The selective oxidation of CH bonds and the use of O2 as a stoichiometric oxidant represent two prominent challenges in organic chemistry. Copper(II) is a versatile oxidant, capable of promoting a ...wide range of oxidative coupling reactions initiated by single‐electron transfer (SET) from electron‐rich organic molecules. Many of these reactions can be rendered catalytic in Cu by employing molecular oxygen as a stoichiometric oxidant to regenerate the active copper(II) catalyst. Meanwhile, numerous other recently reported Cu‐catalyzed CH oxidation reactions feature substrates that are electron‐deficient or appear unlikely to undergo single‐electron transfer to copper(II). In some of these cases, evidence has been obtained for the involvement of organocopper(III) intermediates in the reaction mechanism. Organometallic CH oxidation reactions of this type represent important new opportunities for the field of Cu‐catalyzed aerobic oxidations.
The rapid recent growth of Cu‐catalyzed aerobic oxidative CH functionalization reactions belies the extensive history of such transformations, which can be traced to the discovery of alkyne coupling reactions by Glaser in the 19th century. Recent studies implicate multiple possible mechanisms for these reactions, ranging from classical single‐electron‐transfer pathways to the involvement of novel organometallic intermediates.
Although alkyl complexes of Fe4S4 clusters have been invoked as intermediates in a number of enzymatic reactions, obtaining a detailed understanding of their reactivity patterns and electronic ...structures has been difficult owing to their transient nature. To address this challenge, we herein report the synthesis and characterization of a 3:1 site-differentiated Fe4S42+–alkyl cluster. Whereas Fe4S42+ clusters typically exhibit pairwise delocalized electronic structures in which each Fe has a formal valence of 2.5+, Mössbauer spectroscopic and computational studies suggest that the highly electron-releasing alkyl group partially localizes the charge distribution within the cubane, an effect that has not been previously observed in tetrahedrally coordinated Fe4S4 clusters.
Copper(II)-mediated C–H oxidation is the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions are poorly understood. Here, we observe different products ...from CuII-mediated oxidation of N-(8-quinolinyl)benzamide, depending on the reaction conditions. Under basic conditions, the benzamide group undergoes directed C–H methoxylation or chlorination. Under acidic conditions, the quinoline group undergoes nondirected chlorination. Experimental and computational mechanistic studies implicate an organometallic C–H activation/functionalization mechanism under the former conditions and a single-electron-transfer mechanism under the latter conditions. This rare observation of divergent, condition-dependent mechanisms for oxidation of a single substrate provides a valuable foundation for understanding CuII-mediated C–H oxidation reactions.
The synthesis and characterization of Fe–diphosphineborane complexes are described in the context of N2 functionalization chemistry. Iron aminoimides can be generated at room temperature under 1 atm ...N2 and are shown to react with E–H bonds from PhSiH3 and H2. The resulting products derive from delivery of the E fragment to Nα and the H atom to B. The flexibility and lability of the Fe–BPh interactions in these complexes engender this reactivity.
We report the synthesis and characterization of the first terminal imido complex of an Fe–S cluster, (IMes)3Fe4S4=NDipp (2; IMes=1,3‐dimesitylimidazol‐2‐ylidene, Dipp=2,6‐diisopropylphenyl), which is ...generated by oxidative group transfer from DippN3 to the all‐ferrous cluster (IMes)3Fe4S4(PPh3). This two‐electron process is achieved by formal one‐electron oxidation of the imido‐bound Fe site and one‐electron oxidation of two IMes‐bound Fe sites. Structural, spectroscopic, and computational studies establish that the Fe–imido site is best described as a high‐spin Fe3+ center, which is manifested in its long Fe−N(imido) distance of 1.763(2) Å. Cluster 2 s hydrogen atoms from 1,4‐cyclohexadiene to yield the corresponding anilido complex, demonstrating competency for C−H activation.
The first terminal imido complex of an iron–sulfur cluster has been synthesized and fully characterized. Structural, spectroscopic, and computational analysis suggest an Fe4S42+=NAr2− formulation with a localized high‐spin Fe3+ valence at the imido‐bound site, and reactivity studies demonstrate competence for C−H activation.
This article describes a mechanistic study of copper-catalyzed hydroalkylation of terminal alkynes. Relying on the established chemistry of N-heterocyclic carbene copper hydride (NHCCuH) complexes, ...we previously proposed that the hydroalkylation reaction proceeds by hydrocupration of an alkyne by NHCCuH followed by alkylation of the resulting alkenylcopper intermediate by an alkyl triflate. NHCCuH is regenerated from NHCCuOTf through substitution with CsF followed by transmetalation with silane. According to this proposal, NHCCuH must react with an alkyne faster than with an alkyl triflate to avoid reduction of the alkyl triflate. However, we have determined that NHCCuH reacts with alkyl triflates significantly faster than with terminal alkynes, strongly suggesting that the previously proposed mechanism is incorrect. Additionally, we have found that NHCCuOTf rapidly traps NHCCuX (X = F, H, alkenyl) complexes to produce (NHCCu)2(μ-X)(OTf) (X = F, H, alkenyl) complexes. In this article, we propose a new mechanism for hydroalkylation of alkynes that features dinuclear (NHCCu)2(μ-H)(OTf) (X = F, H, alkenyl) complexes as key catalytic intermediates. The results of our study establish feasible pathways for the formation of these intermediates, their ability to participate in the elementary steps of the proposed catalytic cycle, and their ability to serve as competent catalysts in the hydroalkylation reaction. We also provide evidence that the unusual reactivity of the dinuclear complexes is responsible for efficient hydroalkylation of alkynes without concomitant side reactions of the highly reactive alkyl triflates.
Well-defined molecular catalysts for the reduction of N2 to NH3 with protons and electrons remain very rare despite decades of interest and are currently limited to systems featuring molybdenum or ...iron. This report details the synthesis of a molecular cobalt complex that generates superstoichiometric yields of NH3 (>200% NH3 per Co–N2 precursor) via the direct reduction of N2 with protons and electrons. While the NH3 yields reported herein are modest by comparison to those of previously described iron and molybdenum systems, they intimate that other metals are likely to be viable as molecular N2 reduction catalysts. Additionally, a comparison of the featured tris(phosphine)borane Co–N2 complex with structurally related Co–N2 and Fe–N2 species shows how remarkably sensitive the N2 reduction performance of potential precatalysts is. These studies enable consideration of the structural and electronic effects that are likely relevant to N2 conversion activity, including the π basicity, charge state, and geometric flexibility.
The Fe-S clusters of nitrogenases carry out the life-sustaining conversion of N
to NH
. Although progress continues to be made in modelling the structural features of nitrogenase cofactors, no ...synthetic Fe-S cluster has been shown to form a well-defined coordination complex with N
. Here we report that embedding an MoFe
S
cluster in a protective ligand environment enables N
binding at Fe. The bridging MoFe
S
(μ-η
:η
-N
) complex thus prepared features a substantially weakened N-N bond despite the relatively high formal oxidation states of the metal centres. Substitution of one of the MoFe
S
cubanes with an electropositive Ti metalloradical induces additional charge transfer to the N
ligand with generation of Fe-N multiple-bond character. Structural and spectroscopic analyses demonstrate that N
activation is accompanied by shortened Fe-S distances and charge transfer from each Fe site, including those not directly bound to N
. These findings indicate that covalent interactions within the cluster play a critical role in N
binding and activation.
Hydrogenases use complex metal cofactors to catalyze the reversible formation of hydrogen. In FeFe-hydrogenases, the H-cluster cofactor includes a diiron subcluster containing azadithiolate, three ...CO, and two CN ⁻ ligands. During the assembly of the H cluster, the radical S -adenosyl methionine (SAM) enzyme HydG lyses the substrate tyrosine to yield the diatomic ligands. These diatomic products form an enzyme-bound Fe(CO) ₓ(CN) y synthon that serves as a precursor for eventual H-cluster assembly. To further elucidate the mechanism of this complex reaction, we report the crystal structure and EPR analysis of HydG. At one end of the HydG (βα) ₈ triosephosphate isomerase (TIM) barrel, a canonical 4Fe-4S cluster binds SAM in close proximity to the proposed tyrosine binding site. At the opposite end of the active-site cavity, the structure reveals the auxiliary Fe-S cluster in two states: one monomer contains a 4Fe-5S cluster, and the other monomer contains a 5Fe-5S cluster consisting of a 4Fe-4S cubane bridged by a μ ₂-sulfide ion to a mononuclear Fe ²⁺ center. This fifth iron is held in place by a single highly conserved protein-derived ligand: histidine 265. EPR analysis confirms the presence of the 5Fe-5S cluster, which on incubation with cyanide, undergoes loss of the labile iron to yield a 4Fe-4S cluster. We hypothesize that the labile iron of the 5Fe-5S cluster is the site of Fe(CO) ₓ(CN) y synthon formation and that the limited bonding between this iron and HydG may facilitate transfer of the intact synthon to its cognate acceptor for subsequent H-cluster assembly.
Significance Hydrogenases are a source of environmentally benign bioenergy, catalyzing the reversible reduction of protons to form hydrogen. The most active subclass, the FeFe-hydrogenases, is dependent on a metallocofactor, the H cluster, which contains iron-bound CO and CN ⁻ ligands. Although the HydG maturase is known to catalytically form a CO- and CN ⁻-bound iron precursor to the H cluster, mechanistic insight into this complex process has been hampered by the lack of structural information about HydG. We now describe the high-resolution crystal structure and EPR analysis of HydG. These results reveal a previously unreported 5Fe-5S cluster that features a labile iron center proposed to provide the site of formation for a labile Fe(CO) ₂CN synthon, the precursor of the diiron subcluster hydrogenase H cluster.
To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (CCR2(+)/CD14(+)) as immunotherapeutic targets in the treatment of pancreatic cancer.
Survival analysis was conducted to ...determine if the prevalence of preoperative blood monocytes correlates with survival in patients with pancreatic cancer following tumor resection. Inflammatory monocyte prevalence in the blood and bone marrow of patients with pancreatic cancer and controls was compared. The immunosuppressive properties of inflammatory monocytes and macrophages in the blood and tumors, respectively, of patients with pancreatic cancer were assessed. CCL2 expression by human pancreatic cancer tumors was compared with normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine pancreatic cancer.
Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in patients with pancreatic cancer with resected tumors. Inflammatory monocytes are increased in the blood and decreased in the bone marrow of patients with pancreatic cancer compared with controls. An increased ratio of inflammatory monocytes in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human pancreatic cancer produces CCL2, and immunosuppressive CCR2(+) macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes inflammatory monocytes and macrophages from the primary tumor and premetastatic liver resulting in enhanced antitumor immunity, decreased tumor growth, and reduced metastasis.
Inflammatory monocyte recruitment is critical to pancreatic cancer progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease.
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