Copper Carbazolides in Photoinduced C–N Couplings

Photoinduced, copper-catalyzed reactions of organohalides have emerged in recent years as a powerful tool to construct a wide array of C–N bonds, which are prevalent in organic materials and polymers, pharmaceuticals, natural products, and ligands in transition metal catalysts. Described herein is the study and applications of copper complexes ligated by carbazole and its derivatives in photoinduced, copper-catalyzed C–N bond-constructing transformations. Various areas of synthetic inorganic and organic chemistry are explored, including in-depth mechanistic elucidation, ligand and catalyst design, reaction development, as well as spectroscopic and structural characterization of reactive copper complexes. Chapter 2 describes the mechanistic investigation on photoinduced, copper-catalyzed couplings of carbazoles with unactivated alkyl halides. A wide array of mechanistic tools suggests the viability of an out-of-cage C(sp³)–N coupling pathway. Spectroscopic and structural characterization data of the key intermediates are detailed. Chapter 3 outlines the design and preparation of a new copper-based photoredox catalyst supported by a tridentate bis(phosphino)carbazole ligands. The ground- and excited-state properties of the new photocatalyst are examined. Chapter 4 details the development of photoinduced, copper-catalyzed C(sp³)–N couplings of carbamates with unactivated alkyl bromides using the new copper photoredox system. The scope with respect to the nucleophile and the electrophile and mechanistic investigations are communicated. Chapter 5 illustrates the chemistry of copper complexes supported by bidentate (phosphino)carbazole ligands. A diverse array of copper complexes in both the S = 0 and S = 1/2 states are reported, including a rare, paramagnetic copper–phosphine complex that may serve as a structural model for key copper intermediates of the enantioselective C(sp³)–N couplings of carbazoles

Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides

Despite the long history of S_N2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex serving its intended role as a photoredox catalyst, working in conjunction with a second copper complex that mediates C–N bond formation in an out-of-cage process

Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides

Despite the long history of S_N2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex serving its intended role as a photoredox catalyst, working in conjunction with a second copper complex that mediates C–N bond formation in an out-of-cage process

Photoinduced, Copper-Catalyzed Alkylation of Amines: A Mechanistic Study of the Cross-Coupling of Carbazole with Alkyl Bromides

We have recently reported that a variety of couplings of nitrogen, sulfur, oxygen, and carbon nucleophiles with organic halides can be achieved under mild conditions (−40 to 30 °C) through the use of light and a copper catalyst. Insight into the various mechanisms by which these reactions proceed may enhance our understanding of chemical reactivity and facilitate the development of new methods. In this report, we apply an array of tools (EPR, NMR, transient absorption, and UV–vis spectroscopy; ESI–MS; X-ray crystallography; DFT calculations; reactivity, stereochemical, and product studies) to investigate the photoinduced, copper-catalyzed coupling of carbazole with alkyl bromides. Our observations are consistent with pathways wherein both an excited state of the copper(I) carbazolide complex ([Cu^I(carb)_2]^−) and an excited state of the nucleophile (Li(carb)) can serve as photoreductants of the alkyl bromide. The catalytically dominant pathway proceeds from the excited state of Li(carb), generating a carbazyl radical and an alkyl radical. The cross-coupling of these radicals is catalyzed by copper via an out-of-cage mechanism in which [Cu^I(carb)_2]^− and [Cu^(II)(carb)_3]^− (carb = carbazolide), both of which have been identified under coupling conditions, are key intermediates, and [Cu^(II)(carb)_3]^− serves as the persistent radical that is responsible for predominant cross-coupling. This study underscores the versatility of copper(II) complexes in engaging with radical intermediates that are generated by disparate pathways, en route to targeted bond constructions

Mechanistic insights into photo-induced, copper-catalyzed alkylations of amines

Photoinduced, copper-catalyzed cross-couplings have emerged as an attractive class of lightdriven transformations to construct carbon-nitrogen bonds in recent years. Despite the broadening scope with respect to coupling partners, the understanding of the operating mechanisms has been limited to date. Herein, a mechanistic investigation of a photoinduced, copper-catalyzed cross-coupling of amines and alkyl halides, including spectroscopic evidence for a copper intermediate, is presented

Use of the Imine–Enamine Equilibrium in Cooperative Ligand Design

The imine–phosphine ligands Ph₂PC₅H₇NAr, where Ar = 2,6-Prⁱ₂C₆H₃, 2,6-Me₂C₆H₃, were deprotonated using KH to generate the corresponding potassium salts, which were reacted with [(COD)­IrCl]₂ to generate the enamidophosphine derivatives (COD)­Ir­(Ph₂PC₅H₆NAr) (Ar = 2,6-Prⁱ₂C₆H₃, <b>4a</b>; Ar = 2,6-Me₂C₆H₃, <b>4b</b>). These complexes were exposed to alcohols, H₂, and CO to generate a series of products, some of which involve protonation of the enamido unit to generate the imine tautomer. The reaction of <b>4a</b> with isopropyl alcohol or H₂ generates the dinuclear hexahydride [(Ph₂PC₅H₇N-2,6-Prⁱ₂C₆H₃)­IrH₂]₂(μ-H)₂ (<b>5a</b>), while the reaction with primary alcohols generates the dicarbonyl enamidophosphine complex (CO)₂Ir­(Ph₂PC₅H₆NAr) (<b>6a</b>). The reaction of the hexahydride <b>5a</b> with CO generates <b>6a</b>, for which a mechanism is proposed on the basis of monitoring this reaction as a function of time by NMR spectroscopy. On the basis of these experiments, cooperative ligand effects can be replicated by imine–phosphine ligands by proton transfer to and from the ligand backbone

Role of Aggregation in the Synthesis and Polymerization Activity of SalBinap Indium Alkoxide Complexes

The reaction of racemic SalBinap ligand, (±)-H₂(<b>ONN</b>*<b>O</b>_<b>Me</b>), with InCl₃ and excess NaOEt generated a mixture of two dinuclear compounds [(μ–κ²-ONN*O_Me)­In­(μ-OEt)]₂ (<b>1a</b>) and [κ⁴-ONN*O_Me)­In­(μ-OEt)]₂ (<b>1b</b>), which were isolated and fully characterized. Polymerization of racemic lactide with <b>1a</b> and <b>1b</b> was slow in refluxing THF and showed only modest stereoselectivity. Catalyst <b>1b</b> displayed better control than <b>1a</b>, with the experimental molecular weights of the resulting poly­(lactic acid) in agreement with the expected values. The higher-than-expected molecular weights observed in polymers formed by <b>1a</b> were due to partial initiation of the catalyst. The reaction of (±)-H₂(<b>ONN</b>*<b>O</b>_<b>tBu</b>) with InCl₃ yielded (κ⁴-ONN*O_tBu)­InCl (<b>2</b>); however, further reactivity of the compound formed a mixture of products. An attempt to prevent aggregation by reacting (±)-H₂(<b>ONN</b>*<b>O</b>_<b>Me</b>) with InCl₃ and excess NaO^<i>i</i>Pr yielded an intractable mixture, including [(μ–κ²-ONN*O_Me)­In]₂­(μ-Cl)­(μ-OH) (<b>3</b>). The thermal stabilities of compounds <b>1a</b> and <b>1b</b> under polymerization conditions were investigated. Examination of the polymerization behavior of complexes <b>1a</b> and <b>1b</b> and the reaction equilibrium between the two illustrates the importance of aggregation in indium salen complexes compared to their aluminum counterparts

Platelet-Rich Plasma Increases the Levels of Catabolic Molecules and Cellular Dedifferentiation in the Meniscus of a Rabbit Model

Despite the susceptibility to frequent intrinsic and extrinsic injuries, especially in the inner zone, the meniscus does not heal spontaneously owing to its poor vascularity. In this study, the effect of platelet-rich plasma (PRP), containing various growth factors, on meniscal mechanisms was examined under normal and post-traumatic inflammatory conditions. Isolated primary meniscal cells of New Zealand white (NZW) rabbits were incubated for 3, 10, 14 and 21 days with PRP(−), 10% PRP (PRP(+)), IL(+) or IL(+)PRP(+). The meniscal cells were collected and examined using reverse-transcription polymerase chain reaction (RT-PCR). Culture media were examined by immunoblot analyses for matrix metalloproteinases (MMP) catabolic molecules. PRP containing growth factors improved the cellular viability of meniscal cells in a concentration-dependent manner at Days 1, 4 and 7. However, based on RT-PCR, meniscal cells demonstrated dedifferentiation, along with an increase in type I collagen in the PRP(+) and in IL(+)PRP(+). In PRP(+), the aggrecan expression levels were lower than in the PRP(−) until Day 21. The protein levels of MMP-1 and MMP-3 were higher in each PRP group, i.e., PRP(+) and IL(+)PRP(+), at each culture time. A reproducible 2-mm circular defect on the meniscus of NZW rabbit was used to implant fibrin glue (control) or PRP in vivo. After eight weeks, the lesions in the control and PRP groups were occupied with fibrous tissue, but not with meniscal cells. This study shows that PRP treatment of the meniscus results in an increase of catabolic molecules, especially those related to IL-1α-induced inflammation, and that PRP treatment for an in vivo meniscus injury accelerates fibrosis, instead of meniscal cartilage

Chiral Nematic Stained Glass: Controlling the Optical Properties of Nanocrystalline Cellulose-Templated Materials

Chiral nematic mesoporous materials decorated with metal nanoparticles have been prepared using the templated self-assembly of nanocrystalline cellulose (NCC). By adding small quantities of ionic compounds to aqueous dispersions of NCC and tetramethoxysilane (TMOS), the helical pitch of the chiral nematic structure could be manipulated in a manner complementary to the ratio of NCC/TMOS previously demonstrated by our group. We have studied the transformation of these ion-loaded composites into high surface area mesoporous silica and carbon films decorated with metal nanoparticles through calcination and carbonization, respectively. This general and straightforward approach to prepare chiral nematic metal nanoparticle assemblies may be useful in a variety of applications, particularly for their chiral optical properties