Scheme 2: Catalytic cycle for metathesis proposed by Chauvin. Ruthenium-based catalysts are among the most tolerant and stable metathesis catalysts and are widely employed for metatheses in aqueous media [21,22]. There is a growing interest in performing metathesis reactions in water as a greener alternative to chlorinated or aromatic solvents [23,24].
Green Chemistry and Metathesis Including Benefits and the Applications of Green Chemistry
Water is inexpensive, non-flammable, non-toxic and environmentally friendly, all characteristics that make it an ideal solvent. Furthermore, water is the media of biochemical reactions, and metathesis is a bioorthogonal reaction that can be exploited in a biological setting. This review focuses on the recent improvements of olefin metathesis in aqueous media and the resulting applications in bioinorganic chemistry and chemical biology. Figure 1: Some of the most representative catalysts for aqueous metathesis.
The first examples of aqueous metathesis were reported in the late s [25,26]. However, these catalysts had limited usefulness due to a slow initiation rate and detrimental effect of water on the reaction mixture. Water can lead to the formation of catalytically inactive Ru hydride species. In this specific case, the formation of the metal hydride complex is believed to occur during the work-up with methanol. Dinger and Mol also carried out studies supporting this theory . The detrimental effect of water is more likely to occur at high temperatures and in the presence of a base. Scheme 4: Degradation pathway of first generation Grubbs catalyst G-I in methanol.
The proposed mechanism for the degradation of G-I occurs via alcohol dehydrogenation followed by decarbonylation of the ruthenium hydride Thus, the presence of H 2 O ca. Table 1: RCM of challenging substrate 17 in air and in the presence of water. Hydrophobic catalysts are able to perform metathesis in aqueous mixtures. Scheme 5: Synthesis of Blechert-type catalysts 19 and These results suggest how important the role of the hydrophobic effect is on the catalytic activity of the reaction.
Lipshutz and co-workers generalized the application of a three-component non-ionic surfactant for numerous reactions in water, including olefin metathesis . Figure 2: Chemical structure and components of amphiphilic molecule PTS and derivatives. In water, PTS forms nanomicelles which contribute to the solubilization of water-insoluble substrates and catalysts, thus contributing significantly to improve olefin metathesis yields. The positive effect of this strategy was demonstrated by Lipshutz and co-workers for RCM and for CM reactions [40,41]. The work of Lipshutz and co-workers is extensively reported elsewhere [21,33,42,43].
Conditions a : The reaction was car Pauly et al. Alginate amide beads perform best in neat water as they facilitate the diffusion of hydrophobic substrates through the beads. However, the reaction rates are very low compared to the non-encapsulated catalyst G-II. Despite their high activity and remarkable stability, they are sparingly soluble in neat water, thus challenging their use as homogeneous catalysts in pure water.
To overcome this challenge, a small amount of organic co-solvent or surfactant is frequently used. The removal of residual ruthenium traces is a crucial step for most industrial applications . Some of the difficulties highlighted above can be overcome by the incorporation of quaternary ammonium tags, which simplify product purification as well as olefin metathesis in pure water [52,53].
Grubbs and co-workers were the first to introduce water-soluble catalysts which displayed metathesis activity in aqueous media . In , Grubbs et al. Scheme 8: Living ROMP of norbornene derivatives 35 and 36 with phosphine-based catalysts bearing quaternary ammonium tags 1 and 2. Scheme 8: Living ROMP of norbornene derivatives 35 and 36 with phosphine-based catalysts bearing quaternary a However, catalysts 1 and 2 are unstable in water and their use is limited to ROMP.
A few years later, Grubbs and co-workers reported the use of NHC complexes containing quaternary ammonium tags . Catalysts 3 and 4 showed modest activities in the ROMP of substrate Scheme 9: Synthesis of water-soluble catalysts 3 and 4 bearing quaternary ammonium tags. In , Grela and co-workers reported the synthesis of the metathesis catalyst 5 also bearing a quaternary ammonium tag .
Scheme In situ formation of catalyst 5 bearing a quaternary ammonium group. In a recent publication, catalyst 9 was used for an aqueous living ring-opening metathesis polymerization-induced self-assembly ROMPISA. The authors demonstrated the possibility of performing living ROMP in water selecting a quaternary ammonium-based phenyl norbornene carboximide as core-forming monomer .
This polymer is currently being investigated for possible biomedical applications. There is no obvious explanation why the RCM of 52 does not occur under identical conditions. Catalysts 9 , 47 and 48 display good activities for the ring-closing of substrates 54 and 56 , for the self-metathesis of allyl alcohol 59 and the cis — trans isomerization of cis -butenedienol Z - Table 4: Aqueous metathesis of selected substrates with water-soluble catalysts bearing quaternary ammonium groups.
Metathesis catalysts bearing quaternary ammonium groups provide an attractive alternative to classical ruthenium catalysts.
Safe and generalizable catalyst for carbonyl-olefin metathesis reaction
Although they do not represent a great improvement in terms of catalytic activity, they significantly improve the water solubility and facilitate the removal of ruthenium residues from reaction mixtures [52,59]. Upon reaction completion, the catalyst is extracted from the organic reaction mixture with D 2 O and re -used for the isomerization of cis -butenediol Z - 58 in water. Scheme Catalyst recycling of an ammonium-bearing catalyst. Directed evolution allows an iterative improvement by successive rounds of mutation and screening the performances of genetically-encoded enzymes.
Hypothesizing that this tool may be applicable to the optimization of artificial metalloenzymes ArMs for olefin metathesis, a new-to-nature bioorthogonal reaction might be introduced in a biological system. ArMs result from the incorporation of a catalytically active organometallic moiety within a protein scaffold. Such biohybrid catalysts enable a chemogenetic optimization of their catalytic performances. As olefin metathesis is bioorthogonal, it offers attractive features for the manipulation of biological systems. Comprehensive reviews on ArMs can be found elsewhere [63,64].
Green Chemistry and Metathesis Including Benefits and the Applications of Green Chemistry
Several artificial metalloenzymes able to perform metathesis, coined artificial metathases, have been reported since The artificial metathases rely on different strategies to anchor the organometallic moiety to the protein scaffold and include supramolecular, dative, as well as covalent anchoring. Ward and co-workers reported the first artificial metathase based on the biotin— strept avidin technology in  , thus expanding the set of reported reactions with this class of ArMs . This exceptional affinity warrants the ArM remaining assembled throughout catalysis.
Biotinylated HG-type catalysts anchored within strept avidin through supramolecular interactions were tested in the RCM of N , N -diallyltoluenesulfonamide 21 in aqueous media, achieving encouraging results at pH 4 and in the presence of MgCl 2 . Ward and co-workers reported another artificial metathase based on the dative anchoring of a biotinylated HG-type catalyst to human carbonic anhydrase II hCAII in . Scheme Selection of artificial metathases reported by Ward and co-workers ArM 1 based on biotin— strept a From the different organometallic moieties tested, the catalyst containing 2,6-diisopropylphenyl groups on the NHC ligand afforded the highest activity for the aqueous RCM of N , N -diallyltosylamine Metathase ArM 2 performed best in phosphate buffer at pH 5.
Reactions carried out in triplicate.
Why do ions exchange partners?
Jeschek et al. Tethering an OmpA leader sequence to the N- terminus of streptavidin Sav allowed the secretion and assembly of functional tetrameric Sav in the periplasm of E.
The passive diffusion of the biotinylated Hoveyda—Grubbs catalyst 60 through the outer membrane of E. Figure 3: In vivo metathesis with an artificial metalloenzyme based on the biotin—streptavidin technology. Matsuo et al. Scheme Artificial metathase based on covalent anchoring approach. In , Hilvert and co-workers reported an ArM based on the covalent anchoring of a metathesis catalyst to a small heat shock protein from M. Jannaschii MjHSP . Scheme Assembling an artificial metathase ArM 4 based on the small heat shock protein from M. Jannaschii MjHSP.
HG-type catalysts bearing a maleimide moiety with different spacer lengths 69 — 71 were covalently anchored to a cysteine of the expanded nitrobindin variant NB4exp. The coupling reaction in aqueous buffer at pH 7. The HG All three ArMs converted the three substrates with good yields of products 76 , 77 and Gebbink and co-workers anchored the HG-type catalyst 79 to cutinase, a serine hydrolase . The phosphonate ester moiety acts as a suicide inhibitor forming an irreversible covalent bond to a serine residue present in the active site of the enzyme.
Scheme Artificial metathase based on cutinase ArM 8 and resulting metathesis activities. Synthetic compounds are increasingly being used as chemical tools to scrutinize and modulate biological systems . Olefin metathesis is a prime example of bioorthogonal reactions and the ruthenium catalysts display good stability and chemoselectivity. The development of well-defined ruthenium-based catalysts increased the number of olefin metathesis applications in chemical biology thanks to their tolerance against various functional groups such as amides, alcohols and carboxylic acids.
However, one major hurdle for olefin metathesis in chemical biology remains the necessity to perform catalysis under mild conditions in buffered aqueous media. Kiessling and co-workers were the first to use ROMP for the synthesis of biologically active polymers and for the synthesis of multivalent antigens to probe signaling pathways in vivo [81,82]. In , Davis and co-workers performed site-selective protein modification through aqueous CM  , thus expanding the catalytic repertoire of protein modification with transition-metal catalysts .
A variant of subtilisin from Bacillus lentus containing a single cysteine SBL-SC was modified by direct allylation to install an allyl-sulfide on the surface of the protein. Scheme Site-specific modification of proteins via aqueous cross-metathesis. The protein structure is based To achieve this challenging reaction, equivalents equiv of HG-II catalyst were employed in a reaction mixture containing 0.
Remakably, no conversion was observed in the absence of MgCl 2 , which prevents the non-productive binding of the amino acid side chains to ruthenium. The authors suggested that the positive effect of allyl sulfides may be due to the coordination of the sulfur atom to the ruthenium center, favoring the formation of the metallacyclobutane intermediate. The modest activities of butenyl and pentenyl sulfides were rationalized by the formation of five and six-membered ring chelates. The aqueous CM with allyl sulfides was also exploited by Hunter et al.
The work carried out by Davis and co-workers led to the metabolic incorporation of unnatural amino acids uAAs bearing a terminal alkene as CM substrates for protein modification . The authors investigated the possibility to incorporate methionine Met analogues in a Met-auxotrophic strain of E.
Scheme a Allyl homocysteine Ahc -modified proteins as CM substrates. The conjugated protein can be selectively pulled-down with avidin beads and analyzed by tandem MS after tryptic digestion. This strategy suggests that CM reactions can be integrated in the toolbox of chemical proteomics. Recently, following a similar strategy, Lu et al. However, these reactions are not catalytic as they require equivalents of the G-III catalyst.
Scheme On-DNA cross-metathesis reaction of allyl sulfide Abstract The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon—carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries1. These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism2.
While the corresponding carbonyl—olefin metathesis reaction can also be used to construct carbon—carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl—olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl—olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst.
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This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis. Journal information: Nature. More from Chemistry. Please sign in to add a comment. Registration is free, and takes less than a minute. Read more. Your feedback will go directly to Science X editors.
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Scope of the iron III -catalysed carbonyl—olefin metathesis reaction. Credit: c Jacob R. Schindler, Nature , — 19 May doi More information: Jacob R. Ludwig et al. Iron III -catalysed carbonyl—olefin metathesis, Nature DOI: This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission.
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