N-heterocyclic Carbene Research Articles

Hybrid silver(I) coumarin-carbene and coumarin-triphenylphosphine complexes: Towards more effective antimicrobial therapies

The rise of antimicrobial resistance and the resulting societal burden has highlighted the need for the development of novel therapeutics. Towards that end, a series of hybrid silver(I) coumarin-carbene and coumarin-triphenylphosphine complexes were synthesised and characterised by spectroscopic analysis including IR, 1H and 13C NMR spectroscopy, elemental analysis, and X-ray crystallography. Isolation of coumarin-carbene hybrid complexes was achieved using two methods, with isolation via firstly the in-situ generation of a free carbene under Schlenk conditions, followed by reaction with a coumarin silver(I) complex resulting in the formation of a hybrid complex with two silver ions forming a strong argentophilic Ag(I)–Ag(I) interaction. In this hybrid complex one silver(I) ion was bound to two coumarin carboxylate ligands with the other ion bound to two carbene ligands. Isolation via an ionic carbene route led to more complex aggregates but both types of complexes had good solubility and photostability as did the triphenylphosphine hybrid complexes. All the hybrid complexes showed therapeutic potential as antimicrobial agents against MRSA with the carbene hybrid complexes exhibiting an increased antimicrobial activity against both E. coli and MRSA when compared to the initial silver(I) complexes.

Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells.

The imidazole alkaloid lepidiline A from the root of Lepidium meyenii has a moderate to low in vitro anticancer effect. Our aim was to extend cytotoxicity investigations against a panel of cancer cells, including multidrug-resistant cancer cells, and multipotent stem cells. Lepidiline A is a N-heterocyclic carbene precursor, therefore a suitable ligand source for metal complexes. Thus, we synthesized lepidiline A and its copper(I), gold(I), and silver(I) complexes and tested them against ovarian, gastrointestinal, breast, and uterine cancer cells and bone marrow-derived and adipose-derived mesenchymal stem cells. Lepidiline A and its copper complex demonstrated moderate cytotoxicity, while silver and gold complexes exhibited significantly enhanced and consistent cytotoxicity against both cancer and stem cell lines. ABCB1 in the multidrug-resistant uterine sarcoma line conferred significant resistance against lepidiline A and the copper-lepidiline A complex, but not against the silver and gold complexes. Our results indicate that only the copper complex induced a significant and universal increase in the production of reactive oxygen species within cells. In summary, binding of metal ions to lepidiline A results in enhanced cytotoxicity with the nature of the metal ion playing a critical role in determining its properties.

Structural and Electrochemical Insights into Five Coordinate Cobalt bis(dithiolene) N-heterocyclic Carbene Complexes

Two new cobalt-bis(dithiolene)-IMes (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) complexes have been isolated, and a systematic solid-state structural characterization using single crystal X-ray diffraction studies was undertaken to confirm the identity of the complexes. (IMes)Co(S2C2Ph2)2 (1) crystallizes in a monoclinic space group I2/a, while (IMes)Co(S2C2(C6H4-p-OCH3)2)2 (2) crystallizes in a triclinic space group P1¯. A detailed solid-state structural analysis of 1 and 2 revealed that the extended structure is stabilized by a series of CH…S interactions. As validated using electrochemical studies, the binding of IMes to the cobalt atom may be electrochemically controlled by applying a suitable redox potential. These studies indicate that compounds 1 and 2 are expected to act as an effective electrochemical host, enabling them to be used as precursors to release IMes under environmentally benign conditions.

Charge-Enhanced Reactivity of Esters by a Cationic Substituent.

In this study, the high electrophilicity of carbonyl carbons attached to cationic heterocycles was observed. Triazolium-substituted esters underwent catalyst-free amidation with aliphatic amines at -50 °C and reduction with NaBH4 at -100 °C. The origin and generality of the high reactivity of these esters were systematically investigated. The findings of this work were utilized for the postmodification of N-heterocyclic carbenes, which are utilized as promising ligands in a wide range of transition-metal-catalyzed reactions.

An SN1-Approach to Cross-Coupling: Deoxygenative Arylation Facilitated by the β-Silicon Effect.

We report a dual metal-catalyzed method for the cross-coupling of unprotected alcohols by exploiting the β-Si effect. This deoxygenative Suzuki-Miyaura reaction tolerates a range of primary, secondary, and tertiary alcohol substrates along with diverse functional groups and heterocycles. Mechanistic experiments including KIE, VTNA, and Eyring analyses suggest the existence of a carbocation intermediate on the reaction pathway, consistent with a rare SN1 pathway for the activation of an electrophile in cross-coupling reactions. A novel bis-imidazolium N-heterocyclic carbene (NHC) ligand was found to be optimal for reactivity, and nickel(0)-, nickel(I)- and nickel(II)- complexes of this ligand were isolated and characterized. In contrast to more well-established shorter chain ligands, these long-chain NHCs are found to have characteristically large bite angles, which may be critical for enabling the deoxygenative arylation of aliphatic alcohols.

Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis

Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis

N-heterocyclic carbene-catalyzed atroposelective synthesis of N-Aryl phthalimides and maleimides via activation of carboxylic acids

Traditionally, N-aryl phthalimides are synthesized by the condensation of phthalic anhydride and aniline derivatives, usually proceeding under harsh conditions. The alternative mild and organocatalytic strategies for their synthesis are underdeveloped. Herein, we demonstrate the organocatalytic atroposelective synthesis of N-aryl phthalimides via the traditional N-CC=O disconnection under mild conditions. The in-situ acid activation of phthalamic acid and subsequent N-heterocyclic carbene (NHC)-catalyzed atroposelective amidation allowed the synthesis of well-decorated N-aryl phthalimides in excellent yields and enantioselectivities. Mechanistic studies reveal the addition of NHC to the in situ generated isoimides, thus introducing a unique mode of generating acylazoliums. Interestingly, both enantiomers of the product can be accessed from the same phthalic anhydride and aniline using the same NHC pre-catalyst. Moreover, this strategy has been extended to the atroposelective synthesis of N-aryl maleimides.

Oxidation of Ammonia Catalyzed by a Molecular Iron Complex: Translating Chemical Catalysis to Mediated Electrocatalysis

Ammonia is a promising candidate in the quest for sustainable, clean energy. With its capacity to serve as an energy carrier, the oxidation of ammonia opens avenues for carbon‐neutral approaches to address worldwide growing energy needs. We report the catalytic chemical oxidation of ammonia by an Earth‐abundant transition metal complex, trans‐[LFeII(MeCN)2][PF6]2, where L is a macrocyclic ligand bearing four N‐heterocyclic carbene (NHC) donors. Using triarylaminium radical cations in MeCN, up to 182 turnovers of N2 per Fe were obtained from chemical catalysis with an extremely low loading of the Fe catalyst (0.043 mM, 0.004 mol % catalyst). This chemical catalysis was successfully transitioned to mediated electrocatalysis for the oxidation of ammonia. Molecular electrocatalysis by the Fe catalyst and the mediator (p‐MeOC6H4)3N exhibited a catalytic half‐wave potential (Ecat/2) of 0.18 V vs [Cp2Fe]+/0 in MeCN, and achieved 9.3 turnovers of N2 at an applied potential of 0.20 V vs [Cp2Fe]+/0 at −20 °C in controlled‐potential electrolysis, with a Faradaic efficiency of 75%. Based on computational results, the catalyst undergoes sequential oxidation and deprotonation steps to form [LFeIV(NH2)2]2+, and thereafter bimetallic coupling to form an N−N bond.

Oxidation of Ammonia Catalyzed by a Molecular Iron Complex: Translating Chemical Catalysis to Mediated Electrocatalysis.

Ammonia is a promising candidate in the quest for sustainable, clean energy. With its capacity to serve as an energy carrier, the oxidation of ammonia opens avenues for carbon-neutral approaches to address worldwide growing energy needs. We report the catalytic chemical oxidation of ammonia by an Earth-abundant transition metal complex, trans-[LFeII(MeCN)2][PF6]2, where L is a macrocyclic ligand bearing four N-heterocyclic carbene (NHC) donors. Using triarylaminium radical cations in MeCN, up to 182 turnovers of N2 per Fe were obtained from chemical catalysis with an extremely low loading of the Fe catalyst (0.043 mM, 0.004 mol % catalyst). This chemical catalysis was successfully transitioned to mediated electrocatalysis for the oxidation of ammonia. Molecular electrocatalysis by the Fe catalyst and the mediator (p-MeOC6H4)3N exhibited a catalytic half-wave potential (Ecat/2) of 0.18 V vs [Cp2Fe]+/0 in MeCN, and achieved 9.3 turnovers of N2 at an applied potential of 0.20 V vs [Cp2Fe]+/0 at -20 °C in controlled-potential electrolysis, with a Faradaic efficiency of 75 %. Based on computational results, the catalyst undergoes sequential oxidation and deprotonation steps to form [LFeIV(NH2)2]2+, and thereafter bimetallic coupling to form an N-N bond.

Origin of Reactivity Trends of an Elusive Metathesis Intermediate from NMR Chemical Shift Analysis of Surrogate Analogues.

Olefin metathesis has become an efficient tool in synthetic organic chemistry to build carbon-carbon bonds, thanks to the development of Grubbs- and Schrock-type catalysts. Olefin coordination, a key and often rate-determining elementary step for d0 Schrock-type catalysts, has been rarely explored due to the lack of accessible relevant molecular analogues. Herein, we present a fully characterized surrogate of this key olefin-coordination intermediate, namely, a cationic d0 tungsten oxo-methylidene complex bearing two N-heterocyclic carbene ligands─[WO(CH2)Cl(IMes)2](OTf) (1) (IMes = 1,3-dimesitylimidazole-2-ylidene, OTf-triflate counteranion), resulting in a trigonal bipyramidal (TBP) geometry, along with its neutral octahedral analogue [WO(CH2)Cl2(IMes)2] (2)─and an isostructural oxo-methylidyne derivative [WO(CH)Cl(IMes)2] (3). The analysis of their solid-state 13C and 183W MAS NMR signatures, along with computed 17O NMR parameters, helps to correlate their electronic structures with NMR patterns and evidences the importance of the competition among the three equatorial ligands in the TBP complexes. Anchored on experimentally obtained NMR parameters for 1, computational analysis of a series of olefin coordination intermediates highlights the interplay between σ- and π-donating ligands in modulating their stability and further paralleling their reactivity. NMR spectroscopy descriptors reveal the origin for the advantage of the dissymmetry in σ-donating abilities of ancillary ligands in Schrock-type catalysts: weak σ-donors avoid the orbital-competition with the oxo ligand upon formation of a TBP olefin-coordination intermediate, while stronger σ-donors compromise M≡O triple bonding and thus render olefin coordination step energy demanding.

Pushing the Limits of Organometallic Redox Chemistry with an Isolable Mn(-I) Dianion.

We report an incredibly reducing and redox-active Mn-I dianion, [Mn(CO)3(Ph2B(tBuNHC)2)]2- (NHC = N-heterocyclic carbene), furnished via 2e- reduction of the parent 16e- MnI complex with Na0 or K0. Cyclic voltammograms show a Mn0/-I redox couple at -3.13 V vs Fc+/0 in tetrahydrofuran (THF), -3.06 V in 1,2-dimethoxyethane, and -2.85 V in acetonitrile. The diamagnetic Mn-I dianion is stable in solution and solid-state at room temperature, tolerating a wide range of countercations ([M(2.2.2)crypt]+, [M(18-crown-6)]+, [nBu4N]+; M = Na, K). Countercation identity does not significantly alter 13C NMR spectral signatures with [nBu4N]+ and Na+, suggesting minimal ion pairing in solution. IR spectroscopy reveals a significant decrease in CO stretching frequencies from MnI to Mn-I (ca. 240 cm-1), consistent with a drastic increase in electron density at Mn. State-of-the-art DFT calculations are in excellent agreement with the observed IR spectral data. Moreover, the Mn-I dianion behaves as a chemical reductant, smoothly releasing 1e- or 2e- to regenerate the oxidized Mn0 or MnI species in solution. The reducing potential of [Mn(CO)3(Ph2B(tBuNHC)2)]2- surpasses the naphthalenide anion in THF (-3.09 V) and represents one of the strongest isolable chemical redox agents.

Design of efficient benzimidazole-derived N-heterocyclic carbene Ag(I) catalysts for aldehyde–amine–alkyne coupling

A mild catalytic protocol for aldehyde, amine, and alkyne coupling (A3-coupling) allows for the selective synthesis of propargyl amines using 5,6-dimethylbenzimidazole-derived N-heterocyclic carbene (BNHC) silver(I) catalysts. A series of BNHC Ag(Ⅰ) halide complexes were synthesized and their structures have been elucidated through the use of multinuclear NMR and FT-IR spectroscopy. Furthermore, the pseudo-linear geometry of two different compounds was substantiated by single-crystal X-ray diffraction. Silver-based A3-coupling was achieved for both acyclic and cyclic secondary amines using a diverse set of alkynes to afford propargyl amines with yields of up to 95 %. The present approach is environmentally benign and water is generated as the sole byproduct.

Base-Stabilized Gallium Sulfides and Selenides Supported by a Bis(oxazolinyl)(phenyl)methanide Ligand.

Gallylene supported by a bis(oxazolinyl)(phenyl)methanide (Boxm) ligand was synthesized and structurally characterized. The reaction of this gallylene with triphenylphosphine sulfide/selenide yielded dimeric gallium sulfide and selenide. These compounds could be converted to monomeric terminal sulfide and selenide by coordination of an external Lewis base such as an N-heterocyclic carbene (NHC or IMe4) and 4-dimethylaminopyridiene (DMAP). These doubly-base-stabilized gallium sulfide/selenide reacted with phenyl isocyanate to give the corresponding cycloadducts by releasing the Lewis base, indicating the formation of a single-base-stabilized gallium sulfide/selenide intermediate.

Pd–PEPPSI-type expanded ring N-heterocyclic carbene complexes: synthesis, characterization, and catalytic activity in Suzuki–Miyaura cross coupling

ABSTRACT In this work, we synthesized a series of six unsymmetrical benzimidazolium salts 2 and their pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI)-themed palladium N-heterocyclic carbene complexes [PdCl2(NHC)(Py)]. All the products were isolated in satisfactory yields (75-85%). The synthesis of these novel palladium PEPPSI complexes involved in reacting NHC precursors with PdCl2 in pyridine at 60°C in the presence of excess K2CO3. The structures of all compounds have been characterized by 1H NMR, 13C NMR, HRMS and IR spectroscopy, as well as elemental analysis techniques, which support the proposed structures. The catalytic activity of the six complexes was assessed in the Suzuki-Miyaura cross-coupling of phenylboronic acid and aryl halides. The reactions required only a low catalyst loading (0.1 mol%) and were carried out under mild aerobic conditions in a green, water-based solvent mixture.

CO2 capture by imidazolium-based deep eutectic solvents: the effect of steric hindrance of N-heterocyclic carbenes.

CO2 capture by deep eutectic solvents (DESs) formed between 1,3-bis(isopropyl)imidazolium 1,2,4-triazolide ([IiPim][Triz]) and ethylene glycol (EG) is investigated in this study. [IiPim][Triz]-EG DESs exhibit a capacity of ∼1.0 mol CO2 per mol DES at 1.0 atm and 25 °C. Surprisingly, mechanistic results disclose that CO2 reacts with EG but does not bind with the C-2 site of the [IiPim]+ cation, which may be due to the high steric hindrance of the C-2 site of the N-heterocyclic carbene IiPim present in [IiPim][Triz]-EG DESs.

Silver Complex Bearing N-Heterocyclic Carbene Bidentate Chelating Ligand as an Efficient Catalyst in Solvent-Free KA2 Coupling.

We report a synthesis of silver complexes bearing chelating bidentate N-heterocyclic carbene, with various substitutions at the terminal positions of the imidazole moiety of the NHC units. The long aliphatic substituents proved to be beneficial in terms of the synthetic efficiency of the complexes, compared to previously reported methyl substitution. The complexes demonstrated excellent suitability for the KA2 coupling reaction, providing quaternary carbon-containing propargylic amines in yields up to 95 %, under solvent-free conditions. The method showed high tolerance for a wide range of substrates, including naturally occurring ketones, underscoring its practicality. To our knowledge, this represents the first use of a well-defined silver species in KA2 coupling, marking an advancement in the field.

Solid-state dynamics of binuclear N-heterocyclic carbene Au(I) rotor with para-phenylene rotator

Abstract Molecular dynamics in the crystalline solid state, typically constrained by a densely packed crystal environment, may offer opportunities to control the physical properties of solid-state materials. In this work, a neutral crystalline molecular rotor featuring a para-phenylene rotator encapsulated by N-heterocyclic carbene ligands and connected via a C–Au–C rotational axis is presented. Single-crystal X-ray diffraction studies, along with variable temperature solid-state 2H NMR spin-echo measurements, confirm the presence of 180° 2-fold rotational dynamics of the para-phenylene moiety in the solid state.

(NHC)Pd(OAc)2]: Highly Active Carboxylate Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalysts for Suzuki-Miyaura and Buchwald-Hartwig Cross-Coupling of Amides by N-C(O) Activation.

In the past eight years, the selective cross-coupling of amides by N-C(O) bond activation has emerged as a highly attractive manifold for the manipulation of traditionally unreactive amide bonds. In this Special Issue on Next-Generation Cross-Coupling Chemistry, we report the Suzuki-Miyaura and Buchwald-Hartwig cross-coupling of amides by selective N-C(O) cleavage catalyzed by bench-stable, well-defined carboxylate Pd(II)-NHC (NHC = N-heterocyclic carbene) catalysts {[(NHC)Pd(O2CR)2]}. This class of Pd(II)-NHCs promotes cross-coupling under exceedingly mild room-temperature conditions owing to the facile dissociation of the carboxylate ligands to form the active complex. These readily accessible Pd(II)-NHC precatalysts show excellent functional group tolerance and are compatible with a broad range of amide activating groups. Considering the mild conditions for the cross-coupling and the facile access to carboxylate Pd(II)-NHC complexes, we anticipate that this class of bench-stable complexes will find wide application in the activation of amide N-C(O) and related acyl X-C(O) bonds.

A Tetracarbene Iron(II) Complex with a Long‐lived Triplet Metal‐to‐ligand Charge Transfer State due to a Triplet‐Triplet Barrier

Mixed N‐heterocyclic carbene (NHC) / pyridyl iron(II) complexes have attracted a great deal of attention recently because of their potential as photocatalysts and light sensitizers made from Earth‐abundant elements. The most decisive challenge for their successful implementation is the lifetime of the lowest triplet metal‐to‐ligand charge transfer state (3MLCT), which typically decays via a triplet metal‐centered (3MC) state back to the ground state. We reveal by variable‐temperature ultrafast transient absorption spectroscopy that the tripodal iron(II) bis(pyridine) complex isomers trans‐ and cis‐[Fe(pdmi)2]2+with four NHC donors show 3MLCT→3MC population transfers with very different barriers and rationalize this by computational means. While trans‐[Fe(pdmi)2]2+possesses an unobservable activation barrier, the cis isomer exhibits a barrier of 492 cm–1, which leads to a nanosecond 3MLCT lifetime at 77 K. The kinetic and quantum chemical data were analyzed in the context of semi‐classical Marcus theory revealing a high reorganization energy and small electronic coupling between the two triplet states. This highlights the importance of detailed structural control and kinetic knowledge for the rational design of photosensitizers from first row transition metals such as iron.

Synthesis of Thiourea and Thioamide S-Oxides via SO Transfer from a Thiirane S-Oxide onto N-Heterocyclic Carbenes.

Thiourea S-oxides are labile compounds that suffer from a quick overoxidation when directly prepared from thioureas. Therefore, we have developed an alternative route on the basis of the SO transfer from a thiirane S-oxide onto sterically encumbered N-heterocyclic carbenes, including imidazole- and imidazoline-ylidenes, and a cyclic alkyl amino carbene. Reaction conditions and DFT computations suggest a concerted SO transfer mechanism. Thiourea S-oxides are nucleophiles adding to dimethyl acetylenedicarboxylate under fission of the S-O bond.