General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp3)-Rich Benzene Bioisosteres.

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

Scaffold hopping by net photochemical carbon deletion of azaarenes.

Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline N-oxides with 390-nanometer light followed by acid-promoted rearrangement affords N-acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.

Thermodynamic and kinetic studies of H2 and N2 binding to bimetallic nickel-group 13 complexes and neutron structure of a Ni(η2-H2) adduct.

Understanding H2 binding and activation is important in the context of designing transition metal catalysts for many processes, including hydrogenation and the interconversion of H2 with protons and electrons. This work reports the first thermodynamic and kinetic H2 binding studies for an isostructural series of first-row metal complexes: NiML, where M = Al (1), Ga (2), and In (3), and L = [N(o-(NCH2PiPr2)C6H4)3]3-. Thermodynamic free energies (ΔG°) and free energies of activation (ΔG ‡) for binding equilibria were obtained via variable-temperature 31P NMR studies and lineshape analysis. The supporting metal exerts a large influence on the thermodynamic favorability of both H2 and N2 binding to Ni, with ΔG° values for H2 binding found to span nearly the entire range of previous reports. The non-classical H2 adduct, (η2-H2)NiInL (3-H2), was structurally characterized by single-crystal neutron diffraction-the first such study for a Ni(η2-H2) complex or any d10 M(η2-H2) complex. UV-Vis studies and TD-DFT calculations identified specific electronic structure perturbations of the supporting metal which poise NiML complexes for small-molecule binding. ETS-NOCV calculations indicate that H2 binding primarily occurs via H-H σ-donation to the Ni 4p z -based LUMO, which is proposed to become energetically accessible as the Ni(0)→M(iii) dative interaction increases for the larger M(iii) ions. Linear free-energy relationships are discussed, with the activation barrier for H2 binding (ΔG ‡) found to decrease proportionally for more thermodynamically favorable equilibria. The ΔG° values for H2 and N2 binding to NiML complexes were also found to be more exergonic for the larger M(iii) ions.

Detection of an Iridium-Dihydrogen Complex: A Proposed Intermediate in Ionic Hydrogenation.

Addition of high pressures of H2 to five-coordinate [(tBu)4(POCOP)Ir(CO)(H)]OTf [(tBu)4(POCOP) = κ3-C6H3-2,6-(OP(tBu)2)2] complexes results in observation of two new iridium-dihydrogen complexes. If the aryl moiety of the POCOP ligand is substituted with an electron withdrawing protonated dimethylamino group at the para position, hydrogen coordination is enhanced. Five-coordinate Ir-H complexes generated by addition of triflic acid to (tBu)4(POCOP)Ir(CO) species show an Ir-H 1H NMR chemical shift dependence on the number of equivalents of acid present. It is proposed that excess triflic acid in solution facilitates triflate dissociation from iridium, resulting in unsaturated five-coordinate Ir-H complexes. The five-coordinate iridium-hydride complexes were found to catalyze H/D exchange between H2 and CD3OD. The existence of the dihydrogen complexes, as well as isotope exchange reactions, provide evidence for proposed ionic hydrogenation intermediates for glycerol deoxygenation.

Changing the Mechanism for CO2 Hydrogenation Using Solvent-Dependent Thermodynamics.

A critical scientific challenge for utilization of CO2 is the development of catalyst systems that function in water and use inexpensive and environmentally friendly reagents. We have used thermodynamic insights to predict and demonstrate that the HCoI (dmpe)2 catalyst system, previously described for use in organic solvents, can hydrogenate CO2 to formate in water with bicarbonate as the only added reagent. Replacing tetrahydrofuran as the solvent with water changes the mechanism for catalysis by altering the thermodynamics for hydride transfer to CO2 from a key dihydride intermediate. The need for a strong organic base was eliminated by performing catalysis in water owing to the change in mechanism. These studies demonstrate that the solvent plays a pivotal role in determining the reaction thermodynamics and thereby catalytic mechanism and activity.

A Bimetallic Nickel-Gallium Complex Catalyzes CO2 Hydrogenation via the Intermediacy of an Anionic d10 Nickel Hydride.

Large-scale CO2 hydrogenation could offer a renewable stream of industrially important C1 chemicals while reducing CO2 emissions. Critical to this opportunity is the requirement for inexpensive catalysts based on earth-abundant metals instead of precious metals. We report a nickel-gallium complex featuring a Ni(0)→Ga(III) bond that shows remarkable catalytic activity for hydrogenating CO2 to formate at ambient temperature (3150 turnovers, turnover frequency = 9700 h-1), compared with prior homogeneous Ni-centered catalysts. The Lewis acidic Ga(III) ion plays a pivotal role in stabilizing catalytic intermediates, including a rare anionic d10 Ni hydride. Structural and in situ characterization of this reactive intermediate support a terminal Ni-H moiety, for which the thermodynamic hydride donor strength rivals those of precious metal hydrides. Collectively, our experimental and computational results demonstrate that modulating a transition metal center via a direct interaction with a Lewis acidic support can be a powerful strategy for promoting new reactivity paradigms in base-metal catalysis.

Hydrogenation of CO2 at Room Temperature and Low Pressure with a Cobalt Tetraphosphine Catalyst.

Large-scale implementation of carbon neutral energy sources such as solar and wind will require the development of energy storage mechanisms. The hydrogenation of CO2 into formic acid or methanol could function as a means to store energy in a chemical bond. The catalyst reported here operates under low pressure, at room temperature, and in the presence of a base much milder (7 pKa units lower) than the previously reported CO2 hydrogenation catalyst, Co(dmpe)2H. The Co(I) tetraphosphine complex, [Co(L3)(CH3CN)]BF4, where L3 = 1,5-diphenyl-3,7-bis(diphenylphosphino)propyl-1,5-diaza-3,7-diphosphacyclooctane (0.31 mM), catalyzes CO2 hydrogenation with an initial turnover frequency of 150(20) h-1 at 25 °C, 1.7 atm of a 1:1 mixture of H2 and CO2, and 0.6 M 2-tert-butyl-1,1,3,3-tetramethylguanidine.

Improved Catalytic Activity and Stability of a Palladium Pincer Complex by Incorporation into a Metal-Organic Framework.

A porous metal-organic framework Zr6O4(OH)4(L-PdX)3 (1-X) has been constructed from Pd diphosphinite pincer complexes ([L-PdX](4-) = [(2,6-(OPAr2)2C6H3)PdX](4-), Ar = p-C6H4CO2(-), X = Cl, I). Reaction of 1-X with PhI(O2CCF3)2 facilitates I(-)/CF3CO2(-) ligand exchange to generate 1-TFA and I2 as a soluble byproduct. 1-TFA is an active and recyclable catalyst for transfer hydrogenation of benzaldehydes using formic acid as a hydrogen source. In contrast, the homogeneous analogue (t)Bu(L-PdTFA) is an ineffective catalyst owing to decomposition under the catalytic conditions, highlighting the beneficial effects of immobilization.

1,2-Addition of dihydrogen across rhodium(III)-OMe bonds.

The Rh(III) complexes [((t)bpy)2Rh(OMe)(L)][X]n ((t)bpy = 4,4'-di-tert-butyl-2,2'-bipyridyl; L = MeOH, n = 2, X = OTf (OTf = trifluoromethanesulfonate), TFA (TFA = trifluoroacetate); L = TFA, n = 1, X = OTf) have been shown to activate dihydrogen via net 1,2-addition of the H-H bond across the Rh(III)-OMe bond. The bis(methoxide) complex [((t)bpy)2Rh(OMe)2][OTf] was synthesized by addition of CsOH·H2O in methanol to [((t)bpy)2Rh(OTf)2][OTf] in CH3CN. The addition of HTFA to [((t)bpy)2Rh(OMe)2][OTf] leads to the formation of [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA], which exists in equilibrium with [((t)bpy)2Rh(OMe)(TFA)][OTf]. The mixture of [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA] and [((t)bpy)2Rh(OMe)(TFA)][OTf] activates dihydrogen at 68 °C to give methanol and [((t)bpy)2Rh(H)(TFA)][OTf]. Studies indicate that the activation of dihydrogen has a first-order dependence on the Rh(III) methoxide complex and a dependence on hydrogen that is between zero and first order. Combined experimental and computational studies have led to a proposed mechanism for hydrogen activation by [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA] that involves dissociation of MeOH, coordination of hydrogen, and 1,2-addition of hydrogen across the Rh-OMe bond. DFT calculations indicate that there is a substantial energy penalty for MeOH dissociation and a relatively flat energy surface for subsequent hydrogen coordination and activation.

Activation of carbon-hydrogen bonds and dihydrogen by 1,2-CH-addition across metal-heteroatom bonds.

The controlled conversion of hydrocarbons to functionalized products requires selective C-H bond cleavage. This perspective provides an overview of 1,2-CH-addition of hydrocarbons across d(0) transition metal imido complexes and compares and contrasts these to examples of analogous reactions that involve later transition metal amide, hydroxide and alkoxide complexes with d(6) and d(8) metals.