Tetrazene Complex Research Articles

Improving the anticancer activity of fluorinated glucosamine and galactosamine analogs by attachment of a ferrocene or ruthenium tetrazene motif

Acylated N‐acetyl hexosamine hemiacetals are known for their cytotoxicity. We have previously reported that cytotoxicity can be increased by replacing one or more acyloxy groups with fluorine. Herein, we present the synthesis of 4,6‐difluorinated d‐gluco‐ and 4‐fluorinated d‐galacto‐configured hexosamine‐derived glycoconjugates with organoruthenium or ferrocene complexes and their in vitro cytotoxicity against three cancer cell lines (A2780, SK‐OV‐3, and MDA‐MB‐231) and one noncancerous cell line (HEK‐293). The attachment of the organometallic moiety at the 2‐position significantly enhanced the cytotoxicity, especially against triple‐negative MDA‐MB‐231 and the cisplatin resistant SK‐OV‐3 cancer cells. We observed a clear significance of an unprotected and acetyl protected anomeric hydroxyl for the cytotoxicity. Glycoconjugates with a non‐hydrolysable organic or organometallic group at the anomeric position were generally nontoxic. A more detailed analysis revealed that, in particular, complexes with the ruthenium tetrazene complex induced apoptosis in both SK‐OV‐3 and MDA‐MB‐231 cells, as demonstrated by western blot analysis and Annexin V‐FITC/PI staining. The structures of the two most cytotoxic organoruthenium and ferrocene glycoconjugates were confirmed by X‐ray diffraction analysis.

Reactions of Low-Valent Gallium Species with Organic Azides: Formation of Imido-, Azoimido-, and Tetrazene Complexes.

The reactivity of two α-diimine-ligated digallanes, [L2-Ga-GaL2-] (La = [(2,6-iPr2C6H3)NC(CH3)]2, dpp-dad, 1; Lb = 1,2-[(2,6-iPr2C6H3)NC]2C10H6, dpp-bian, 2), and a gallylene, [(La)2-GaNa(THF)3] (3), toward organic azides was studied. Reaction of digallane 1 or 2 with trimethylsilyl azide (Me3SiN3), 2-azido-benzonitrile (2-CNC6H4N3), or tosylazide (TosN3) results in imido-bridged complexes, [(La)·-Ga(μ-NSiMe3)2Ga(La)·-] (4) [(Lb)·-Ga(μ-NSiMe3)2Ga(Lb)·-] (5), [(Lb)·-Ga(μ-2-CNC6H4N)2Ga(Lb)·-] (6), and [(Lb)·-Ga(μ-NTos)2Ga(Lb)·-] (7), with elimination of dinitrogen. Treatment of 1 or 2 with 1-adamantyl azide (1-AdN3), on the other hand, affords the unsymmetrical dinuclear complexes [(La)·-Ga(NAd)(N3Ad)Ga(La)·-] (8) and [(Lb)·-Ga(NAd)(N3Ad)Ga(Lb)·-] (9), which contain both imido and triazene bridges. Different from the Ga(II) complexes 1 and 2, the reactions of Ga(I) species 3 with benzylazide or trimethylsilyl azide result in the tetrazene complex {Na(THF)}2[(La)2-Ga(benzyl-N4-benzyl)]2 (10) and amide complex {Na(THF)4}[(La)2-Ga(NHSiMe3)(benzyl)] (11). It is likely that these latter transformations proceed via the transient formation of the corresponding Ga═N imide complex, which undergoes either cycloaddition with a second azide (to form 10) or activation of the C-H bond of methyl in one solvent toluene molecule (to yield 11).

Heterometallic Iridium, Rhodium and Ruthenium Nitrido Complexes Supported by Oxygen and Sulfur Donor Ligands

Heterometallic μ-nitrido complexes have been synthesized from organometallic complexes containing O/S-donor ligands and a ruthenium(VI) nitride. The treatment of [Ir(tpip)(L)2] (tpip−=[N(Ph2PO)2]−; L=cyclooctene (coe) or 2,6-dimethylphenylisocyanide (xylNC)) and [Ir{N(iPr2PS)2}(coe)] with [Ru(LOEt)(N)Cl2] (LOEt−=[Co(η5-C5H5){P(O)(OEt)2}3]−) (1) afforded [(L)(tpip)Ir(μ-N)Ru(LOEt)Cl2] (L=coe (2) or xylNC (3)) and [(coe){N(iPr2PS)2}Ir(μ-N)Ru(LOEt)Cl2] (4), respectively, in which the Ir−N(nitride) bonds show double bond character. The bonding in 2–4 can be described by two resonance forms: Ir(I)−N≡Ru(VI) and Ir(III)=N=Ru(IV). The treatment of [Ph4P][Ir(CO)2Cl2] with 1 afforded (PPh4)[(CO)Cl2Ir(μ-N)Ru(LOEt)Cl2] (5) that reacted with [Tl(SR)] to give (PPh4)[(CO)(RS)2Ir(μ-N)Ru(LOEt)Cl2] (R=xyl (6), C6F4H (7)). The reaction of [M(acac)(CO)2)] or [Ru(acac)2(coe)2] (acac−=acetylacetonate) with 1 gave [(CO)(acac)M(μ-N)Ru(LOEt)Cl2] [M=Ir (8), Rh (9)] or [(H2O)(acac)2Ru(μ-N)Ru(LOEt)Cl2] (10), whereas the treatment of [Ru(acac)2(MeCN)2] with 1-azidoadamantane (AdN3) yielded a Ru(II) tetrazene complex, [Ru(acac)2(N4Ad2)] (11).

Ruthenium tetrazene complexes bearing glucose moieties on their periphery: Synthesis, characterization, and in vitro cytotoxicity

Ruthenium tetrazene complexes with general formula [Cp*RuCl(1,4‐R2N4)] (Cp* = η5‐C5Me5), where R = benzyl (1), 2‐fluorobenzyl (2), β‐d‐glucopyranosyl‐unprotected (3a) and acyl‐protected (3b–d), 2‐acetamido‐β‐d‐glucopyranosyl‐unprotected (4a) and acyl‐protected (4b–d), propyl‐β‐d‐glucopyranoside‐unprotected (5a), and O‐acetylated (5b), were synthesized and characterized using nuclear magnetic resonance and electrospray ionization–mass spectrometry. In addition, the molecular structure of 3b was determined using X‐ray crystallography. The cytotoxicity of complexes against ovarian (A2780, SK‐OV‐3) and breast (MDA‐MB‐231) cancer cell lines and noncancerous cell line HEK‐293 was evaluated and compared to cisplatin activity. The carbohydrate‐modified complexes bearing acyl‐protecting groups exhibited higher efficacy (in low micromolar range) than unprotected ones, where the most active 4d was superior to cisplatin up to five times against all investigated cancer cell lines; however, no significant selectivity was achieved. The complex induced apoptotic cell death at low micromolar concentrations (0.5 μM for A2780 and HEK293; 2 μM for SK‐OV‐3 and MDA‐MB‐231).

Reactivity of Pyridine Dipyrrolide Iron(II) Complexes with Organic Azides: C-H Amination and Iron Tetrazene Formation.

Reaction of (MesPDPPh)Fe(thf) (H2MesPDPPh = 2,6-bis(5-(2,4,6-trimethylphenyl)-3-phenyl-1H-pyrrol-2-yl)pyridine) with organic azides has been studied. The identity of the azide substituent had a profound impact on the transformation type and nature of the observed products. Reaction with aromatic p-tolyl azide, N3Tol, resulted in exclusive formation of the corresponding iron tetrazene complex (MesPDPPh)Fe(N4Tol2). In contrast, the use of bulky 1-adamantyl azide led to clean intramolecular C-H amination of one of the benzylic C-H bonds of a mesityl substituent on the pyridine dipyrrolide, PDP, supporting ligand. The smaller aliphatic substituent in benzyl azide allowed for the isolation of two different compounds from distinct reaction pathways. One product is the result of double C-H amination of the PDP ligand via nitrene transfer, while the second one contains a dibenzyltetrazene and a benzaldimine ligand. All isolated complexes were characterized using a combination of X-ray crystallography, solid state magnetic susceptibility measurements, 1H NMR and 57Fe Mössbauer spectroscopy, and density functional theory (DFT), and their electronic structures were elucidated. Potential electronic structures for putative iron(IV) imido or iron(III) imidyl radical complexes were explored via DFT calculations.

Catalytic Nitrene Homocoupling by an Iron(II) Bis(alkoxide) Complex: Bulking Up the Alkoxide Enables a Wider Range of Substrates and Provides Insight into the Reaction Mechanism.

The reaction of HOR' (OR' = di-t-butyl-(3,5-diphenylphenyl)methoxide) with an iron(II) amide precursor forms the iron(II) bis(alkoxide) complex Fe(OR')2(THF)2 (2). 2 (5-10 mol %) serves as a catalyst for the conversion of aryl azides into the corresponding azoarenes. The highest yields are observed for aryl azides featuring two ortho substituents; other substitution patterns in the aryl azide precursor lead to moderate or low yields. The reaction of 2 with stoichiometric amounts (2 equiv) of the corresponding aryl azide shows the formation of azoarenes as the only organic products for the bulkier aryl azides (Ar = mesityl, 2,6-diethylphenyl). In contrast, formation of tetrazene complexes Fe(OR')2(ArNNNNAr) (3-6) is observed for the less bulky aryl azides (Ar = phenyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl). The electronic structure of selected tetrazene complexes was probed by spectroscopy (field-dependent 57Fe Mössbauer and high-frequency EPR) and density functional theory calculations. These studies revealed that Fe(OR')2(ArNNNNAr) complexes contain high-spin ( S = 5/2) iron(III) centers exchange-coupled to tetrazene radical anions. Tetrazene complexes Fe(OR')2(ArNNNNAr) produce the corresponding azoarenes (ArNNAr) upon heating. Treatment of a tetrazene complex Fe(OR')2(ArNNNNAr) with a different azide (N3Ar') produces all three possible products ArNNAr, ArNNAr', and Ar'NNAr'. These experiments and quantum mechanics/molecular mechanics calculations exploring the reaction mechanism suggest that the tetrazene functionality serves as a masked form of the reactive iron mono(imido) species.

Electronic Structure of Manganese Complexes of the Redox‐Non‐innocent Tetrazene Ligand and Evidence for the Metal‐Azide/Imido Cycloaddition Intermediate

The first synthetic manganese tetrazene complexes are described as a redox pair comprising anionic [Mn(N4 Ad2 )2 ](-) (1) and neutral Mn(N4 Ad2 )2 (2) complexes (N4 Ad2 =[Ad-N-N=N-N-Ad](2-) ). Compound 1 is obtained in two forms as lithium salts, one as a cationic Li2 Mn cluster, and one as a Mn-Li 1D ionic polymer. Compound 1 is electronically described as a Mn(III) center with two [N4 Ad2 ](2-) ligands. The one-electron oxidized 2 is crystalized in two morphologies, one as pure 2 and one as an acetonitrile adduct. Despite similar composition, the behavior of 2 differs in the two morphologies. Compound 2-MeCN is relatively air and temperature stable. Crystalline 2, on the other hand, exhibits a compositional, dynamic disorder wherein the tetrazene metallacycle ring-opens into a metal imide/azide complex detectable by X-ray crystallography and FTIR spectroscopy. Electronic structure of 2 was examined by EPR and XPS spectroscopies and DFT calculations, which indicate 2 is best described as a Mn(III) ion with an anion radical delocalized across the two ligands through spin-polarization effects.

ChemInform Abstract: Synthesis of Enamides by Ruthenium‐Catalyzed Reaction of Alkyl Azides with Acid Anhydrides in Ionic Liquid

Abstract50 examples

Synthesis of Enamides by Ruthenium‐Catalyzed Reaction of Alkyl Azides with Acid Anhydrides in Ionic Liquid

AbstractEnamides were synthesized by a ruthenium‐catalyzed one‐pot, one‐step procedure from alkyl azides and acid anhydrides. The substrate scope includes not only secondary azides, but also primary aliphatic ones to give a wide range of enamides containing various functional groups. This one‐step procedure was based on the newly discovered activity of Severin's diruthenium complex ([Cp^RuCl2]2: Cp^=η5‐1‐methoxy‐2,4‐di‐tert‐butyl‐3‐neopentylcyclopentadienyl) for the transformation of alkyl azides into the corresponding N−H imine intermediates in ionic liquids. The formation of ruthenium tetrazene complexes was observed in the stoichiometric reaction of Severin's complex with alkyl azides, which acted as the catalyst for the formation of N−H imine intermediates.

Probing the role of an FeIVtetrazene in catalytic aziridination

An iron(IV) tetrazene complex has been synthesized that is an important addition to a previously proposed catalytic aziridination cycle. It provides two key insights about the aziridination: an iron(IV) imide is formed and this imide can bind an additional ligand in the cis position.

Dinuclear Iron(0) Complexes of N-Heterocyclic Carbenes

The synthesis, structures, and reactivity of dinuclear Fe0 complexes of N-heterocyclic carbenes (NHCs, denoted as L) are reported. The NHC adducts of ferric chloride (L)FeCl3 were prepared from the reactions of FeCl3 with L in toluene. The reduction of (L)FeCl3 with KC8 resulted in the formation of the dinuclear Fe0 complexes Fe2{μ-η1(C):η6(arene)-L}2 (2a, L = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes); 2b, L = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr)), in which NHC ligands bridge two iron atoms using one of the arene rings as an η6 ligand. Their magnetic properties are different: 2a is paramagnetic and 2b is diamagnetic. The dinuclear complexes 2a,b serve as precursors for monomeric (NHC)Fe0 species, and treatment of 2a,b with 1 atm of CO led to the formation of (L)Fe(CO)4. Complex 2a was found to react with 1-azidoadamantane, giving rise to the dinuclear tetrazene complex (IMes)Fe(μ-NAd)2Fe(AdNNNNAd) (4).

Beyond Click-Chemistry: Transformation of Azides with Cyclopentadienyl Ruthenium Complexes

The cyclopentadienyl Ru complexes Cp*RuCl(cod) (cod = 1,5-cyclooctadiene), Cp*RuCl(PPh3)2, and [Cp∧RuCl2]2 (Cp∧ = η5-1-methoxy-2,4-di-tert-butyl-3-neopentylcyclopentadienyl) are able to catalyze the decomposition of benzyl azides to give 1,3,5-triphenyl-2,4-diazapenta-1,4-diene (“hydrobenzamide”), benzyl-benzylideneamine, and benzonitrile. Reactions with the catalyst precursor [Cp∧RuCl2]2 are particularly fast and give hydrobenzamide with high selectivity. A similar coupling reaction is observed for other benzylic azides but not for (2-azidoethyl)benzene and ethyl-4-azidobutanoate. If the reactions are performed in the presence of water, benzylic azides are converted into aldehydes. Mononuclear tetrazene complexes are formed in stoichiometric reactions of [Cp∧RuCl2]2 with benzyl azide and (2-azidoethyl)benzene.

Iron(II) Complexes with Redox-Active Tetrazene (RNNNNR) Ligands

This paper describes the redox chemistry of a tetrazene ligand on (beta-diketiminato)iron complexes. Addition of 1-adamantyl azide to an iron(I) source gives the tetrazene complex L(Me)Fe(AdNNNNAd), most likely through an imidoiron(III) intermediate. Spectroscopic, magnetic, crystallographic, and computational investigations of the tetrazene complex show that one unpaired spin occupies a primarily ligand-based orbital, and is antiferromagnetically coupled to a high-spin iron(II) ion to give an S = 3/2 ground state. Reversible single-electron reduction occurs at the ligand singly occupied molecular orbital (SOMO), affording a dianionic tetrazene ligand while leaving the metal oxidation state and spin state unchanged.

Formation of a Bridging-Imido d6Rhodium Compound by Nitrene Capture. Insertion and Cycloaddition Reactions

The first d (6) rhodium imido complex, [{(C 5Me 5)Rh(mu-NSO 2C 6H 4Me- p)} 2] ( 2), has been obtained from the reaction of [(C 5Me 5)Rh(C 2H 4) 2] with chloramine-T. Carbon monoxide inserts into the N-Rh bonds in 2 to give the dinuclear ureylene complex [(C 5Me 5)Rh(mu-{(Ts) N-CO-N(Ts)}Rh(CO)(C 5Me 5)], while the azide C 6F 5N 3 adds to 2 to give the mononuclear tetrazene complex [(C 5Me 5)Rh{( p-MeC 6H 4SO 2)N 4(C 6F 5)}].

Oxidation Reactions of Dithiocarbamate Complexes of Ruthenium(II).

The reaction of Ru(Et(2)dtc)(2)(DMSO)(2) (Et(2)dtc = N,N-diethyldithiocarbamate; DMSO = dimethyl sulfoxide) with t-BuNC gave trans-Ru(Et(2)dtc)(2)(CN-t-Bu)(2), 1. Complex 1 crystallizes in the monoclinic space group P2(1)/n with a = 9.753(2) Å, b = 11.583(2) Å, c = 12.974(2) Å, and beta = 91.8(2) degrees for Z = 2. The crystal structure of 1 shows the trans disposition of the two isocyanides; the mean Ru-S and Ru-C distances are 2.409 and 1.977(2) Å, respectively. Treatment of [Ru(diene)Cl(2)](n)() with Na(Et(2)dtc) afforded Ru(Et(2)dtc)(2)(diene) (diene = bicyclo[2.2.1]hepta-2,5-diene (NBD), 2, 1,5-cyclooctadiene (COD), 3). Complex 2 crystallizes in the triclinic space group P&onemacr; with a = 7.316(1) Å, b = 10.346(1) Å, c = 15.123(2) Å, alpha = 103.69(2) degrees, beta = 93.54(2) degrees, and gamma = 100.61(2) degrees for Z = 2. The mean Ru-S and Ru-C distances in 2 are 2.416 and 2.137 Å, respectively. The reaction of cis-Ru(Et(2)dtc)(2)(CO)(2) with iodine gave the 2:1 molecular iodine complex cis-Ru(Et(2)dtc)(2)(CO)(2).(1)/(2)I(2) 4, which crystallizes in the monoclinic space group P2(1)/c with a = 7.347(2), b = 22.227(2) Å, c = 12.891(2) Å, and beta =95.98 (2) degrees for Z = 4. The mean Ru-S and Ru-C and the I-I distances in complex 4 are 2.427, 1.903, and 2.745(1) Å, respectively. Treatment of Ru(Et(2)dtc)(2)(DMSO)(2) with I(2) gave the linear Ru(II)-Ru(III)-Ru(III) trimer [Ru(3)(Et(2)dtc)(6)(DMSO)(2)](I(3))(2), 5, which crystallizes in the triclinic space group P&onemacr; with a = 14.125(3) Å, b = 20.829(6) Å, c = 13.658(3) Å, alpha = 97.57(2) degrees, beta = 110.01(2) degrees, and gamma = 71.25(2) degrees for Z = 2. The structure of complex 6 can be viewed as consisting of a {Ru(2)(III)(Et(2)dtc)(4)}(2+) core and a {Ru(II)(Et(2)dtc)(2)(DMSO)(2)} moiety, which are linked together via the two dithiocarbamate sulfurs of the latter. While the two Ru(III) centers are connected by a Ru-Ru single bond (Ru-Ru = 2.826(2) Å), there is no direct interaction between the Ru(III) and Ru(II) centers. Oxidation of Ru(Et(2)dtc)(2)L(2) (L = PPh(3), t-BuNC) by I(2) gave the respective [Ru(Et(2)dtc)(2)L(2)](+) cations. The reaction of cis-Ru(Et(2)dtc)(2)(PPh(3))(2) with excess tosyl azide gave the diamagnetic Ru(IV) tetrazene complex Ru(Et(2)dtc)(2)(Ts(2)N(4)), 7. Complex 7 crystallizes in the triclinic space group P&onemacr; with a = 10.380(1) Å, b = 11.322(1) Å, c = 15.310(1) Å, alpha = 106.84(2) degrees, beta = 106.87(2) degrees, and gamma = 92.63(2) degrees for Z = 2. The Ru-S and Ru-N(alpha) distances in 7 are 2.385 and 1.98 Å, respectively. The formal potentials of the Ru dithiocarbamate complexes were determined by cyclic voltammetry.

Reactions of iridium and ruthenium complexes with organic azides

Interaction of N 3 R with Ir(mes) 3 (mes = mesityl, C 6 H 2 Me 3 -2,4,6) gave products dependent on the nature of the azide. When R = mes, the tetrazenido amide complex 1 is obtained in which dehydrogenative coupling of the mesityl groups via the o-methyls has occurred; thermolysis of 1 in toluene resulted in cleavage of the tetrazene ring and formation of amide complex 2. When R = Ph, the aryl tetrazenido amide complex 3 is formed. Photolysis of a mixture of N 3 (mes) and [RuCl 2 (PPh 3 ) 3 ] followed by phosphine exchange gave the tetrazene complex [Ru II Cl 2 {N 4 (mes) 2 }(PMe 3 ) 2 ] 4. Thermal reaction of [RuCl 2 H 2 (PPr i 3 ) 2 ] with N 3 (mes) gave the triazenophosphorane complex [RuCl 3 (PPr i 3 ){N 3 (mes) PPr i 3 }] 5. The ruthenium allyl amide [Ru(PMe 3 ) 3 {NHC 6 H 3 Pr i (η 3 -CH 2 CCH 2 )}] 6 bearing a new hybrid ligand was obtained by interaction of trans-[RuCl 2 (PMe 3 ) 4 ] with Li[NH(C 6 H 3 Pr i 2 -2,6)] in di-n-butyl ether. Plausible reaction mechanisms accounting for the formation of the new compounds are proposed. Finally, the crystal structures of the complexes 1–6 have been determined. Complexes 1 and 2 have pseudo-square planar geometries involving the olefin formed by the coupled methyl groups of two mesityls and three (1) or two (2) amide nitrogens and a chlorine atom (2). Compound 3 has a trigonal bipyramidal metal centre with the axial Ir–N amide bonds longer than the equatorial ones; 4 has an octahedral structure with a bidentate tetragonal ligand and trans phosphines whilst 5 is distorted octahedral with a N,N-chelating phosphazide ligand. Complex 6 is also octahedral with the allyl groups occupying cis sites and the three Ru–P bonds in a facial arrangement.