NHC Precursors Research Articles

Coumarin substituted 4–aryl–1,2,4–triazolium salts and their silver(I) N–heterocyclic carbene complexes: Effects of counterions on the antioxidant and antihaemolytic properties

Although numerous silver complexes have been found to target human derived leukemia cells, the nature and reactivity of such species with normal human red blood cells and targeting oxidants remain unexplored. In this contribution, we report the synthesis and characterization of three series of structurally varied silver complexes derived from biologically active coumarin substituted 1,2,4–triazol–5–ylidine ligands. 1,2,4–Triazolium salts (6–13) that serve as NHC precursors have been prepared by treating 4–(2,6–dimethylphenyl) triazole with substituted 4–bromomethylcoumarin derivatives, and corresponding silver NHC complexes (14–25) by in situ deprotonation method using appropriate silver sources. Complexes 14, 15 and 18 have been studied for their structure following single crystal X–ray diffraction technique, which adjudicates the presence of silver atom in an almost linear coordination geometry. Complexes 21 and 22 displayed promising antioxidant potential with the IC50 (a concentration of test sample required to neutralize DPPH radicals by 50%) value of 7.49 ± 0.702, 7.42 ± 0.125 μM, respectively; while the triazolium salt displayed no activity in the working concentration range (10–250 μM). Likewise, at a concentration of 100 μM the silver complexes showed significantly less percentage lysis of human red blood cells in the range 2.36 ± 0.59 to 8.49 ± 0.27% (except 18, 24 and 25).

Monosubstituted, Anionic Imidazolyl Ligands from N−H NHC Precursors and Their Activity in Pd‐Catalyzed Cross‐Coupling Reactions

AbstractWe report that treatment of several 2‐diphenylphosphinoimidazoles with Pd(II) salts generates monosubstituted N−H NHC−Pd complexes via insertion into the C−P bond. Removal of the N−H proton in situ leads to anionic (X‐type) or imidazolyl‐Pd complexes that are highly stable and catalytically active, achieving up to 340,000 turnovers at 1 ppm catalyst loading in Suzuki‐Miyaura reactions. DFT‐calculated Tolman electronic parameters for the sterically small ligands suggest that these ligands are significantly more donating than traditional NHCs, which provides a rationale for rapid cross‐coupling catalysis. Excellent reactivity is also demonstrated in Sonogashira reactions.magnified image

Oxidative NHC catalysis for base-free synthesis of benzoxazinones and benzoazoles by thermal activated NHCs precursor ionic liquid catalyst using air as oxidant

A reusable thermal activated NHC precursor ionic liquid catalyst ([BMIm]2[WO4]) has been prepared and developed for the synthesis of nitrogen-containing heterocycles such as benzoxazinones and benzoazoles through imines activation. [BMIm]2[WO4] exhibited the good activity for the base-free condensation and oxidative NHC catalysis tandem under air atmosphere. The catalyst can be recovered and reused for at least five runs in gram scale synthesis without any decrease in catalytic activity. Furthermore, the control experiments demonstrated that the reaction involved formation of aromatic aldimines, NHC-catalyzed oxidative formation of imidoyl azoliums and intramolecular cyclization to generate the product.

Reduction hydrogenation of imines by in situ generated rhodium NHC complexes

In this paper we examined the catalytic activity of in situ prepared bidentate azolium salt/[RhCl(COD)]2 catalyst system in the transfer hydrogenation of imines with i-propanol to the corresponding amine. The first in situ transfer hydrogenation of imines to amines is described using [RhCl(COD)]2 with bidentate azolium ligands. New bidentate azolium salts (1a-c, 2a-c) as NHC precursors have been synthesized and characterized. The in situ prepared three-component bidentate azolium salts (LHX)/[RhCl(COD)]2 and t-BuOK catalyzes quantitatively the transfer hydrogenation of imines under mild reaction conditions in i-propanol. The results show that bidentate benzimidazolium salts were observed to be more active in reducing imines. Moreover, the method is simple and effective against various imines.

Insertion of Ni(0) and Pd(0) precursors into the Si-Si bond of a disilane with two hypercoordinate silicon atoms.

The activation of the silicon-silicon bond in disilane Ph2Si(μ-PzMe2)2SiPh2 (1), which possesses two five-coordinate silicon centers, was achieved by a reaction with Pd(0) or Ni(0) precursors of modest steric demand to afford a dinuclear Pd complex (2) or two types of mononuclear Ni complexes (3 and 4), respectively.

Bioactive NHC-derived palladium complexes: synthesis, catalytic activity for the Suzuki-Miyaura coupling of aryl chlorides and bromides and their antibacterial activities

Pd(II)-bis(NHC) complexes (where NHC = N-heterocyclic carbene) bearing asymmetrically and symmetrically substituted NHC-ligand have been synthesized via deprotonation of 5,6-dimethylbenzimidazolium salts. The NHC precursors have been achieved via the two step N-alkylation of 5,6-dimethylbenzimidazole. The resultant salts were deprotonated with PdCl2 and K2CO3 in dry THF for 2(a–e). The obtained complexes were identified and characterized by 1H and 13C NMR, FT-IR, DART-TOF mass spectrometry and elemental analysis. These new Pd(II)-bis(NHC) complexes were applied as catalyst precursors for Suzuki-Miyaura cross-coupling reactions of aryl bromides and chlorides with phenylboronic acid to afford the corresponding products in good yields. This catalytic reaction was evaluated in the presence of KOtBu/toluene. The antibacterial activities of 2(a–e) were investigated against Gram (+)/(−) bacteria using the agar dilution procedure. The antibacterial activities of 2 vary with the nature of the ligands; MIC values of 2(a–e) were determined.

Polynuclear Ag(I)-N-heterocyclic carbene complexes: synthesis, electrochemical and in vitro anticancer study against human breast cancer and colon cancer

Four new bis-imidazolium salts 3–6 and their di- and polynuclear silver(I)–N-heterocyclic carbene (Ag(I)–NHC) complexes 7–10 were synthesized and characterized by using various analytical techniques. Single-crystal studies of 8 revealed a dinuclear structure whereas that of 9 revealed an interesting polynuclear structure. The quasi-reversibility of redox events in electrochemical study of 9 indicated that reduction produces unstable decomposed species and oxidation may be ascribed to these decomposed species. All the compounds were studied for their in vitro anticancer study against human breast cancer (MDA-MB-231) and colon cancer (HCT-116) cells. The study revealed that Ag(I)–NHC complexes are comparatively more potent than NHC precursors (salts). MDA-MB-231 cells appeared more sensitive to complexes than HCT-116 cells while reverse is the case for NHC salts.

A Practical and Stereoselective In Situ NHC-Cobalt Catalytic System for Hydrogenation of Ketones and Aldehydes

Summary Homogeneous catalytic hydrogenation of carbonyl groups is a synthetically useful and widely applied organic transformation. Sustainable chemistry goals require replacing conventional noble transition metal catalysts for hydrogenation by earth-abundant base metals. Herein, we report how a practical in situ catalytic system generated by easily available pincer NHC precursors, CoCl2, and a base enabled efficient and high-yielding hydrogenation of a broad range of ketones and aldehydes (over 50 examples and a maximum turnover number [TON] of 2,610). This is the first example of NHC-Co-catalyzed hydrogenation of C=O bonds using flexible pincer NHC ligands consisting of a N-H substructure. Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized by fine-tuning of the steric bulk of pincer NHC ligands. Additionally, a bis(NHCs)-Co complex was successfully isolated and fully characterized, and it exhibits excellent catalytic activity that equals that of the in-situ-formed catalytic system.

Acidity Scale of N-Heterocyclic Carbene Precursors: Can We Predict the Stability of NHC-CO2 Adducts?

The acidity scale (∼14 p K units) of more than 90 triazolium, imidazolium, and imidazolinium based NHC precursors in DMSO was established systematically by a well-developed computational model. The substituent effects on the acidities of these NHC precursors were analyzed through acidity comparison and Hammett correlation. The binding energy (Δ G1) of the reaction between NHC and CO2 was also calculated and linearly correlates with the basicity of the corresponding NHC, which implies that the stability of the NHC-CO2 adduct is essentially dictated by the basicity of NHC.

Palladium(II) N-heterocyclic carbene complexes: synthesis, structures and cytotoxicity potential studies against breast cancer cell line

Mononuclear trans-Pd(II)–NHC complexes (where NHC = N-heterocyclic carbene) bearing asymmetrically substituted NHC-ligand have been synthesized via transmetalation reaction between Ag(I)–NHC complexes and [Pd(NCCH3)2Cl2]. The NHC precursors are accessible in two steps by N-n-alkyl reactions of benzimidazole. The resultant benzimidazolium salts were deprotonated with Ag2O by in situ deprotonation to facilitate the formation of mononuclear Ag(I)–NHC complexes. Single-crystal structural study for Pd(II)–NHC shows that the palladium(II) ion exhibits a square-planar geometry of two NHC ligands and two chloride ions. The cytotoxicity study was investigated against breast cancer cell line (MCF-7). The Ag(I)–NHC complexes exhibit better activities than their corresponding Pd(II)–NHC complexes, whereas all benzimidazolium salts are inactive toward MCF-7 cancer cell line.

Efficient Synthesis of Aryl Boronates via Cobalt-Catalyzed Borylation of Aryl Chlorides and Bromides

An efficient catalytic system based on a Co(II)-NHC precursor has been developed for the cross coupling of bis(pinacolato)diboron with aryl halides including aryl chlorides, affording the aryl boronates in good to excellent yields. A wide range of functional groups are tolerated under mild reaction conditions. The reaction shows excellent chemoselectivity for bromide over chloride. Preliminary mechanistic investigations show that the catalytic cycle may rely on a cobalt(I)–(III) redox couple.

An efficient synthesis of triazolium ion based NHC precursors using diaryliodonium salts and their photophysical properties.

Copper-catalysed N-arylation of fused triazoles using diaryliodonium salts as an aryl source is described. This scalable protocol displayed good compatibility towards diverse sensitive functional groups like ester, alkyl and nitro groups and halogens (F, Cl, Br). The synthetic usefulness of the prepared triazolium salts was proved by preparing α-hydroxyketone through benzoin condensation. Photophysical studies of these compounds showed promising Stokes-shifted fluorescence emission in aqueous medium, so this molecular framework could be a proficient probe for biological applications.

Anion influences on reactivity and NMR spectroscopic features of NHC precursors.

A series of 16 benzimidazolium salts of the type iPr2-bimyH+X− with various anions X were synthesized and characterized by various spectroscopic and spectrometric methods. Significant anion and solvent effects on the chemical shifts of the C2–H protons were found, which allows for a ranking of the anions in terms of their hydrogen-bond acceptor properties. Stronger acceptors could increase the acidity of their respective salts leading to a faster H/D exchange. Similar but less pronounced anion influences were detected for the 13CC2 NMR resonances, while 1JC2–H coupling constants appear to be anion and solvent independent.

Increasing the Reactivity of Diborenes: Derivatization of NHC-Supported Dithienyldiborenes with Electron-Donor Groups.

A series of NHC-supported 1,2-dithienyldiborenes was synthesized from the corresponding (dihalo)thienylborane NHC precursors. NMR and UV/Vis spectroscopic data, as well as X-ray crystallographic analyses, were used to assess the electronic and steric influences on the B=B double bond of various NHCs and electron-donating substituents on the thienyl ligands. Crystallographic data showed that the degree of coplanarity of the diborene core and thienyl groups is highly dependent on the sterics of the substituents. Furthermore, any increase in the electron-donating ability of the substituents resulted in the destabilization of the HOMO and greater instability of the resulting diborenes.

N-Propylphthalimide-substituted bis-(NHC)PdX2 complexes: synthesis, characterization and catalytic activity in direct arylation reactions

Palladium-catalyzed direct arylation of heteroaromatics has become a popular method for producing carbon–carbon bonds via C–H bond activation. A wide diversity of heteroaromatics such as furan, thiophenes and thiazoles can be used for this reaction. This paper reports the synthesis of N-propylphthalimide-substituted bis-(NHC)PdX2 complexes (NHC = N-heterocyclic carbene), and their catalytic activity in direct arylation reactions. The complexes have been prepared from Ag(I)NHC precursors by transmetallation and characterized by spectroscopy and elemental analysis. The bis-(NHC)PdX2 complexes show excellent activity as catalysts in the direct arylation reactions of 2-n-butylfuran, 2-n-butylthiophene and 2-isopropylthiazole.

Tritopic NHC Precursors: Unusual Nickel Reactivity and Ethylene Insertion into a C(sp3)–H Bond

AbstractThe imidazolium chloride [C3H3N(C3H6NMe2)N{C(Me)(=NDipp)}]Cl (1; Dipp=2,6‐diisopropyl phenyl), a potential precursor to a tritopic NimineCNHCNamine pincer‐type ligand, reacted with [Ni(cod)2] to give the NiI‐NiI complex 2, which contains a rare cod‐derived η3‐allyl‐type bridging ligand. The implied intermediate formation of a nickel hydride through oxidative addition of the imidazolium C−H bond did not occur with the symmetrical imidazolium chloride [C3H3N2{C(Me)(=NDipp)}2]Cl (3). Instead, a Ni−C(sp3) bond was formed, leading to the neutral NimineCHNimine pincer‐type complex Ni[C3H3N2{C(Me)(=NDipp)}2]Cl (4). Theoretical studies showed that this highly unusual feature in nickel NHC chemistry is due to steric constraints induced by the N substituents, which prevent Ni−H bond formation. Remarkably, ethylene inserted into the C(sp3)−H bond of 4 without nickel hydride formation, thus suggesting new pathways for the alkylation of non‐activated C−H bonds.

Tritopic NHC Precursors: Unusual Nickel Reactivity and Ethylene Insertion into a C(sp3 )-H Bond.

The imidazolium chloride [C3 H3 N(C3 H6 NMe2 )N{C(Me)(=NDipp)}]Cl (1; Dipp=2,6-diisopropyl phenyl), a potential precursor to a tritopic Nimine CNHC Namine pincer-type ligand, reacted with [Ni(cod)2 ] to give the NiI -NiI complex 2, which contains a rare cod-derived η3 -allyl-type bridging ligand. The implied intermediate formation of a nickel hydride through oxidative addition of the imidazolium C-H bond did not occur with the symmetrical imidazolium chloride [C3 H3 N2 {C(Me)(=NDipp)}2 ]Cl (3). Instead, a Ni-C(sp3 ) bond was formed, leading to the neutral Nimine CHNimine pincer-type complex Ni[C3 H3 N2 {C(Me)(=NDipp)}2 ]Cl (4). Theoretical studies showed that this highly unusual feature in nickel NHC chemistry is due to steric constraints induced by the N substituents, which prevent Ni-H bond formation. Remarkably, ethylene inserted into the C(sp3 )-H bond of 4 without nickel hydride formation, thus suggesting new pathways for the alkylation of non-activated C-H bonds.

Fluorinated Unsymmetrical N,N'-Diaryl Imidazolium Salts-New Functionalized NHC-Ligand Precursors.

An efficient and scaled-up synthesis of the imidazol-2-ylidene-based unsymmetrical NHC precursors bearing the sterically demanding hexafluoroisopropylalkoxy group [(CF3 )2 (OR)C-] at the ortho position of the N-aryl substituent was developed. The key step of the method involved the transformation of a Mes-substituted oxazolinium tetrafluoroborate salt through the reaction with the corresponding binucleophilic fluoroalkyl-substituted aniline. The subsequent post-modification of the resulting hydroxyl-containing salt through a simple one-step O-alkylation protocol provided access to a new family of unsymmetrical fluorinated NHC precursors. These compounds were successfully utilized for the preparation of several novel metal complexes. The molecular structures of some NHC precursors and their metal complexes have been unambiguously characterized by single-crystal X-ray diffraction analysis. A preliminary evaluation of the catalytic activity of the palladium complexes was performed on a Buchwald-Hartwig amination reaction. As a result, two PEPPSI-type (PEPPSI=pyridine-enhanced pre-catalyst preparation stabilization and initiation) Pd complexes have demonstrated promising activity in alkane solvents.

4,5-Substituted C^C* cyclometalated thiazol-2-ylidene platinum(ii) complexes - synthesis and photophysical properties.

We report the synthesis of seven novel backbone functionalized N-phenyl-1,3-thiazol-2-ylidene platinum(ii) complexes and their photophysical properties. Electronically diverse N-phenyl-1,3-thiazol-2-thiones were prepared by a reaction of aniline with carbon disulfide and different α-haloketone compounds. Oxidative desulfuration and salt metathesis yielded the desired NHC-precursors with hexafluorophosphate counterions. In addition, a new route for the synthesis of N-phenyl-1,3-benzo[d]thiazole tetrafluoroborate via N-arylation using hypervalent iodine species is presented. All complexes were prepared from the corresponding NHC precursor in a one-pot process using silver(i)oxide, transmetalation to platinum and reaction with the β-diketone acetylacetone under basic conditions. These complexes exhibit strong phosphorescence with quantum yields up to 72% in 2 wt% PMMA films with decay lifetimes of 8.8-12.3 μs. The influence of methyl- and phenyl-groups, and an ester-substituent at the 4- and/or 5-position of the 1,3-thiazole moiety, as well as the N-phenyl-1,3-benzo[d]thiazole-derived motif is discussed. The 4,5-unsubstituted-N-phenyl-1,3-thiazol-2-ylidene platinum(ii) acetylacetonato complex served as a reference in this study to evaluate the electronic effects originating from the backbone substitution. All complexes emit in a narrow range of the bluish-green spectrum of the visible light (510 ± 10 nm).

Phosphorescent Platinum(II) Complexes with C∧C* Cyclometalated NHC Ligands.

This Account describes our achievements toward the development of a new class of platinum(II) complexes with interesting photophysical properties. The general motif of a strongly donating N-heterocyclic carbene with a cyclometalating phenyl group attached to the nitrogen atom together with β-diketonate based counterligands enabled us to synthesize a new class of phosphorescent emitters for use in organic light-emitting diodes (OLEDs). This Account is divided into sections and introduces imidazolium based as well as triazolium based structures and discusses the effects of structural changes on the photophysical properties. Starting from the basic methylated (substituted) phenylimidalium presursors, we initially extended the π-system of the phenyl ring to the dibenzofuran ligand, its regioisomer, and thio-derivative. As the substituents of the β-diketonate ligands turned out to have a strong influence on the photophysical properties (higher quantum yields as well as shorter decay times) a series of dibenzofuranyl-3-methylimidazol as well as diphenylbenzimidazol platinum complexes were synthesized to investigate the different steric and electronic effects, which are described in a separate section. The next section of the Account then describes other extensions of the π-system. Exchange of the methyl group against a phenyl ring, as well as the extension of the π-system in the backbone of the NHC-ligand lead to a significant improvement of the photophysical properties, which reached a maximum for the diphenylbenzimidazole (DPBIC) system. Further extension of the π-system to the diphenylnaphthylimidazol then lead to a unfavorable long decay time. The effect of substitution is discussed for cyano groups, which change the electronic situation and lead to highly emissive complexes. We are currently working on studying the effect of other substituents on the photophysical properties, as well as the introduction of additional heteroatoms into the general motif. Our initial work in that area had been on 1,2,4-triazole complexes. For the basic phenyl/methyl substituted system, two different isomers are accessible, the 4-phenyl-4H-1,2,4-triazoles as well as the 1-phenyl-1H-1,2,4 triazoles. It was interesting to note that the photophysical properties of the corresponding complexes are strongly dependent on the substituent R of the β-diketonate ligand. For R = methyl, the properties are significantly different, while we found almost identical photophysical results for R = mesityl for both 1,2,4-triazole isomers. The last section describes the synthesis of bimetallic complexes. To investigate whether it is possible to cyclometalate twice into the same phenyl ring, we synthesized dicationic NHC precursors from para- and meta-disubstituted bis(imidazole)benzenes. The bimetallic complexes show interesting photophysical properties with quantum yields of up to 93%. All experimental work was accompanied by quantum chemical calculations, which turned out to be very useful for the prediction of the emission wavelengths as well as the interpretation of the emissive states of the platinum complexes.