N-Aryloxide-Amidinate Thorium Complexes.

An N-aryloxide-amidine ligand (1), [ONNO] ligand, integrating phenoxide (PhO-) and amidine ligands through methylene linkers, was employed in actinide chemistry. Upon reaction of the deprotonated ligand with ThCl4(DME)2 in ether, the corresponding dimer complex 2 was obtained. Upon treatment of 2 with KCp* (Cp* = Cp(Me)5) in tetrahydrofuran, the corresponding {[ONNO]ThIVCp*(LiCl)}2 (4) was obtained. In complex 2, the two ArO- arms bonded from the same ligand to different ThIV centers. In contrast, both ArO- arms coordinated to the same metal center in 4. Notably, when a mixture of 2 and bipyridine was treated with one or two equiv of KC8, the [ONNO]ThIV-bipyridyl•̅ radical dimer complex (5) and [ONNO]ThIV-bipyridyl2- dianionic dimer species (6) were obtained, respectively.

Unusual Electronic Structures of an Electron Transfer Series of [Cr(µ-η1 : η1 -N2 )Cr]0/1+/2.

In dinitrogen (N2 ) fixation chemistry, bimetallic end-on bridging N2 complexes M(µ-η1 : η1 -N2 )M can split N2 into terminal nitrides and hence attract great attention. To date, only 4d and 5d transition complexes, but none of 3d counterparts, could realize such a transformation. Likewise, complexes {[Cp*Cr(dmpe)]2 (µ-N2 )}0/1+/2+ (1-3) are incapable to cleave N2 , in contrast to their Mo congeners. Remarkably, cross this series the N-N bond length of the N2 ligand and the N-N stretching frequency exhibit unprecedented nonmonotonic variations, and complexes 1 and 2 in both solid and solution states display rare thermally activated ligand-mediated two-center spin transitions, distinct from discrete dinuclear spin crossovers. In-depth analyses using wave function based ab initio calculations reveal that the Cr-N2 -Cr bonding in complexes 1-3 is distinguished by strong multireference character and cannot be described by solely one electron configuration or Lewis structure, and that all intriguing spectroscopic observations originate in their sophisticate multireference electronic structures. More critical is that such multireference bonding of complexes 1-3 is at least a key factor that contributes to their kinetic inertness toward N2 splitting. The mechanistic understanding is then used to rationalize the disparate reactivity of related 3d M(µ-η1 : η1 -N2 )M complexes compared to their 4d and 5d analogs.

Direct Synthesis of Phosphoryltriacetates from White Phosphorus via Visible Light Catalysis.

Organophosphorus compounds (OPCs) are widely used in many fields. However, traditional synthetic routes in the industry usually involve multistep and hazardous procedures. Therefore, it's of great significance to construct such compounds in an environmentally-friendly and facile way. Herein, a photoredox catalytic method has been developed to construct novel phosphoryltriacetates. Using fac-Ir(ppy)3 (ppy=2-phenylpyridine) as the photocatalyst and blue LEDs (456 nm) as the light source, white phosphorus can react with α-bromo esters smoothly to generate phosphoryltriacetates in moderate to good yields. This one-step approach features mild reaction conditions and simple operational process without chlorination.

Dinitrogen Activation and Functionalization Affording Chromium Diazenido and Hydrazido Complexes.

ConspectusThe activation and functionalization of N2 to form nitrogen-element bonds have long posed challenges to industrial, biological, and synthetic chemists. The first transition-metal dinitrogen complex prepared by Allen and Senoff in 1965 provoked researchers to explore homogeneous N2 fixation. Despite intensive research in the last six decades, efficient and quantitative conversion of N2 to diazenido and hydrazido species remains problematic. Relative to a plethora of reactions to generate N2 complexes, their functionalization reactions are rather rare, and the yields are often unsatisfactory, emphasizing the need for systematic investigations of the reaction mechanisms.In this Account, we summarize our recent work on the synthesis, spectroscopic features, electronic structures, and reactivities of several Cr-N2 complexes. Initially, a series of dinuclear and trinuclear Cr(I)-N2 complexes bearing cyclopentadienyl-phosphine ligands were accessed. However, they cannot achieve N2 functionalization but undergo oxidative addition reactions with phenylsilane, azobenzene, and other unsaturated organic compounds at the low-valent Cr(I) centers rather than at the N2 unit. Further reduction of these Cr(I) complexes leads to the formation of more activated mononuclear Cr(0) bis-dinitrogen complexes. Remarkably, silylation of the cyclopentadienyl-phosphine Cr(0)-N2 complex with Me3SiCl afforded the first Cr hydrazido complex. This process follows the distal pathway to functionalize the Nß atom twice, yielding an end-on η1-hydrazido complex, Cr(III)═N-N(SiMe3)2. In contrast, upon substitution of the phosphine ligand in the Cr(0)-N2 complex with a N-heterocyclic carbene (NHC) ligand, the corresponding reaction with Me3SiCl proceeds via the alternating pathway; the silylation occurs at both Nα and Nß atoms and generates a side-on η2-hydrazido complex, Cr(III)(η2-Me3SiN-NSiMe3). Both silylation reactions are inevitably accompanied by the formation of Cr(III) hydrazido complexes and Cr(II) chlorides with a 2:1 ratio. These processes exhibit a peculiar '3-4-2-1' stoichiometry (i.e., treating 3 equiv of Cr(0)-N2 complexes with 4 equiv of Me3SiCl yields 2 equiv of Cr(III) disilyl-hydrazido complexes and 1 equiv of Cr(II) chloride). Upon replacing the monodentate phosphine and/or NHC ligand with a bisphosphine ligand, a monodinitrogen Cr(0) complex, instead of the bis-dinitrogen Cr(0) complexes, is obtained; consequently, the silylation reactions progress via the normal two-electron route, which passes through Cr(II)-N═N-R diazenido species as an intermediate and furnishes [Cr(IV)═N-NR2]+ hydrazido as the final products. More importantly, this type of Cr(0)-N2 complex can be not only silylated but also protonated and alkylated proficiently. All of the second-order reaction rates of the first and second transformations are determined along with the lifetimes of the intervening diazenido species. Based on these findings, we have successfully carried out nearly quantitative preparations of the Cr(IV) hydrazido species with unmixed or hybrid substituents.The studies of Cr-N2 systems provide effective approaches for the activation and functionalization of N2, deepening the understanding of N2 electrophilic attack. We hope that this Account will inspire more discoveries related to the transformation of gaseous N2 to high-value-added nitrogen-containing organic compounds.

Syntheses and Characterizations of Hetero-Bimetallic Chromium-Dinitrogen Transition-Metal Complexes.

In the domain of N2 activation, hetero-bimetallic dinitrogen complexes are garnering substantial interest due to their potential to induce polarization in nonpolar N2 gas. Herein, we present the syntheses and characterizations of three novel hetero-multimetallic dinitrogen complexes: Cp*Cr(depe)N2V(depe)Me[O, P, O] 5, Cp*Cr(depe)N2V(depe)Tipp[O, P, O] 6, and [Cp*Cr(depe)N2]2TiTipp[O, P, O] 7. These complexes were synthesized via a transmetalation process involving the treatment of [Cr0-N2]- complex 4 with vanadium and titanium chloride complexes bearing alkyl or aryl substituted bis(o-hydroxyphenyl)-phenyl phosphine R[O, P, O] ligand (alkyl = methyl, aryl = 2,4,6-tri-isopropylbenzene). X-ray analysis shows that complexes 5 and 6 exhibit heterodinuclear structures, while complex 7 exhibits a heterotrinuclear core with two N2 ligands concurrently coordinated to two chromium and one titanium atoms. Raman spectroscopic data show that the N-N stretching vibration of the N2 moiety is clearly downshifted relative to free N2 and to mononuclear [Cr0-N2]- complex 4.

N-aryloxide-amidinate group 4 metal complexes.

A N-aryloxide-amidine ligand (H3L), integrating phenoxide (PhO-) and amidine ligands through methylene linkers, has been synthesized from 2-(aminomethyl)-6-(tert-butyl)phenol in two steps. Upon reacting the deprotonated H3L ligand with group 4 metal chloride MIVCl4, a corresponding (LMIV-Cl)2 dimer could be obtained. The coordination modes exhibit variation depending on the radius of the metal ions. In the case of (LTiIV-Cl)2, the two ArO- arms from the same ligand bond to two different Ti(IV) centers, while in the case of (LZrIV/HfIV-Cl)2, both ArO- arms coordinate with the same metal center. Moreover, the two C-N bonds in the amidinate moiety are localized in (LTiIV-Cl)2, whereas they delocalize in (LZrIV-Cl)2. Notably, (LHfIV-Cl)2 could further react with one equivalent of HfCl4, yielding the binuclear metal azide in the presence of KN3 and LiCl, where the coordination mode of the amidinate moiety changed from the bidentate chelating type to the bimetallic bridging coordination.

Photochemical Benzylation of White Phosphorus.

Organophosphorus compounds (OPCs) have wide application in organic synthesis, material sciences, and drug discovery. Generally, the vast majority of phosphorus atoms in OPCs are derived from white phosphorus (P4). However, the large-scale preparation of OPCs mainly proceeds through the multistep and environmentally toxic chlorine route from P4. Herein, we report the direct benzylation of P4 promoted by visible light. The cheap and readily available benzyl bromide was used as a benzylation reagent, and tetrabenzylphosphonium bromide was directly synthesized from P4. In addition, the metallaphotoredox catalysis strategy was applied to functionalize P4 for the first time, which significantly improved the application range of the substituted benzyl bromide.

Insight into the Ligand-to-Ligand Charge-Transfer Process in Rare-Earth-Metal Diradical Complexes.

While a ligand-to-ligand charge-transfer (LLCT) process is an important way to understand the interactions between metal-bridged radicals for late-transition-metal complexes, there is little clear and evident observation of the LLCT process for rare-earth-metal complexes. In this work, rare-earth-metal diradical complexes supported by diazabutadiene (DAD) ligands [(DAD)2RE(BH4)] [RE = Yb (1), Sm (2)] were synthesized and studied. The coordination geometries of 1 and 2 are different due to the different ionic radii. Reduction of 1 or 2 generated monoradical complexes, with one of their DAD radical anions being reduced. In all of the complexes, Sm and Yb remain at the 3+ valence state. In their UV-vis spectra, the LLCT transition of 1 could be clearly observed, but complex 2 did not show the same transition. These results could be related to the geometric structures of the complexes as well as exchange coupling between diradicals, thus clearly expanding the model for late-transition-metal-bridged diradicals to rare-earth systems experimentally.

Snapshots of Early-Stage Quantitative N2 Electrophilic Functionalization.

Electrophilic functionalization of N2 moieties in metal dinitrogen complexes typically initiates the catalytic synthesis of N-containing molecules directly from N2. Despite intensive research in the last six decades, how to efficiently and even quantitatively convert N2 into diazenido and hydrazido species still poses a great challenge. In this regard, systematic and comprehensive investigations to elucidate the reaction intricacies are of profound significance. Herein, we report a kinetic dissection on the first and second electrophilic functionalization steps of a new Cr0-N2 system with HOTf, MeOTf, and Me3SiOTf. All reactions pass through fleeting diazenido intermediates and furnish long-lived final hydrazido products, and both steps are quantitative conversions at low temperatures. All of the second-order reaction rates of the first and second transformations were determined as well as the lifetimes of the intervening diazenido species. Based on these findings, we succeeded in large-scale and near-quantitative preparation of all hydrazido species.

From Dinitrogen to N-Containing Organic Compounds: Using Li2 CN2 as a Synthon.

Through the synergies of a heterogeneous synthetic approach and a homogeneous synthetic methodology, N-containing organic compounds can be synthesized via activated N-containing species prepared from N2 gas and suitable carbon sources. From N2 , carbon, and LiH, we have previously succeeded in the high-yield preparation of Li2 CN2 as the activated N-containing species. In this work, we applied Li2 CN2 as a novel synthetic synthon for constructing N-containing organic compounds. A series of reaction models, including a substitution reaction, cycloaddition reaction, and transition metal-catalyzed coupling reaction, were successfully performed using Li2 CN2 under mild conditions. Various valuable cyanamides, carbodiimides, N-aryl cyanamides and 1,2,4-triazole derivatives were readily synthesized in moderate to excellent yields. With this method, the 15 N-labeled products, including oxazolidine derivatives with anti-cancer activity, could also be facilely prepared from 15 N2 gas.

Selective Cleavage of the Strong or Weak C-C Bonds in Biphenylene Enabled by Rare-Earth Metals.

Selective cleavage of C-C bonds within arene rings is of great interest but remains elusive, especially for the molecules possessing the active and inert C-C bonds. Here, we report that the active and inert C-C bonds of biphenylene could be controllably cleaved by the reaction of biphenylene, potassium graphite, and rare-earth complexes with different metal centers. For scandium, the bond activation occurs at the Caryl-Caryl single bond, yielding 9-scandafluorene. For Lu, the reaction goes through ring contraction of the aromatic ring in biphenylene to provide benzopentalene dianionic lutetium. The origin of the selectivity and the reaction mechanism were illustrated by the isolation of intermediates and DFT calculations.

Dinitrogen Functionalization Affording Chromium Diazenido and Side-on η2-Hydrazido Complexes.

Isolation of key intermediate complexes in dinitrogen functionalization is crucial for elucidating the mechanistic details and further investigation. Herein, the synthesis and characterization of (µ-η1:η1-N2)(η1-N2)-Cr(I) 3 and (η1-N2)2-Cr(0) complexes 4 supported by Cp* (Cp* = C5Me5) and NHC ligands were reported. Further functionalization of Cr(0)-N2 complex 4 with silyl halides delivered the key intermediates in the alternating pathway, the chromium diazenido complex 5 and the chromium side-on η2-hydrazido complex 6. Protonation of 6 led to the quantitative formation of N2H4. Moreover, the [η2-Me3SiNNSiMe3]2- unit in 6 enabled N-C bond formation reactions with CO2 and tBuNCO, giving the corresponding N,O-chelating hydrazidochromium complexes 7 and 8, respectively.

Dinitrogen activation by a phosphido-bridged binuclear cobalt complex.

By reacting the semi-rigid PNP ligand with CoBr2, the corresponding complex PNPCoBr (1) was obtained. The reduction of 1 with excess amounts of KC8 in THF under a N2 atmosphere yielded a binuclear cobalt dinitrogen anion complex [Co(µ-Cy2P)PCyN2]2K (2) via the C-P bond cleavage of the PNP ligand. By adding 2,2,2-cryptand into complex 2, an ion pair Co complex, [Co(µ-Cy2P)PCyN2]2K(crypt-222) (3), could be effectively prepared. The structures of 1, 2, and 3 have been determined by single-crystal X-ray diffraction analysis, and N2 is moderately activated in complexes 2 and 3. There is a Co-Co bond in 2 and 3 suggested by DFT calculations. Compounds 1 and 2 display catalytic activity for the transformation of N2 into N(SiMe3)3.

Cobalt Cyclopentadienyl-Phosphine Dinitrogen Complexes.

By applying the potassium salts of cyclopentadienyl-phosphine ligands LK to CoCl2 , the corresponding cobalt chlorides (1, LCoII Cl) were prepared. By reducing complexes 1 with KHBEt3 under a N2 atmosphere, bridging end-on complexes, LCoI -N2 -CoI L (2 a and 2 b), were successfully obtained. 15 N2 -labeled [15 N2 ]-2 a was prepared under 15 N2 /14 N2 exchange in THF solution. LCoI -N2 -CoI L complex 2 a could react with P4 molecules to release N2 and generate a Co-P4 -Co moiety 4. Further reduction of complex 2 b led to cleavage of a P-C bond in the cyclopentadienyl-phosphine ligand to provide novel µ-PCy2 -bridged Co0 -N2 complex 5. DFT calculations confirmed the experimental observations.

Synthesis and isolation of dinuclear N,C-chelate organoboron compounds bridged by neutral, anionic, and dianionic 4,4'-bipyridine via reductive coupling of pyridines.

The reaction of Bppy(Mes)2 (BN1; ppy = 2-phenylpyridine) and BCH2ppy(Mes)2 (BN3) with the reducing reagent KC8 resulted in C-C bond formation via intermolecular radical coupling to generate the 4,4'-bipyridyl ligand compounds BN2 and BN4. Adding 1 equivalent of KC8 to a THF solution of BN2 and BN4 generated the 4,4'-bipyridyl radical anions BN2K and BN4K. The dianion species BN2K2 and BN4K2 could be obtained by adding 2 equivalents of KC8 to the THF solution of BN2 and BN4. In the presence of 2,2,2-cryptand or 18-crown-6, the radical anion salt BN2K(crypt) and the dianion salt BN2K2(18c6)2 were isolated for single-crystal X-ray diffraction analysis. Structural, spectroscopic, and computational studies were performed on the three species of BN2 derivatives (neutral, radical anion, and dianion species). BN2 and BN4 were stable and did not undergo photoisomerization or photoelimination under UV light irradiation.

Switchable assembly and function of antibody complexes in vivo using a small molecule.

The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies.

Trisyl-based multidentate ligands: synthesis and their transition-metal complexes.

Herein we report the synthesis and applications of unusual trisyl-based multidentate ligands [trisyl = tris(trimethylsilyl)methyl, -C(SiMe3)3]. First, by applying a new trisyl synthon (Me3Si)2CH(SiMe2CH2Cl) 1, trisyl-based S- or N-containing compounds 2 were efficiently obtained. On treatment of these compounds 2 with MeLi, their corresponding S- or N-coordinated pincer-like trisyl-based lithium salts 3, including the S-bridged ditrisyl compound 3a [Li{C(SiMe3)2SiMe2CH2SCH2SiMe2C(SiMe3)2}Li(DME)3] and the N-coordinated monotrisyl compounds 3b [(NacNacDippLiCH2SiMe2C(SiMe3)2Li(THF)], 3c [Li(THF){C(SiMe3)2SiMe2CH2N(Me)CH2C5H4N-2}], and 3d [Li{C(SiMe3)2SiMe2CH2N(Me)CH2CH2N(iPr)2}] were synthesized and structurally characterized by single-crystal X-ray structural analysis. Second, to test these novel lithium salts as straightforward precursors for the synthesis of transition-metal complexes with unique structures, these lithium salts were applied to react with MCl2 (M = Cr, Mn, Fe, Co). Their corresponding transition-metal complexes 4-8 were obtained in high yields and structurally characterized by single-crystal X-ray structural analysis. Third, the preliminary reactivities of compound 4 were explored.

Preparation of Radiolabeled Antibodies for Nuclear Medicine Applications in Immuno-Oncology.

The mixed patient responses to antibodies targeting immune checkpoint proteins (e.g., CTLA-4, PD-1, PD-L1) have generated tremendous interest in discovering biomarkers that predict which patients will best respond to these treatments. To complement molecular biomarkers obtained from biopsies, the nuclear medicine community has begun developing radiopharmaceuticals that may provide a more holistic assessment of the biological character of all disease sites in patients. On the leading edge of clinical translation are a spectrum of radiolabeled antibodies targeting immune checkpoint proteins or T cell-specific antigens. The adoption of these reagents requires development of efficient and versatile methods for antibody bioconjugation and radiochemistry. We report herein protocols for the preparation of an anti-PD-L1 IgG1 (termed C4) labeled with zirconium-89. The approach is time and cost economical, high yielding, and adaptable to numerous antibody clones and platforms of interest to the immune-oncology community. Included also are representative methods for characterizing the pharmacology of the antibody post bioconjugation, and conducting an in vivo assessment of radiotracer biodistribution in tumor bearing mouse models.

Synthesis of pyrimidines from dinitrogen and carbon.

The element nitrogen and nitrogenous compounds are vital to life. The synthesis of nitrogen-containing compounds using dinitrogen as the nitrogen source, not through ammonia, is of great interest and great value but remains a grand challenge. Herein, we describe a strategy to realize this transformation by combining the heterogeneous approach with the homogeneous methodology. The N2 molecule was first fixed with carbon and LiH through a one-pot heterogeneous process, forming Li2CN2 as an 'activated' nitrogen source with high efficiency. Then subsequent homogeneous treatments of Li2CN2 to construct the organic synthon carbodiimide and the RNA/DNA building block pyrimidines were fulfilled. By using 15N2 as the feedstock, their corresponding 15N-labeled carbodiimide and pyrimidines were readily obtained. This homogeneous-heterogeneous synergy strategy will open a new chapter for N2 transformation.

Insertion Chemistry of Lutetacyclopropene toward Unsaturated C-O/C-N Bonds.

Although the reaction chemistry of transition metallacyclopropenes has been well-established in the last decades, the reactivity of rare-earth metallacyclopropenes remains elusive. Herein, we report the reaction of lutetacyclopropene 1 toward a series of unsaturated molecules. The reaction of 1 with one equiv. of PhCOMe, Ar1 CHO (Ar1 =2,6-Me2 C6 H3 ), W(CO)6 , and PhCH=NPh provided oxalutetacyclopentenes, metallacyclic lutetoxycarbene, and azalutetacyclopentene via 1,2-insertion of C=O, C≡O, or C=N bonds into Lu-Csp2 bond, respectively. However, the reaction between 1 and Ar2 N=C=NAr2 (Ar2 =4-MeC6 H4 ) gave an acyclic lutetium complex with a diamidinate ligand by the coupling of one molecule of 1 with two carbodiimides, irrespective of the amount of carbodiimide employed. More interestingly, when 1 was treated with two equiv. of Ar1 CHO, the reductive coupling of two C=O bonds was discovered to give a lutetium pinacolate complex along with the release of tolan. Remarkably, the reactivity of 1 is significantly different from that of scandacyclopropenes; these metallacycles derived from 1 all represent the first cases in rare-earth organometallic chemistry.