124I Radiolabeling of a AuIII‐NHC Complex for In Vivo Biodistribution Studies

Au^III complexes with N‐heterocyclic carbene (NHC) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Reported herein is the synthesis of new Au^III‐NHC complexes by direct oxidation with radioactive [¹²⁴I]I₂ as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET). While in vitro analyses provide direct evidence for the importance of Au^III‐to‐Au^I reduction to achieve full anticancer activity, in vivo studies reveal that a fraction of the Au^III‐NHC prodrug is not immediately reduced after administration but able to reach the major organs before metabolic activation.     

Preparation of Stable Low‐Oxidation‐State Group 14 Element Amidohydrides and Hydride‐Mediated Ring‐Expansion Chemistry of N‐Heterocyclic Carbenes

Various low oxidation state (+2) group 14 element amidohydride adducts, IPr ? EH(BH₃)NHDipp (E=Si or Ge; IPr=[(HCNDipp)₂C:], Dipp=2,6‐iPr₂C₆H₃), were synthesized. Thermolysis of the reported adducts was investigated as a potential route to Si‐ and Ge‐based clusters; however, unexpected transmetallation chemistry occurred to yield the carbene–borane adduct, IPr ? BH₂NHDipp. When a solution of IPr ? BH₂NHDipp in toluene was heated to 100 °C, a rare C? N bond‐activation/ring‐expansion reaction involving the bound N‐heterocyclic carbene donor (IPr) transpired.     

Expanded‐Ring N‐Heterocyclic Carbenes Efficiently Stabilize Gold(I) Cations,Leading to High Activity in π‐Acid‐Catalyzed Cyclizations

A series of six‐ and seven‐membered expanded‐ring N‐heterocyclic carbene (er‐NHC) gold(I) complexes has been synthesized using different synthetic approaches. Complexes with weakly coordinating anions [(er‐NHC)AuX] (X^?=BF₄^?, NTf₂^?, OTf^?) were generated in solution. According to their ¹³C NMR spectra, the ionic character of the complexes increases in the order X^?=Cl^?<NTf₂^?<OTf^?<BF₄^?. Additional factors for stabilization of the cationic complexes are expansion of the NHC ring and the attachment of bulky substituents at the nitrogen atoms. These er‐NHCs are bulkier ligands and stronger electron donors than conventional NHCs as well as phosphines and sulfides and provide more stabilization of [(L)Au⁺] cations. A comparative study has been carried out of the catalytic activities of five‐, six‐, and seven‐membered carbene complexes [(NHC)AuX], [(Ph₃P)AuX], [(Me₂S)AuX], and inorganic compounds of gold in model reactions of indole and benzofuran synthesis. It was found that increased ionic character of the complexes was correlated with increased catalytic activity in the cyclization reactions. As a result, we developed an unprecedentedly active monoligand cationic [(THD‐Dipp)Au]BF₄ (1,3‐bis(2,6‐diisopropylphenyl)‐3,4,5,6‐tetrahydrodiazepin‐2‐ylidene gold(I) tetrafluoroborate) catalyst bearing seven‐membered‐ring carbene and bulky Dipp substituents. Quantitative yields of cyclized products were attained in several minutes at room temperature at 1 mol % catalyst loadings. The experimental observations were rationalized and fully supported by DFT calculations.     

Serendipitous Observation of AlI Insertion into a C−O Bond in L2PhB (L=Oxazol‐2‐ylidene)

Oxidative addition of the C?O bond in L₂PhB: (L=oxazol‐2‐ylidene) to an Al^I center induced ring expansion of an oxazol‐2‐ylidene ring, affording a unique organoboron species formally involving either an Al, N, O mixed heterocyclic carbene or anionic (amino)(boryl)carbene fragment.     

Expanded‐Ring N‐Heterocyclic Carbenes for the Stabilization of Highly Electrophilic Gold(I) Cations

Strategies for the synthesis of highly electrophilic Au^I complexes from either hydride‐ or chloride‐containing precursors have been investigated by employing sterically encumbered Dipp‐substituted expanded‐ring NHCs (Dipp=2,6‐iPr₂C₆H₃). Thus, complexes of the type (NHC)AuH have been synthesised (for NHC=6‐Dipp or 7‐Dipp) and shown to feature significantly more electron‐rich hydrides than those based on ancillary imidazolylidene donors. This finding is consistent with the stronger σ‐donor character of these NHCs, and allows for protonation of the hydride ligand. Such chemistry leads to the loss of dihydrogen and to the trapping of the [(NHC)Au]⁺ fragment within a dinuclear gold cation containing a bridging hydride. Activation of the hydride ligand in (NHC)AuH by B(C₆F₅)₃, by contrast, generates a species (at low temperatures) featuring a [HB(C₆F₅)₃]^? fragment with spectroscopic signatures similar to the “free” borate anion. Subsequent rearrangement involves B?C bond cleavage and aryl transfer to the carbophilic metal centre. Under halide abstraction conditions utilizing Na[BAr^f₄] (Ar^f=C₆H₃(CF₃)₂‐3,5), systems of the type [(NHC)AuCl] (NHC=6‐Dipp or 7‐Dipp) generate dinuclear complexes [{(NHC)Au}₂(μ‐Cl)]⁺ that are still electrophilic enough at gold to induce aryl abstraction from the [BAr^f₄]^? counterion.     

Template Synthesis,Metalation, and Self‐Assembly of Protic Gold(I)/(NHC)2 Tectons Driven by Metallophilic Interactions

A new protocol for the synthesis of protic bis(N‐heterocyclic carbene) complexes of Au^I by a stepwise metal‐controlled coupling of isocyanide and propargylamine is described. They are used as tectons for the construction of supramolecular architectures through metalation and self‐assembly. Notably a unique polymeric chain of Cu^I with alternate Au^I/bis(imidazolate) bridging scaffolds and strong unsupported Cu^I–Cu^I interactions has been generated, as well as a 28‐metal‐atoms cluster containing a nanopiece of Cu₂O trapped by peripheral Au^I/bis(imidazolate) moieties.     

Template Synthesis,Metalation, and Self‐Assembly of Protic Gold(I)/(NHC)2 Tectons Driven by Metallophilic Interactions

A new protocol for the synthesis of protic bis(N‐heterocyclic carbene) complexes of Au^I by a stepwise metal‐controlled coupling of isocyanide and propargylamine is described. They are used as tectons for the construction of supramolecular architectures through metalation and self‐assembly. Notably a unique polymeric chain of Cu^I with alternate Au^I/bis(imidazolate) bridging scaffolds and strong unsupported Cu^I–Cu^I interactions has been generated, as well as a 28‐metal‐atoms cluster containing a nanopiece of Cu₂O trapped by peripheral Au^I/bis(imidazolate) moieties.     

Synthesis of a Metallo‐Iminosilane via a Silanone–Metal π‐Complex

Facile oxygenation of the acyclic amido‐chlorosilylene bis(N‐heterocyclic carbene) Ni⁰ complex [{N(Dipp)(SiMe₃)ClSi:→Ni(NHC)₂] ( 1 ; Dipp=2,6‐ⁱPr₂C₆H₄; N‐heterocyclic carbene=C[(ⁱPr)NC(Me)]₂) with N₂O furnishes the first Si‐metalated iminosilane, [DippN=Si(OSiMe₃)Ni(Cl)(NHC)₂] ( 3 ), in a rearrangement cascade. Markedly, the formation of 3 proceeds via the silanone (Si=O)–Ni π‐complex 2 as the initial product, which was predicted by DFT calculations and observed spectroscopically. The Si=O and Si=N moieties in 2 and 3 , respectively, show remarkable hydroboration reactivity towards H−B bonds of boranes, in the former case corroborating the proposed formation of a (Si=O)–Ni π‐complex at low temperature.     

Facile Access to an NHC‐Coordinated Silicon Ring Compound with a Si=N Group and a Two‐Coordinate Silicon Atom

Reaction of the bicyclo[1.1.0]tetrasilatetraamide Si₄{N(SiMe₃)Dipp}₄ 1 (Dipp=2,6‐diisopropylphenyl) with 5 equiv of the N‐heterocyclic carbene NHC^Me4 (1,3,4,5‐tetramethylimidazol‐2‐ylidene) affords a bifunctional carbene‐coordinated four‐membered‐ring compound with a Si=N group and a two‐coordinate silicon atom Si₄{N(SiMe₃)Dipp}₂(NHC^Me4)₂(NDipp) 2 . When 2 reacts with 0.25 equiv sulfur (S₈), two sulfur atoms add to the divalent silicon atom in plane and perpendicular to the plane of the Si₄ ring, which confirms the silylone character of the two‐coordinate silicon atom in 2 .     

Solvent‐Induced Cluster‐to‐Cluster Transformation of Homoleptic Gold(I) Thiolates between Catenane and Ring‐in‐Ring Structures

Supramolecular ensembles adopting ring‐in‐ring structures are less developed compared with catenanes featuring interlocked rings. While catenanes with inter‐ring closed‐shell metallophilic interactions, such as d¹⁰–d¹⁰ Au^I–Au^I interactions, have been well‐documented, the ring‐in‐ring complexes featuring such metallophilic interactions remain underdeveloped. Herein is described an unprecedented ring‐in‐ring structure of a Au^I‐thiolate Au₁₂ cluster formed by recrystallization of a Au^I‐thiolate Au₁₀ [2]catenane from alkane solvents such as hexane, with use of a bulky dibutylfluorene‐2‐thiolate ligand. The ring‐in‐ring Au^I‐thiolate Au₁₂ cluster features inter‐ring Au^I–Au^I interactions and underwent cluster core change to form the thermodynamically more stable Au₁₀ [2]catenane structure upon dissolving in, or recrystallization from, other solvents such as CH₂Cl₂, CHCl₃, and CH₂Cl₂/MeCN. The cluster‐to‐cluster transformation process was monitored by ¹H NMR and ESI‐MS measurements. Density functional theory (DFT) calculations were performed to provide insight into the mechanism of the “ring‐in‐ring? [2]catenane” interconversions.     

Synthesis and Rearrangement of Stable NHC→Silylene Adducts and Their Unique Reactivity towards Cyclohexylisocyanide

The syntheses and reactivity of the two N‐heterocyclic carbene (NHC)→ silylene complexes 2 and 4 have been investigated. The latter are easily accessible by reaction of the zwitterionic, N‐heterocyclic silylene LSi: 1 [L=Ar‐N‐C(=CH₂)CH?C(Me)‐N‐Ar, Ar=2,6‐iPr₂C₆H₃] with 1,3,4,5‐tetramethylimidazol‐2‐ylidene and 1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene, respectively. While compound 2 undergoes facile rearrangement above ?20 °C to give the unsymmetrical N‐heterocyclic silylcarbene 3 , the derivative 4 remains unchanged even after boiling in benzene. The remarkable reactivity of 3 and 4 towards cyclohexylisocyanide has been examined which leads in a unique series of C? H, Si? H, and C? N bond activations to the new triaminosilanes 5 and 6 , respectively. The novel compounds 3 , 4 , 5 , and 6 were fully characterized by ¹H, ¹³C, and ²⁹Si NMR spectroscopy, EI‐MS, elemental analysis, and single‐crystal X‐ray diffraction.     

Investigation of N‐Heterocyclic Carbene‐Supported Group 12 Triflates as Pre‐catalysts for Hydrosilylation/Borylation

N‐Heterocyclic carbene (NHC) complexes of Cd and Hg triflates (OTf) were prepared and their attempted conversion into rare cadmium and mercury hydrides was explored. In contrast to zinc, which forms stable [ZnH]⁺ complexes with NHCs, the heavier Cd and Hg congeners could not be formed; the increased instability of Cd‐H and Hg‐H units was rationalized with the aid of computations. It was also discovered that the dimeric adduct [IPr?Cd(μ‐OTf)₂]₂ (IPr=[(HCNDipp)₂C:]; Dipp=2,6‐iPr₂C₆H₃) is an active precatalyst for the hydrosilylation and hydroborylation of hindered aldehydes and ketones. The related zinc congener was inactive as a catalyst highlighting a distinct advantage of using heavy Group 12 metals to promote catalytic hydrosilylation/borylation.     

N‐Heterocyclic Carbene–Gold(I) Complexes Conjugated to a Leukemia‐Specific DNA Aptamer for Targeted Drug Delivery

This report describes the synthesis and characterization of novel N‐heterocyclic carbene (NHC)–gold(I) complexes and their bioconjugation to the CCRF‐CEM‐leukemia‐specific aptamer sgc8c. Successful bioconjugation was confirmed by the use of fluorescent tags on both the NHC–Au^I complex and the aptamer. Cell‐viability assays indicated that the NHC–Au^I–aptamer conjugate was more cytotoxic than the NHC–gold complex alone. A combination of flow cytometry, confocal microscopy, and cell‐viability assays provided clear evidence that the NHC–Au^I–aptamer conjugate was selective for targeted CCRF‐CEM leukemia cells.     

A Bis(Diphosphanyl N‐Heterocyclic Carbene) Gold Complex: A Synthon for Luminescent Rigid AuAg2 Arrays and Au5 and Cu6 Double Arrays

A mononuclear bis(NHC)/Au^I (NHC=N‐heterocyclic carbene) cationic complex with a rigid bis(phosphane)‐functionalized NHC ligand (PC_NHCP) was used to construct linear Au₃ and Ag₂Au arrays, a Au₅ cluster with two intersecting crosslike Au₃ arrays, and an unprecedented Cu₆ complex with two parallel Cu₃ arrays. The impact of metallophilic interactions on photoluminescence was studied experimentally.     

Copper,Silver and Sodium Salt‐Mediated Quaternization by Arylation: Syntheses of N‐Heterocyclic Carbene Precursors and 6‐H‐Phenanthridine Derivatives

We have developed a Cu^II‐, Ag^I‐, and NaOTf‐mediated intramolecular quaternization by arylation reactions to synthesize a variety of N‐heterocyclic carbene (NHC) precursors with a benzene‐fused backbone. The methodology also provides a convenient alternative route for the synthesis of 6‐H‐phenanthridine derivatives. A novel silver–NHC complex was prepared by treatment of Ag₂O with the free carbene, which was in situ prepared from the deprotonation of a representative quinazolinonium salt.     

Amine‐Responsive Disassembly of AuI–CuI Double Salts for Oxidative Carbonylation

A sensitive amine‐responsive disassembly of self‐assembled Au^I‐Cu^I double salts was observed and its utilization for the synergistic catalysis was enlightened. Investigation of the disassembly of [Au(NHC)₂][CuI₂] revealed the contribution of Cu‐assisted ligand exchange of N‐heterocyclic carbene (NHC) by amine in [Au(NHC)₂]⁺ and the capacity of [CuI₂]^? on the oxidative step. By integrating the implicative information coded in the responsive behavior and inherent catalytic functions of d¹⁰ metal complexes, a catalyst for the oxidative carbonylation of amines was developed. The advantages of this method were clearly reflected on mild reaction conditions and the significantly expanded scope (51 examples); both primary and steric secondary amines can be employed as substrates. The cooperative reactivity from Au and Cu centers, as an indispensable prerequisite for the excellent catalytic performance, was validated in the synthesis of (un)symmetric ureas and carbamates.     

Theory of the Formation and Decomposition of N‐Heterocyclic Aminooxycarbenes through Metal‐Assisted [2+3]‐Dipolar Cycloaddition/Retro‐Cycloaddition

The theoretical background of the formation of N‐heterocyclic oxadiazoline carbenes through a metal‐assisted [2+3]‐dipolar cycloaddition (CA) reaction of nitrones R¹CH?N(R²)O to isocyanides C?NR and the decomposition of these carbenes to imines R¹CH?NR² and isocyanates O?C?NR is discussed. Furthermore, the reaction mechanisms and factors that govern these processes are analyzed in detail. In the absence of a metal, oxadiazoline carbenes should not be accessible due to the high activation energy of their formation and their low thermodynamic stability. The most efficient promotors that could assist the synthesis of these species should be “carbenophilic” metals that form a strong bond with the oxadiazoline heterocycle, but without significant involvement of π‐back donation, namely, Au^I, Au^III, Pt^II, Pt^IV, Re^V, and Pd^II metal centers. These metals, on the one hand, significantly facilitate the coupling of nitrones with isocyanides and, on the other hand, stabilize the derived carbene heterocycles toward decomposition. The energy of the LUMO_CNR and the charge on the N atom of the C?N group are principal factors that control the cycloaddition of nitrones to isocyanides. The alkyl‐substituted nitrones and isocyanides are predicted to be more active in the CA reaction than the aryl‐substituted species, and the N,N,C‐alkyloxadiazolines are more stable toward decomposition relative to the aryl derivatives.     

Trapping a Silicon(I) Radical with Carbenes: A Cationic cAAC–Silicon(I) Radical and an NHC–Parent‐Silyliumylidene Cation

The trapping of a silicon(I) radical with N‐heterocyclic carbenes is described. The reaction of the cyclic (alkyl)(amino) carbene [cAAC_Me] (cAAC_Me=:C(CMe₂)₂(CH₂)NAr, Ar=2,6‐i Pr₂C₆H₃) with H₂SiI₂ in a 3:1 molar ratio in DME afforded a mixture of the separated ion pair [(cAAC_Me)₂Si:^.]⁺I⁻ ( 1 ), which features a cationic cAAC–silicon(I) radical, and [cAAC_Me−H]⁺I⁻. In addition, the reaction of the NHC–iodosilicon(I) dimer [I_Ar(I)Si:]₂ (I_Ar=:C{N(Ar)CH}₂) with 4 equiv of I_Me (:C{N(Me)CMe}₂), which proceeded through the formation of a silicon(I) radical intermediate, afforded [(I_Me)₂SiH]⁺I⁻ ( 2 ) comprising the first NHC–parent‐silyliumylidene cation. Its further reaction with fluorobenzene afforded the C_Ar−H bond activation product [1‐F‐2‐I_Me‐C₆H₄]⁺I⁻ ( 3 ). The isolation of 2 and 3 confirmed the reaction mechanism for the formation of 1 . Compounds 1 – 3 were analyzed by EPR and NMR spectroscopy, DFT calculations, and X‐ray crystallography.     

Stabilization of a Silaaldehyde by its η2 Coordination to Tungsten

Treatment of pyridine‐stabilized silylene complexes [(η⁵‐C₅Me₄R)(CO)₂(H)W?SiH(py)(Tsi)] (R=Me, Et; py=pyridine; Tsi=C(SiMe₃)₃) with an N‐heterocyclic carbene ^MeIⁱPr (1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene) caused deprotonation to afford anionic silylene complexes [(η⁵‐C₅Me₄R)(CO)₂W?SiH(Tsi)][H^MeIⁱPr] (R=Me ( 1‐Me ); R=Et ( 1‐Et )). Subsequent oxidation of 1‐Me and 1‐Et with pyridine‐N‐oxide (1 equiv) gave anionic η²‐silaaldehydetungsten complexes [(η⁵‐C₅Me₄R)(CO)₂W{η²‐O?SiH(Tsi)}][H^MeIⁱPr] (R=Me ( 2‐Me ); R=Et ( 2‐Et )). The formation of an unprecedented W‐Si‐O three‐membered ring was confirmed by X‐ray crystal structure analysis.