Thiol and H2S-Mediated NO Generation from Nitrate at Copper(II).

Reduction of nitrate is an essential, yet challenging chemical task required to manage this relatively inert oxoanion in the environment and biology. We show that thiols, ubiquitous reductants in biology, convert nitrate to nitric oxide at a Cu(II) center under mild conditions. The ß-diketiminato complex [Cl2NNF6]Cu(κ2-O2NO) engages in O-atom transfer with various thiols (RSH) to form the corresponding copper(II) nitrite [CuII](κ2-O2N) and sulfenic acid (RSOH). The copper(II) nitrite further reacts with RSH to give S-nitrosothiols RSNO and [CuII]2(µ-OH)2 en route to NO formation via [CuII]-SR intermediates. The gasotransmitter H2S also reduces nitrate at copper(II) to generate NO, providing a lens into NO3-/H2S crosstalk. The interaction of thiols with nitrate at copper(II) releases a cascade of N- and S-based signaling molecules in biology.

Electrocatalytic Ammonia Oxidation by a Low-Coordinate Copper Complex.

Molecular catalysts for ammonia oxidation to dinitrogen represent enabling components to utilize ammonia as a fuel and/or source of hydrogen. Ammonia oxidation requires not only the breaking of multiple strong N-H bonds but also controlled N-N bond formation. We report a novel ß-diketiminato copper complex [iPr2NNF6]CuI-NH3 ([CuI]-NH3 (2)) as a robust electrocatalyst for NH3 oxidation in acetonitrile under homogeneous conditions. Complex 2 operates at a moderate overpotential (η = 700 mV) with a TOFmax = 940 h-1 as determined from CV data in 1.3 M NH3-MeCN solvent. Prolonged (>5 h) controlled potential electrolysis (CPE) reveals the stability and robustness of the catalyst under electrocatalytic conditions. Detailed mechanistic investigations indicate that electrochemical oxidation of [CuI]-NH3 forms {[CuII]-NH3}+ (4), which undergoes deprotonation by excess NH3 to form reactive copper(II)-amide ([CuII]-NH2, 6) unstable toward N-N bond formation to give the dinuclear hydrazine complex [CuI]2(µ-N2H4). Electrochemical studies reveal that the diammine complex [CuI](NH3)2 (7) forms at high ammonia concentration as part of the {[CuII](NH3)2}+/[CuI](NH3)2 redox couple that is electrocatalytically inactive. DFT analysis reveals a much higher thermodynamic barrier for deprotonation of the four-coordinate {[CuII](NH3)2}+ (8) by NH3 to give the copper(II) amide [CuII](NH2)(NH3) (9) (ΔG = 31.7 kcal/mol) as compared to deprotonation of the three-coordinate {[CuII]-NH3}+ by NH3 to provide the reactive three-coordinate parent amide [CuII]-NH2 (ΔG = 18.1 kcal/mol) susceptible to N-N coupling to form [CuI]2(µ-N2H4) (ΔG = -11.8 kcal/mol).

Lewis acid-assisted reduction of nitrite to nitric and nitrous oxides via the elusive nitrite radical dianion.

Reduction of nitrite anions (NO2-) to nitric oxide (NO), nitrous oxide (N2O) and ultimately dinitrogen (N2) takes place in a variety of environments, including in the soil as part of the biogeochemical nitrogen cycle and in acidified nuclear waste. Nitrite reduction typically takes place within the coordination sphere of a redox-active transition metal. Here we show that Lewis acid coordination can substantially modify the reduction potential of this polyoxoanion to allow for its reduction under non-aqueous conditions (-0.74 V versus NHE). Detailed characterization confirms the formation of the borane-capped radical nitrite dianion (NO22-), which features a N(II) oxidation state. Protonation of the nitrite dianion results in the facile loss of nitric oxide (NO), whereas its reaction with NO results in disproportionation to nitrous oxide (N2O) and nitrite (NO2-). This system connects three redox levels in the global nitrogen cycle and provides fundamental insights into the conversion of NO2- to NO.

NO Coupling at Copper to cis-Hyponitrite: N2O Formation via Protonation and H-Atom Transfer.

Copper nitrite reductases (CuNIRs) convert NO2- to NO as well as NO to N2O under high NO flux at a mononuclear type 2 Cu center. While model complexes illustrate N-N coupling from NO that results in symmetric trans-hyponitrite [CuII]-ONNO-[CuII] complexes, we report NO assembly at a single Cu site in the presence of an external reductant Cp*2M (M = Co, Fe) to give the first copper cis-hyponitrites [Cp*2M]{[CuII](κ2-O2N2)[CuI]}. Importantly, the κ1-N-bound [CuI] fragment may be easily removed by the addition of mild Lewis bases such as CNAr or pyridine to form the spectroscopically similar anion {[CuII](κ2-O2N2)}-. The addition of electrophiles such as H+ to these anionic copper(II) cis-hyponitrites leads to N2O generation with the formation of the dicopper(II)-bis-µ-hydroxide [CuII]2(µ-OH)2. One-electron oxidation of the {[CuII](κ2-O2N2)}- core turns on H-atom transfer reactivity, enabling the oxidation of 9,10-dihydroanthracene to anthracene with concomitant formation of N2O and [CuII]2(µ-OH)2. These studies illustrate both the reductive coupling of NO at a single copper center and a way to harness the strong oxidizing power of nitric oxide via the neutral cis-hyponitrite [Cu](κ2-O2N2).

Uncovering Redox Non-innocent Hydrogen-Bonding in Cu(I)-Diazene Complexes.

The life-sustaining reduction of N2 to NH3 is thermoneutral yet kinetically challenged by high-energy intermediates such as N2H2. Exploring intramolecular H-bonding as a potential strategy to stabilize diazene intermediates, we employ a series of [xHetTpCu]2(µ-N2H2) complexes that exhibit H-bonding between pendant aromatic N-heterocycles (xHet) such as pyridine and a bridging trans-N2H2 ligand at copper(I) centers. X-ray crystallography and IR spectroscopy clearly reveal H-bonding in [pyMeTpCu]2(µ-N2H2) while low-temperature 1H NMR studies coupled with DFT analysis reveals a dynamic equilibrium between two closely related, symmetric H-bonded structural motifs. Importantly, the xHet pendant negligibly influences the electronic structure of xHetTpCuI centers in xHetTpCu(CNAr2,6-Me2) complexes that lack H-bonding as judged by nearly indistinguishable ν(CN) frequencies (2113-2117 cm-1). Nonetheless, H-bonding in the corresponding [xHetTpCu]2(µ-N2H2) complexes results in marked changes in ν(NN) (1398-1419 cm-1) revealed through resonance Raman studies. Due to the closely matched N-H BDEs of N2H2 and the pyH0 cation radical, the aromatic N-heterocyclic pendants may encourage partial H-atom transfer (HAT) from N2H2 to xHet through redox-non-innocent H-bonding in [xHetTpCu]2(µ-N2H2). DFT studies reveal modest thermodynamic barriers for concerted transfer of both H-atoms of coordinated N2H2 to the xHet pendants to generate tautomeric [xHetHTpCu]2(µ-N2) complexes, identifying metal-assisted concerted dual HAT as a thermodynamically favorable pathway for N2/N2H2 interconversion.

Mechanism of O-Atom Transfer from Nitrite: Nitric Oxide Release at Copper(II).

Nitric oxide (NO) is a key signaling molecule in health and disease. While nitrite acts as a reservoir of NO activity, mechanisms for NO release require further understanding. A series of electronically varied ß-diketiminatocopper(II) nitrite complexes [CuII](κ2-O2N) react with a range of electronically tuned triarylphosphines PArZ3 that release NO with the formation of O═PArZ3. Second-order rate constants are largest for electron-poor copper(II) nitrite and electron-rich phosphine pairs. Computational analysis reveals a transition-state structure energetically matched with experimentally determined activation barriers. The production of NO follows a pathway that involves nitrite isomerization at CuII from κ2-O2N to κ1-NO2 followed by O-atom transfer (OAT) to form O═PArZ3 and [CuI]-NO that releases NO upon PArZ3 binding at CuI to form [CuI]-PArZ3. These findings illustrate important mechanistic considerations involved in NO formation from nitrite via OAT.

Thionitrite and Perthionitrite in NO Signaling at Zinc.

NO and H2 S serve as signaling molecules in biology with intertwined reactivity. HSNO and HSSNO with their conjugate bases - SNO and - SSNO form in the reaction of H2 S with NO as well as S-nitrosothiols (RSNO) and nitrite (NO2- ) that serve as NO reservoirs. While HSNO and HSSNO are elusive, their conjugate bases form isolable zinc complexes Ph,Me TpZn(SNO) and Ph,Me TpZn(SSNO) supported by tris(pyrazolyl)borate ligands. Reaction of Na(15-C-5)SSNO with Ph,Me TpZn(ClO4 ) provides Ph,Me TpZn(SSNO) that undergoes S-atom removal by PEt3 to give Ph,Me TpZn(SNO) and S=PEt3 . Unexpectedly stable at room temperature, these Zn-SNO and Zn-SSNO complexes release NO upon heating. Ph,Me TpZn(SNO) and Ph,Me TpZn(SSNO) quickly react with acidic thiols such as C6 F5 SH to form N2 O and NO, respectively. Increasing the thiol basicity in p-substituted aromatic thiols 4-X ArSH in the reaction with Ph,Me TpZn(SNO) turns on competing S-nitrosation to form Ph,Me TpZn-SH and RSNO, the latter a known precursor for NO.

Copper(ii) ketimides in sp3 C-H amination.

Commercially available benzophenone imine (HN[double bond, length as m-dash]CPh2) reacts with ß-diketiminato copper(ii) tert-butoxide complexes [CuII]-O t Bu to form isolable copper(ii) ketimides [CuII]-N[double bond, length as m-dash]CPh2. Structural characterization of the three coordinate copper(ii) ketimide [Me3NN]Cu-N[double bond, length as m-dash]CPh2 reveals a short Cu-Nketimide distance (1.700(2) Å) with a nearly linear Cu-N-C linkage (178.9(2)°). Copper(ii) ketimides [CuII]-N[double bond, length as m-dash]CPh2 readily capture alkyl radicals R˙ (PhCH(˙)Me and Cy˙) to form the corresponding R-N[double bond, length as m-dash]CPh2 products in a process that competes with N-N coupling of copper(ii) ketimides [CuII]-N[double bond, length as m-dash]CPh2 to form the azine Ph2C[double bond, length as m-dash]N-N[double bond, length as m-dash]CPh2. Copper(ii) ketimides [CuII]-N[double bond, length as m-dash]CAr2 serve as intermediates in catalytic sp3 C-H amination of substrates R-H with ketimines HN[double bond, length as m-dash]CAr2 and t BuOO t Bu as oxidant to form N-alkyl ketimines R-N[double bond, length as m-dash]CAr2. This protocol enables the use of unactivated sp3 C-H bonds to give R-N[double bond, length as m-dash]CAr2 products easily converted to primary amines R-NH2 via simple acidic deprotection.

Quantification of Ni-N-O Bond Angles and NO Activation by X-ray Emission Spectroscopy.

A series of ß-diketiminate Ni-NO complexes with a range of NO binding modes and oxidation states were studied by X-ray emission spectroscopy (XES). The results demonstrate that XES can directly probe and distinguish end-on vs side-on NO coordination modes as well as one-electron NO reduction. Density functional theory (DFT) calculations show that the transition from the NO 2s2s σ* orbital has higher intensity for end-on NO coordination than for side-on NO coordination, whereas the 2s2s σ orbital has lower intensity. XES calculations in which the Ni-N-O bond angle was fixed over the range from 80° to 176° suggest that differences in NO coordination angles of ∼10° could be experimentally distinguished. Calculations of Cu nitrite reductase (NiR) demonstrate the utility of XES for characterizing NO intermediates in metalloenzymes. This work shows the capability of XES to distinguish NO coordination modes and oxidation states at Ni and highlights applications in quantifying small molecule activation in enzymes.

Three-Coordinate Copper(II) Alkynyl Complex in C-C Bond Formation: The Sesquicentennial of the Glaser Coupling.

Copper(II) alkynyl species are proposed as key intermediates in numerous Cu-catalyzed C-C coupling reactions. Supported by a ß-diketiminate ligand, the three-coordinate copper(II) alkynyl [CuII]-C≡CAr (Ar = 2,6-Cl2C6H3) forms upon reaction of the alkyne H-C≡CAr with the copper(II) tert-butoxide complex [CuII]-OtBu. In solution, this [CuII]-C≡CAr species cleanly transforms to the Glaser coupling product ArC≡C-C≡CAr and [CuI](solvent). Addition of nucleophiles R'C≡C-Li (R' = aryl, silyl) and Ph-Li to [CuII]-C≡CAr affords the corresponding Csp-Csp and Csp-Csp2 coupled products RC≡C-C≡CAr and Ph-C≡CAr with concomitant generation of [CuI](solvent) and {[CuI]-C≡CAr}-, respectively. Supported by density functional theory (DFT) calculations, redox disproportionation forms [CuIII](C≡CAr)(R) species that reductively eliminate R-C≡CAr products. [CuII]-C≡CAr also captures the trityl radical Ph3C· to give Ph3C-C≡CAr. Radical capture represents the key Csp-Csp3 bond-forming step in the copper-catalyzed C-H functionalization of benzylic substrates R-H with alkynes H-C≡CR' (R' = (hetero)aryl, silyl) that provide Csp-Csp3 coupled products R-C≡CR via radical relay with tBuOOtBu as oxidant.

Lewis Acid Coordination Redirects S-Nitrosothiol Signaling Output.

S-Nitrosothiols (RSNOs) serve as air-stable reservoirs for nitric oxide in biology. While copper enzymes promote NO release from RSNOs by serving as Lewis acids for intramolecular electron-transfer, redox-innocent Lewis acids separate these two functions to reveal the effect of coordination on structure and reactivity. The synthetic Lewis acid B(C6 F5 )3 coordinates to the RSNO oxygen atom, leading to profound changes in the RSNO electronic structure and reactivity. Although RSNOs possess relatively negative reduction potentials, B(C6 F5 )3 coordination increases their reduction potential by over 1 V into the physiologically accessible +0.1 V vs. NHE. Outer-sphere chemical reduction gives the Lewis acid stabilized hyponitrite dianion trans-[LA-O-N=N-O-LA]2- [LA=B(C6 F5 )3 ], which releases N2 O upon acidification. Mechanistic and computational studies support initial reduction to the [RSNO-B(C6 F5 )3 ] radical anion, which is susceptible to N-N coupling prior to loss of RSSR.

Tris(pyrazolyl)borate Copper Hydroxide Complexes Featuring Tunable Intramolecular H-Bonding.

A modular synthesis provides access to a series of new tris(pyrazolyl)borate ligands XpyMeTpK that possess a single functionalized pendant pyridyl (py) or pyrimidyl (pyd) arm designed to engage in tunable intramolecular H-bonding to metal-bound functionalities. To illustrate such H-bonding interactions, a series of [XpyMeTpCu]2(µ-OH)2 (6a-6e) complexes were synthesized from the corresponding XpyMeTpCu-OAc (5a-5e) complexes. Single crystal X-ray structures of three new dinuclear [XpyMeTpCu]2(µ-OH)2 complexes reveal H-bonding between the pendant heterocycle and bridging hydroxide ligands while the donor arm engages the copper center in an unusual monomeric DMAPMeTpCu-OH complex. Vibrational studies (IR) of each bridging hydroxide complex reveal reduced νOH frequencies that tracks with the H-bond accepting ability of the pendant arm. Reversible protonation studies that interconvert [XpyMeTpCu]2(µ-OH)2 and [XpyMeTpCu(OH2)]OTf species indicate that the acidity of the corresponding aquo ligand decreases with increasing H-bond accepting ability of the pendant arm.

Nitrosyl Linkage Isomers: NO Coupling to N2O at a Mononuclear Site.

Linkage isomers of reduced metal-nitrosyl complexes serve as key species in nitric oxide (NO) reduction at monometallic sites to produce nitrous oxide (N2O), a potent greenhouse gas. While factors leading to extremely rare side-on nitrosyls are unclear, we describe a pair of nickel-nitrosyl linkage isomers through controlled tuning of noncovalent interactions between the nitrosyl ligands and differently encapsulated potassium cations. Furthermore, these reduced metal-nitrosyl species with N-centered spin density undergo radical coupling with free NO and provide a N-N coupled cis-hyponitrite intermediate whose protonation triggers the release of N2O. This report outlines a stepwise molecular mechanism of NO reduction to form N2O at a mononuclear metal site that provides insight into the related biological reduction of NO to N2O.

Copper-Catalyzed C(sp3 )-H Amidation: Sterically Driven Primary and Secondary C-H Site-Selectivity.

Undirected C(sp3 )-H functionalization reactions often follow site-selectivity patterns that mirror the corresponding C-H bond dissociation energies (BDEs). This often results in the functionalization of weaker tertiary C-H bonds in the presence of stronger secondary and primary bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger primary and secondary C-H bonds over tertiary and benzylic C-H sites. Herein, we report a Cu catalyst that exhibits a high degree of primary and secondary over tertiary C-H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N3 . Mechanistic and DFT studies indicate that C-H amidation involves H-atom abstraction from R-H substrates by nitrene intermediates [Cu](κ2 -N,O-NC(O)Ar) to provide carbon-based radicals R. and copper(II)amide intermediates [CuII ]-NHC(O)Ar that subsequently capture radicals R. to form products R-NHC(O)Ar. These studies reveal important catalyst features required to achieve primary and secondary C-H amidation selectivity in the absence of directing groups.

Three-Coordinate Copper(II) Aryls: Key Intermediates in C-O Bond Formation.

Copper(II) aryl species are proposed key intermediates in Cu-catalyzed cross-coupling reactions. Novel three-coordinate copper(II) aryls [CuII]-C6F5 supported by ancillary ß-diketiminate ligands form in reactions between copper(II) alkoxides [CuII]-OtBu and B(C6F5)3. Crystallographic, spectroscopic, and DFT studies reveal geometric and electronic structures of these Cu(II) organometallic complexes. Reaction of [CuII]-C6F5 with the free radical NO(g) results in C-N bond formation to give [Cu](η2-ONC6F5). Remarkably, addition of the phenolate anion PhO- to [CuII]-C6F5 directly affords diaryl ether PhO-C6F5 with concomitant generation of the copper(I) species [CuI](solvent) and {[CuI]-C6F5}-. Experimental and computational analysis supports redox disproportionation between [CuII]-C6F5 and {[CuII](C6F5)(OPh)}- to give {[CuI]-C6F5}- and [CuIII](C6F5)(OPh) unstable toward reductive elimination to [CuI](solvent) and PhO-C6F5.

Elusive Terminal Copper Arylnitrene Intermediates.

We report herein three new modes of reactivity between arylazides N3 Ar with a bulky copper(I) ß-diketiminate. Addition of N3 ArX3 (ArX3 =2,4,6-X3 C6 H2 ; X=Cl or Me) to [i Pr2 NN]Cu(NCMe) results in triazenido complexes from azide attack on the ß-diketiminato backbone. Reaction of [i Pr2 NN]Cu(NCMe) with bulkier azides N3 Ar leads to terminal nitrenes [i Pr2 NN]Cu]=NAr that dimerize via formation of a C-C bond at the arylnitrene p-position to give the dicopper(II) diketimide 4 (Ar=2,6-i Pr2 C6 H3 ) or undergo nitrile insertion to give diazametallocyclobutene 8 (Ar=4-Ph-2,6-iPr2 C6 H2 ). Importantly, reactivity studies reveal both 4 and 8 to be "masked" forms of the terminal nitrenes [i Pr2 NN]Cu=NAr that undergo nitrene group transfer to PMe3 , t BuNC, and even into a benzylic sp3 C-H bond of ethylbenzene.

Copper(II) Activation of Nitrite: Nitrosation of Nucleophiles and Generation of NO by Thiols.

Nitrite (NO2-) and nitroso compounds (E-NO, E = RS, RO, and R2N) in mammalian plasma and cells serve important roles in nitric oxide (NO) dependent as well as NO independent signaling. Employing an electron deficient ß-diketiminato copper(II) nitrito complex [Cl2NNF6]Cu(κ2-O2N)·THF, thiols mediate reduction of nitrite to NO. In contrast to NO generation upon reaction of thiols at iron nitrite species, at copper this conversion proceeds through nucleophilic attack of thiol RSH on the bound nitrite in [CuII](κ2-O2N) that leads to S-nitrosation to give the S-nitrosothiol RSNO and copper(II) hydroxide [CuII]-OH. This nitrosation pathway is general and results in the nitrosation of the amine Ph2NH and alcohol tBuOH to give Ph2NNO and tBuONO, respectively. NO formation from thiols occurs from the reaction of RSNO and a copper(II) thiolate [CuII]-SR intermediate formed upon reaction of an additional equiv thiol with [CuII]-OH.

Nitric oxide release via oxygen atom transfer from nitrite at copper(ii).

Nitric oxide is a vital signaling molecule that controls blood flow and oxygenation and nitrite serves as an important reservoir for nitric oxide in biology. While copper containing enzymes are known to reduce nitrite to nitric oxide, herein we report a new pathway to release nitric oxide via oxygen atom transfer from nitrite at a copper(ii) site.

The Chemistry of a Non-Interacting Vicinal Frustrated Phosphane/Borane Lewis Pair.

The dimesitylphosphinocyclopentene/HB(C6 F5 )2 -derived vicinal trans-1,2-P/B frustrated Lewis pair (FLP) 4 shows no direct phosphane-borane interaction. Toward some reagents it behaves similar to an intermolecular FLP; it cleaves dihydrogen, deprotonates terminal alkynes, and adds to organic carbonyl compounds including CO2 . It shows typical intramolecular FLP reaction modes (cooperative 1,1-additions) to mesityl azide, to carbon monoxide, and to NO. The latter reaction yields a persistent P/B FLPNO nitroxide radical, which undergoes H-atom abstraction reactions. The FLP 4 serves as a template for the CO reduction by [HB(C6 F5 )2 ] to generate a FLP-η2 -formylborane. The formylborane moiety is removed from the FLP template by reaction with pyridine to yield a genuine pyridine stabilized formylborane that undergoes characteristic borane carbaldehyde reactions (Wittig olefination, imine formation). Most new products were characterized by X-ray diffraction.

Copper Catalyzed sp3 C-H Etherification with Acyl Protected Phenols.

A variety of acyl protected phenols AcOAr participate in sp3 C-H etherification of substrates R-H to give alkyl aryl ethers R-OAr employing tBuOOtBu as oxidant with copper(I) ß-diketiminato catalysts [CuI]. Although 1°, 2°, and 3° C-H bonds may be functionalized, selectivity studies reveal a preference for the construction of hindered, 3° C-OAr bonds. Mechanistic studies indicate that ß-diketiminato copper(II) phenolates [CuII]-OAr play a key role in this C-O bond forming reaction, formed via transesterification of AcOAr with [CuII]-OtBu intermediates generated upon reaction of [CuI] with tBuOOtBu.