-ol) and the other half the isomerized ketone (ethyl pentyl ketone).

compared to complex Ir-2, reaching 1600 TON in a 2 M aqueous KOH solution. Complex Ir-5 (first developed by Crabtree)382 provided a TON of 243, while complex Ir-4 provided a TON of 122; however, raising the temperature to 200 °C improved the Ir-4 TON to 9500. Nonetheless, control experiments in the absence of iridium also showed some product formation under these extreme conditions (the reported TONs under these conditions were corrected accordingly). Complexes Ir-6−7 under the same reaction conditions delivered TONs around 1500. Notably, at lower concentrations (0.002 mM) and higher temperature (200 °C) complex Ir-6 delivered a TON over 80 000, and complex Ir-7 even reached 190 000 after longer reaction times (75 h). The results with Ir-6−7 seem to indicate that solubility of the complexes is important for raising the effectiveness of the catalysts. In addition, the superiority observed with the abnormal NHC in Ir-7 indicates that this stronger electrondonor ligand has a positive effect on the catalyst stability. The reduction of carbon dioxide by hydrogen transfer was also tested using isopropanol as the hydrogen source instead of H2. The reactions were conducted in 0.5 M KOH in H2O/iPrOH (9:1) solution at 110−200 °C for 16 h (Scheme 89b). At catalyst concentrations of 0.175 mM, complex Ir-3 failed to catalyze the reaction and complex Ir-2 provided very low turnovers, although optimizing conditions as in the previous case improved the TONs up to a few thousand. As in the case of the water-soluble NHC ruthenium Ru-44− 46 (Figure 70) and rhodium Rh-21−23 (Figure 97) complexes reported by Kühn and co-workers, sulfoalkyl-NHC iridium Ir-8 (Figure 111) was prepared in situ by deprotonation of the azolium salt and reaction with (Ir(COD)Cl)2.246 The aqueous hydrogenation of acetophenone under 40 atm H2 at room temperature with Ir-8 (2.5 mol %) afforded 51% conversion and 37% yield, less efficient results when compared to the analogous rhodium catalyst. More COD-based water-soluble mixed NHC-phosphine complexes, Ir-9−11 (Figure 111), were studied by Joó and co-workers.383 The hydrogenation of unsaturated acids was

7.3. C−H Bond Activation

Complexes Ir-6−7 (Figure 110) were also explored in the selective deuteration reaction of heterocyclic amines using D2O both as solvent and as deuterium source.381 Complex Ir-7 provided excellent conversions for all substrates, while Ir-6 afforded somewhat less satisfactory results, depending on the substrate used (Figure 112).

Figure 112. Several deuterated heterocyclic amine products (conditions 120 °C, 5 mol % catalyst loadings, 12 h, D2O).

A series of Cp* (pentamethylcyclopentadiene)-based NHC− Ir complexes, Ir-12a−g (Figure 113), was studied in the catalytic H/D exchange of benzene with various deuterium solvents (Scheme 90).384 Reactions in CD3OD provided higher exchange rates (TON = 62) than in CF3COOD, CD3COCD3, or D2O (TON = 0). Due to the appealing use of D2O as a safer solvent and cheaper deuterium source, mixtures of CD3OD/ D2O were tested in different ratios with Ir-12a. A 1:1 ratio afforded a TON of 219, even higher than in pure CD3OD. This trend of acceleration was also observed for the other complexes. BM


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Figure 113. Cp*-based NHC−Ir complexes.

complex Ir-13b was more efficient and presented TONs above 2000 and 1.5 s−1 TOF. Additionally, complex Ir-13b was found to be an effective catalyst in the related hydrogen peroxide disproportionation reaction. Recent theoretical studies by Venturini, Hetterscheid, et al. discuss the mechanism of this reaction and the influence of the NHC ligand.394 Moreover, the related complexes Ir-14−15, explored by the Lloret−Fillol group, provided around 400 TON and 0.3 s−1 TOF under similar conditions.395 Yet, with NaIO4 as the oxidant, >11 000 TON values could be reached with complexes Ir-14−15 and an impressive >95 000 TON with Ir-14a. Next, Cp*−Ir(III)(NHC)X-type complex Ir-16 (Figure 114) was described by Crabtree and co-workers using a relatively simple synthesis.396 This precatalyst affords only 0.13 and 0.20−0.26 s−1 TONs with CAN and NaIO4, respectively. Furthermore, cationic dicarbene−NHC−Ir(III)-type complexes Ir-17−18 were also examined (Figure 114). Complex Ir-17a contributed 0.13 s−1 TOF value with NaIO4.397 Complexes Ir-17b and Ir-18 provided similar results with 0.38 M CAN, about 1419 TON and 0.1 s−1 TOF and about 2800 TON and 0.2 s−1 TOF, respectively, while with NaIO4 as the oxidant, complex Ir-18 presented lower catalytic activity.398 Additionally, a photoactivated (visible light) water oxidation route was tested with Ir-18 using a photosensitizer ([Ru(2,2′-bipyridine)3]2+) and electron acceptor (sodium persulfate), providing low, yet promising catalytic activities (TON ≈ 8 and 0.004 s−1 TOF). Moreover, abnormal NHC ligands were explored in the water oxidation reaction (Figure 115). Two water-soluble Cp*−NHC−Ir complexes, Ir-19−20, were reported by Bernhard, Albrecht, and co-workers.399 Interestingly, just mixing the complexes in water in the presence of CAN revealed oxygen evolution. The longevity and activity of these complexes was examined, and after 5 days, Ir-19 and Ir-20 delivered TONs of about 10 000 and 8350, respectively. These impressive results translate to almost 1.2 L of O2 per milligram of iridium, a more efficient result when compared to the benchmark complex [Ir(ppy)2(OH2)2]OTf.400 Furthermore, a Cp*Ir(III)(NHC)Cl2, Ir-21, suffering from lower solubility was measured at a 1:200 000 ratio of complex to CAN and provided a TON of 22 800 after 10 days with constant production of O2 during the initial 60 h.401 However, the initial TOFs (120 h−1) were lower than the chelating complexes, Ir-19−20. In addition, Ir-21 was found to be active at cerium-free conditions in a photoelectrochemical cell. Another abnormal complex, Ir22, was studied by Crabtree et al. with NaIO4 and supplied 0.2 0.1 s−1 TOF.397

Scheme 90. H/D Exchange Promoted by Ir-12

7.4. Water Oxidation

Water splitting is probably one of the most sought after developments in energy-related research.385,386 The remarkable machinery that nature evolved to oxidize water has been a source of admiration and inspiration for generations of chemists. In this regard iridium has recently come up as a viable active metal center to carry out this important chemical transformation.387,388 Moreover, the use of NHCs as ligands has proven to be extremely useful for this purpose, as in many other NHC−metal-catalyzed reactions. As commonly seen in this field, there is an ongoing debate regarding the identity of the active species during the catalytic cycle, either a nanoparticle or a well-defined molecular entity389−391 (especially when strong oxidants are typically used during this reaction). Cerium ammonium nitrate (CAN) and NaIO4 were commonly used as the oxidants in the water oxidation studies reported in this section. Complexes Ir-13a-b (Figure 114) were studied by Hetterscheid et al. using CAN (0.33 M) as the oxidant.392,393 Complex Ir-13a provided a modest 120 TON and 0.5 s−1 TOF, while

Figure 114. Cp*−Ir(III)−NHC-type complexes for water oxidation. BN


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Figure 115. Cp*−Ir(III)−abnormal NHC complexes for water oxidation.

7.5. Addition of Boronic Acids to Aldehydes

The Li and Liu groups have been developing methods to catalyze addition of terminal alkynes to carbonyls and are also quite interested in developing new on-water reactions to promote environmentally benign processes. Thus, several NHC−Ag(I)Cl complexes were synthesized and screened for the direct alkynylation of isatins on water open to air.414 First, complexes Ag-3f-g and Ag-4−8 (Figure 117) were tested in a model reaction between phenylacetylene and benzylisatin at 40 °C, with the addition of diisopropylethylamine (DIPEA) on water (Scheme 91). Complexes Ag-6−8 provided very poor

In addition to rhodium tetrahydropyrimidin-2-ylidene COD complexes, the Buchmeiser group prepared also iridium tetrahydropyrimidin-2-ylidene COD complexes (Figure 116) and studied them in the addition of arylboronic acids to aldehydes and α,β-unsaturated ketones.316 Complexes Ir-23− 24 showed reduced reactivity compared to rhodium analogues.

Scheme 91. Direct Alkynylation of Isatins on Water, Catalyzed by NHC−Ag(I)Cl Complexes

Figure 116. Iridium tetrahydropyrimidin-2-ylidene−COD complexes.

8. SILVER Silver complexes are not as commonly used in coupling reactions when compared to other transition metals such as palladium or copper and are mainly applied as precursors to other organometallic catalysts.402−405 However, a few NHC− Ag-catalyzed organic transformations appear in the literature.406−411 Four of these examples were carried out in aqueous solvents and are detailed herein.

results; however, complexes Ag-3f-g and Ag-4−5 delivered over 92% conversions of the desired product; notably, complex Ag-4 provided the best results with 98% conversion. When the reaction was conducted with Ag-4 without the addition of base, or when replacing the chloride counterion by triflate, the conversions dramatically dropped. Carrying out the reaction in a variety of solvents determined that high conversions were only obtained when the solvent mixture was polar enough to generate a heterogeneous system, suggesting an on-water reaction mechanism is operating in this case. Scope experiments were conducted with complex Ag-4 on water at 40−60 °C and provided moderate to excellent results for a variety of acetylene derivatives and isatin derivatives (Figures 118).

8.1. Alkynylation of Isatins

The addition of terminal alkynes to electrophiles is a synthetically useful reaction for the generation of C−C bonds. The use of organometallic complexes to catalyze this reaction is well studied;412,413 however, the use of NHC−silver complexes to catalyze addition of terminal alkynes to ketones is much less known.

Figure 117. NHC−Ag(I)Cl complexes. BO


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Figure 118. Alkynes used for alkynilation of benzylisatin and isatins used for alkynilation of phenylacetylene catalyzed by Ag-4.

NHC−Ag−Cl system (Figure 117)417 for the aqueous A3coupling reaction. The reaction between phenylacetylene, 3phenylpropionaldehyde, and piperidine (Scheme 92) was conducted using 3 mol % of catalyst at 100 °C, producing only 31% isolated yield in pure water. Improved results and reduced times were obtained when the reaction was carried out in 1,4-dioxane.

8.2. A3-Coupling (Aldehyde−Alkyne−Amine)

Wang and co-workers expanded the study of the threecomponent coupling reaction between aldehyde−alkyne− amine to NHC−Ag(I)Cl catalysis.415 Polystyrene-supported NHC−Ag(I) complex Ag-9 (Figure 117) was synthesized and tested in the coupling of phenylacetylene, paraformaldehyde, and piperidine at room temperature (Scheme 92). Again, a

9. PLATINUM The first example of water-soluble NHC−Pt(0) complexes Pt-1 and Pt-2 (Figure 119) was reported by Flores and de Jesús.418 The NHC ligands in these complexes not only increase their solubility in water but also prevent the formation of colloidal Pt(0) particles. Pt-1 and Pt-2 were found to be active in the hydrosilylation of terminal alkynes by triethylsilane in water (Scheme 93). Using Pt-2 quantitative conversions were

Scheme 92. A3-Coupling Reaction Catalyzed by NHC−Ag(I)

solvent survey determined that water and ethanol provided poor results (less than 50% yields); THF and toluene delivered moderate yields, while DMF, DMSO, MeCN, CH2Cl2, and acetone produced excellent isolated yields. In addition, as in the copper system, neat conditions provided the best results, affording 97% isolated yield. Therefore, scope and recyclability experiments were conducted in a solvent-free condition and provided very promising results. Due to the importance of bead swelling in supported systems, possibly the use of water hindered the availability of the catalytic centers, arresting the reaction and leading to poor results. Similar results obtained with Ag-3g in the reaction between phenylacetylene, cyclohexanecarbaldehyde, and piperidine.416 Reaction in water afforded only 19% conversion, while other organic solvents (like MeOH, MeCN) delivered excellent results. Zou and co-workers reported complex Ag-10, N-cyclohexylN′-naphthalen-2-ylmethylimidazolylidene silver chloride, designed with a bulky ligand in order to produce a monomeric

Scheme 93. Hydrosilylation of Alkynes

attainable with loadings even as low as 0.05 mol % (however with reduced chemoselectivity). The optimal loading was set to 0.1 mol %, which provided quantitative conversions and 90:10 selectivity in favor of the β-E isomer. Under the same conditions, Pt-1 provided lower yields (67%) and much lower selectivity (60:40). Additionally, the activity of Pt-2 was compared to the commercially available Karstedt platinum catalyst (Figure 119)419 that gave slightly inferior results in terms of activity and selectivity. From the scope of the reaction, conducted with various terminal alkynes and both Pt-1 and Pt-

Figure 119. Water-soluble Pt(0) complexes used for hydrosilylation of alkynes. BP


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2, no decisive conclusion could be drawn in terms of reactivity. Selectivity, it seemed, depended on both the substrate and the catalyst of choice; yet when aryl-substituted alkynes were employed as substrates the selectivity improved to a great extent. Both catalysts were unable to promote hydrosilylation of propargyl alcohol or propiolic acid. The fact that colloidal platinum particles were not observed by TEM microscopy at the end of the reaction and both catalysts afford very different regioselectivities supports the proposal that the ligands play an active role in the catalysis. Pt-1 and Pt-2 were also found to be stable in D2O at room temperature for a month and for at least 3 days at 70 °C as evidenced by NMR spectroscopy. Furthermore, 0.5 mol % of Pt-1 and Pt-2 were recycled for 8 and 9 cycles, respectively, as catalysts for the hydrosilylation of trimethylsilylacetylene without apparent loss in the quantitative conversion. Less impressive results were observed for the recycling of Pt-1 and Pt-2 in the hydrosilylation of phenylacetylene; here, only 2 cycles could be run before loss in conversion ensued. This work on water-soluble NHC−Pt(0) complexes was expanded to include novel dichloro NHC−Pt(II) complexes Pt-3−4 (Figure 120), which promoted alkyne hydration

Scheme 94. Synthesis of Pt−NPs form Dimethyl NHC− Pt(II) Complexes

reductive elimination, hydrolysis, or selective protonolysis, yielding ethane or methane. The NHC−Pt bond, on the other hand, is completely inert under the above conditions.421 This behavior assisted in the formation of water-soluble platinum nanoparticles (Pt−NPs) stabilized by the sulfonated NHC ligands (Scheme 94).422 Pt−NPs Pt-6a−d are stable in solution with no sign of Pt(0) agglomeration. The size of the Pt−NPs ranges between 1.3 and 2.0 ± 0.4 nm, and the complexes with bulkier NHCsPt-5c-d produced the smaller particles. During the formation of Pt-6a, DNHC−Pt complex Pt-7a (Figure 121) was also obtained, and it is presumed to create a second

Figure 120. Dichloro NHC−Pt(II) complexes.

(Scheme 43).420 All complexes satisfactorily converted phenylacetylene to acetophenone with 2% mol catalyst loadings in pure water at 80 °C. As the leading catalyst, Pt-3c was able to produce 100% conversion at room temperature in 1 day. In addition, Pt-3c provided good results in the catalysis of selected terminal and internal alkynes. Although reaction kinetics in the hydration of substituted phenylacetylene could be correlated to electron density on the aromatic ring, the unsuccessful hydration of m-nitrophenylacetylene and diphenylacetylene can also be attributed to insolubility of the substrates in the aqueous media. In this regard, hydration of different watersoluble alkynols was readily achieved at lower catalyst loadings of 0.5 mol %. The catalytic activity of Pt-3 is quite comparable to that obtained by sulfonated NHC−Au(I) complexes Au15a−e (Scheme 44)273 and Au-17−19 and Au-21 (Figure 81).274,275 In general, both metal complexes provided similar conversions for the hydration of phenylacetylene; however, as the gold complexes usually required MeOH/H2O 1:1 solvent system and either a cocatalyst or prolonged reaction time, the platinum complexes offer better catalysis protocols. Moreover, while Au-15a−e were unable to catalyze hydration of internal alkynes at all and Au-17−18 required 5 mol % loading and acid cocatalyst to produce 38% conversion in the hydration of diphenylacetylene, 0.5 mol % of Pt-3c produced 100% conversion within 18 min in neat water in the hydration of 3-pentynol. Dimethyl NHC−Pt(II) complexes Pt-5a−d (Scheme 94) are stable at room temperature in aqueous solutions (neutral and basic). An extensive study on the stability of the platinum− carbon bonds in these complexes showed that when heated to 80 °C or treated with acid the CH3−Pt bonds are susceptible to

Figure 121. DNHC−Pt(II) complexes.

coordination sphere around Pt-6a by electrostatic interactions. Pt-7b with a N-methyl substituent was also detected; however, it was removed during the dialysis purification process of Pt-6b. Thus, Pt−NP formed by Pt-5a exists as a nanoparticle Pt-6/7a with two stabilizing coordination spheres. The Pt−NPs were probed as catalysts in the hydrogenation of styrene in neat water. All Pt−NPs provided excellent yields within 2 h and at low catalyst loadings of 0.2−0.3 mol % (2.5 mg of NP). Exceptionally, Pt-6/7a required twice the amount to produce the same results. Complexes Pt-5 were not so efficient and produced only 15−39% yields during 2 h even with 1 mol % catalyst loadings. Pt-6d was recycled by re-employing the aqueous phase of toluene extractions of the organic compounds. Curiously, during 9 successive cycles there was no drop in yields; however, at the end of the overall process the platinum content was reduced by 0.44%. The addition of water caused an activating effect to some extent with Pt-8 and an inhibiting effect with Pt-9 in the reaction of benzamide with ethylene (5.5 bar) to produce Nethylbenzamide in the presence of 10 mol % of complex (Figure 122) and 20 mol % of AgBF4 at 100 °C in deuterated nitrobenzene (Scheme 95).423 ESI-HRMS studies led to the proposal of a bridged Pt μ-OH complex in the reaction mixture. These bridged species have been previously described for bidentate phosphine platinum ligands424 and are actually considered to be the formal catalytic species in some gold hydration reactions.265,269 Thus, the formation of such active BQ


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over water. Even though the nickel complexes proved their efficiency by maintaining high selectivity at rising concentrations of water, their activity was only moderate in terms of TOFs, yielding 3.9, 4.2, and 5.9 h−1, for Ni-1, Ni-2, and Ni-3, respectively. The NHC ligands have clearly granted the complexes catalytic advantages; however, they do possess an Achilles heel: under high cathodic potentials the NHCs double bonds undergo hydrogenation, deactivating the catalysts.

Figure 122. Pt(II)−NHC complexes.

11. NHCS AS ORGANOCATALYSTS N-Heterocyclic carbenes are not just excellent metal ligands, they also display strong reactivity toward electron-deficient carbon atoms. Consequently, NHCs have taken an important position in the area of organocatalysis,426−429 especially in asymmetric reactions. NHCs are excellent neutral nucleophiles and readily react with electrophiles such as carbonyls and catalyze Umpolung reactions.430 Whereas numerous NHC organocatalyzed reactions can be found in the literature, free carbenes in water are somehow counterintuitive, and therefore, not many examples are still to be found. The pioneering works on NHC synthesis and isolation were carried out under extreme care using glovebox techniques and dry solvents,10,431,432 usually by deprotonation of a carbon in N-heterocycles using a strong base. Having said this, it is quite curious that the first suggestion for an NHC intermediate finds its roots in organocatalytic biochemistry in water. Breslow studied Vitamin B1 (coenzyme thiamine), which is able to catalyze several carbon−carbon bond formation reactions in water.17,433 He proposed that the thiazolium salt of the thiamine could be deprotonated and act as a catalyst for those reactions.434 Using small molecule model reactions, the thiazolium C2 hydrogen atom was shown to exchange for a deuterium atom at room temperature at high rates, even without the presence of a base (Scheme 96).435 Decades later, after NHCs established themselves as important organocatalysts, the pKas of their conjugate acids were studied to check their availability in basic water. Similar to Breslow’s original experiments, Amyes et al. used H−D exchange to measure pKa values ranging from 16.9 in oxazoles to 23.9 in imidazoles.436 More recently, the O’Donoghue group studied the effect of N substituents on the pKa of imidazoles, imidazolines, tetrahydropyrimidines, and bis-imidazoles, measuring acidities in the same range.437 All measured pKa values are above that of H2O, indicating that the actual concentration of carbene in water solutions must be very low. While thermodynamics disfavor NHCs for catalysis in water (the dominant species is protonated), the fast deprotonation kinetics can shift the equilibrium when NHCs are consumed through reaction with appropriate electrophiles. The most widely explored organocatalytic reaction of NHCs is addition to aldehydes.438,439 On the basis of Breslow’s study, naturally one of the first reactions studied in water was the benzoin condensation, shown to be very effective in organic solvents.440 The commonly accepted mechanism for NHCcatalyzed activation of aldehydes is described in Scheme 97. After deprotonation, the nucleophilic free carbene reacts with the aldehyde followed by tautomerization to afford the Breslow intermediate. This activated enol then reacts with different reagents to yield diverse products, as described below. In 2006, Iwamoto et al. showed that benzimidazolium salts could catalyze the benzoin condensation in water in the presence of triethylamine (TEA) as a base.441 Several N substituents were tried, and surprisingly, benzimidazolium

Scheme 95. Hydroamination of Ethylene

complexes can be easily promoted by addition of water. Another explanation for the increased reactivity might be the stabilization of a cationic intermediate in which two of the bromide ligands are removed and the platinum center is coordinated to the bidentate NHC ligand, a water molecule, and the ethylene substrate. In any case, the addition of 2 equiv of water causes a drop in the conversion, probably due to coordination of two water molecules leaving a saturated complex without additional room for the substrate. This may also explain the inhibition behavior observed for the addition of water to reactions catalyzed by Pt-9. For this tridentate complex any addition of water results in occupation of the only active available site for the substrate. Other aprotic coordinating solvents such as THF, DMSO, and 1,4-dioxane also arrested hydroaminations catalyzed by Pt-9, supporting the previous theory.

10. NICKEL To the best of our knowledge, a single example of Ni−NHC catalysis in water has been reported to date. Tetradentate bis(N-imidazolylepyridine)-bridged ligands were used in the synthesis of DNHC−nickel(II) complexes Ni-1−3 (Figure 123) in the work by Chang group.425 These unique complexes were found to be active for the electrocatalytic reduction of carbon dioxide. When the complexes were employed in a mixture of CO2 and H2O in 0.1 M Bu4NPF6 in MeCN around potentials comprised between −1.4 and −1.6 V, CO was produced as the major product accompanied by traces of H2, making the reaction highly selective toward reduction of CO2

Figure 123. DNHC−Ni(II) complexes for carbon dioxide reduction. BR


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Scheme 96. (a) Breslow’s H−D Exchange; (b) Enzymatic Reactions of Thiamine Diphosphate (TDP)

Scheme 97. NHC Activation of Aldehydes

Scheme 98. Benzoin Condensation Catalyzed by a Thiazolium Salt in Water

molecules having long aliphatic chain substituents such as linear dodecane proved to be the most efficient. The authors proposed that the benzimidazolium salts probably formed micelles as they were introduced into the aqueous media, and the longer aliphatic tails facilitated their formation. Later, Jing and co-workers optimized the reaction conditions by increasing temperature and changing bases and found that the best yields in water were obtained with linear octane as N substituents.442 Yao et al. further expanded this NHC-catalyzed benzoin condensation in water by treating the crude products with acids and different anilines with the purpose of preparing 2,3-diaryl indoles in a cascade reaction.443 However, optimization experiments indicated that the NHC used in this case, a thiazolium salt, provided better results under solvent-free conditions. Thus, water was probed only for the first step of the benzoin condensation (Scheme 98), while indole synthesis was carried out only neat. Benzoin condensation in water was further recently explored on the surface of silicon oxide in order to functionalize the silicon surfaces with biomolecules. The surfaces were pretreated with 3-aminopropyltriethoxysilane followed by reaction with aqueous terephthalaldehyde. Benzoin condensation reactions were then performed in an aqueous solution with substituted benzaldehydes using thiamine as catalyst and TEA as base.444

Water may also act as a nucleophile and assist a reaction by attacking keto forms of the Breslow intermediate (Scheme 99). Yoshida et al. demonstrated the air oxidation of electron-poor benzaldehydes catalyzed by sulfoxyalkyl-substituted NHCs at room temperature in excellent yields.445 Recently, Zeitler and Connon extended the oxidation of aldehydes to NHC-catalyzed aerobic oxidative esterification in the absence of alkylating agents446 (Scheme 100). While these reactions were mainly studied in organic solvents, a significant mechanistic study was carried out in aqueous media.447 The authors isolated benzoin products at low reaction times and determined that oxidation of benzoin and not the Breslow intermediate (as previously suggested) leads to the products under aerobic conditions. Water or alcohol as noninnocent solvents react at a later stage with the benzyl intermediate. By changing the ratio of water and alcohol, the reaction could be directed toward the carboxylic acid or the ester products. Rovis used a chiral 1,2,4-triazole-based NHC to develop an enantioselective synthesis of α-substituted carboxylic acids in a BS


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Scheme 99. Mechanistic Proposal for the NHC-Catalyzed Aldehyde Oxidation in Aqueous Media

Scheme 100. Oxidative Esterification of Aromatic Aldehydes

Scheme 101. Preparation of α-Chloro Carboxylic Acids

biphasic reaction.448 In the presence of a base, the catalyst reacted with α,α-dichloro aldehydes to form a Breslow intermediate, which in turn lost a chloride to form an enol in equilibrium with the α-chloro ketone (Scheme 101). The chloride elimination was sterically directed by the N substituents of the NHC in both tautomers, leading to the formation of enantiomerically enriched products. Further reaction with water regenerated the catalyst and released the final product in good yields and excellent enantioselectivity. As expected, if D2O was used instead of water, the α-chloro-αdeutero-substituted carboxylic acid was obtained. In a related reaction it was shown that NHCs react with CO to form amino ketenes.449,450 Li expanded this concept to prepare formamides.451 For example, in the presence of an NHC catalyst, CO reacted with dimethylamine in water to produce DMF (Scheme 102). The reaction worked well both in MeOH and in water, but the optimization was carried out in MeOH since this was more easily separated from the formamide products.

Scheme 102. Preparation of Formamides from CO and Amines in Water

Recently, Chi and co-workers studied the NHC-catalyzed enal−enone coupling in water (Scheme 103).452 Using pure water as a solvent at 40 °C, 5 mol % of NHC precursor, and 2 Scheme 103. Enal−Enone Coupling in Water

BT


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significant difficulty. Furthermore, water can also act as a nucleophile and attack the Breslow intermediate, obtaining a different product than the desired one. Notwithstanding these challenges, several impressive reactions have been developed in water and provided excellent yields and enantioselectivity. Some of these reactions use water as a reagent,445,448 while in others the role of water is still unclear. The field of NHC organocatalysis in water is still vastly unexplored, and several new reactions will probably inspire the scientific community in the coming years.

equiv of NaOH as base, the authors observed that the addition of surfactants only decreased conversion. The reaction was highly diastereoselective, and the product was obtained in more than 70% isolated yield with one of the racemic pairs in an 11:1 ratio over the other. Interestingly, when the reaction was carried out in D2O, deuterium was incorporated in three positions (Scheme 103) with different percentages, highlighting the active role of water in this reaction. Boron compounds are yet another type of electrophiles that may react with NHCs in water.453 NHCs together with boranes and boronates were prepared and used in combination as catalysts. In a creative approach, Hoveyda used NHCs to activate B−Si bonds and catalyze the enantioselective C−Si bond formation in α,β-unsaturated carbonyls in aqueous mixtures (Scheme 104).454 During reaction optimization it

12. CONCLUSIONS It is becoming clear that the reticence to use water in catalytic organic reactions, mainly using transition metals, is slowly fading. In the past few years a growing number of new reactions have appeared in the literature alongside the already established classical reactions accommodated to water. A deeper understanding of organometallic mechanisms and the important role that stabilizing N-heterocyclic carbenes play in this game have certainly contributed to this paradigm shift. The evolution of the NHC and its surrounding substituents, from the pioneering Arduengo’s NHCs to the nonconventional abnormal NHCs, provides new pathways and handles to develop this important chemistry. The aqueous reactions toolbox now holds a large reservoir of NHC ligands in general and water-soluble NHC ligands in particular, allowing numerous synthetic transformations which may eventually lead to more facile and economical approaches. Naturally, in order for aqueous NHC catalysis to become industrially viable many issues still need to be solved. A reaction that is carried out in triply distilled water under argon will probably not be more economical than the same reaction in hexane. Treatment of wastewater is also an important handicap; the reuse of the aqueous systems and easy workup procedures are thus extremely important if all the benefits of using water as a solvent are to be exploited. Thus, ideal green reactions should be able to be carried out in “dirty” water and readily recycled. In addition, asymmetric catalysis in this field still needs further development. There is still much work to do in order to achieve this level of proficiency in aqueous catalysis to the field of catalysis with water. This will require the synthesis of new NHC ligands,457 maybe the expansion to other metals such as the f-block group,458 or the development of uncommon NHCs, such as the abnormal NHCs.459 However, today the first seeds are being planted and certainly they will grow and have a major role in the future of chemical reactions. Hand in hand with its practical usage is the wide range of roles that water can play in the system. Whether it is taking an active part in the catalytic cycle (by coordinating to the metal center or the substrate), raising the conversion and turnover frequency by hydrophobic constriction of the substrates, or just being an innocent solvent (solvating the mixture), the use of water may bring about new discoveries and many benefits. Undoubtedly, the use of water as part of the solvent system in combination with N-heterocyclic carbenes, both for developing new types of reactions and for the simple fact that water is per definition the benign solvent, will continue to grow in the near future, not just in the already developed metals like ruthenium, gold, and palladium but also for other unnoticed metals and metal-free catalytic reactions.

Scheme 104. NHC-Boronate-Catalyzed Silane Chiral Addition to α,β-Unsaturated Carbonyls

was shown that the best yields were obtained when water was used as a solvent. However, enantioselectivity was found to be higher when the reactions were carried out in a 3:1 H2O/THF mixture under N2 at room temperature with 15% DBU (1,8diazabicyclo[5.4.0]undec-7-ene) as base. Lower quantities of water decreased the yields significantly, indicating that water plays a very important role in this novel organocatalyzed reaction. Some NHC-boranes, while prepared in organic solvents, can also carry out catalysis in water.455 Lalevée and co-workers recently investigated the photopolymerization of acrylates in water using an intriguing catalytic system.456 In water, 1,2,4triazole-3-ylidene borane efficiently initiated radical polymerization and even outperformed other co-initiators in lightactivated radical polymerizations in air (Scheme 105). One of the drawbacks of organocatalysts is the usually high catalyst loadings needed, compared to those used in typical transition metal catalysis. The fact that NHCs only exist in very low equilibrium concentrations in water also represents a Scheme 105. Polymerization of Acrylates Catalyzed by NHC-Borane

BU


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AUTHOR INFORMATION Corresponding Author

*E-mail: lemcoff@bgu.ac.il. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies Charles E. Diesendruck received his B.Sc. degree in Analytical and Environmental Chemistry from Ben-Gurion University of the Negev in 2003. After working as a project manager at Chemada Fine Chemicals, he returned to BGU to receive his Ph.D. degree under the supervision of Prof. N. G. Lemcoff in 2011, where his research focused on bimetallic bis-N-heterocyclic carbene complexes. After postdoctoral studies at the University of Illinois at Urbana−Champaign with Prof. Jeffrey S. Moore, he joined the Schulich Faculty of Chemistry at the Technion as an assistant professor.

Efrat Levin (1984, Israel) received her B.Sc. degree in Chemistry from Ben-Gurion University of the Negev. In 2009 she joined Professor Lemcoff’s research group for her M.Sc. studies and she is now in her Ph.D. studies. Her interests include organosulfur reactions in water and the field of light-induced chemical reactions with latent sulfur chelated NHC−ruthenium metathesis catalysts. N. Gabriel Lemcoff finished his undergraduate studies at Tel-Aviv University, where he also received his Ph.D. degree in Chemistry in 2002 on novel macromolecular diacetal systems under the supervision of Prof. Benzion Fuchs. He then joined Prof. Steven C. Zimmerman’s group at the University of Illinois at Urbana−Champaign working on molecularly imprinted dendrimers and developing intramolecular cross-linking strategies using Grubbs’ catalysts. In 2004 he joined Ben-Gurion University of the Negev as a Senior Lecturer and was promoted to Associate Professor in 2011. Since 2012 he is the Head of the Chemistry Department at Ben-Gurion University of the Negev.

ACKNOWLEDGMENTS The Israel Science Foundation is gratefully acknowledged for funding.

Elisa Ivry (1986, Israel) finished her B.Sc. studies in Chemistry from Ben-Gurion University of the Negev in 2011. She joined Prof. Lemcoff’s research group in the same year for her M.Sc. studies, which

DEDICATION

focused on the organic synthesis of new polymers using known

This paper is dedicated in memory of Dr. Guy Lavigne from the Laboratoire de Chimie de Coordination in Toulouse.

ruthenium catalysts. In 2013 she began her Ph.D. studies at the lab of Prof. Lemcoff, and her interest of research includes the development of

REFERENCES

novel ruthenium complexes bearing natural amino acids as ligands for

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the promotion of asymmetric metathesis reaction. BV


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CH


Self-healing catalysis in water.

Progress in base-metal water oxidation catalysis.

Environmental control of nucleophilic catalysis in water.

One-electron activation of water oxidation catalysis.

Enzymatic catalysis and dynamics in low-water environments.

The water catalysis at oxygen cathodes of lithium-oxygen cells.

Water oxidation catalysis by birnessite@iron oxide core-shell nanocomposites.

CATALYSIS. A speedy marriage in supramolecular catalysis.

Hydrolysis of glyoxal in water-restricted environments: formation of organic aerosol precursors through formic acid catalysis.

Direct arylation of N-heteroarenes with aryldiazonium salts by photoredox catalysis in water.

Micellar catalysis-enabled sustainable ppm Au-catalyzed reactions in water at room temperature.

Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis.

On the role of interfacial hydrogen bonds in "on-water" catalysis.

Air- and water-tolerant rare earth guanidinium BINOLate complexes as practical precatalysts in multifunctional asymmetric catalysis.

Cooperative effects in homogenous water oxidation catalysis by mononuclear ruthenium complexes.

Enhanced imine synthesis in water: from surfactant-mediated catalysis to host-guest mechanisms.

Recyclable catalytic dendrimer nanoreactor for part-per-million Cu(I) catalysis of "click" chemistry in water.

1-Bromobutane Interface: Molecular Insight into Reverse Phase Transfer Catalysis.

A Co(II)-Ru(II) dyad relevant to light-driven water oxidation catalysis.

Non-Thermal Plasma Activation of Gold-Based Catalysts for Low-Temperature Water-Gas Shift Catalysis.

general-base catalysis under acidic conditions.

Catalysis at the room temperature ionic liquid|water interface: H2O2 generation.

Partially Oxidized Sub-10 nm MnO Nanocrystals with High Activity for Water Oxidation Catalysis.

Catalysis seen in action.