Carbene Ligand Precursors Research Articles

N-Heterocyclic Carbene Coinage Metal Complexes Containing Naphthalimide Chromophore: Design, Structure, and Photophysical Properties

A series of novel N-heterocyclic carbene coinage metal complexes containing a naphthalimide (NI) chromophore has been prepared and fully characterized. Two types of molecules are described those where the NI unit is directly attached to the carbene unit with the general formulae [(L1)–M–X], M = Cu, X = Cl (1a); M = Ag, X = I (1b) and M = Au, X = Cl, (1c). While in the second family, a π-extended carbene ligand precursor L2–H+I− (3) was prepared where the NI unit is distant from the imidazole unit via a phenyl-alkyne bridge. Only two N-heterocyclic carbene metal complexes were prepared [(L2)–M–Cl], M = Cu (2a) and M = Au (2c). The related silver carbene compound could not be isolated. The molecular structure of the carbene complex 1c was determined and confirmed the formation of the target compound. Interestingly, the structure shows the presence of an aurophilic interaction Au···Au at 3.407 Å between two individual molecules. The photophysical properties of the compounds were investigated in solution at room temperature. Preliminary results suggested that all compounds are luminescent and act as blue emitters (420–451 nm). These transition emissions can be attributed to the intraligand origin of the NI chromphore. Moreover, the carbene complexes featuring L2 ligand with π-extended system were found to be more luminescent.

Sugar-Incorporated Chelating Bis-N-Heterocyclic Carbene Palladium Complexes. Synthesis, Structures, and Catalytic Ability for Suzuki-Miyaura Cross-Coupling Reactions in Water

Abstract Sugar-incorporated chelating bis-N-heterocyclic carbene ligand precursors 1,1′-bis(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-3,3′-ethylene-diimidazolyl ([(bisNHC-C2)H2]2+) and 1,1′-bis(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-3,3′-propylene-diimidazolyl ([(bisNHC-C3)H2]2+) were synthesized and used to prepare palladium complexes [Pd(bisNHC-C2)Cl2] and [Pd(bisNHC-C3)Cl2], respectively, by direct metallation reaction using dichlorobis(acetonitrile)palladium as a metal source. Catalytic abilities of the complexes for Suzuki-Miyaura coupling in aqueous media were examined and moderate TON (85,000) and TOF (170,000 h−1) were obtained. Because the terminal chloro ligands in the complexes were substituted with solvent molecules or chloride anion and hence 1H NMR spectra of the chloro complexes were complicated, hydrosulfido complexes [Pd(bisNHC-Cn)(SH)2] (n = 2 and 3) were prepared to confirm structures in solution. Dynamic behavior of flapping-wing motion of the bisNHC ligand in [Pd(bisNHC-C3)(SH)2] in solution was evaluated using the signals of the SH protons, which are inequivalent in 1H NMR spectra attributed to the chirality of the glucopyranosyl units.

Bicyclic N-heterocyclic carbene (NHC) ligand precursors and their palladium complexes

Eight bicyclic amidinium precursors (3), prepared from R,S-tmcp (R,S-tmcp: (1R,3S)-diamino-1,2,2-trimethylcyclopentane) were described. Only five of the precursors (3a–e) could be converted to palladium complexes, (PdX2(6,7-NHC)PEPPSI) (4) by treatment with PdCl2, K2CO3, and pyridine (additional KBr was used for (PdBr2(6,7-NHC)PEPPSI)). The salts and complexes were fully characterized by spectroscopic methods and X-ray crystallography.

Novel multicharged silver(I)–NHC complexes derived from zwitterionic 1,3-symmetrically and 1,3-unsymmetrically substituted imidazoles and benzimidazoles: Synthesis and cytotoxic properties

Novel zwitterionic N-heterocyclic carbenes (NHCs) precursors, 1,3-symmetrically substituted NaHIm1R,3R,4R″ (R = (CH2)3SO3−, R″ = H or CH3), NaHBzim1R,3R (R = (CH2)3SO3−), and 1,3-unsymmetrically substituted NaHIm1R,3R′,4R″ (R = (CH2)3SO3−, R′ = CH2C6H5, R″ = H or CH3), [HBzim1R,3R′]Br (R = (CH2)3SO3Na, R′ = R or CH2C6H5) have been synthesized and used in the synthesis of multicharged silver(I)–NHC complexes. These compounds have been characterized using IR and NMR spectroscopy and by electrospray mass spectrometry. The N-heterocyclic carbene ligand precursor Him1 and the intermediate HBzimPrSO3 were also characterized by X-ray crystallography. Silver(I)-NHCs and the corresponding silver free ligands were assayed for their cytotoxic properties against a panel of human tumour cell lines including lung (A549), colon (HCT-15), breast (MCF-7) and cervical (A431) cancers, along with melanoma (A375). Their antiproliferative activity was further investigated on a human ovarian cell line pair which has been selected for sensitivity/resistance to cisplatin, i.e. 2008/C13* cancer cells. All complexes elicited a similar cytotoxic profile both in cisplatin-sensitive and -resistant cell lines, with resistance factors (R.F.) up to 9 times lower than that of cisplatin, attesting the ability of these derivatives to overcome acquired cisplatin resistance.

ChemInform Abstract: Expedient Synthesis of Homochiral 1‐Aryl‐Substituted 4,5‐Dihydro‐1H‐Imidazoles and Their Modification to N‐Heterocyclic Carbene Precursors.

The amidoamines (S)-Ar1CONHCHRCH2NHAr2 [Ar1 = o-C6H4SO3H, R = Bn, iBu, iPr; Ar2 = 2,6-iPr2C6H4, 2,6-Et2C6H4, 2,4,6-Me3C6H2] cyclise to (S) 1-aryl-substituted 4,5-dihydro-1H-imidazolinium species with HC(OEt)3 in moderate-to-excellent yields on heating to 150–175 °C (nine examples, four isolated yields of 48 to >97 %). They are attained as their o-C6H4(SO3–)(CO2Et) salts. The latter are readily deprotonated to afford analytically pure (S) 1-aryl-substituted 4,5-dihydro-1H-imidazoles (imidazolines). The purification of the intermediate sulfonate salts is not always necessary, and analytically pure imidazolines are isolated by simple kugelrohr distillation (nine examples, 45–95 %) after basification. Imidazoline alkylation provides a library of (S)-N-alkylimidazolinium salts (23 examples, 74–97 %). As the initially required amidoamines are available in simple one-pot reactions, the overall approach constitutes a rather efficient approach to this useful family of chiral N-heterocyclic carbene (NHC) ligand precursors (effectively three steps from commercial N-Boc-α-amino alcohols; BOC = tert-butyloxycarbonyl).

ChemInform Abstract: Palladium‐Catalyzed Arylation of Aldehydes with Bromo‐Substituted 1,3‐Diaryl‐imidazoline Carbene Ligand.

Abstract The combination of 0 valent palladium precursor and bromo-substituted 1,3-diaryl-imidazoline carbene ligand precursor such as 1-(2-bromophenyl)-3-(2,6-diisopropylphenyl)-imidazolinium chloride 1a exhibited high catalytic activity for the 1,2-addition of arylboronic acids to aldehydes including aqueous formaldehyde.

Expedient Synthesis of Homochiral 1‐Aryl‐Substituted 4,5‐Dihydro‐1H‐imidazoles and Their Modification to N‐Heterocyclic Carbene Precursors

AbstractThe amidoamines (S)‐Ar1CONHCHRCH2NHAr2 [Ar1 = o‐C6H4SO3H, R = Bn, iBu, iPr; Ar2 = 2,6‐iPr2C6H4, 2,6‐Et2C6H4, 2,4,6‐Me3C6H2] cyclise to (S) 1‐aryl‐substituted 4,5‐dihydro‐1H‐imidazolinium species with HC(OEt)3 in moderate‐to‐excellent yields on heating to 150–175 °C (nine examples, four isolated yields of 48 to >97 %). They are attained as their o‐C6H4(SO3–)(CO2Et) salts. The latter are readily deprotonated to afford analytically pure (S) 1‐aryl‐substituted 4,5‐dihydro‐1H‐imidazoles (imidazolines). The purification of the intermediate sulfonate salts is not always necessary, and analytically pure imidazolines are isolated by simple kugelrohr distillation (nine examples, 45–95 %) after basification. Imidazoline alkylation provides a library of (S)‐N‐alkylimidazolinium salts (23 examples, 74–97 %). As the initially required amidoamines are available in simple one‐pot reactions, the overall approach constitutes a rather efficient approach to this useful family of chiral N‐heterocyclic carbene (NHC) ligand precursors (effectively three steps from commercial N‐Boc‐α‐amino alcohols; BOC = tert‐butyloxycarbonyl).

Palladium-catalyzed arylation of aldehydes with bromo-substituted 1,3-diaryl-imidazoline carbene ligand

The combination of 0 valent palladium precursor and bromo-substituted 1,3-diaryl-imidazoline carbene ligand precursor such as 1-(2-bromophenyl)-3-(2,6-diisopropylphenyl)-imidazolinium chloride 1a exhibited high catalytic activity for the 1,2-addition of arylboronic acids to aldehydes including aqueous formaldehyde.

Efficient Electronic Communication of Two Ruthenium Centers through a Rigid Ditopic N‐Heterocyclic Carbene Linker

A ditopic benzobis(carbene) ligand precursor was prepared that contained a chelating pyridyl moiety to ensure co-planarity of the carbene ligand and the coordination plane of a bound octahedral metal center. Bimetallic ruthenium complexes comprising this ditopic ligand [L4Ru-C,N-bbi-C,N-RuL4] were obtained by a transmetalation methodology (C,N-bbi-C,N=benzobis(N-pyridyl-N'-methyl-imidazolylidene). The two metal centers are electronically decoupled when the ruthenium is in a pseudotetrahedral geometry imparted by a cymene spectator ligand (L4=[(cym)Cl]). Ligand exchange of the Cl(-)/cymene ligands for two bipyridine or four MeCN ligands induced a change of the coordination geometry to octahedral. As a consequence, the ruthenium centers, separated through space by more than 10 Å, become electronically coupled, which is evidenced by two distinctly different metal-centered oxidation processes that are separated by 134 mV (L4=[(bpy)2]; bpy=2,2'-bipyridine) and 244 mV (L4=[(MeCN)4]), respectively. Hush analysis of the intervalence charge-transfer bands in the mixed-valent species indicates substantial valence delocalization in both complexes (delocalization parameter Γ=0.41 and 0.37 in the bpy and MeCN complexes, respectively). Spectroelectrochemical measurements further indicated that the mixed-valent Ru(II)/Ru(III) species and the fully oxidized Ru(III)/Ru(III) complexes gradually decompose when bound to MeCN ligands, whereas the bpy spectators significantly enhance the stability. These results demonstrate the efficiency of carbenes and, in particular, of the bbi ligand scaffold for mediating electron transfer and for the fabrication of molecular redox switches. Moreover, the relevance of spectator ligands is emphasized for tailoring the degree of electronic communication through the benzobis(carbene) linker.

Synthesis and in vitro antitumor activity of water soluble sulfonate- and ester-functionalized silver(I) N-heterocyclic carbene complexes

The novel N-heterocyclic carbene ligand precursor NaHImPrSO3 (sodium 3,3′-(1H-imidazole-3-ium-1,3-diyl)dipropane-1-sulfonate) and the related silver carbene complex [Na4(ImPrSO3)2]AgCl have been synthesized and characterized. Recrystallization of the analogous [ImAcEt]AgCl complex allowed the development of X-ray analysis which led to achieve relevant structural information concerning this silver(I) derivative. Both sulfonate- and ester-functionalized silver(I) N-heterocyclic carbenes (NHCs) were evaluated for their antiproliferative activities in a wide panel of human cancer cells. Complex [Na4(ImPrSO3)2]AgCl showed a significant in vitro antiproliferative activity that was correlated with its strong ability to inhibit thioredoxin reductase. The inhibition of this selenoenzyme determined an alteration of the cellular redox environment thus leading to the induction of the apoptotic cell death through the activation of the ASK-1 pathway.

Silver(I)‐N‐heterocyclic carbene complexes of bis‐imidazol‐2‐ylidenes having different aromatic‐spacers: synthesis, crystal structure, and in vitro antimicrobial and anticancer studies

A series of Ag(I) complexes (6, 7, 8, 9) derived from imidazol‐2‐ylidenes was synthesized by reacting Ag2O with an o‐, m‐, p‐xylyl or 1,3,5‐triazine‐linked imidazolium salts (1, 2, 3, 4) and then characterizing these using various spectro‐analytical techniques. Additionally, triazine‐linked bis‐imidazolium salt 5 was characterized using the single‐crystal X‐ray diffraction method. Complexes 6–9 were formed from the N‐heterocyclic carbene ligand precursors 1–3 as PF6‐ salts in good yields. Conversely, salt 5 does not form Ag(I) complex even under various reaction conditions. Using ampicillin as a standard, complexes 6–9 were tested against bacteria strains Escherichia coli and Staphylococcus aureus as Gram‐negative and Gram‐positive bacteria, respectively, showing potent antimicrobial activities against the tested bacteria even at minimum inhibition concentration and bacterial concentration levels. Furthermore, the potential anticancer activities of the reported complexes were evaluated against the human colorectal cancer (HCT 116) cell lines, using 5‐fluorouracil as a standard drug. The highest anticancer activities were observed for complex 8 with an IC50 value of 3.4 μm, whereas the lowest was observed for complex 9 with an IC50 value of 18.1 μm. Copyright © 2013 John Wiley & Sons, Ltd.

Binuclear meta‐xylyl‐linked Ag(I)‐N‐heterocyclic carbene complexes of N‐alkyl/aryl‐alkyl‐substituted bis‐benzimidazolium salts: synthesis, crystal structures and in vitro anticancer studies

Salts of meta‐xylyl‐linked N‐ethyl/n‐butyl/benzyl‐substituted bis‐benzimidazolium having hexafluorophosphate counterions have been synthesized. The corresponding binuclear Ag(I)‐N‐heterocyclic carbene complexes were prepared by the reaction of Ag2O. The N‐heterocyclic carbene (NHC) ligand precursor 7 and Ag(I)–NHC complexes 10 and 11 have been structurally characterized by single‐crystal X‐ray diffraction technique. All of the reported compounds have been tested for their anticancer activity using human colorectal (HCT 116) cancer cell lines. Sterically varied benzimidazolium salts displayed significant activity against HCT 116 cell line, yielding IC50 values in the range 0.1–19.4 µ m, while Ag(I)–carbene complexes showed exceptionally good activity (0.2–1.3 µ m) against tested cancer cell lines. Copyright © 2013 John Wiley & Sons, Ltd.

Direct synthesis of cis-dihalido-bis(NHC) complex of nickel(ii) and catalytic application in olefin addition polymerization: Effect of halogen co-ligands and density functional theory study

Two novel amine-containing N-heterocyclic carbene ligand precursors [H(1a-b)]Br have been prepared in good yield and fully characterized. Direct syntheses of cis- and trans-dihalido-bis(NHC) nickel complexes [Ni(NHC)2X2] (X = Cl, Br) are reported. The solid structures of trans-[Ni(1a-b)2Br2] (2a-b) and cis-[Ni(1a)2Cl2] (3) were determined by single-crystal X-ray analysis and 3 was found to be the first example of cis-configuration coordination of monodentate NHC ligands to a metal center for dihalido-bis(NHC) nickel complexes. DFT calculations were conducted to determine the energy difference between cis- and trans-isomers of complexes 2a and 3 bearing bromide and chloride co-ligands. The cis-[Ni(1a)2Cl2] (cis-3) is 1.77-1.55 kcal mol(-1) lower in energy than its trans-isomer in polar solvents including CH2Cl2 and THF, while the trans-[Ni(1a)2Br2] (trans-2a) is more stable than the cis-isomer similarly in the gas phase. The cis nickel complex 3 with two coordinated monodentate NHCs was tested for olefin addition polymerization at standard conditions. It was found that cis-3 was inactive in ethylene polymerization but showed moderate catalytic activities (0.5-3.0 × 10(6) g of PNB (mol of Ni)(-1) h(-1)) in the addition polymerization of norbornene in the presence of methylaluminoxane (MAO) as cocatalyst.

Synthesis of chiral N-heterocyclic carbene (NHC) ligand precursors and formation of ruthenium(II) complexes for transfer hydrogenation catalysts

The S enantiomers of ester functionalized NHC ligand precursors, 1-[(2S)-1-ethoxy-3-methyl-1-oxobutan-2-yl]-3-ethyl-1H-imidazol-3-ium bromide (3a) and the methyl ester analog 3b, were synthesized from l-valine and fully characterized. The absolute stereochemistry of the chiral center was confirmed by single crystal X-ray diffraction (for 3a) and enantiopurity (of 3a and 3b) was determined by micellar electrokinetic chromatography. Deprotonation of this NHC ligand precursor (3a or 3b) and coordination to [RuCl2(p-cymene)]2 resulted in the isolation of a monodentate complex (with only NHC coordination) (4a or 4b) and a bidentate complex (5). In the bidentate complex, in addition to NHC coordination, a carboxylate donor group (from in situ hydrolysis of the ester) coordinates to Ru. All ruthenium complexes have been characterized by spectroscopic and analytical methods, plus single crystal X-ray diffraction for 4a and 5. The evidence shows that both Ru complexes are racemic, but with alternate synthetic methods perhaps racemization during complexation of 3a or 3b to metals could be avoided. The ruthenium complexes described herein serve as catalysts for ketone transfer hydrogenation in basic isopropanol.

Synthesis and Biological Activity of Ester- and Amide-Functionalized Imidazolium Salts and Related Water-Soluble Coinage Metal N-Heterocyclic Carbene Complexes

N-Heterocyclic carbene (NHC) ligand precursors, namely, HIm(A)Cl [1,3-bis(2-ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride] and HIm(B)Cl {1,3-bis[2-(diethylamino)-2-oxoethyl]-1H-imidazol-3-ium chloride}, functionalized with hydrophilic groups on the imidazole rings have been synthesized and were used in the synthesis of corresponding carbene complexes of silver(I) and copper(I), {[Im(A)]AgCl}, {[Im(A)]CuCl}, and {[Im(B)](2)Ag}Cl. Related Au(I)NHC complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} have been obtained by transmetalation using the silver carbene precursor. These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. HIm(B)Cl and the gold(I) complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} were also characterized by X-ray crystallography. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin-sensitive and -resistant cells. The silver(I) complex {[Im(B)](2)Ag}Cl was found to be the most active, with IC(50) values about 2-fold lower than those achieved with cisplatin in C13*-resistant cells. Growth-inhibitory effects evaluated in human nontransformed cells revealed a preferential cytotoxicity of {[Im(B)](2)Ag}Cl versus neoplastic cells. Gold(I) and silver(I) carbene complexes were also evaluated for their ability to in vitro inhibit the enzyme thioredoxin reductase (TrxR). The results of this investigation showing that TrxR appeared markedly inhibited by both gold(I) and silver(I) derivatives at nanomolar concentrations clearly point out this selenoenzyme as a protein target for silver(I) in addition to gold(I) complexes.

Thiol-functionalized 1,2,4-triazolium salt as carbene ligand precursor

A thiol-functionalized 1,2,4-triazolylidene ligand precursor salt was synthesized from 2-(4-methoxybenzylthio)aniline. Removal of the protecting group under strongly acidic conditions (trifluoroacetic acid/trifluoromethanesulfonic acid) yielded a 1,2,4-triazolium salt comprising a free thiophenol moiety as was confirmed by X-ray analysis. The fairly air-stable thiophenol was oxidized by DMSO resulting in ring closure to a benzothiazole. Deprotonation and metalation resulted in the cis- and trans-isomers of the square-planar bis(NHC-thiolato) Ni(II), Pd(II) and Pt(II) complexes. The palladium complex was successfully employed as catalyst in C–C, C–N and C–S cross-coupling reactions. Chlorobenzene was activated only in the amination reaction. Cobalt dichloride formed an octahedral Co(III) complex under oxidation of the metal center. A η3−allyldicarbonylmolybdenum(II) complex of the C,S-ligand was prepared.

Binaphthyl-bridged bis-imidazolinium salts as N-heterocyclic carbene ligand precursors in the palladium-catalyzed Heck reaction

Two new bis-imidazolinium salts (4a, 4b) have been synthesized as precursors of N-heterocyclic carbenes (NHCs) from the commercially available (R)-2,2′-dihydroxy-1,1′-binaphthalene. The two bis-imidazolinium salts were used as efficient precursor of NHC ancillary ligands in the palladium-catalyzed Heck reaction. Good to excellent yields and high stereoselectivities were obtained with ethyl acrylate, acrylonitrile, and acrylamide as starting materials. The structure of bis-imidazolinium salt 4b was further characterized by single crystal X-ray diffraction analysis.

Water-soluble gold(I)–NHC complexes of sulfonated IMes and SIMes and their catalytic activity in hydration of alkynes

The water-soluble carbene ligand precursors sIMesH +Cl − and sSIMesH +Cl − were synthesized in high yields by direct sulfonation of IMesH +Cl − (1,3-bis(2,4,6-trimethylphenyl) imidazolium chloride) and SIMesH +Cl − (1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride). Gold(I)-N-heterocyclic carbene complexes [AuCl(sIMes)] and [AuCl(sSIMes)] were prepared by carbene transfer from the zwitterionic [Ag(sIMes) 2] and [Ag(sSIMes) 2] to [AuCl(tht)] (tht = tetrahydrothiophene). In methanol–water mixtures or in neat water, the new gold(I)–NHC complexes showed high catalytic activity in Markovnikov type hydration of terminal alkynes (up to a turnover frequency 1990 h −1; ethynyltoluene, 0.1 mol% catalyst) but were markedly less active in case of internal alkynes (TOF = 3.6 h −1; diphenylethyne, 1 mol% catalyst). These new Au(I)-NHC catalysts do not require acid co-catalysts or activation by Ag(I)-additives.

Synthesis and characterisation of quinoline functionalised imidazolium salts

A series of quinoline based imidazolium salts were prepared and characterised as nucleophilic heterocyclic carbene (NHC) ligand precursors. The symmetrically saturated imidazolium salt prepared by ring closure of achiral tetradentate diquinolyl-diamine with triethyl orthoformate is a tridentate ligand and can function as pincer ligand while the two asymmetric imidazolium salts are bidentate and have different steric bulk which may have interesting implication in catalysis. The solubility of the symmetrical dihydroimidazolium salt was enhanced by replacing the counter ion tetraflouroborate with tetrakis (3,5-bis(triflouromethyl)phenyl)borate (Barf ) and its structure confirmed by X- ray crystallography. Keywords: Nucleophilic heterocyclic carbene (NHC), Imidazolium salt, ligand, ring closure.

Highly Efficient Palladacycle/Dihydroimidazolium Chloride System for the Suzuki‐Miyaura Cross‐Coupling of Aryl Halides (I, Br, Cl) with Arylboronic Acids

AbstractA combination of a tertiary amine‐based palladacycle and an N‐heterocyclic carbene ligand precursor (1, N,N‐bis‐mesityl‐4,5‐dihydroimidazolium chloride) has been applied to catalyze the Suzuki‐Miyaura cross‐coupling of aryl halides with arylboronic acids. The substrate scope is general: a variety of electron rich and deficient aryl halides (I, Br, Cl) and arylboronic acids were found to undergo the cross‐coupling reaction in good to excellent yields at low catalyst loading of 0.01–1 mol%.