Jason M. Lynam

Recent Mechanistic and Synthetic Developments in the Chemistry of Transition-Metal Vinylidene Complexes

Transition-metal vinylidene complexes are intermediates in a number of synthetically important transformations of alkynes. Underpinning these applications is the ability of various electron-rich transition-metal complexes to effectively facilitate the conversion of alkynes into their vinylidene tautomers. Recent experimental and theoretical studies have provided considerable insight into the mechanisms by which this process occurs and they are detailed herein. In particular, it has been demonstrated that different substituents on both the metal and the alkyne may have profound effects on both the kinetic and thermodynamic profiles of the alkyne/vinylidene tautomerisation. An important finding is that internal alkynes may be employed to prepare disubstituted vinylidene complexes under easily accessible conditions. This discovery brings to light a new facet of the potential synthetic applications of transition metal vinylidene complexes.

Bioactive Properties of Iron-Containing Carbon Monoxide-Releasing Molecules

Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro-(glycinato)ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that η-4-(4-bromo-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [η-4-(4-chloro-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [η-4-(4-methyl-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F11)] or a hydrogen [η-4-(4-chloro-2-pyrone)tricarbonyl iron (0) (CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4-position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.

Ruthenium-mediated C-H functionalization of pyridine: the role of vinylidene and pyridylidene ligands.

A combined experimental and theoretical study has demonstrated that [Ru(η(5)-C(5)H(5))(py)(2)(PPh(3))](+) is a key intermediate, and active catalyst for, the formation of 2-substituted E-styrylpyridines from pyridine and terminal alkynes HC≡CR (R = Ph, C(6)H(4)-4-CF(3)) in a 100% atom efficient manner under mild conditions. A catalyst deactivation pathway involving formation of the pyridylidene-containing complex [Ru(η(5)-C(5)H(5))(κ(3)-C(3)-C(5)H(4)NCH═CHR)(PPh(3))](+) and subsequently a 1-ruthanaindolizine complex has been identified. Mechanistic studies using (13)C- and D-labeling and DFT calculations suggest that a vinylidene-containing intermediate [Ru(η(5)-C(5)H(5))(py)(═C═CHR)(PPh(3))](+) is formed, which can then proceed to the pyridylidene-containing deactivation product or the desired product depending on the reaction conditions. Nucleophilic attack by free pyridine at the α-carbon in this complex subsequently leads to formation of a C-H agostic complex that is the branching point for the productive and unproductive pathways. The formation of the desired products relies on C-H bond cleavage from this agostic complex in the presence of free pyridine to give the pyridyl complex [Ru(η(5)-C(5)H(5))(C(5)H(4)N)(═C═CHR)(PPh(3))]. Migration of the pyridyl ligand (or its pyridylidene tautomer) to the α-carbon of the vinylidene, followed by protonation, results in the formation of the 2-styrylpyridine. These studies demonstrate that pyridylidene ligands play an important role in both the productive and nonproductive pathways in this catalyst system.

Diversity and design of metal-based carbon monoxide-releasing molecules (CO-RMs) in aqueous systems: revealing the essential trends

The CO-releasing ability of a diverse library of primary metal carbonyl complexes has been assessed using a deoxymyoglobin-carbonmonoxymyglobin assay. A wide spectrum of rates for the CO-release process was observed in aqueous systems. For octahedral d(6) complexes, the rate was found to decrease in the sequence FeI(2)(CO)(4) > [NEt(4)][V(CO)(6)] > MnBr(CO)(5) > Cr(CO)(6) implying that CO-release is not controlled by the metal-carbon bond strengths. Within the series, [NEt(4)][MX(CO)(5)] (M = Cr, Mo, W; X =Cl, Br, I), the rate of CO-release was found to decrease down the group (Cr > Mo > W), whilst within the chromium series a similar trend was observed for the halide (Cl > Br > I). The d(4) complexes [NEt(4)][MI(3)(CO)(4)] (M = Mo, W) exhibit faster release than their d(6) congeners. A mechanistic investigation into the [NEt(4)][MX(CO)(5)] series revealed the intermediacy of [[M(CO)(5)](2)(mu-X)](-) in the CO-release process and that the hydrolysis of the M-X bond, rather than the intrinsic strength of M-CO bonds, controls the rate of CO-release in aqueous systems.

Manganese(I)‐Catalyzed C−H Activation: The Key Role of a 7‐Membered Manganacycle in H‐Transfer and Reductive Elimination

Abstract Manganese‐catalyzed C−H bond activation chemistry is emerging as a powerful and complementary method for molecular functionalization. A highly reactive seven‐membered MnI intermediate is detected and characterized that is effective for H‐transfer or reductive elimination to deliver alkenylated or pyridinium products, respectively. The two pathways are determined at MnI by judicious choice of an electron‐deficient 2‐pyrone substrate containing a 2‐pyridyl directing group, which undergoes regioselective C−H bond activation, serving as a valuable system for probing the mechanistic features of Mn C−H bond activation chemistry.

The Elusive Structure of Pd2(dba)3. Examination by Isotopic Labeling, NMR Spectroscopy, and X-ray Diffraction Analysis: Synthesis and Characterization of Pd2(dba-Z)3 Complexes

Pd(0)2(dba)3 (dba = E,E-dibenzylidene acetone) is the most widely used Pd(0) source in Pd-mediated transformations. Pd(0)2(dba-Z)3 (Z = dba aryl substituents) complexes exhibit remarkable and differential catalytic performance in an eclectic array of cross-coupling reactions. The precise structure of these types of complexes has been confounding, since early studies in 1970s to the present day. In this study the solution and solid-state structures of Pd(0)2(dba)3 and Pd(0)2(dba-Z)3 have been determined. Isotopic labeling ((2)H and (13)C) has allowed the solution structures of the freely exchanging major and minor isomers of Pd(0)2(dba)3 to be determined at high field (700 MHz). DFT calculations support the experimentally determined major and minor isomeric structures, which show that the major isomer of Pd(0)2(dba)3 possesses bridging dba ligands found exclusively in a s-cis,s-trans conformation. For the minor isomer one of the dba ligands is found exclusively in a s-trans,s-trans conformation. Single crystal X-ray diffraction analysis of Pd(0)2(dba)3·CHCl3 (high-quality data) shows that all three dba ligands are found over two positions. NMR spectroscopic analysis of Pd(0)2(dba-Z)3 reveals that the aryl substituent has a profound effect on the rate of Pd-olefin exchange and the global stability of the complexes in solution. Complexes containing the aryl substituents, 4-CF3, 4-F, 4-t-Bu, 4-hexoxy, 4-OMe, exhibit well-resolved (1)H NMR spectra at 298 K, whereas those containing 3,5-OMe and 3,4,5-OMe exhibit broad spectra. The solid-state structures of three Pd(0)2(dba-Z)3 complexes (4-F, 4-OMe, 3,5-OMe) have been determined by single crystal X-ray diffraction methods, which have been compared with Goodsons X-ray structure of Pd(0)2(dba-4-OH)3.

Insights into the intramolecular acetate-mediated formation of ruthenium vinylidene complexes: a ligand-assisted proton shuttle (LAPS) mechanism

The ruthenium bis-acetate complex Ru(κ(2)-OAc)(2)(PPh(3))(2) reacts with HC≡CPh to afford the vinylidene-containing species Ru(κ(1)-OAc)(κ(2)-OAc)(=C=CHPh)(PPh(3))(2). An experimental study has demonstrated that this reaction occurs under very mild conditions, with significant conversion being observed at 255 K. At lower temperatures, evidence for a transient metallo-enol ester species Ru(κ(1)-OAc)(OC{Me}O-C=CHPh)(PPh(3))(2) was obtained. A comprehensive theoretical study to probe the nature of the alkyne/vinylidene tautomerisation has been undertaken using Density Functional Theory. Calculations based on a number of isomers of the model system Ru(κ(1)-OAc)(κ(2)-OAc)(=C=CHMe)(PH(3))(2) demonstrate that both the η(2)(CC) alkyne complex Ru(κ(1)-OAc)(κ(2)-OAc)(η(2)-HC≡CMe)(PH(3))(2) and the C-H agostic σ-complex Ru(κ(1)-OAc)(κ(2)-OAc)(η(2){CH}-HC≡CMe)(PH(3))(2) are minima on the potential energy surface. The lowest energy pathway for the formation of the vinylidene complex involves the intramolecular deprotonation of the σ-complex by an acetate ligand followed by reprotonation of the subsequently formed alkynyl ligand. This process is thus termed a Ligand-Assisted Proton Shuttle (LAPS). Calculations performed on the full experimental system Ru(κ(1)-OAc)(κ(2)-OAc)(=C=CHPh)(PPh(3))(2) reinforce the notion that lowest energy pathway involves the deprotonation/reprotonation of the alkyne by an acetate ligand. Inclusion of the full ligand substituents in the calculations are necessary to reproduce the experimental observation of Ru(κ(1)-OAc)(κ(2)-OAc)(=C=CHPh)(PPh(3))(2) as the thermodynamic product.

Ruthenium alkynyl, carbene and alkenyl complexes containing pendant uracil groups: an investigation into the formation of alkenyl-phosphonio complexes

The vinylidene complex [Ru(eta(5)-C(5)H(5))(PPh(3))(2)(=C=CHUr)][X] (X = PF(6), OTf, Ur = uracil) is a versatile precursor for a range of organometallic complexes containing pendant uracil groups. Using appropriate conditions the vinylidene complex may be selectively transformed into alkynyl Ru(-C[triple bond]CUr)(eta(5)-C(5)H(5))(PPh(3))(2), carbene [Ru(eta(5)-C(5)H(5))(PPh(3))(2)(=C{OMe}-CH(2)Ur)][X] and alkenyl-phosphonio species [Ru(E-CH=C{PPh(3)}Ur)(eta(5)-C(5)H(5))(PPh(3))(2)][X]. The synthesis of the related alkenyl-phosphonio complexes [Ru(E-CH=C{PPh(3)}R)(eta(5)-C(5)H(5))(PPh(3))(2)][X] (R = Ph, C(6)H(4)-3-OMe) is described; these undergo a further orthometallation reaction: the mechanism of this latter reaction appears to proceed via dissociation of a ruthenium-bound PPh(3) ligand.

Visible-Light-Induced CO Release from a Therapeutically Viable Tryptophan-Derived Manganese(I) Carbonyl (TryptoCORM) Exhibiting Potent Inhibition against E. coli

The first visible-light-activated carbon-monoxide-releasing molecule (CO-RM) to exhibit a potent effect against Escherichia coli is described. The easily prepared tryptophan-derived manganese-containing complex (TryptoCORM) released 1.4 moles of CO at 465 nm, and 2 moles at 400 nm. A comprehensive synthetic, mechanistic and microbiological study into the behaviour of TryptoCORM is reported. The complex is thermally stable (i.e., does not release CO in solution in the absence of light), shows low toxicity against mammalian cells and releases tryptophan on photoinduced degradation, all of which point to TryptoCORM being therapeutically viable.

Formation and catalytic activity of Pd nanoparticles on silica in supercritical CO2

Metal complexes of polydimethylsiloxane-derived ligands can be adsorbed onto silica and subsequently reduced in-situ in supercritical CO2 (scCO2) to generate metal nanoparticles. Pd nanoparticles on silica, generated during C–C coupling reactions in scCO2, can be recycled several times without any loss in activity. Focusing on Heck and Suzuki coupling reactions, the products showed no contamination of the organic products with Pd using quantitative ICP emission spectroscopy. The use of scCO2 prevents the desorption of the Pd nanoparticles from their support. Build-up of ammonium salts as by-products in these coupling reactions leads to reduced activity for these heterogeneous catalysts after four runs.