Stephanie Cronje

Carbene complexes of gold: preparation, medical application and bonding

New preparative methods for gold carbene complexes have been developed and older ones modified to prepare compounds with specific inherent properties for targeted applications. One of the important areas of application that has grown rapidly and wherein carbene complexes are increasingly significant falls within the field of medicine. Sophisticated theoretical calculations have accompanied many synthetic studies. These aspects are covered in this critical review (65 references).

A cytotoxic bis(carbene)gold(I) complex of ferrocenyl complexes: Synthesis and structural characterisation

The N-heterocyclic carbene (NHC) precursors 1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)imidazolium bromide (2) and 1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)imidazolium tetrafluoroborate (3) were derived from 1-(4-ferrocenylphenyl)imidazole. Ferrocenyl complex 3 reacts with Ag2O and chloro(dimethylsulfide)gold(I) in the presence of tetraethylammonium chloride to produce the mixed metal species bis{1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)-2H-imidazol-2-ylidene}gold(I) tetrafluoroborate (4). Single crystal X-ray structure analyses of 1, 3 and 4 indicate that the NCHN-hydrogen in 3 is hydrogen bonded to the BF4− anion [C(H1)⋯F, 3.265(4) A], as is also reflected in the position of its 1H NMR chemical shift. Cytotoxicity studies show that complex 4 is selective for cancer cells and active against the tumour cell lines Jurkat and MCF 7.

Carbene complexes derived from lithiated heterocycles, mainly azoles, by transmetallation

Abstract Heterocyclic carbene complex formation can be achieved by lithiation of CH-acidic azoles, transmetallation involving a variety of transition metal complexes and, finally, protonation or alkylation. This article describes the synthetic methodology involved with a special emphasis on unexpected or (presently) unusual features of the reactions or products. The procedure can be extended to allow carbene complex formation by reaction at remote heteroatoms and also for diorgano(carbene) complex formation. Certain azolyls do not substitute but add to coordinated carbonyls and the resulting anionic Fischer-type carbene complexes can function as bidentate ligands. With gold(I) as central metal, many azolyls as well as carbene complexes participate in homoleptic rearrangement.

Group 6 carbene complexes derived from lithiated azoles and the crystal structure of a molybdenum thiazolinylidene complex

Fischer-type (alkoxy)azolyl carbene complexes and Ofele–Lappert-type azolylinylidene complexes were synthesised by reaction of 1-phenylpyrazol-3-yllithium, 4-methylthiazol-2-yllithium, benzothiazol-2-yllithium, 1-methylimidazol-2-yllithium with M(CO) 5 L (L=CO, THF or Cl − ; M=Cr, Mo or W) and subsequent alkylation with CF 3 SO 3 CH 3 . The alkylation of Fischer-type carbene complexes containing an azolyl as the organic substituent proceeded via ring opening of tetrahydrofuran. When the alkylation is carried out in THF, the carbocation CH 3 O(CH 2 ) 4 + acts as an electrophile. Protonation rather than alkylation of coordinated imidazolyl furnished cyclic imine complexes. Changing the donor atom of a coordinated thiazole from N to C by deprotonation and alkylation afforded a carbene complex.

Tetrazolyl and tetrazolylidene complexes of gold: a synthetic and structural study

Lithiation of 1-benzyl-1H-tetrazole followed by transmetallation with [AuCl(PPh3)], [Au(C6F5)(tht)] or [AuCl(tht)] (tht = tetrahydrothiophene) and subsequent alkylation afforded cationic 1-benzyl-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene(triphenylphosphine)gold(I), 1, neutral 1-benzyl-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene(pentafluorophenyl)gold(I), 2, and a cationic biscarbene complex, bis(1-benzyl-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene)gold(I), 3. The first complex underwent a homoleptic rearrangement in solution to form 3. Reaction of [Au(N3)PPh3] with the three isocyanides (CH3)2C6H3NC, tBuNC and CyNC, respectively, yielded the corresponding neutral tetrazolyl(phosphine) complexes of gold, [1-(2,6-dimethylphenyl)-1H-tetrazol-5-yl](triphenylphosphine)gold(I), 4, [1-(tert-butyl)-1H-tetrazol-5-yl](triphenylphosphine)gold(I), 6, and [1-(cyclohexyl)-1H-tetrazol-5-yl](triphenylphosphine)gold(I), 7. Alkylation of 4 with methyl triflate on N4 allowed isolation of the crystalline carbene complex 1-(2,6-dimethylphenyl)-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene)(triphenylphosphine)gold(I), 5. Complex 7 was not isolable in pure form but converts by isocyanide substitution of triphenylphosphine into [1-cyclohexylisocyanide][1-(cyclohexyl)-1H-tetrazol-5-yl]gold(I), 8. From a product mixture of 7 and 8 the transformed molecules [(cyclohexylamino)(ethoxy)carbene](1-cyclohexyl-1H-tetrazol-5-yl)gold(I), 9, and [bis(cyclohexylamino)carbene](1-cyclohexyltetrazol-5-yl)gold(I), 10, co-crystallised spontaneously after a long time at −20 °C.

Novel N-heterocyclic ylideneamine gold(I) complexes : synthesis, characterisation and screening for antitumour and antimalarial activity

Ylideneamine functionalised heterocyclic ligands, 1,3-dimethyl-1,3-dihydro-benzimidazol-2-ylideneamine (I), 3-methyl-3H-benzothiazol-2-ylideneamine (II) or 3,4-dimethyl-3H-thiazol-2-ylideneamine (III), were employed in the preparation of a series of both charged and neutral gold(I) complexes consisting either of a Au(C(6)F(5)) fragment (1-3), a [Au(PPh(3))](+) unit (4-6) or a [Au(NHC)](+) unit (7) coordinated to the imine nitrogen of the neutral ylideneamine ligand. These complexes were fully characterised by various techniques including X-ray diffraction. In addition, the antitumour and antimalarial potential of selected compounds were assessed in a preliminary study aimed at determining the medicinal value of such compounds. Complexation of the azol-2-ylideneamine ligands with [Au(PPh(3))](+) increases their antitumour as well as antimalarial activity.

Anionic Fischer-type carbene complexes as bidentate (N,O) ligandsElectronic supplementary information (ESI) available: molecular structures of 4b, 5, 7 and 8. See http://www.rsc.org/suppdata/dt/b3/b316998g/

New polynuclear complexes, (L1)3M2 [M2 = Cr(III) (4a,4b), Fe(III) (5), Co(III) (8)], (L1)2M2(L2)2 [M2 = Co(II) (7), Ni(II) (9)], (L1)2M2(O)L2 [M2 = V(IV) (6)] and L1M2Cp2 [M2 = Ti(III) (10)] with L1 = (CO)5M1=C[C=NC(CH3)=CHS](O-)(M1 = Cr or W) and L2 = 4-methylthiazole or THF, are described. The molecular structures of these complexes determined by X-ray diffraction show that the Fischer-type carbene complexes act as bidentate ligands towards the second metal centre, coordinating through C(carbene)-attached O-atoms and imine N-atoms of the thiazolyl groups to form five-membered chelates with the oxygen atoms in the mer configuration. Isostructural complexes have similar characteristic band patterns in their far-IR spectra. Cyclic voltammetry of selected complexes reveals the oxidation of the carbene complex ligand between 1.01 and 1.29 V. Oxidation of the central metal (M2) takes place at 0.56 and 0.86 V for 7 and 9, respectively. Three stepwise reductions of Cr(III) to Cr(0) occur for 4a and 4b in the region -0.51 to -1.58 V. These new ligand types and other variants thereof should find application in ligand design with the first metal -- and other ligands attached thereto -- in the carbene complex ligand, playing an important role.

Fischer-type tungsten acyl (carbeniate), carbene and carbyne complexes bearing C5-attached thiazolyl substituents: interaction with gold(I) fragments

2-(1-Piperidinyl)thiazole and 2-phenylthiazole were deprotonated at C5 of the thiazole rings and both reacted with [W(CO)6] to form Fischer-type tungsten carbeniate complexes 1a and 1b of the type [(CO5)WC(O){}] (R = 1-piperidinyl for 1a and phenyl for 1b). Reaction of carbeniate 1b with [(Ph3P)AuCl] afforded by acyl ligand transfer a tungstenoxycarbene complex of gold(I), [(Ph3P)AuC{OW(CO)5}{}] (2), in which the W(CO)5 fragment remains coordinated to the acyl oxygen atom. Alkylation of 1a and 1b with [Me3O][BF4] afforded the carbene complexes [(CO)5WC(OMe){}], 3a and 3b. A rare example of a hydroxycarbene complex of 1a stabilised by a hydrogen bond to 1a, [NMe4][{}C{W(CO)5}OH...(O)C{W(CO)5}{}], 4, (R = 1-piperidinyl) was crystallised while attempting to prepare 3a by a different route. Reaction of 3b with [ClAu(tht)] (tht = tetrahydrothiophene) furnished the corresponding alkoxycarbene gold(I) complex [ClAuC(OMe){}], 5. Subsequent reaction of 1a and 1b with bis(trichloromethyl)carbonate and pyridine yielded the carbyne complexes [Cl(CO)2(py)2WC{}], 6a and 6b. Reaction of 6a with [ClAu(tht)] afforded an unstable addition compound, 7, in which the gold atom is coordinated to the formal carbyne triple bond. Interaction between gold and the proton of the thiazole ring in this complex was observed by variable temperature NMR. The crystal and molecular structures of complexes 1a, 1b, 2, 3b, 4, 5, 6a and 6b were all determined by single crystal X-ray diffraction.

Synthesis and characterisation of N-coordinated pentafluorophenyl gold(i) thiazole-derived complexes and an unusual self-assembly to form a tetrameric gold(i) complexElectronic supplementary information (ESI) available: Characterisation data for 1. See http://www.rsc.org/suppdata/dt/b3/b303625a/

Treatment of [Au(C6F5)(SC4H8)] (1) (SC4H8 = tetrahydrothiophene or tht) with HCNC(CH3)C(H)S, CH3SCNC(CH3)C(H)S, (I) or piperidine yields the neutral mononuclear imine complexes [Au(C6F5){NC(H)SC(H)CCH3}] (2) and [Au(C6F5){NC(SCH3)SC(H)CCH3}] (3), or the amine complex [Au(C6F5){N(H)CH2(CH2)3CH2}] (4). The reaction of 1 with SCN(H)C(CH3)C(H)S, (II) affords the thione complex [Au(C6F5){SCN(H)C(CH3)C(H)S}] (5), which, in CH2Cl2via spontaneous intermolecular deprotonation of the thione ligand, self-assembles to an unique tetramer of Au(I), [Au{SCNC(CH3)C(H)S}]4 (6) containing a folded rectangle of Au-atoms with aurophlilic interactions [av. Au⋯Au distance, 3.02(4) A and av. Au–Au–Au angle, 87(2)°]. N-coordination of the imine complexes has been confirmed by 15N NMR and the crystal structure determination of 2 which exhibits the expected linear N-coordination and intermolecular Au⋯Au [3.345(1) A] contacts. The crystal structure of 5 shows thione S-coordination of II to the central Au atom.

Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity

A series of new neutral mononuclear or dinuclear gold(I) complexes and a cyclic cationic tetranuclear amidogold(I) complex comprising of the phosphines 1,2-bis(dimethylphosphino)ethane (dmpe), μ-1,2-bis(diphenylphosphino)ethane (dppe), μ-1,3-bis(diphenylphosphino)propane (dppp), μ-1,5-bis(diphenylphosphino)pentane (dpppe), μ-1,6-bis(diphenylphosphino)hexane (dpph) or trimethylphosphine, and several N-heterocyclic ring systems (imidazolate, pyrazolate, 1,2,3-triazolate, 1,2,4-triazolate, pyrrolate, 9H-purine-9-ate or 9H-purine-6-amine-9-ate) as ligands, reveal intermolecular aurophilic interactions and 2D channels available for solvent molecules in some of their crystal structures. The antitumour activity of the acyclic gold(I) compounds is highly dependent on the substituents on the phosphorus atoms being highest for phenyl groups and lower for methyl groups. The activity of these compounds against selected cell lines is linked to the length of the carbon bridge between the two phosphorus atoms being highest with a bridge consisting of 5 or 6 carbons. Two compounds with the highest tumour specifities that contain dpppe and pyrazolate (a lipophilic compound) or 1,2,4-triazolate (a hydrophilic compound) induce an apoptotic cell death pathway and a maximum dose to Balb/C mice is tolerated.