Nickel(I)-Phenolate Complexes: The Key to Well-Defined Ni(I) Species.

Phosphine-stabilized monovalent nickel complexes play an important role in catalysis, either as catalytically active species or as decomposition products. Most routes to access these complexes are highly ligand specific or rely on strong reducing agents. Our group recently disclosed a path to access nickel(I)-phenolate complexes from bis(1,5-cyclooctadiene)nickel(0) (Ni(cod)2). Herein, we demonstrate this protocol's broad applicability by ligating a wide range of mono- and bidentate phosphine ligands. We further show the versatility of the phenolate fragment as a precursor to nickel(I)-alkyl or aryl species, which are relevant to Ni catalysis or synthetically useful nickel(I)-chloride and hydride complexes. We also demonstrate that the chloride complex can be synthesized in a one-pot procedure starting from Ni(cod)2 in good yield, making this protocol a valuable alternative to current procedures. Single-crystal X-ray diffraction, IR, and EPR (or NMR) spectroscopy were employed to characterize all of the synthesized nickel complexes.

Skeletal metalation of lactams through a carbonyl-to-nickel-exchange logic.

Classical metalation reactions such as the metal-halogen exchange have had a transformative impact on organic synthesis owing to their broad applicability in building carbon-carbon bonds from carbon-halogen bonds. Extending the metal-halogen exchange logic to a metal-carbon exchange would enable the direct modification of carbon frameworks with new implications in retrosynthetic analysis. However, such a transformation requires the selective cleavage of highly inert chemical bonds and formation of stable intermediates amenable to further synthetic elaborations, hence its development has remained considerably challenging. Here we introduce a skeletal metalation strategy that allows lactams, a prevalent motif in bioactive molecules, to be readily converted into well-defined, synthetically useful organonickel reagents. The reaction features a selective activation of unstrained amide C-N bonds mediated by an easily prepared Ni(0) reagent, followed by CO deinsertion and dissociation under mild room temperature conditions in a formal carbonyl-to-nickel-exchange process. The underlying principles of this unique reactivity are rationalized by organometallic and computational studies. The skeletal metalation is further applied to a direct CO excision reaction and a carbon isotope exchange reaction of lactams, underscoring the broad potential of metal-carbon exchange logic in organic synthesis.

Crystal structure analysis of N-acetylated proline and ring size analogs.

Crystal structures of N-acetylated proline and homologs with four- and six-membered rings (azetidine carboxylic acid and piperidine carboxylic acid) were obtained and compared. The distinctly different conformations of the four-, five-, and six-membered rings reflect Bayer strain, n → π* interaction, and allylic strain, and result in crystal lattices with a zigzag structure.

Mechanistic Investigation of the Nickel-Catalyzed Metathesis between Aryl Thioethers and Aryl Nitriles.

Functional group metathesis is an emerging field in organic chemistry with promising synthetic applications. However, no complete mechanistic studies of these reactions have been reported to date, particularly regarding the nature of the key functional group transfer mechanism. Unraveling the mechanism of these transformations would not only allow for their further improvement but would also lead to the design of novel reactions. Herein, we describe our detailed mechanistic studies of the nickel-catalyzed functional group metathesis reaction between aryl methyl sulfides and aryl nitriles, combining experimental and computational results. These studies did not support a mechanism proceeding through reversible migratory insertion of the nitrile into a Ni-Ar bond and provided strong support for an alternative mechanism involving a key transmetalation step between two independently generated oxidative addition complexes. Extensive kinetic analysis, including rate law determination and Eyring analysis, indicated the oxidative addition complex of aryl nitrile as the resting state of the catalytic reaction. Depending on the concentration of aryl methyl sulfide, either the reductive elimination of aryl nitrile or the oxidative addition into the C(sp2)-S bond of aryl methyl sulfide is the turnover-limiting step of the reaction. NMR studies, including an unusual 31P-2H HMBC experiment using deuterium-labeled complexes, unambiguously demonstrated that the sulfide and cyanide groups exchange during the transmetalation step, rather than the two aryl moieties. In addition, Eyring and Hammett analyses of the transmetalation between two Ni(II) complexes revealed that this central step proceeds via an associative mechanism. Organometallic studies involving the synthesis, isolation, and characterization of all putative intermediates and possible deactivation complexes have further shed light on the reaction mechanism, including the identification of a key deactivation pathway, which has led to an improved catalytic protocol.

One to Find Them All: A General Route to Ni(I)-Phenolate Species.

The past 20 years have seen an extensive implementation of nickel in homogeneous catalysis through the development of unique reactivity not easily achievable by using noble transition metals. Many catalytic cycles propose Ni(I) complexes as potential reactive intermediates, yet the scarcity of nickel(I) precursors and the lack of a general, non-ligand-specific protocol for their synthesis have hampered progress in this field of research. This has in turn also limited the access to novel, well-defined Ni(I) species for the development of new catalytic reactions. Herein, we report a simple, general route to access a wide variety of Ni(I)-phenolate complexes via an unusual example of an olefinic Ni(I) complex, [Ni(COD)(OPh*)] (COD = 1,5-cyclooctadiene, OPh* = O(tBu)3C6H2). This route has proven to be highly efficient for several coordination numbers and ligand classes enabling access to the following complexes: [Ni(IPr)(OPh*)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), [Ni(dcype)(OPh*)] (dcype = 1,2-bis(dicyclohexylphosphino)ethane), [Ni(dppe)(OPh*)] (dppe = 1,2-bis(diphenylphosphino)ethane), and [Ni(terpy)(OPh*)] (terpy = 2,2':6',2″-terpyridine). Moreover, reacting [Ni(dcype)(OPh*)] with trimethylsilyl triflate has led to the isolation of a unique example of a cationic binuclear Ni(I)-arene complex. All these complexes have been characterized by single-crystal X-ray, DFT, and EPR analyses, thus providing crucial experimental and theoretical information about their coordination environment and confirming a d9 electronic structure for all complexes involved. Overall, this new synthetic approach offers exciting opportunities for the discovery of new stoichiometric and catalytic reactivity as well as the mechanistic elucidation of Ni-based catalytic cycles.

The Supramolecular Structural Chemistry of Pentafluorosulfanyl and Tetrafluorosulfanylene Compounds.

The analysis of crystal structures of SF5 - or SF4 -containing molecules revealed that these groups are often surrounded by hydrogen or other fluorine atoms. Even though fluorine prefers F⋅⋅⋅H over F⋅⋅⋅F contacts, the latter appeared to be important in many compounds. In a significant number of datasets, the closest F⋅⋅⋅F contacts are below 95 % of the van der Waals distance of two F atoms. Moreover, a number of repeating structural motifs formed by contacts between SF5 groups was identified, including different supramolecular dimers and infinite chains. Among SF4 -containing molecules, the study focused on SF4 Cl compounds, including the first solid-state structure analyses of these reactive species. Additionally, electrostatic potential surfaces of a series of Ph-SF5 derivatives were calculated, pointing out the substituent influence on the ability of F⋅⋅⋅X contact formation (X=F or other electronegative atom). Interaction energies were calculated for different dimeric arrangements of Ph-SF5 , which were extracted from experimental crystal structure determinations.

Peptide-Metal Frameworks with Metal Strings Guided by Dispersion Interactions.

Despite impressive advances in the construction of metal-organic frameworks (MOFs), the formation of networks from peptidic ligands is difficult, though they are sought after for their modularity and biocompatibility. Herein we present a peptide-metal framework that consists of helical oligoproline ligands and Zn/K (or Zn/Rb). The crystalline network contains pleated nanosheets with the metal ions aligned in strings. This unprecedented architecture derives from under-appreciated London dispersion interactions between the oligoproline ligands that play in concert with the metal coordination to create the network. Hence, the secondary structure of the peptidic ligand represents an additional control element for the creation of new MOF architectures. We anticipate that our results will instruct the design of further peptidic MOFs and enable the generation of versatile biocompatible materials.

Ruthenium-Catalyzed Dehydrogenation Through an Intermolecular Hydrogen Atom Transfer Mechanism.

The direct dehydrogenation of alkanes is among the most efficient ways to access valuable alkene products. Although several catalysts have been designed to promote this transformation, they have unfortunately found limited applications in fine chemical synthesis. Here, we report a conceptually novel strategy for the catalytic, intermolecular dehydrogenation of alkanes using a ruthenium catalyst. The combination of a redox-active ligand and a sterically hindered aryl radical intermediate has unleashed this novel strategy. Importantly, mechanistic investigations have been performed to provide a conceptual framework for the further development of this new catalytic dehydrogenation system.

Concentration-Dependent Self-Assembly of an Unusually Large Hexameric Hydrogen-Bonded Molecular Cage.

The sizes of available self-assembled hydrogen-bond-based supramolecular capsules and cages are rather limited. The largest systems have volumes of approximately 1400-2300 Å3 . Herein, we report a large, hexameric cage based on intermolecular amide-amide dimerization. The unusual structure with openings, reminiscent of covalently linked cages, is held together by 24 hydrogen bonds. With a diameter of 2.3 nm and a cavity volume of ∼2800 Å3 , the assembly is larger than any previously known capsule/cage structure relying exclusively on hydrogen bonds. The self-assembly process in chlorinated, organic solvents was found to be strongly concentration dependent, with the monomeric form prevailing at low concentrations. Additionally, the formation of host-guest complexes with fullerenes (C60 and C70 ) was observed.

Deoxygenative Fluorination of Phosphine Oxides: A General Route to Fluorinated Organophosphorus(V) Compounds and Beyond.

Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1) occasional handling of toxic or pyrophoric PIII starting materials and 2) a dependence on hazardous fluorinating reagents such as XeF2 . Herein, we present a simple solution and introduce a deoxygenative fluorination (DOF) approach that utilizes easy-to-handle phosphine oxides as starting materials and effectively replaces harsh fluorinating reagents by a combination of oxalyl chloride and potassium fluoride. The reaction has proven to be general, as R3 PF2 , R2 PF3 , and RPF4 compounds (as well as various cations and anions derived from these) are accessible in good yields and on up to a multi-gram scale. DFT calculations were used to bolster our observations. Notably, the discovery of this new method led to a convenient synthesis of 1) new difluorophosphonium ions, 2) hexafluorophosphate salts, and 3) fluorinated antimony- and arsenic- compounds.

Stimuli-Responsive Resorcin[4]arene Cavitands: Toward Visible-Light-Activated Molecular Grippers.

Resorcin[4]arene cavitands, equipped with diverse quinone (Q) and [Ru(bpy)2 dppz]2+ (bpy=2,2'-bipyridine, dppz=dipyrido[3,2-a:2',3'-c]phenazine) photosensitizing walls in different configurations, were synthesized. Upon visible-light irradiation at 420 nm, electron transfer from the [Ru(bpy)2 dppz]2+ to the Q generates the semiquinone (SQ) radical anion, triggering a large conformational switching from a flat kite to a vase with a cavity for the encapsulation of small guests, such as cyclohexane and heteroalicyclic derivatives, in CD3 CN. Depending on the molecular design, the SQ radical anion can live for several minutes (≈10 min) and the vase can be generated in a secondary process without need for addition of a sacrificial electron donor to accumulate the SQ state. Switching can also be triggered by other stimuli, such as changes in solvent, host-guest complexation, and chemical and electrochemical processes. This comprehensive investigation benefits the development of stimuli-responsive nanodevices, such as light-activated molecular grippers.

Molecular Recognition and Cocrystallization of Methylated and Halogenated Fragments of Danicalipin A by Enantiopure Alleno-Acetylenic Cage Receptors.

Enantiopure (P)4- and (M)4-configured alleno-acetylenic cage (AAC) receptors offer a highly defined interior for the complexation and structure elucidation of small molecule fragments of the stereochemically complex chlorosulfolipid danicalipin A. Solution (NMR), solid state (X-ray), and theoretical investigations of the formed host-guest complexes provide insight into the conformational preferences of 14 achiral and chiral derivatives of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic environment, extending previously reported studies in polar solvents. The conserved binding mode of the guests permits deciphering the effect of functional group replacements on Gibbs binding energies ΔG. A strong contribution of conformational energies toward the binding affinities is revealed, which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association. Enantioselective binding of chiral guests, with energetic differences ΔΔG293 K up to 0.7 kcal mol-1 between diastereoisomeric complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy ΔH but at the cost of a larger entropic penalty TΔS stemming from tighter binding.

Substituent-controlled, mild oxidative fluorination of iodoarenes: synthesis and structural study of aryl I(iii)- and I(v)-fluorides.

We report a mild approach to the synthesis of difluoro(aryl)-λ3-iodanes (aryl-IF2 compounds) and tetrafluoro(aryl)-λ5-iodanes (aryl-IF4 compounds) using trichloroisocyanuric acid (TCICA) and potassium fluoride (KF). Under these reaction conditions, selective access to either the I(iii)- or I(v)-derivatives is predictable based solely on the substitution pattern of the iodoarene starting material. Moreover, the discovery of this TCICA/KF approach prompted detailed dynamic NMR, kinetic, computational, and crystallographic studies on the relationship between the IF2 group and the ortho-substituents on carefully designed probe molecules. It was during these experiments that the role of the ortho-substituent in inhibiting further oxidative fluorination of I(iii)-compounds to I(v)-compounds during the reaction with TCICA and KF was revealed. Additionally, a notable exception to this empirical trend is discussed herein.

Difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and Selanes: Missing Links of Trichloroisocyanuric Acid/Potassium Fluoride Chemistry.

The TCICA/KF approach to oxidative fluorination of heteroatoms has emerged as a surprisingly simple, safe, and versatile surrogate to classically challenging fluorination reactions. Although polyfluorination (or chlorofluorination) of diaryl disulfides, diaryl diselenides, diaryl ditellurides, aryl iodides, and aryl(perfluoroalkyl)tellanes has been described, the application of this TCICA/KF methodology to aryl(perfluoroalkyl)sulfanes and selanes remains an area of unexplored chemical space. Accordingly, to address the "missing links" in the developing series of chalcogen-based substrate reactivity, we report mild syntheses of metastable difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and selanes. As only limited examples of these species exist in the current literature (accessible only by using F2 or XeF2 /HF), we have carried out detailed structural analyses, primarily using NMR and SC-XRD data. In addition, we investigate the effect of the perfluoroalkyl chain on the outcome of oxidative fluorination, and, finally, we provide preliminary evidence that difluoro(aryl)(trifluoro-methyl)-λ4 -sulfanes may act as fluorinating reagents.

Pentafluoro(aryl)-λ6 -tellanes and Tetrafluoro(aryl)(trifluoromethyl)-λ6 -tellanes: From SF5 to the TeF5 and TeF4 CF3 Groups.

The TeF5 group is significantly underexplored as a highly fluorinated substituent on an organic framework, despite it being a larger congener of the acclaimed SF5 group. In fact, only one aryl-TeF5 compound (phenyl-TeF5 ) has been reported to date, synthesized using XeF2 . Our recently developed mild TCICA/KF approach to oxidative fluorination provides an affordable and scalable alternative to XeF2 . Using this method, we report a scope of extensively characterized aryl-TeF5 compounds, along with the first SC-XRD data on this compound class. The methodology was also extended to the synthesis and structural study of heretofore unknown aryl-TeF4 CF3 compounds. Additionally, preliminary reactivity studies unveiled some inconsistencies with previous literature regarding phenyl-TeF5 . Although our studies conclude that the arene-based TeF5 (and TeF4 CF3 ) group is not quite as robust as the SF5 group, we find that the TeF5 group is more stable than previously thought, thus opening a door to explore new applications of this motif.

Site-Selectivity of Prato Additions to C70: Experimental and Theoretical Studies of a New Thermodynamic Product at the dd-[5,6]-Junction.

Three Prato monoadduct isomers were synthesized and structurally characterized by 1H, 13C NMR spectra and single-crystal X-ray diffraction, and one adduct on the dd-[5,6]-bond was found as the first example of a Prato [5,6]-adduct of C70. To investigate the mechanism in the generation of this dd-[5,6]-adduct, computational studies were employed to show that it was thermodynamically obtained by sigmatropic rearrangement from the presumed initial kinetic product de-[6,6]-adduct.

Iterative Assembly of Polycyclic Saturated Heterocycles from Monomeric Building Blocks.

Polycyclic saturated heterocycles with predictable shapes and structures are assembled by iterative couplings of bifunctional stannyl amine protocol (SnAP) reagents and a single morpholine-forming assembly reaction. Combinations of just a few monomers enable the programmable construction of rotationally restricted, nonplanar heterocyclic arrays with discrete sizes and molecular shapes. The three-dimensional structures of these constrained scaffolds can be quickly and reliably predicted by DFT calculations and the target structures immediately decompiled into the constituent building blocks and assembly sequences. As a demonstration, in silico combinations of the building blocks predict saturated heptacyclic structures with elementary shapes including helices, S-turns and U-turns, which are synthesized in 5-6 steps from the monomers using just three chemical reactions.

Combined experimental and theoretical study of long-range H-F interactions in α-fluoro amides.

A combined experimental and computational approach provided insight into the nature and conformational dependence of long-range 4JHF couplings in α-fluoro amides. The dependence of 4JHF on substituents and the solvent was investigated. H-F coupling constants determined by NMR spectroscopy are in agreement with DFT calculations. NBO analysis revealed that a favourable nF→σNH* interaction correlates with the magnitude of 4JHF.

Chalcogen Bonding "2S-2N Squares" versus Competing Interactions: Exploring the Recognition Properties of Sulfur.

Chalcogen bonding (CB) is the focus of increased attention for its applications in medicinal chemistry, materials science, and crystal engineering. However, the origin of sulfur's recognition properties remains controversial, and experimental evidence for supporting theories is still emerging. Here, a comprehensive evaluation of sulfur CB interactions is presented by investigating 2,1,3-benzothiadiazole X-ray crystallographic structures gathered from the Cambridge Structure Database (CSD), Protein Data Bank (PDB), and own laboratory findings. Through the systematic analysis of substituent effects on a subset library of over thirty benzothiadiazole derivatives, the competing interactions have been categorized into four main classes, namely 2S-2N CB square, halogen bonding (XB), S⋅⋅⋅S, and hydrogen-bonding (HB). A geometric model is employed to characterize the 2S-2N CB square motifs and discuss the role of electrostatic, dipole, and orbital contributions toward the interaction.

Larger Substituents on Amide Cavitands Induce Bigger Cavities.

A series of quinoxaline cavitands bearing pendant amide groups with various substituent sizes (Et, iPr, tBu) were synthesized, and their cavity size/structure were investigated by X-ray and NMR analyses. In the case of the Et or iPr amide cavitand, the conformation of the molecule was in the vase form, while the bulky tBu amide cavitand gave the kite conformation at room temperature. X-ray crystal structures of Et and iPr cavitands clearly showed the intramolecular H-bondings to influence the conformation and the cavity sizes dependent on the bulkiness of functional groups. The 1H NMR spectrum revealed that the Et cavitand can encapsulate an adamantane guest compound with slow exchange.