Forged and fashioned for faithfulness—ruthenium olefin metathesis catalysts bearing ammonium tags

Anupam Jana and Karol Grela *
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland. E-mail:; Fax: +48-22-8220211; Tel: +48-22-8220211 ext. 420

Received 20th August 2017 , Accepted 8th November 2017

First published on 8th November 2017

In this article, the synthesis and applications of selected ammonium tagged Ru-alkylidene metathesis catalysts were described. Because of the straightforward synthesis, the first generation of onium-tagged catalysts have the ammonium group installed in the benzylidene ligand. Such catalysts usually give relatively pure metathesis products, and are used in polar solvents and water, or immobilised on various supports. Later, catalysts tagged in the N-heterocyclic carbene ligand (NHC) were developed to offer higher stability and even lower metal contamination levels. Due to minimal leaching, the non-dissociating ligand tagged systems were successfully immobilised on various supports, including zeolites and Metal Organic Frameworks (MOFs) and used in batch and in continuous flow conditions.

image file: c7cc06535c-p1.tif

Anupam Jana

Anupam Jana was born in Tarakeswar, India in 1988. He graduated from the Scottish Church College, Kolkata and received his MSc in organic chemistry from the University of Calcutta, India. In 2010, he joined the Indian Association for the Cultivation of Science, Kolkata where he worked on total synthesis of natural products under the supervision of Professor Subrata Ghosh. He completed his PhD in 2015 and accepted a post-doctoral position with Professor Karol Grela at the Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw. He is currently working on the synthesis and applications of NHC-containing complexes.

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Karol Grela

Karol Grela obtained his MSc and Engineering degree from the Faculty of Chemistry, Warsaw University of Technology and PhD degree from Institute of Organic Chemistry, Polish Academy of Sciences (PAS) in 1998. He subsequently held a postdoctoral position at the Max-Planck-Institute for Carbon Research, Mülheim, Germany. Afterwards he came back to PAS, obtained habilitation in 2003 and became a Full Professor in 2008. Since 2008 he has worked at the Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, where he is the head of the Organometallic Synthesis Laboratory. The research interests of Karol Grela are focused on improving the synthetic efficiency of organic reactions, organometallic chemistry and catalysis.

An anchor is forged and fashioned for faithfulness; give it ground that it can bite, and it will hold till the cable parts

“The Mirror of the Sea”

Józef Teodor Konrad Korzeniowski (Joseph Conrad)


Olefin metathesis has emerged as one of the most powerful transformations in the toolbox of modern organic synthesis. The rapid expansion of its usance is largely attributed to the discovery of the stable ruthenium alkylidene catalysts combining high activity with excellent tolerance to a variety of functional groups.1,2 Its high yielding, atom-economic, selective nature and ease of by-product (e.g. ethylene) separation has assisted its widespread acceptance by chemists. After, the first well-defined ruthenium alkylidene complexes such as G-I were introduced by Grubbs (Fig. 1), a further crucial development was the introduction of N-heterocyclic carbene (NHC) ligands in Ru based catalysts in 1999, proposed simultaneously by Nolan,3 Grubbs,4 and Fürstner and Herrmann.5 The NHC ligand having strong σ-donor and poor π-acceptor properties, helps to stabilize the 14-electron ruthenium intermediates during metathesis and gives a large improvement in activity and stability over first-generation bisphosphine catalysts. They proved to be easy to handle, tolerant to diverse functional groups and highly amenable to molecular editing, yielding a great variety of tailored catalysts of high activity and excellent stability.6,7 Despite the supremacy offered by these catalysts, they share some disadvantages. One of these is difficulties associated with removing the ruthenium by-product from the final products.8 The removal of the Ru-metal by-product is a critically important task in pharmaceutical production, where final products must meet stringent purity requirements.9 According to the recent ICH Harmonized Guideline (December 2014), Ru belongs to Class 2B, with the same ICH limits as Pd (max. 10 ppm in APIs (active pharmaceutical ingredients), when the drug is taken orally, and max. 0.1 ppm when taken by inhalation).10 Furthermore, the presence of metal complexes after an olefin metathesis step may cause undesired side reactions such as product isomerization,11 or degradation12 during workup. Therefore, the development of an efficient, practical, and economical method to remove the Ru by-products is crucial for propagation of the metathesis methodology in industry. A number of efforts to remove the catalyst or the product of catalyst decomposition by addition of various scavengers,13 biphasic extraction,14 silica gel chromatography,15 silica immobilised catalyst,16 or peroxides17 have been carried out, however, none are universally attractive so far. This situation has led to a tremendous interest in supported or tagged versions of olefin metathesis catalysts.18.19 In addition, for industrial-scale syntheses, a key emerging consideration as a part of the sustainability drive is now being directed toward development of metathesis reactions in alternative media as a replacement for those that are less sustainable and pose adverse health and safety issues or demonstrate a detrimental environmental impact.20 Therefore, the focus of studies on ruthenium-based catalysts has advanced from basic research on achieving the highest possible activity and selectivity towards simple model substrates to the application stage, where the effectiveness of post-reaction workup and economic and environmental constraints are equally important. This development can be seen by an increasing number of reports on catalysts designed to exhibit auxiliary traits such as simplified handling, compatibility with green solvents, immobilisation and product purification, whereas high activity is not always a primary goal. In this context, in this feature article we are trying to convince the reader that Ru-complexes bearing onium (usually: quaternary ammonium) tagged ligands21,22 show a number of advantages and have already created a privileged family of olefin metathesis catalysts.
image file: c7cc06535c-f1.tif
Fig. 1 Selected ruthenium precatalyst for olefin metathesis.

Early designs: ammonium tags on the benzylidene part

Historically, the first systems of this type have ammonium (NR3+) tags placed on the benzylidene ligands.23 Tagging on the benzylidene ligand, although synthetically more easy than applying modifications to the NHC ligand, requires some comments in the context of the catalyst's mode of action. It is well established that the benzylidene ligand dissociates during the initiation phase of the metathesis reaction, forming propagating catalyst species (see Fig. 2). After the reaction is complete, the active form could in theory react back with styrene C (a precursor of the benzylidene ligand) thereby regenerating the pre-catalyst. This is known as the release–return mechanism or the “boomerang effect.” This phenomenon was proposed to explain why Hoveyda-type complexes (usually used in amounts of 5 mol% or more) can be isolated in the unchanged form from the reaction mixture with yields exceeding 95%.24 A study using deuterium labelling provided evidence that this mechanism is indeed operative under high catalyst loading conditions (5 mol%).25 However, the boomerang mechanism was later questioned, and for example Plenio et al.26 found no evidence for a release–return pathway when conducting olefin metathesis with a fluorophore-tagged Hoveyda–Grubbs catalyst. Fogg et al. undertook recently a study revisiting some experiments and adding new ones based on crossover studies with the 13C-labeled Hoveyda–Grubbs ligand to find results that are convincing in favor of the release–return mechanism in some cases at least.27 Although no consensus has been reached about the validity of the “Boomerang” mechanism, there are a large number of literature reports exploring tagging (not only by onium groups) or immobilising the Ru catalysts via the benzylidene fragment. This is at least in part because of the straightforward synthesis of such benzylidene-tagged complexes, as it is basically sufficient to mix the commercially available Grubbs-type catalysts with a precursor of the tagged-benzylidene ligand.
image file: c7cc06535c-f2.tif
Fig. 2 The mechanism of olefin metathesis for precatalyst HG-II.

Gułajski et al. reported on a novel ruthenium complex 4 (Scheme 1) bearing a diethylamino-substituent on a 2-isopropoxybenzylidene ligand.28 Interestingly, this complex showed no reactivity in olefin metathesis, because of the electron-donating (EDG) diethyl amino group. As it is well established that an electron-withdrawing group (EWG) on the benzylidene fragment weakens the O → Ru coordination and facilitates faster initiation of the catalytic cycle,29 the authors treated 4 with a Brønsted acid leading to the formation of an ammonium cation with electron-withdrawing properties, this making the thus formed 1 active in metathesis.30

image file: c7cc06535c-s1.tif
Scheme 1 Synthesis of catalyst 1.

Complex 1 was synthesized from reaction of complex 4 (1 equiv.) and PTSA·H2O (1 equiv.) in CH2Cl2. Gratifyingly, the tosylate salt 1 showed very good reactivity for not only simple substrates but also complex macrocycles, intermediates in natural-product synthesis (Scheme 2).30 Importantly, the quaternary ammonium group increased the catalyst's affinity to silica gel, thus making catalyst removal after termination of the reaction easier. Accordingly, the catalyst was removed by simple filtration of the crude reaction mixture through a small pad of silica gel or basic aluminium oxide. Thus, switching from an electron-donating group (EDG) to an electron-withdrawing group (EWG) offered two advantages at once—making the catalyst more active and facilitating workup by filtration.

image file: c7cc06535c-s2.tif
Scheme 2 Applications of catalyst 1 in target oriented synthesis.

It is believed that immobilisation of homogeneous ruthenium catalysts shows a number of inherent advantages over the parent soluble catalysts.31 Several approaches have been reported for immobilizing different catalysts like Grubbs-type G-II, and HG-II on solid or soluble supports either via ligand L (or X) or via a carbene moiety.18,19 Grubbs–Hoveyda type catalysts (HG-II) immobilised on different resins or soluble supports (preferentially via the benzylidene ligand) are well known in the literature.18,19 A new concept for a noncovalent immobilisation of a ruthenium olefin metathesis catalyst was presented by Kirschning in 2006.32 The authors used catalyst 4, bearing a 2-isopropoxybenzylidene ligand tagged with an amino group. Immobilisation was achieved by treatment of sulfonated polystyrene with a solution of 4, forming the corresponding ammonium salt attached to the support. Again, in this strategy for the noncovalent immobilisation, the amino group plays a two-fold role, being first an active anchor for immobilisation and second, after protonation, activating the catalyst (electron donating to electron withdrawing activity switch). The polymeric support was prepared by precipitation polymerisation of styrene which led to small bead sizes (0.2–2 μm) and large surface area. Similar polymerisation was also carried out in the presence of glass Raschig rings, which led to the formation of a composite glass–polymer material, shown in Fig. 3. Such obtained polystyrene was then sulfonated with conc. H2SO4 leading to a powder (A) or glass–polymer composite material B (Scheme 3). Both supports and the commercial ion-exchange resin Dowex 50wx2 (10–50 μm) were used to synthesize the immobilised catalysts by impregnation with catalyst 4 solutions and washing (dichloromethane). The performance of the thus obtained systems was examined in an RCM reaction and showed superior properties of complex 4 immobilised on the in-house prepared polymer powder (A) or Raschig rings over the commercial Dowex resin.

image file: c7cc06535c-f3.tif
Fig. 3 Megaporous glass Raschig rings. Figure reproduced from ref. 32 with permission from the American Chemical Society.

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Scheme 3 Preparation of immobilised catalysts 4A and 4B.

Catalyst 4B (3 μmol Ru/ring loading) on Raschig rings was used under batch conditions in various metathesis reactions, including ring-closing (RCM), cross- (CM) and enyne metathesis, to give products of high chemical purity with relatively low ruthenium contamination levels – 21–102 ppm (although this is low, it is still above the requirements by the industry). Crude products were obtained after the mechanical removal of the Raschig ring (with tweezers), washing with dichloromethane, and evaporation of the organic phase under reduced pressure. The same ring can be used for up to 6 cycles of metathesis, however with gradual loss of activity. Then, the solid phase can easily be reactivated by a washing protocol (1 N HCl, 1 N NaOH, 1 N HCl, H2O, methanol, and dichloromethane and then the reloading of the ring with the fresh portion of 4). The possibility of reloading the deactivated solid phase can be made to make the above method of particular interest in continuous-flow processes33,34 using reactors filled with immobilised catalyst monolithic beds.35 Two important features must be fulfilled before this concept will be of relevance for industrial applications. The attachment should be strong enough to suppress leaching of the catalyst and after inactivation of the catalyst it should be possible to have it removed from the solid phase by simple washing protocols, so the reactor can be reactivated using a fresh catalyst. The same concept of catalyst 4 immobilisation was also applied to a glass–polymer composite material shaped as a monolithic glass rod inside a metal jacketed reactor. This device, the so-called PASSflow reactor, was equipped with HPLC-fittings at both ends of the tube for allowing connection to an HPLC-pump (Fig. 4).35 The immobilisation was carried out by pumping a solution of Ru-complex 4 and an excess of aniline derivative 3 (1[thin space (1/6-em)]:[thin space (1/6-em)]19 mol ratio) in CH2Cl2 through the reactor in a circular mode (Scheme 4). A metathesis reaction using immobilised Ru-catalyst 4C in the PASSflow reactor under continuous flow conditions was performed and gave the expected product 8 in a quantitative yield (for more examples see Table 1). However, the recyclability of this system was very poor (only 2 successful reuses). Apparently the tag-free propagating species formed during the initiation phase of metathesis were almost immediately leached out under nonstatic conditions terminating the “boomerang” process. However, after developing a system that is anchored via a not so easily dissociating ligand, this method of noncovalent immobilisation should be reinvestigated, because of the number of advantages it obviously offers.

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Fig. 4 PASSflow reactor (without HPLC connector). Figure reproduced from ref. 32 with permission from the American Chemical Society.

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Scheme 4 Immobilisation of Ru-complex 4 inside a PASSflow reactor and RCM under continuous flow conditions. Scheme reproduced from ref. 32 with permission from the American Chemical Society.
Table 1 RCM and CM reactions with Raschig ring immobilised catalyst 4Ba,b
Substrate Product Temp. [°C] Time (h) Conv. (%)
a Conditions: one Raschig ring 4B (loading 3 μmol Ru/ring, 5 mol%) per reaction was used. b Crude products were obtained after the removal of the Raschig ring, washing with dichloromethane, and evaporation of solvent. Conversions were calculated by 1H NMR spectroscopy and/or GC.
image file: c7cc06535c-u1.tif image file: c7cc06535c-u2.tif 45 2 99
image file: c7cc06535c-u3.tif image file: c7cc06535c-u4.tif 45 24 68
image file: c7cc06535c-u5.tif image file: c7cc06535c-u6.tif 45 16 99

Despite the failure in continuous flow, immobilised benzylidene tagged catalyst 4 found some uses in an industrial context.36 Catalyst 4A (powder) showed excellent reactivity in the cross-metathesis reaction of 15-allylestrone 9 in batch conditions leading to several 17β-hydroxysteroid dehydrogenase type 1 inhibitors (Scheme 5). The immobilised Ru-complex 4A performed with similar or better efficiency (although after longer time) than the homogeneous G-II. A number of cross metathesis reactions of allylestrone 9 were evaluated using homogeneous and heterogeneous Ru-catalysts (G-II and 4A, Scheme 5). Additional merits of immobilised complex 4A as compared to G-II are easy purification of reaction mixtures and facile regeneration32 without substantial loss of reactivity. Like the previous case, after completion of the reaction, catalyst 4A can be simply filtered off and washed with minimal amounts of dichloromethane, producing negligible solvent waste. The ruthenium contamination in the crude products was <3500 ppm which is not an excellent value, but still lower than that obtained with homogeneous G-II. Anyway, this example cleanly shows that immobilisation via the dissociating benzylidene ligand exhibits inherent limitations.

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Scheme 5 Cross-metathesis of 15-propenyl estrone 9.

As the electron withdrawing amine salt (–NR2H+) on the benzylidene fragment of 4A weakens the O → Ru chelation and facilitates faster initiation of the catalytic cycle29 Grela and coworkers synthesized complex 13,37 bearing a quaternary ammonium group (–NR3+) that allowed various metathesis reactions to be conducted not only in traditional organic solvents but also in aqueous media.20d,e Complex 13 was synthesized by the reaction of 12 (1.1 equiv.) with G-II (1.0 equiv.) and CuCl (1.4 equiv.). Washing of the crude product with ethyl acetate and methanol afforded pure 13 (Scheme 6) as an air-stable, green micro-crystalline solid, soluble in acetonitrile, dichloromethane, methanol, methanol–water and ethanol–water 5[thin space (1/6-em)]:[thin space (1/6-em)]2 (v/v), respectively.

image file: c7cc06535c-s6.tif
Scheme 6 Synthesis of quaternary benzylidene tagged catalyst 13.

Due to the presence of the electron withdrawing group, this catalyst showed enhancement in the initial rate of reaction in the ring closing metathesis of diethyl 2-allyl-2-methallylmalonate (Table 2, entry 1) compared to catalyst HG-II. While the latter gave 81% yield after 1.5 h, catalyst 13 afforded 96% under the same conditions. Catalyst 13 showed also excellent activity in different RCM, enyne and cross metathesis reactions. Furthermore, complex 13 efficiently catalysed metathesis of various substrates in non-distilled, non-degassed protic media in air (Table 2, entries 2 and 3). Interestingly, the electron withdrawing quaternary ammonium group not only activated the catalyst chemically, but at the same time allowed its efficient separation after the reaction. Therefore, simple silica-gel filtration through a short pad of silica gel (20–40 × weight of the product) allowed for significant removal of ruthenium by-products (up to 12–68 ppm of residual Ru level in the crude products).

Table 2 Metathesis reaction catalysed by catalyst 13a
Entry Substrate Product Solvent Catalyst (mol%) Time (h) Conv. (%)
a Conditions c = 0.02 mol L−1, 25 °C. Conversions were determined by analysis of 1H NMR or GC-MS of the crude reaction mixture.
1 image file: c7cc06535c-u7.tif image file: c7cc06535c-u8.tif CH2Cl2 HG-II (5) 1.5 81
4 (5) 1.5 <1
13 (5) 1.5 96
2 image file: c7cc06535c-u9.tif image file: c7cc06535c-u10.tif CH2Cl2 13 (5) 0.5 98
MeOH/H2O (5[thin space (1/6-em)]:[thin space (1/6-em)]2 v/v) 13 (5) 0.5 92
EtOH/H2O (5[thin space (1/6-em)]:[thin space (1/6-em)]2 v/v) 13 (5) 0.5 99
3 image file: c7cc06535c-u11.tif image file: c7cc06535c-u12.tif MeOH/H2O (5[thin space (1/6-em)]:[thin space (1/6-em)]2 v/v) 13 (10) 25 99
4 image file: c7cc06535c-u13.tif image file: c7cc06535c-u14.tif CD3OD/D2O (5[thin space (1/6-em)]:[thin space (1/6-em)]2 v/v) 13 (5) 24 0
CD3OD/D2O (2[thin space (1/6-em)]:[thin space (1/6-em)]5 v/v) 13 (5) 24 99
5 image file: c7cc06535c-u15.tif image file: c7cc06535c-u16.tif EtOH/H2O (5[thin space (1/6-em)]:[thin space (1/6-em)]2 v/v) 13 (5) 24 83
H2O 13 (5) 24 99

It was also demonstrated that despite low water solubility, catalyst 13 is efficient for metathesis in neat water.38 Interestingly, increasing the water content in the water–methanol mixture led to much better results. For example, the CM of p-methoxystyrene (14d) did not proceed in a homogeneous mixture of MeOD/D2O (5[thin space (1/6-em)]:[thin space (1/6-em)]2 v/v), while the same reaction conducted in a heterogeneous fashion in MeOD/D2O (2[thin space (1/6-em)]:[thin space (1/6-em)]5 v/v) gave 99% of the corresponding stilbene 15d (Table 2, entry 4). The authors explained that catalyst 13 can be considered a weak amphiphile because it contains the hydrophilic ammonium iodide head group and the hydrophobic NHC ruthenium part and this complex can interact with both polar- and nonpolar-phase-forming micelles and therefore can act during the metathesis process as a surfactant.38 The advantageous effect of water was visible also in the RCM reaction of 7 (Table 2, entry 5) conducted under heterogeneous conditions. The above “micellar effect” was also observed in the case of metathesis reactions in water, using other tagged catalysts39 or with untagged ones but in the presence of various additives40 or ultrasound.41

Robinson et al. utilised the same quaternary ammonium tagged olefin metathesis catalyst 13, to be immobilised onto magnetically separable nanosized iron oxide particles.42 Due to poor substrate diffusion catalysts immobilised onto polymeric supports often result in lower activity.43 However, the new catalyst, reversibly immobilised on sulphonic acid-functionalised silica-coated iron oxide magnetic particles exhibited good activity in olefin metathesis combined with easy removal, reuse and regeneration. Iron oxide magnetic particles coated with a shell of silica were synthesized via a co-precipitation reaction. The sulphonic acid groups were introduced by reacting 3-mercaptotrimethoxysilane with freshly prepared Si-coated Fe3O4 MPs followed by oxidation of the mercapto groups with 30% H2O2. Salt 13 was then immobilised via the anion metathesis onto the sodium sulphonated iron oxide particles in dry, degassed CH2Cl2 to form the MP-appended catalyst 18 (see Scheme 7).

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Scheme 7 Electrostatic immobilisation of an Ru-catalyst on oxide magnetic particles.

Ring closing metathesis (RCM) of diethyl diallylmalonate (19) in dichloroethane and toluene was carried out using 0.68 mol% loading of 18 and showed >95% conversion after 2 hours. Importantly, magnetic separation of the catalyst particles gave a solution containing product 20 (the ICP-MS analysis showed 200 ppm of residual ruthenium contamination in the product). After recovery, the catalyst was reused for the same RCM reaction and this protocol was repeated up to five cycles. After the first two cycles, a gradual decrease in conversion was observed (smaller in toluene and greater in CH2Cl2). The observed decline of activity might be because of physical loss of the catalyst–MP construct, catalyst deactivation, or ruthenium alkylidene leaching from the MPs. The use of a high strength recovery magnet (0.45 T) minimised the problem of gradual loss of magnetic particles.

Towards contemporary ammonium NHC-tagged systems

Due to environmental concerns, there is increasing attention being paid to the use of alternative solvents, methanol, ethanol and water in particular, as reaction media. Although working in aqueous media, catalyst 13 cannot be called truly water soluble, and its applicability in neat water is limited. In this context the other tagged olefin metathesis catalysts found a number of applications.23,44,45 Grubbs and coworkers23,45 explored a number of modified catalysts 21–24, that show water solubility, thereby allowing reactions using water as the reaction medium (Fig. 5). Catalysts 21, 22, and 23 are quite unstable in water and only show limited activity for aqueous metathesis reactions other than ROMP.23,45a,b High molecular-weight Hoveyda-type catalyst 24 exhibits excellent activity towards ring-closing metathesis in an aqueous environment.45b However, 24 is a macromolecular, polydisperse catalyst that forms aggregates in water. Therefore, in 2007, the same authors described46 improved, small molecule ammonium-tagged Hoveyda-type catalysts, 25 and 26 (Scheme 8), that are active and stable in water, and showed good activity in ROMP, RCM and cross-metathesis reactions in an aqueous medium.
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Fig. 5 Different types of water soluble catalysts.

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Scheme 8 Synthesis and application of water soluble catalysts 25 and 26.

Catalysts 25 and 26 were synthesized by reacting the appropriate ruthenium benzylidene with styrenes 27 and 29 (Scheme 8). Treatment of 27 and 29 in the presence of CuCl with complexes G-II and 28 resulted in catalyst 25 and the corresponding Boc-protected complex, respectively. Deprotection of Boc with HCl/benzene solution gave catalyst 26. Importantly, catalyst 25 is soluble in water only at low concentrations (<0.01 M) while 26 readily dissolves in water. Both catalysts showed high reactivity toward challenging endo-norbornene monomer 30.45c,47 Importantly catalysts 25 and 26 also exhibited excellent activity in a range of ring-closing metathesis reactions in water. Even the RCM formation of trisubstituted olefin proceeds in good conversion with catalyst 25 (however somehow poorer for catalyst 26—the difference in reactivity was attributed to the relative stabilities of the two catalysts under the reaction conditions). Notably, catalyst 25 fully transformed the challenging substrate 32c to the desired product 33c (Table 3) while both 24 and 26 yielded significant amounts of cycloisomerised side product 33c′, which is believed to be produced by ruthenium hydrides generated during catalyst decomposition.45c,48,49 While this result is not properly understood, it is speculated to be related to the moderate aqueous solubility of 25 and/or its ruthenium hydrides. These solubility properties may make catalyst 25 more stable than catalysts 26 and/or its hydrides less active than those formed from catalysts 26. It should be also noted that 26, being a hydrochloride salt of a weak organic base (RNH2 × HCl) can act as a Brønsted acid in aqueous solutions. Surprisingly, 25 and 26 were not very successful in a ring-closing reaction of substrate 32b, nor in aqueous cross metathesis.

Table 3 Ring closing metathesis in watera
Catalyst Substrate Product Time (h) Conv. (%)
a Conditions: reactions were performed at 30 °C for cat 25 and 26 and room temp for cat 2445b with 5 mol% catalyst and an initial substrate concentration of 0.2 M in D2O. Conversions were determined by 1H NMR spectroscopy. b Conversion to 33c′.
24 image file: c7cc06535c-u17.tif image file: c7cc06535c-u18.tif 12 >95
25 24 >95
26 0.5 >95
24 image file: c7cc06535c-u19.tif image file: c7cc06535c-u20.tif 24 <5
25 24 <5
26 24 <5
24 image file: c7cc06535c-u21.tif image file: c7cc06535c-u22.tif 36 67 (+28)b
25 24 >95
26 4 36 (+59)b

Schanz and coworkers have developed two new types of ammonium tagged catalysts 35′ (a dynamic mixture of Ru-complexes) and 36′ where ammonium groups were introduced into the aryl rings of the NHC ligand.50 Both the catalysts were synthesized from the corresponding tertiary amine containing NHC-based catalyst 35 and 36 by the treatment of 2 equiv. of HCl (Scheme 9). Catalysts 35 and 36 exhibited interesting pH-sensitive solubility and activity profiles and showed excellent activity in an ROMP reaction of cyclooctene and RCM reactions. Catalysts 35 and 36 exhibited RCM of diallylmalonic acid in acidic protic media with only moderate activity at 50 °C and gave no response in an ROMP reaction of cationic 7-oxanorbornene derivative 37 under the same conditions. Complex 35′ was soluble in methanol but decomposed within a few hours at room temperature. Catalyst 36 had low solubility in water, being only soluble in its protonated form which is stable in aqueous solution in air for >4 h. Unfortunately, the protonation caused the aryl rings to become electron withdrawing, which in turn reduced the σ-donating properties of the NHC ligand and negatively affected the activity of the catalyst.

image file: c7cc06535c-s9.tif
Scheme 9 pH-Responsive phase tagged catalysts by Schanz.

The pH-dependent solubility profile was utilised to separate catalyst 36 from RCM reaction mixtures. After protonation, the Ru-complexes were converted into the dicationic species which should exhibit low solubility in the organic solvent. RCM of DEDAM or 3,3-diallypentadione (DAP) was conducted in low-polar organic solvents and the Ru-species were subsequently precipitated by addition of a strong acid. The Ru-species were removed by filtration, which could be followed by extraction with water to remove Ru more efficiently and the residual Ru level was measured without the use of chromatography or other purification. The residual Ru-levels were reached using filtration and subsequent extraction to 11 ppm, (close to pharmacopoeia requirements) and 24 ppm when only filtration was used.

Decorating the non-dissociating NHC ligand with hydrophilic groups to maintain homogeneity of the active propagating catalyst in aqueous solvent throughout the entire reaction cycle was also demonstrated nicely by Robinson and coworkers.51 As the ammonium groups directly attached to the aryl NHC-wings reduced the metathesis activity due to the electron withdrawing effect, Robinson designed a system where the ammonium groups were separated from the NHC aryl substituents by one –CH2 unit. Efforts towards this end had been met with success in terms of catalyst activity and practicality. Ru alkylidene catalyst 41 (Scheme 10) was synthesized from stable precursor 40 by treatment with trifluoroacetic acid (TFA) in CH2Cl2 followed by the removal of volatiles under reduced pressure. Precursor 40 was prepared in six steps from the benzonitrile 38 (Scheme 10). Reduction of 38 with LiAlH4, followed by treatment with Boc anhydride afforded carbamate 39. Polar catalyst 41 was tested in ring-closing metathesis (RCM) and cross-metathesis (CM) reactions in water for selected substrates that are insoluble in organic solvents.

image file: c7cc06535c-s10.tif
Scheme 10 Synthesis of water soluble di-ammonium complex 41.

Complex 41 in D2O showed high activity at 80 °C allowing for complete conversion of a model diene 42a to the cyclised product 43a in 10 minutes (Scheme 11). Remarkably, this catalyst showed lower activity at 50 °C and at room temperature. The RCM of diene 42a proceeded to 91% conversion in the presence of 41, equating to a TON of greater than 900. Similarly, the RCM of dienes 42b gave complete conversion to desired products 43b respectively. However, ring closing reaction of 32c gave the isomerised product along with the desired product. The catalyst also proved its excellent activity in CM in water. They reported for the first time CM of amine salts in aqueous systems. Self CM of long alkenyl ammonium salts both with a nonterminal alkene and a terminal methylene group resulted in almost quantitative conversion to the desired di-ammonium salts. Unfortunately, olefins containing linkers shorter (e.g.42d) than three carbons have no reactivity, possibly due to the formation of a non-productive Ru-nitrogen chelate 44.51 Curiously this type of substrate gave a CM product in organic solvents like dichloromethane.52

image file: c7cc06535c-s11.tif
Scheme 11 RCM and CM in D2O catalysed by 41.

Ru-complexes which contained quaternary ammonium chloride tagged on the benzylidene and/or the NHC backbone were developed (46, 48, 50) by Skowerski et al.53 The introduction of quaternary ammonium tagged on the NHC backbone was made in a hope to retain the catalytic activity similar to the parent HG-II and eliminate the disadvantages associated with the primary ammonium group.46 This was the first example of pH-neutral Ru-catalysts bearing a quaternary ammonium fragment, not just the protonated amine (–NH2 × HCl) on the NHC ligand. However, the synthesis of the catalysts was proven to be difficult using conventional methods, mostly because of high polarity of the ammonium fragments. Therefore, a completely new, more universal and user-friendly strategy of synthesis and purification of ammonium-tagged olefin metathesis catalysts was developed. Instead of using the quaternary ammonium group bearing precursors, the authors synthesized compounds 45, 47, and 49 containing tertiary amine groups, which were quaternarized in the last stage of the synthesis. This method made it possible to work with uncharged non polar compounds, which can be conveniently purified by standard techniques (distillation, column chromatography etc.). The synthesized Ru-complexes (45, 47, and 49), bearing basic trialkylamino groups, were easily and in high yield converted to ammonium tagged complexes (46, 48, and 50, Scheme 12) after treatment with methyl chloride. As expected, the alkylation reaction in the last step was selective to the piperazinic position only (Scheme 12). Complexes 46, 48 and 50 showed very good activity in RCM, CM and enyne metathesis reactions of challenging substrates, even in non-degassed solvents under an air atmosphere. As the catalysts are low molecular weight and pH-neutral, it is expected that they can be used for modification of water soluble biomolecules.54

image file: c7cc06535c-s12.tif
Scheme 12 Synthesis of quaternary ammonium tagged catalysts.

As the problems related to purification of the product from ruthenium residues are one of the main concerns in pharmaceutical and fine chemical production, the authors demonstrated a strategy for easy removal of Ru-residues from the product utilising the special traits of the newly synthesized catalysts. The authors decided to perform a metathesis reaction with a model water-insoluble substrate with the intention to extract 50 and any ruthenium containing impurities with water. Therefore, an RCM reaction of diethyl diallylmalonate 19 was conducted with 50 in non-degassed DCM in air. After 30 min the reaction was completed (Fig. 6a). To a green coloured reaction mixture D2O was added (Fig. 6b) and the two phase mixture was vigorously shaken. After the phases separated, the CH2Cl2 phase containing product 20 became colourless, and the Ru-complex migrated to D2O (Fig. 6c).55 Next, to check if the water phase contains the catalyst which is still active, a model substrate, Z-52 was added to the green D2O fraction and the reaction mixture was analysed by NMR, showing that the metathesis product, E-52 was formed with 94% yield after 1 h (Table 4).

image file: c7cc06535c-f6.tif
Fig. 6 Example of catalyst 50 extraction and reuse. Reproduced from ref. 53.
Table 4 Metathesis reactions in neat water (D2O)a
Substrate Product [Ru] (mol%) Time (h) Yield (%)
a Yields calculated from NMR.
image file: c7cc06535c-u23.tif image file: c7cc06535c-u24.tif 48 (5) 24 77
image file: c7cc06535c-u25.tif image file: c7cc06535c-u26.tif 48 (2.5) 2.5 96
image file: c7cc06535c-u27.tif image file: c7cc06535c-u28.tif 46 (5) 5 71

Another type of quaternary ammonium tagged catalyst was reported by Skowerski et al. in the same year.56 The authors showed that the presence of a polar quaternary ammonium group helped for efficient separation of ruthenium impurities after the reaction leading to surprisingly low ruthenium contamination levels (usually below 5 ppm) after a simple and inexpensive purification step. Again synthesis via quaternary tag containing precursors was judged problematic. Although imidazolium salt 53 was prepared successfully, the next step of carbene generation and assembly of the complex failed to generate the expected product.57 Hence, the already elaborated procedure of the last-stage quarternization was used to obtain catalysts 57, 58, and 60 from commercially available N,N-dimethyl allylamine. The final step consisted of methylation of the neutral complexes with methyl iodide or methyl chloride to afford catalysts 57, 58, and 60 in high yields (Scheme 13). As in the previous case, the synthesis does not require purification other than crystallization. Complexes 57, 58, and 60 showed excellent activity in RCM, CM and enyne reactions in refluxing dichloromethane (see Table 5) in the presence of 1 mol% of the catalyst. After completion, the reaction mixture was either extracted five times with water or filtered through a short plug of silica gel, followed by elution of the products with a small amount of CH2Cl2. These procedures were usually very effective, and the ruthenium concentrations in the products were lower than 5 ppm (Table 5).

image file: c7cc06535c-s13.tif
Scheme 13 Synthesis of catalysts 57, 58 and 60.
Table 5 Metathesis reactions catalysed by Ru-complexes 57, 59, and 61a
Substrate Product Cat Yield (%) Ru (ppm)
a Conditions: catalyst 1 mol%, DCM, 40 °C, C = 0.05 M. b Filtration. c Extraction.
image file: c7cc06535c-u29.tif image file: c7cc06535c-u30.tif 57 97 2.8b
58 98 2.6b
60 93 0.8b
60 89 <0.004c
image file: c7cc06535c-u31.tif image file: c7cc06535c-u32.tif 57 97 1.7b
58 98 0.8b
60 90 <0.04c

Taking into account such low levels of Ru contamination in crude unpurified products, it can be considered that the above mentioned quaternary ammonium tagged complexes can act as self-scavenging catalysts.13e However, in the case of some “problematic substrates” such as proline derivative 61a and aromatic amide 61b, that are known to bind to ruthenium, the residual Ru-level in the crude products after the RCM was still relatively high (Table 6). However, in recent work it was shown that catalyst 58 works very well with the newly developed Ru-scavenger SnatchCat (64).13e For example, crude products 62a and 63b obtained in a reaction with 58 showed ruthenium levels equal to 5.9 and 15 ppm. But, the same products contained only 1.2 and 3 ppm of Ru (see Table 6) when the scavenger was added at the end of the reaction.

image file: c7cc06535c-u33.tif

Table 6 Self-scavenging catalyst 5
Substrate Catalyst Scavenger Ru (ppm)
61a HG-II 1530
61a HG-II 64 30
61a 58 5.9
61a 58 64 1.2
61b 58 15.0
61b 58 64 3.0

To check the influence of the length of the spacer between the NHC ligand and the onium tag, Kośnik et al. prepared quaternary ammonium tagged Ru-catalyst 68.58 The NHC salt 65 was conveniently obtained from 9-decen-1-ol. Having NHC salt 65 in hand, Grubbs type complex 66 was synthesized and then converted to 2-isopropoxybenzylidene complex 67 following the usual method of last stage quaternisation. N-Alkylation of the neutral complex with methyl chloride afforded catalysts 68 in high yield (Scheme 14). The complex showed good activity in RCM and CM reactions at 40 °C (see Scheme 15). Products of olefin metathesis reactions can be readily purified from Ru-residues by simple filtration of the reaction mixture through a small amount of silica gel and the Ru content in such isolated crude products by ICP-MS was shown to be in the range of 0.13–0.79 ppm. Though this catalyst works well for model substrates (Scheme 15), the authors concluded that the longer spacer does not show a much better result than just one –CH2-unit present in the original Skowerski's tagged complexes.

image file: c7cc06535c-s14.tif
Scheme 14 Synthesis of catalyst 68.

image file: c7cc06535c-s15.tif
Scheme 15 Metathesis reaction using catalyst 68.

Another type of ruthenium-based pre-catalyst containing an ionic tag covalently connected to an N-heterocyclic carbene (NHC) ligand was reported by Maduit et al.59 These novel complexes, bearing a polar benzimidazolium group, were easily prepared from commercially available N-allyl benzimidazoles. Final quaternization was successfully carried out by microwave irradiation in neat methyl iodide at 120 °C and led to the desired pre-catalysts 75a and b in very good isolated yields, 90% and 88%, respectively (Scheme 16).

image file: c7cc06535c-s16.tif
Scheme 16 Quaternary ammonium tagged catalysts 75a, and 75b.

Both catalysts showed good activity in RCM, CM (Scheme 17) as well as enyne metathesis. In order to separate the catalyst, the reaction mixture was deposited on dry silica (2 g of SiO2 per 0.0025 mmol of catalyst used) and the metathesis product was eluted with the appropriate organic solvent. The presence of highly polar N-methyl benzimidazolium tags on the NHC ligand in catalysts 75a and b allowed for very efficient separation of the residual ruthenium, yielding crude products containing as low as 1 ppm of residual Ru. However, these catalysts exhibited rather low activity towards sterically hindered olefins.

image file: c7cc06535c-s17.tif
Scheme 17 Metathesis in the presence of catalysts 75a and b.

2-Alkoxybenzylidene catalysts like HG-II and its analogues were previously immobilised on silica, however, these systems are stable only in nonpolar solvents like pentane or hexane, and even toluene can wash the Ru-complex completely off the support.16 As it was described above, the quaternary ammonium tag on the NHC ligand brings a bonus to the catalyst making it cling strongly to silica gel. Exploring this interesting property Skowerski et al. demonstrated a new heterogeneous catalytic system, compatible with more polar solvents and substrates.60 The ammonium-tagged ruthenium complex, 81 (Scheme 18) was noncovalently immobilised in a straightforward and universal manner on several widely available commercial solid materials. At first, the catalyst was immobilised on activated carbon (charcoal, C*), which is known to have a high surface area.61 Addition of activated carbon to a solution of 81 in dichloromethane or AcOEt/MeOH 95[thin space (1/6-em)]:[thin space (1/6-em)]5 v/v and subsequent removal of the solvent in vacuo resulted in complete deposition of the catalyst. The obtained material was dried and used directly in metathesis reactions. The catalyst supported on activated carbon was first tested in an RCM reaction of 19. The reaction was carried out at 80 °C in toluene at 0.2 M concentration, and full conversion of 19 was observed after 20 minutes. Then, 81 was deposited on several other widely available solid supports, like silica gel (flash chromatography grade), neutral aluminium oxide, cotton-viscose wool (cosmetic) and even filter paper. The immobilised catalysts were used under the same RCM reaction conditions in order to compare their reactivity. The catalyst supported on neutral aluminium oxide (81/Al2O3) showed the lowest activity, whereas the catalyst supported on silica gel (81/SiO2) exhibited the fastest initiation rate among all tested materials, giving over 99% of conversion of 19 within 10 minutes. Notably, the split test during RCM was also performed to prove the heterogeneity of the process.

image file: c7cc06535c-s18.tif
Scheme 18 Synthesis of ammonium-tagged complex 81.

Both RCM and CM were studied for a range of substrates, using the most active supported complex (81/SiO2) in toluene and in all cases the immobilised catalyst showed excellent activity. Importantly, filtration through a piece of cotton and evaporation of the volatiles were enough to obtain pure products with a very low Ru content of less than 1 ppm.

The quaternary ammonium tagged catalyst can be immobilised on iron-powder to prepare a very simple magnetically separable catalyst which can be removed from the reaction mixture easily to get a highly pure product with a very low residual ruthenium content. Complex 81 was immobilised on iron powder, to form 81/Fe and was tested in RCM of 19. After turning off the stirrer, the Fe-supported material clung to the mixing element (Fig. 7B) and then it was mechanically removed, providing the colourless product in excellent yield (93%) with a low ruthenium content (25 ppm, Fig. 7C). Notably, this quaternary ammonium tagged catalyst can also be immobilised on commercially available palladium on carbon (10 wt% Pd/C) resulting in a novel heterogeneous catalyst for a tandem olefin metathesis-hydrogenation transformation.60 The above examples show the universality and simplicity of the immobilisation of ammonium tagged 81. The disadvantage of this system is, however, the low recyclability.

image file: c7cc06535c-f7.tif
Fig. 7 Removal of 81/Fe and subsequent recovery of 81. (A) Stirred reaction mixture containing 81/Fe, (B) after stirring ceased, (C) catalysts 81-Fe attached to the magnetic rod and removed, (D) catalyst 81/Fe being washed with CH2Cl2, (E) CH2Cl2 solution of 81 removed from Fe powder. Reproduced from ref. 60.

Ammonium tagged catalysts 48, and 83 (Fig. 8) were linker-free immobilised on the surface of lamellar zeolitic supports (MCM-22, MCM-56, MCM-36) and were compared with the same complexes on SBA-15.62 Usually zeolites were not considered as perspective supports for the immobilisation of Ru metathesis catalysts due to the small diameters of their pores (<1 nm). Hence, a lamellar (also called two-dimensional) zeolite with a high surface area and layered structure was synthesized by using a newly reported method.63 Then, complexes 48 and 83 were immobilised by mixing their solutions with dry supports at room temperature to prepare immobilised systems 48/MCM-22 (1.1 wt% Ru), 48/MCM-56 (1.1 wt% Ru), 48/MCM-36 (0.7 wt% Ru), 83/MCM-22 (0.9 wt% Ru), and 48/SBA-15 (1.2 wt% Ru). The immobilised catalysts exhibited high stability, which was established by a very low Ru leaching (from 0.1 to 0.6% of original Ru content) and increased possibility of catalyst reuse (five times with 99% conversion).

image file: c7cc06535c-f8.tif
Fig. 8 Catalysts used for immobilisation on zeolites.

The catalytic activity of MCM-immobilised catalysts was studied in RCM of (−)-β-citronellene 84 and N,N-diallyl-2,2,2-trifluoroacetamide 87, and in self-metathesis and cross-metathesis of methyl oleate 89 and also was compared with that of an SBA-15 system (48/SBA-15, pore diameter 6.6 nm) (Scheme 19). In RCM reactions, the activity decreased in the following order MCM-22 ≈ MCM-56 > SBA-15 > MCM-36. The layered structure of MCM-22 and MCM-56 most likely ensured better access of the reactants to the catalytically active centers as compared to the case of the SBA-15 based hybrid catalyst. Interestingly, in self-metathesis of methyl oleate, 48/SBA-15 was found to be the most active; the reaction with 48 on zeolite supports proceeded slowly exhibiting a large induction period. In contrast to that, in the cross-metathesis of methyl oleate with cis-3-hexenyl acetate over 48/MCM-22, the induction period was negligible and the reaction rate slightly exceeded that catalysed by 48/SBA-15. This behavior may indicate a slow initiation by methyl oleate due to its slow coordination to the Hoveyda–Grubbs type catalysts immobilised on the zeolite supports.64

image file: c7cc06535c-s19.tif
Scheme 19 Metathesis in the presence of immobilised catalysts.

Work on making the immobilised NHC–ammonium tagged catalysts fully recyclable was progressing and soon Skowerski and co-workers reported an exceptionally stable and able to be multiply recycled highly recyclable SBA-15 supported catalyst 91 bearing an ammonium tagged N-heterocyclic carbene ligand.65 A light-green solid 91/SBA-15 containing 1 wt% of the ruthenium complex was synthesized by addition of 91 (Table 7) to a suspension of SBA-15 in CH2Cl2 and then, used in a metathesis reaction. Interestingly, the supported catalyst 91/SBA-15 provided the product of the RCM reaction of 7 with higher TON than those exhibited by an unsupported catalyst (TON 5600 and 8100 for 91 and 91/SBA-15, respectively). It also showed higher TON than sterically less hindered catalyst 48/SBA-15 (TON 3800). Importantly, the RCM reactivity of 7 (1 M concentration and 45 °C), in the presence of 20 ppm 91/SBA-15 resulted in 71% GC yield which corresponds to a TON of 35 500 (TOF10min 1590 min−1). The catalyst showed excellent conversion in the RCM reactions leading to the five- to seven membered rings in the presence of only 50–200 ppm of catalyst. Notably, even more challenging CM reactions required only slightly higher catalyst loading of 250–500 ppm. Simple filtration of the reaction mixtures through a Schott funnel and removal of solvent was sufficient for product purification and resulted in residual ruthenium in the crude products in the range of 0.33–6.3 ppm.

image file: c7cc06535c-u34.tif

Table 7 Metathesis promoted by 92/SBA-15a
Sub Cat (ppm) Conv.b (%) TON TOF Ru (ppm)
a Reaction conditions: toluene, 1 M, 45 °C. b Determined by GC. c 60 °C, 4 equiv. of 72. d Time after which TOF was calculated. e E/Z 7/3.
92 50 87 17[thin space (1/6-em)]400 1126d (10 min) 0.73
93 + 72c 250 68e 2720 141 (10 min) 0.34

This unprecedentedly stable heterogeneous olefin metathesis catalyst showed also excellent recyclability. In RCM of 7 in toluene (0.2 M) at 30 °C with 0.1 mol% of the catalyst it was possible to recycle 91/SBA-15 23 times (average conversion of 66%, cumulative TON 15 180) when each run was conducted for 1 h. The promising stability made the authors test this catalyst in a continuous flow (CF) reactor. In the RCM of 7 carried out in the CF mode (tubular flow reactor equipped with degassers) in ethyl acetate (0.2 M, 30 °C, flow rate 40 μL min−1) the activity of 91/SBA-15 (0.25 wt%) was sufficient to stay active for more than 16 h (average conversion 66%, TON 9149). Addition of 2-isopropoxystyrene (required for the catalyst's self-regeneration according to the “boomerang” mechanism) to the solution of 7 improved the stability of 91/SBA-15 allowing for up to 50 h of continuous reaction (average conversion 50%, TON 21[thin space (1/6-em)]660). The role of styrene was explained as helping to restore the resting state of the catalyst according to the boomerang mechanism. The high stability and recyclability of catalyst 91 allowed the authors to conclude that replacement of Mes substituents in the NHC ligand with more bulky DIPP “wings” is the most probable reason for the such dramatic stabilization and recyclability improvement of this ruthenium complex.

A small library of ammonium tagged Ru-catalysts were immobilised by Chmielewski et al.66 inside the Metal–Organic Framework (MOF)67 material (Al)MIL-101-NH2. Ruthenium alkylidene complexes bearing ammonium-tagged NHC ligands were successfully supported inside (Al)MIL-101-NH2·HCl and then the catalytic activity in metathesis was investigated. Heterogeneous 48@(Al)MIL-101-NH2·HCl showed high activity with a range of RCM substrates even at 0.5 mol% loading (Scheme 20). Again, the more stable complex 91 immobilised inside (Al)MIL-101-NH2·HCl exhibited very high TON up to 8900 in the RCM reaction of 19 in toluene at room-temperature.68

image file: c7cc06535c-s20.tif
Scheme 20 Metathesis promoted by 48@MOF.

After obtaining excellent result with 91@MOF in batch reactions, the authors extended the applications of the MOF supported catalyst to continuous flow conditions. The flow reactor was made from a short Teflon tube of 1.5 mm internal diameter, filled with (Al)MIL-101-NH2·HCl containing 1% of 91 (0.30 μmol, 120 ppm with respect to the total amount of substrate passing through), forming a ca. 5 cm thick catalyst bed. The reactor was connected to a syringe pump. Then, 0.5 M solution of 19 was passed through the bed at 40 °C at a rate of 10 μL min−1 for 9 h. The retention time of the substrate on the bed was less than 7 min and the conversion was >90% after the first 1 h, giving an average value of 57% after 9 h showing relatively high TON of 4700. Gratifyingly, due to very strong bonding of the catalyst by noncovalent forces, low leaching was observed and Ru-contamination in the crude product was found to be below the detection limit of ICP MS (0.02 ppm).

The results shown in Scheme 20 suggest that the crystalline, highly porous, and easily tunable structures of MOFs67 offer unique environments for noncovalent immobilisation of ammonium tagged Ru-catalysts. After immobilisation, catalytic centers in MOFs are located inside well-defined nanoscopic voids in a crystalline framework, showing new opportunities to control shape selectivity, regioselectivity, and enantioselectivity of the immobilised catalysts.


The ideal tagged or immobilised catalyst shall exhibit, if well designed, at least the same level of activity and selectivity as its non-tagged analogue, but at the same time shall display some additional traits, such as being effortlessly separated from the reaction mixture, possessing compatibility with polar solvents, high recyclability and others. Ru-complexes bearing onium (usually: quaternary ammonium) tagged ligands show many of the above advantages and can be used in both homogeneous and heterogeneous systems, including water.69,70

Even if the scientific debate about the validity of the “Boomerang” mechanism is not yet concluded,71 the experimental results presented in the literature are rather strongly suggesting that tagging via the non-dissociating ligand, even if more difficult synthetically, is in the long term a much better strategy, as it allows the homogeneity of the active propagating catalyst species to be maintained throughout the entire reaction cycle. This can result in low leaching even in polar solvents, and minimal residual ruthenium content in the crude products, a factor that is important not only in pharmaceutical production. Notably, the ammonium NHC-tagged catalysts were recently observed to give very promising results also in a continuous flow reaction.

We hope that with these selected72,73 and only very briefly described examples we were able to convince the reader that the Ru-complexes bearing quaternary ammonium tagged NHC ligands create a privileged family of olefin metathesis catalysts that can offer a new premises also in the industrial context.

Conflicts of interest

There are no conflicts to declare.


The authors are grateful to the Foundation for Polish Science for the Team-Tech Grant. The idea of the title and motto of this Feature Article appeared during a visiting professorship in Singapore, for which KG is grateful to the Foundation for Polish Science.

Notes and references

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