Reactivity and Selectivity in Ruthenium Sulfur‐Chelated Diiodo Catalysts

Eivgi O., Phatake R.S., Nechmad N.B., Lemcoff N.G.

The most important means for tuning and improving a catalyst's properties is the delicate exchange of the ligand shell around the central metal atom. Perhaps for no other organometallic-catalyzed reaction is this statement more valid than for ruthenium-based olefin metathesis. Indeed, even the simple exchange of an oxygen atom for a sulfur atom in a chelated ruthenium benzylidene about a decade ago resulted in the development of extremely stable, photoactive catalysts. This Account presents our perspective on the development of dormant olefin metathesis catalysts that can be activated by external stimuli and, more specifically, the use of light as an attractive inducing agent.The insight gained from a deeper understanding of the properties of cis-dichlororuthenium benzylidenes opened the doorway for the systematic development of new and efficient light-activated olefin metathesis catalysts and catalytic chromatic-orthogonal synthetic schemes. Following this, ways to disrupt the ligand-to-metal bond to accelerate the isomerization process that produced the active precatalyst were actively pursued. Thus, we summarize herein the original thermal activation experiments and how they brought about the discoveries of photoactivation in the sulfur-chelated benzylidene family of catalysts. The specific wavelengths of light that were used to dissociate the sulfur-ruthenium bond allowed us to develop noncommutative catalytic chromatic-orthogonal processes and to combine other photochemical reactions with photoinduced olefin metathesis, including using external light-absorbing molecules as sunscreens to achieve novel selectivities. Alteration of the ligand sphere, including modifications of the N-heterocyclic carbene (NHC) ligand and the introduction of cyclic alkyl amino carbene (CAAC) ligands, produced more efficient light-induced activity and special chemical selectivity. The use of electron-rich sulfoxides and, more prominently, phosphites as the agents that induce latency widened the spectrum of light-induced olefin metathesis reactions even further by expanding the colors of light that may now be used to activate the catalysts, which can be used in applications such as stereolithography and 3D printing of tough metathesis-derived polymers.

Kovačič S., Slugovc C.

This review article summarises the academic work in the fields of initiator development, polymer chemistry and physics, composites, self-healing composites, novel processing opportunities and macro-as well as microporous materials.

Segalovich-Gerendash G., Rozenberg I., Alassad N., Nechmad N.B., Goldberg I., Kozuch S., Lemcoff N.G.

Herein we show the design and synthesis of an electron rich, sulfoxide-chelated, ruthenium benzylidene. In contrast to previously reported sulfoxide-chelated ruthenium benzylidenes, this complex is...

Kand D., Liu P., Navarro M.X., Fischer L.J., Rousso-Noori L., Friedmann-Morvinski D., Winter A.H., Miller E.W., Weinstain R.

Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable photoprotecting groups has the potential to further expand the established utility of the photoactivation strategy in biological applications by offering higher tissue penetration, diminished phototoxicity, and compatibility with other light-dependent techniques. Nevertheless, a critical barrier to such applications remains the significant hydrophobicity of most visible-light excitable photocaging groups. Here, we find that applying the conventional 2,6-sulfonation to meso-methyl BODIPY photocages is incompatible with their photoreaction due to an increase in the excited state barrier for photorelease. We present a simple, remote sulfonation solution to BODIPY photocages that imparts water solubility and provides control over cellular permeability while retaining their favorable spectroscopic and photoreaction properties. Peripherally disulfonated BODIPY photocages are cell impermeable, making them useful for modulation of cell-surface receptors, while monosulfonated BODIPY retains the ability to cross the cellular membrane and can modulate intracellular targets. This new approach is generalizable for controlling BODIPY localization and was validated by sensitization of mammalian cells and neurons by visible-light photoactivation of signaling molecules.

Nechmad N.B., Phatake R., Ivry E., Poater A., Lemcoff N.G.

The development of selective olefin metathesis catalysts is crucial to achieving new synthetic pathways. Herein, we show that cis-diiodo/sulfur-chelated ruthenium benzylidenes do not react with strained cycloalkenes and internal olefins, but can effectively catalyze metathesis reactions of terminal dienes. Surprisingly, internal olefins may partake in olefin metathesis reactions once the ruthenium methylidene intermediate has been generated. This unexpected behavior allows the facile formation of strained cis-cyclooctene by the RCM reaction of 1,9-undecadiene. Moreover, cis-1,4-polybutadiene may be transformed into small cyclic molecules, including its smallest precursor, 1,5-cyclooctadiene, by the use of this novel sequence. Norbornenes, including the reactive dicyclopentadiene (DCPD), remain unscathed even in the presence of terminal olefin substrates as they are too bulky to approach the diiodo ruthenium methylidene. The experimental results are accompanied by thorough DFT calculations.

Nechmad N.B., Phatake R., Ivry E., Poater A., Lemcoff N.G.

Herman J.A., Seazzu M.E., Hughes L.G., Wheeler D.R., Washburn C.M., Jones B.H.

We report a novel approach whereby cross-linked polybutadiene (PB) networks can be depolymerized in situ based on thermally activated alkene metathesis. A commercially available latent Ru catalyst,...

Wyrębek P., Małecki P., Sytniczuk A., Kośnik W., Gawin A., Kostrzewa J., Kajetanowicz A., Grela K.

A wide set of 65 diverse Ru metathesis catalysts was investigated in the ethenolysis reaction of biosourced ethyl oleate to allow the comparison between the catalyst structure and its activity and selectivity. Handling of the oleic substrate, weighing of the catalysts, and charging the reactor were done in air, with exclusion of a glovebox or Schlenk techniques. A catalyst bearing the unsymmetrical N-heterocyclic ligand featuring a thiophene fragment (Ru-63) was selected to offer the best combination between high selectivity and sufficient activity under conditions mimicking oil industry practice. A proof-of-concept large-scale ethenolysis experiment was also done with the selected catalyst to prove its high selectivity at the 1 L scale reaction with a 90% pure non-distilled substrate.

Ivry E., Nechmad N.B., Baranov M., Goldberg I., Lemcoff N.G.

Four new cis-dianionic S-chelated ruthenium benzylidenes were synthesized by chloride ligand exchange. The special cis-dianionic conformation of these complexes contributed to a particularly facile anion exchange process, producing room-temperature-latent precatalysts. Their catalytic activity was strongly influenced by the solvent used. The latent iodide complex very efficiently promoted ring-closing metathesis by heating in toluene. Conversely, carboxylate ligands produced quite poor catalysts, but could abstract chlorides from chlorinated solvents to transform into active precatalysts. In tetrahydrofuran (THF), the S-chelated dichloro complex was shown to promote cycloisomerization instead of metathesis; however, the metathesis activity in THF could be recovered in the presence of phenylacetylene as a cocatalyst. Under the same conditions, all the other complexes required addition of LiCl to mimic this dichotomous behavior.

Fu L., Zhang T., Fu G., Gutekunst W.R.

The covalent coupling of complex macromolecules is a modern challenge in both chemistry and biology. The development of efficient and chemoselective methods for polymer coupling and functionalization are increasingly important for designing new advanced materials and interfacing with biochemical systems. Herein, we present a new strategy to directly conjugate living polymers prepared using ring-opening metathesis polymerization (ROMP) to both small molecules and synthetic macromolecules. Central to this methodology is a terminal alkyne that serves as a directing group to promote a rapid, intramolecular reaction with an otherwise unreactive olefin. This highly chemoselective relay conjugation is compatible with a range of monomer families and uses a bench-stable enyne motif that can be easily introduced to functional targets. The rapid rate of the conjugation reaction paves the way for greatly streamlined construction of complex macromolecular systems derived from metathesis polymerization techniques without the need for specialized equipment.

Rozenberg I., Eivgi O., Frenklah A., Butilkov D., Kozuch S., Goldberg I., Lemcoff N.G.

Sulfur-chelated ruthenium olefin metathesis precatalysts that possess cyclic (alkyl)(amino)carbenes (CAAC) can benefit from the synergetic effect of both ligands. Changing the steric bulk of the CAAC ligand by using different substitution patterns was shown to affect the geometry of the complexes produced and determined whether the complexes could be catalytically dormant. The cis-dichloro latent catalysts could be activated both by heat or light, even in the visible region, for representative acyclic diene metathesis and ring-opening metathesis polymerization reactions, olefin cross-metathesis, and ring-closing metathesis without isomerization byproducts. Thus, these complexes were shown to combine the uniqueness of CAAC-containing Ru olefin metathesis catalysts with the advantage of the thermal and photolatency imposed by sulfur chelation of the benzylidene.

Yu M., Lou S., Gonzalez-Bobes F.

Ring-closing metathesis (RCM) has become indispensable in organic synthesis for both academic investigations and industrial applications. This review provides an overview of RCM reactions, focusing on the practical aspects that researchers in an industrial environment may find of interest. Key elements of reaction design and lessons learned from these applications are discussed to help those considering implementing RCM reactions on scale, particularly in manufacturing active pharmaceutical ingredients (APIs). Advances in the development of more effective catalysts and new methodologies, such as enantioselective RCM and stereoselective macrocyclic RCM, are also briefly discussed.

Sutar R., Sen S., Eivgi O., Segalovich G., Schapiro I., Reany O., Lemcoff N.G.

Allylic and acrylic substrates may be efficiently transformed by a sequential bichromatic photochemical process into derivatives of levulinates or butenolides with high selectivity when phenanthrene is used as a regulator.

Ivry E., Frenklah A., Ginzburg Y., Levin E., Goldberg I., Kozuch S., Lemcoff N.G., Tzur E.

Efficient light- and thermal-activated metathesis reactions of tetra-substituted olefins were obtained by the S-chelated ruthenium precatalyst Tol-SCF3. Its reactivity in a series of benchmark olefin metathesis reactions was compared to previously reported Mes-SCF3 and a novel sterically congested S-chelated complex, Dipp-SCF3. Tol-SCF3 is thus the first latent catalyst proven to be capable of promoting olefin metathesis of demanding substrates upon light stimulation at room temperature.

Slanina T., Shrestha P., Palao E., Kand D., Peterson J.A., Dutton A.S., Rubinstein N., Weinstain R., Winter A.H., Klán P.

A detailed investigation of the photophysical parameters and photochemical reactivity of meso-methyl BODIPY photoremovable protecting groups was accomplished through systematic variation of the leaving group (LG) and core substituents as well as substitutions at boron. Efficiencies of the LG release were evaluated using both steady-state and transient absorption spectroscopies as well as computational analyses to identify the optimal structural features. We find that the quantum yields for photorelease with this photocage are highly sensitive to substituent effects. In particular, we find that the quantum yields of photorelease are improved with derivatives with higher intersystem crossing quantum yields, which can be promoted by core heavy atoms. Moreover, release quantum yields are dramatically improved by boron alkylation, whereas alkylation in the meso-methyl position has no effect. Better LGs are released considerably more efficiently than poorer LGs. We find that these substituent effects are additive, for example, a 2,6-diiodo-B-dimethyl BODIPY photocage features quantum yields of 28% for the mediocre LG acetate and a 95% quantum yield of release for chloride. The high chemical and quantum yields combined with the outstanding absorption properties of BODIPY dyes lead to photocages with uncaging cross sections over 10 000 M-1 cm-1, values that surpass cross sections of related photocages absorbing visible light. These new photocages, which absorb strongly near the second harmonic of an Nd:YAG laser (532 nm), hold promise for manipulating and interrogating biological and material systems with the high spatiotemporal control provided by pulsed laser irradiation, while avoiding the phototoxicity problems encountered with many UV-absorbing photocages. More generally, the insights gained from this structure-reactivity relationship may aid in the development of new highly efficient photoreactions.

Sun T., Gao Y., Zhang Z., Jia A., Zhang Q.

Giger A.I., Voldrich J.C., Michel B.W.

Iudanov K., Nechmad N.B., Poater A., Lemcoff N.G.

AbstractA diiodo ruthenium olefin metathesis pre‐catalyst was employed to achieve remarkably selective cross‐metathesis reactions of prenylated 1,6‐dienes, effectively overcoming the entropically favored intramolecular ring‐closing metathesis. This reaction was investigated using Density Functional Theory (DFT) computations and fine‐tuned through the application of a Design of Experiments (DoE) approach. The potential of this innovative process was demonstrated through the unprecedented functionalization of various terpene natural products via cross‐metathesis, resulting in the synthesis of new derivatives in a single step.

Iudanov K., Nechmad N.B., Poater A., Lemcoff N.G.

AbstractA diiodo ruthenium olefin metathesis pre‐catalyst was employed to achieve remarkably selective cross‐metathesis reactions of prenylated 1,6‐dienes, effectively overcoming the entropically favored intramolecular ring‐closing metathesis. This reaction was investigated using Density Functional Theory (DFT) computations and fine‐tuned through the application of a Design of Experiments (DoE) approach. The potential of this innovative process was demonstrated through the unprecedented functionalization of various terpene natural products via cross‐metathesis, resulting in the synthesis of new derivatives in a single step.

Ingram A.A., Wang D., Schwaneberg U., Okuda J.

The effect of halide substitution in Grubbs-Hoveyda II catalysts (GHII catalysts) embedded in the engineered β-barrel protein nitrobindin (NB4exp) on metathesis activity in aqueous media was studied. Maleimide tagged dibromido and diiodido derivates of the GHII catalyst were synthesized and covalently conjugated to NB4exp. The biohybrid catalysts were characterized spectroscopically confirming the structural integrity. When the two chloride substituents at ruthenium center were exchanged against bromide and iodide, the diiodo derivative was found to show significantly higher catalytic activity in ring-closing metathesis of α,ω-diolefins, whereas the dibromido derivative was less efficient when compared with the parent dichlorido catalyst. Using the diiodido catalyst, high turnover numbers of up to 75 were observed for ring-closing metathesis (RCM) yielding unsaturated six- and seven-membered N-heterocycles.

Greenlee A.J., Weitekamp R.A., Foster J.C., Leguizamon S.C.

Martínez J.P., Trzaskowski B.

Tarannam N., Alassad N., Lemcoff N.G., Kozuch S.

Segalovich-Gerendash G., Baranov M., Lemcoff N.G., Phatake R.S.

Gao Y., Qian B., Wang J., Jia A., Mei Q., Zhang Q.

Treatment of [(Me3tacn)RuCl3·H2O] with equivalent of sodium dialkyldithiocarbamate in the presence of KPF6 afforded the mononuclear species [(Me3tacn)RuIII(κ2-S2CNR2)Cl]PF6 (Me3tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane; R = Me 1, Et 2, nPr 3, iPr 4). The similar reactions using O-alkyldithiocarbonate gave dinuclear species [{(Me3tacn)RuIII}2(κ2-S2COR)(κ2-S2C = O)(μ-S2)]PF6 (R = Me 5, Et 6, nPr 7, iPr 8), in which SS bond formed and partial conversion of η2-dithioxanthate to η2-dithiocarbonate occurred. The crystal structures of 2, 3, 4, 6, and 8 have been determined. The complexes have been characterized by infrared, UV–vis-NIR spectroscopies and mass spectrometry, and their electrochemical properties were also investigated. The dinuclear complexes (6–8) showed absorptions in the near-infrared (NIR) region around 1700 nm. Density functional theory calculation was performed on complexes 6 and 8 to explain the NIR performance. The visible-light-induced catalytic properties of dinuclear complexes 5–8 for H2 evolution by water splitting were explored in the paper.

Musso J.V., Gebel P., Gramm V., Frey W., Buchmeiser M.R.

Kumandin P.A., Antonova A.S., Novikov R.A., Vasilyev K.A., Vinokurova M.A., Grigoriev M.S., Novikov A.P., Polianskaia D.K., Polyanskii K.B., Zubkov F.I.

This work continues our group’s research into the synthesis and study of the catalytic activity of ruthenium chelates with various heteroatoms (O, S, N, and Se) in a six-membered ring. It was found that second-generation Hoveyda–Grubbs-type catalysts containing a sulfur-ruthenium coordinate bond in a six-membered chelate ring can be prepared easily and in high yields using standard procedures, based on the interaction between (2-vinylbenzyl)sulfanes and Ind II (the common precursor for Ru-complex synthesis). The obtained ruthenium derivatives, with a donor-acceptor S → Ru bond, can exist in two isomeric forms according to the arrangement of substituents around the central metal atom. Kinetically controlled trans-isomers are formed at temperatures below 80 °C in heptane and are less thermodynamically stable compared with cis-isomers, which arise under heating of trans-S-chelates in 1,2-dichloroethane at 110 °C. The structures of all the cis- and trans-isomers were determined and characterized in detail by X-ray diffraction and nuclear magnetic resonance. The study of the activity of the catalysts in standard ring-closing metathesis and ring-opening metathesis polymerization reactions showed that the cis-isomers are inactive in the absence of thermal or UV activation, while trans-complexes of the same type display excellent catalytic properties at r.t. that are superior to those of the commercially available HG-II catalyst. The structure, spectral characteristics, and catalytic activity of the catalysts containing an S → Ru bond in a six-membered chelate ring were compared with their five-membered analogues obtained in previous works.

Lemcoff N., Nechmad N.B., Eivgi O., Yehezkel E., Shelonchik O., Phatake R.S., Yesodi D., Vaisman A., Biswas A., Lemcoff N.G., Weizmann Y.

Light-induced catalysis and thermoplasmonics are promising fields creating many opportunities for innovative research. Recent advances in light-induced olefin metathesis have led to new applications in polymer and material science, but further improvements to reaction scope and efficiency are desired. Herein, we present the activation of latent ruthenium-based olefin metathesis catalysts via the photothermal response of plasmonic gold nanobipyramids. Simple synthetic control over gold nanobipyramid size results in tunable localized surface plasmon resonance bands enabling catalyst initiation with low-energy visible and infrared light. This approach was applied to the ROMP of dicyclopentadiene, affording plasmonic polymer composites with exceptional photoresponsive and mechanical properties. Moreover, this method of catalyst activation was proven to be remarkably more efficient than activation through conventional heating in all the metathesis processes tested. This study paves the way for providing a wide range of photoinduced olefin metathesis processes in particular and photoinduced latent organic reactions in general by direct photothermal activation of thermally latent catalysts. Current strategies for photoinduced olefin metathesis lack wavelength tunability. Now, plasmonic nanoparticles have been used to activate latent ruthenium catalysts, enabling light-induced olefin metathesis in the infrared range with several advantages when compared with conventional heating. Implementing this approach in ring-opening metathesis polymerization resulted in photoresponsive polymer–nanoparticle composites with enhanced mechanical properties.

Vasilyev K.A., Antonova A.S., Volchkov N.S., Logvinenko N.A., Nikitina E.V., Grigoriev M.S., Novikov A.P., Kouznetsov V.V., Polyanskii K.B., Zubkov F.I.

An efficient approach to the synthesis of olefin metathesis HG-type catalysts containing an N→Ru bond in a six-membered chelate ring was proposed. For the most part, these ruthenium chelates can be prepared easily and in high yields based on the interaction between 2-vinylbenzylamines and Ind II (the common precursor for Ru-complex synthesis). It was demonstrated that the increase of the steric volume of substituents attached to the nitrogen atom and in the α-position of the benzylidene fragment leads to a dramatic decrease in the stability of the target ruthenium complexes. The bulkiest iPr substituent bonded to the nitrogen atom or to the α-position does not allow the closing of the chelate cycle. N,N-Diethyl-1-(2-vinylphenyl)propan-1-amine is a limiting case; its interaction with Ind II makes it possible to isolate the corresponding ruthenium chelate in a low yield (5%). Catalytic activity of the synthesized complexes was tested in RCM reactions and compared with α-unsubstituted catalysts obtained previously. The structural peculiarities of the final ruthenium complexes were thoroughly investigated using XRD and NMR analysis, which allowed making a reliable correlation between the structure of the complexes and their catalytic properties.

Nechmad N.B., Iudanov K., Tarannam N., Kobernik V., Kozuch S., Lemcoff N.G.