Scope and Mechanistic Probe into Asymmetric Synthesis of α-Trisubstituted-α-Tertiary Amines by Rhodium Catalysis.

Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition-metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium-catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π-σ-π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin-Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between ß-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched-linear >99:1, up to 99% enantiomeric excess).

Stereoselective 1,2-cis Furanosylations Catalyzed by Phenanthroline.

Stereoselective formation of the 1,2-cis furanosidic linkage, a motif of many biologically relevant oligosaccharides and polysaccharides, remains an important synthetic challenge. We herein report a new stereoselective 1,2-cis furanosylation method promoted by phenanthroline catalysts under mild and operationally simple conditions. NMR experiments and density functional theory calculations support an associative mechanism in which the rate-determining step occurs from an inverted displacement of the faster-reacting phenanthrolinium ion intermediate with an alcohol nucleophile. The phenanthroline catalysis system is applicable to a number of furanosyl bromide donors to provide the challenging 1,2-cis substitution products in good yield with high anomeric selectivities. While arabinofuranosyl bromide provides ß-1,2-cis products, xylo- and ribofuranosyl bromides favor α-1,2-cis products.

Distinct Bimetallic Cooperativity Among Water Reduction Catalysts Containing [CoIII CoIII ], [NiII NiII ], and [ZnII ZnII ] Cores.

Three binuclear species [LCoIII 2 (µ-Pz)2 ](ClO4 )3 (1), [LNiII 2 (CH3 OH)2 Cl2 ]ClO4 (2), and [LZnII 2 Cl2 ]PF6 (3) supported by the deprotonated form of the ligand 2,6-bis[bis(2-pyridylmethyl) amino-methyl]-4-methylphenol were synthesized, structurally characterized as solids and in solution, and had their electrochemical and spectroscopic behavior established. Species 1-3 had their water reduction ability studied aiming to interrogate the possible cooperative catalytic activity between two neighboring metal centers. Species 1 and 2 reduced H2 O to H2 effectively at an applied potential of -1.6 VAg/AgCl , yielding turnover numbers of 2,820 and 2,290, respectively, after 30 minutes. Species 3 lacked activity and was used as a negative control to eliminate the possibility of ligand-based catalysis. Pre- and post-catalytic data gave evidence of the molecular nature of the process within the timeframe of the experiments. Species 1 showed structural, rather than electronic cooperativity, while species 2 displayed no obvious cooperativity. DFT methods complemented the experimental results determining plausible mechanisms.

Phenanthroline-Catalyzed Stereoselective Formation of α-1,2-cis 2-Deoxy-2-Fluoro Glycosides.

Phenanthroline is a heterocyclic aromatic organic compound and commonly used in coordination chemistry acting as a bidentate ligand. The C4 and C7 positions of phenanthroline can often be substituted to change the binding capabilities of the ligand. Recently, there has been a push in the field of chemistry to create environmental-friendly chemical methodologies by utilizing catalysts and minimizing solvent. Herein, we have illustrated how, at high concentrations with minimal use of solvent, the C4 and C7 positions of phenanthroline can be tuned to develop an efficient and stereoselective catalyst for the formation of α-1,2-cis-fluorinated glycosides. By activating 2-deoxy-2-fluoro glycosyl halides with phenanthroline-based catalysts, we have been able to achieve glycosylations with high levels of α-selectivities and moderate to high yields. The catalytic system has been applied to several glycosyl halide electrophiles with a range of glycosyl nucleophilic acceptors. The proposed mechanism for this catalytic glycosylation system has been investigated by density functional theory calculations, indicating that the double SN2 displacement pathways with phenanthroline catalysts have lower barriers and ensure stereoselective formation of α-1,2-cis-2-fluoro glycosides.

Alkyl Radical-Free Cu(I) Photocatalytic Cross-Coupling: A Theoretical Study of Anomerically Specific Photocatalyzed Glycosylation of Pyranosyl Bromide.

Previously, we reported a visible light-activated Cu(I) photocatalyst capable of facilitating C-O bond formation of glycosyl bromides and aliphatic alcohols with a high degree of diastereoselectivity. This catalyst functions equally well in the presence of radical traps, suggesting an entirely inner sphere mechanism atypical for heteroleptic Cu photocatalysis. Further, experimental estimates put the chromophore reducing power at -1.30 V vs Ag/AgCl. This is much more positive than the ∼-2.0 V vs Ag/AgCl onset observed for irreversible reduction of glycosyl bromides in our experiments. Theoretical investigations were undertaken to explain the function of the catalyst. Outer sphere electron transfer from a chromophore to substrate was discounted based on thermodynamics and electron transfer barriers determined by Marcus theory and non-equilibrium solvation calculations. Unactivated and activated chromophores were found to disproportionate to Cu(0) and Cu(II) species. The resulting Cu(0) species undergoes oxidative addition with a glycosyl bromide generating a Cu(II) species. Addition of a nucleophilic alcohol and oxidation of the Cu(II) species to Cu(III) result in rapid reductive elimination forming products and resetting the catalytic cycle.

Diastereoselective sp3 C-O Bond Formation via Visible Light-Induced, Copper-Catalyzed Cross-Couplings of Glycosyl Bromides with Aliphatic Alcohols.

Copper-catalyzed cross-coupling reactions have become one of the most powerful methods for generating carbon-heteroatom bonds, an important framework of many organic molecules. However, copper-catalyzed C(sp3)-O cross-coupling of alkyl halides with alkyl alcohols remains elusive because of the sluggish nature of oxidative addition to copper. To address this challenge, we have developed a catalytic copper system, which overcomes the copper oxidative addition barrier with the aid of visible light and effectively facilitates the cross-couplings of glycosyl bromides with aliphatic alcohols to afford C(sp3)-O bonds with high levels of diastereoselectivity. Importantly, this catalytic system leads to a mild and efficient method for stereoselective construction of α-1,2-cis glycosides, which are of paramount importance, but challenging. In general, stereochemical outcomes in α-1,2-cis glycosidic C-O bond-forming processes are unpredictable and dependent on the steric and electronic nature of protecting groups bound to carbohydrate coupling partners. Currently, the most reliable approaches rely on the use of a chiral auxiliary or hydrogen-bond directing group at the C2- and C4-position of carbohydrate electrophiles to control α-1,2-cis selectivity. In our approach, earth-abundant copper not only acts as a photocatalyst and a bond-forming catalyst, but also enforces the stereocontrolled formation of anomeric C-O bonds. This cross-coupling protocol enables highly diastereoselective access to a wide variety of α-1,2-cis-glycosides and biologically relevant α-glycan oligosaccharides. Our work provides a foundation for developing new methods for the stereoselective construction of natural and unnatural anomeric carbon(sp3)-heteroatom bonds.

Seeking Redox Activity in a Tetrazinyl Pincer Ligand: Installing Zerovalent Cr and Mo.

Reaction of the readily reduced pincer ligand bis-tetrazinylpyridine, btzp, with the zerovalent metal source M(CO)3(MeCN)3 yields M(btzp)2 for M = Cr, Mo. These diamagnetic molecules show intrapincer bond lengths consistent with major charge transfer from metal to ligand, a result which is further supported by X-ray photoelectron spectroscopy. These molecules show up to five reversible outer-sphere electron transfers by cyclic voltammetry. The electronic structure of neutral M(btzp)2 is analyzed by DFT and CASSCF calculations, which reveal the degree of back-donation from the metal into pincer π* orbitals and also subtle differences in metal-ligand interaction for Mo vs Cr. Near-IR absorptions exhibited by both M(btzp)2 species originate from charge transfer among differently reduced tetrazine rings, which thus further support pincer reduction in these species.

Redox "Innocence" of Re(I) in Electrochemical CO2 Reduction Catalyzed by Nanographene-Re Complexes.

Improving energy efficiency of electrocatalytic CO2 conversion to useful chemicals poses a significant scientific challenge. Recently we reported on using a colloidal nanographene as the diimine ligand to form a molecular complex Re(diimine)(CO)3Cl to tackle this challenge, leading to significantly improved CO2 reduction potential. In this work, we use theoretical computations to investigate the roles of the nanographene ligand in the reduction and the reaction pathways. Remarkably, our results show that the metal center merely provides a binding site for CO2 and a conduit for electron transfer between the nanographene ligand and the substrate instead of changing its own oxidation state in the processes. Thus, despite its multiple oxidation states, the Re is redox "innocent" in the CO2 reduction catalyzed by the nanographene complex.

Mechanistic Role of Two-State Reactivity in a Molecular MoS2 Edge-Site Analogue for Hydrogen Evolution Electrocatalysis.

We report a first-principles quantum chemical study of the mechanistic pathways for the hydrogen evolution reaction (HER) by the molecular electrocatalyst [(PY5Me2)Mo(S2)]2+. By determining the relative thermodynamics of many possible species, we propose a mechanism fully consistent with all experimental observations. We also show the presence of two close-lying spin surfaces with the high spin state having a slightly less favorable reactivity profile than the low spin state. The energy of the high spin state is related to the ease of reduction of the S2 moiety and can be disrupted by interaction between S2 and a Lewis base. From this understanding, an explanation for the nearly 400 000-fold increase in turnover frequency on Hg drop electrode compared to glassy carbon is demonstrated. A next-generation catalyst based on the same motif has been designed to stabilize the more reactive low spin state and improve catalytic function without the need of Hg. Calculations indicate that this new species would have greatly improved HER reactivity and operate at a similar overpotential as the original system.

Insight into ethylene interactions with molybdenum suboxide cluster anions from photoelectron spectra of chemifragments.

Recent studies on reactions between MoxOy- cluster anions and H2O/C2H4 mixtures revealed a complex web of addition, hydrogen evolution, and chemifragmentation reactions, with chemifragments unambiguously connected to cluster reactions with C2H4. To gain insight into the molecular-scale interactions along the chemifragmentation pathways, the anion photoelectron (PE) spectra of MoC2H2-, MoC4H4-, MoOC2H2-, and MoO2C2H2- formed directly in MoxOy- + C2H4 (x > 1; y ≥ x) reactions, along with supporting CCSD(T) and density functional theory calculations, are presented and analyzed. The complexes have spectra that are all consistent with η2-acetylene complexes, though for all but MoC4H4-, the possibility that vinylidene complexes are also present cannot be definitively ruled out. Structures that are consistent with the PE spectrum of MoC2H2- differ from the lowest energy structure, suggesting that the fragment formation is under kinetic control. The PE spectrum of MoO2C2H2- additionally exhibits evidence that photodissociation to MoO2- + C2H2 may be occurring. The results suggest that oxidative dehydrogenation of ethylene is initiated by Lewis acid/base interactions between the Mo centers in larger clusters and the π orbitals in ethylene.

Molybdenum Oxide Cluster Anion Reactions with C2H4 and H2O: Cooperativity and Chemifragmentation.

To probe the mechanism of sacrificial reagents in catalytic processes, product distributions from MoxOy- clusters reacting individually with C2H4 and H2O are compared with those from reactions with a C2H4 + H2O mixture, with the thermodynamics explored computationally. These molecules were chosen to model production of H2 from H2O via H2O + C2H4 → H2 + CH3CHO, mediated by MoxOy- clusters. H2O is known to sequentially oxidize MoxOy- suboxide clusters while producing H2, resulting in less reactive clusters. MoxOy- (y ∼ x) clusters undergo chemi-fragmentation reactions with C2H4, with MoxOyC2Hz- complexes forming as the cluster oxidation state increases. Unique species observed in reactions with the C2H4 + H2O mixture, Mo2O5C2H2- and MoO3C2H4-, suggest that the internal energy gained in new Mo-O bond formation from oxidation by H2O opens additional reaction channels. C2H3O- is observed uniquely in reactions with the C2H4 + H2O mixture, giving indirect evidence of CH3CHO formation via the cluster mediated H2O + C2H4 → H2 + CH3CHO reaction; C2H3O- can form via dissociative electron attachment to CH3CHO. Calculations support mechanisms that invoke participation of two ethylene molecules on thermodynamically favorable pathways leading to experimentally observed products.

A Stereoselective Michael-Mannich Annelation Strategy for the Construction of Novel Tetrahydrocarbazoles.

A novel annelation strategy has been devised for stereoselective synthesis of tetrahydrocarbazoles. The pathway features a regio- and stereocontrolled condensation of indole and its substituted derivatives with electron-deficient 1,3-dienes via a Michael-Mannich reaction sequence. An extension of this method to include cross-conjugated allenes as substrates also results in a Michael-Mannich-Michael cascade, incorporating 2 equiv of indole with increasing product complexity. The formal 4π + 2π cyclization describes a concise route to polycyclic alkaloids of this family.

Well-Defined Nanographene-Rhenium Complex as an Efficient Electrocatalyst and Photocatalyst for Selective CO2 Reduction.

Improving energy efficiency of electrocatalytic and photocatalytic CO2 conversion to useful chemicals poses a significant scientific challenge. We report on using a colloidal nanographene to form a molecular complex with a metal ion to tackle this challenge. In this work, a well-defined nanographene-Re complex was synthesized, in which electron delocalization over the nanographene and the metal ion significantly decreases the electrical potential needed to drive the chemical reduction. We show the complex can selectively electrocatalyze CO2 reduction to CO in tetrahydrofuran at -0.48 V vs NHE, the least negative potential reported for a molecular catalyst. In addition, the complex can absorb a significant spectrum of visible light to photocatalyze the chemical transformation without the need for a photosensitizer.

Methionine Ligand Interaction in a Blue Copper Protein Characterized by Site-Selective Infrared Spectroscopy.

The reactivity of metal sites in proteins is tuned by protein-based ligands. For example, in blue copper proteins such as plastocyanin (Pc), the structure imparts a highly elongated bond between the Cu and a methionine (Met) axial ligand to modulate its redox properties. Despite extensive study, a complete understanding of the contribution of the protein to redox activity is challenged by experimentally accessing both redox states of metalloproteins. Using infrared (IR) spectroscopy in combination with site-selective labeling with carbon-deuterium (C-D) vibrational probes, we characterized the localized changes at the Cu ligand Met97 in the oxidized and reduced states, as well as the Zn(II) or Co(II)-substituted, the pH-induced low-coordinate, the apoprotein, and the unfolded states. The IR absorptions of (d3-methyl)Met97 are highly sensitive to interaction of the sulfur-based orbitals with the metal center and are demonstrated to be useful reporters of its modulation in the different states. Unrestricted Kohn-Sham density functional theory calculations performed on a model of the Cu site of Pc confirm the observed dependence. IR spectroscopy was then applied to characterize the impact of binding to the physiological redox partner cytochrome (cyt) f. The spectral changes suggest a slightly stronger Cu-S(Met97) interaction in the complex with cyt f that has potential to modulate the electron transfer properties. Besides providing direct, molecular-level comparison of the oxidized and reduced states of Pc from the perspective of the axial Met ligand and evidence for perturbation of the Cu site properties by redox partner binding, this study demonstrates the localized spatial information afforded by IR spectroscopy of selectively incorporated C-D probes.