The importance of understanding (pre)catalyst activation in versatile C-H bond functionalisations catalysed by [Mn2(CO)10].

Mn-catalysed reactions offer great potential in synthetic organic and organometallic chemistry and the success of Mn carbonyl complexes as (pre)catalysts hinges on their stabilisation by strong field ligands enabling Mn(i)-based, redox neutral, catalytic cycles. The mechanistic processes underpinning the activation of the ubiquitous Mn(0) (pre)catalyst [Mn2(CO)10] in C-H bond functionalisation reactions is now reported for the first time. By combining time-resolved infra-red (TRIR) spectroscopy on a ps-ms timescale and in operando studies using in situ infra-red spectroscopy, insight into the microscopic bond activation processes which lead to the catalytic activity of [Mn2(CO)10] has been gained. Using an exemplar system, based on the annulation between an imine, 1, and Ph2C2, 2, TRIR spectroscopy enabled the key intermediate [Mn2(CO)9(1)], formed by CO loss from [Mn2(CO)10], to be identified. In operando studies demonstrate that [Mn2(CO)9(1)] is also formed from [Mn2(CO)10] under the catalytic conditions and is converted into a mononuclear manganacycle, [Mn(CO)4(C^N)] (C^N = cyclometallated imine), a second molecule of 1 acts as the oxidant which is, in turn, reduced to an amine. As [Mn(CO)4(C^N)] complexes are catalytically competent, a direct route from [Mn2(CO)10] into the Mn(i) catalytic reaction coordinate has been determined. Critically, the mechanistic differences between [Mn2(CO)10] and Mn(i) (pre)catalysts have been delineated, informing future catalyst screening studies.

Deciphering complexity in Pd-catalyzed cross-couplings.

Understanding complex reaction systems is critical in chemistry. While synthetic methods for selective formation of products are sought after, oftentimes it is the full reaction signature, i.e., complete profile of products/side-products, that informs mechanistic rationale and accelerates discovery chemistry. Here, we report a methodology using high-throughput experimentation and multivariate data analysis to examine the full signature of one of the most complicated chemical reactions catalyzed by palladium known in the chemical literature. A model Pd-catalyzed reaction was selected involving functionalization of 2-bromo-N-phenylbenzamide and multiple bond activation pathways. Principal component analysis, correspondence analysis and heatmaps with hierarchical clustering reveal the factors contributing to the variance in product distributions and show associations between solvents and reaction products. Using robust data from experiments performed with eight solvents, for four different reaction times at five different temperatures, we correlate side-products to a major dominant N-phenyl phenanthridinone product, and many other side products.

Correction: On the mercuration, palladation, transmetalation and direct auration of a C

Correction for 'On the mercuration, palladation, transmetalation and direct auration of a C^N^C pincer ligand' by Alice Jane McEllin et al., Dalton Trans., 2023, 52, 872-876, https://doi.org/10.1039/d2dt04114f.

Gold(III), Mercury(II), and Palladium(II) Complexes of a Series of Isomeric Bis(mono- and dialkoxyphenyl)pyridines: Introduction of Gold through Transmetalation and Catalysis.

A series of isomeric bis-2,6-(monoalkoxyphenyl)pyridine and bis-2,6-(dialkoxyphenyl)pyridine ligands were synthesized and characterized. In order to prepare their chlorogold(III) complexes, intermediate chloromercury(II) complexes were first prepared, but unlike observations from previous studies where they were obtained impure and at best in moderate yield, here pure complexes were synthesized, many in rather high yields. Depending on the substitution pattern of the alkoxy chains on the ligands, mono- and/or dimercurated complexes were obtained, characterized by 1H, 13C{1H}, and 199Hg NMR spectroscopy as well as, in several cases, by X-ray crystallography. Factors that may explain this unusual reactivity are discussed. In most cases, transmetalation to the related chlorogold(III) complex proceeded smoothly, although lower yields were obtained when starting from doubly mercurated precursors. Prompted by the propensity of these ligands to mercurate, attempts were made to effect direct auration, but none was successful. However, dimeric, orthometalated complexes of palladium(II) could be prepared and were also amenable to transmetalation to the chlorogold(III) complex, providing for a mercury-free synthesis.

Understanding the [NiFe] Hydrogenase Active Site Environment through Ultrafast Infrared and 2D-IR Spectroscopy of the Subsite Analogue K[CpFe(CO)(CN)2] in Polar and Protic Solvents.

The [CpFe(CO)(CN)2]- unit is an excellent structural model for the Fe(CO)(CN)2 moiety of the active site found in [NiFe] hydrogenases. Ultrafast infrared (IR) pump-probe and 2D-IR spectroscopy have been used to study K[CpFe(CO)(CN)2] (M1) in a range of protic and polar solvents and as a dry film. Measurements of anharmonicity, intermode vibrational coupling strength, vibrational relaxation time, and solvation dynamics of the CO and CN stretching modes of M1 in H2O, D2O, methanol, dimethyl sulfoxide, and acetonitrile reveal that H-bonding to the CN ligands plays an important role in defining the spectroscopic characteristics and relaxation dynamics of the Fe(CO)(CN)2 unit. Comparisons of the spectroscopic and dynamic data obtained for M1 in solution and in a dry film with those obtained for the enzyme led to the conclusion that the protein backbone forms an important part of the bimetallic active site environment via secondary coordination sphere interactions.

Unveiling Mechanistic Complexity in Manganese-Catalyzed C-H Bond Functionalization Using IR Spectroscopy Over 16 Orders of Magnitude in Time.

ConspectusAn understanding of the mechanistic processes that underpin reactions catalyzed by 3d transition metals is vital for their development as potential replacements for scarce platinum group metals. However, this is a significant challenge because of the tendency of 3d metals to undergo mechanistically diverse pathways when compared with their heavier congeners, often as a consequence of one-electron transfer reactions and/or intrinsically weaker metal-ligand bonds. We have developed and implemented a new methodology to illuminate the pathways that underpin C-H bond functionalization pathways in reactions catalyzed by Mn-carbonyl compounds. By integrating measurements performed on catalytic reactions with in situ reaction monitoring and state-of-the-art ultrafast spectroscopic methods, unique insight into the mode of action and fate of the catalyst have been obtained.Using a combination of time-resolved spectroscopy and in situ low-temperature NMR studies, we have shown that photolysis of manganese-carbonyl precatalysts results in rapid (<5 ps) CO dissociation─the same process that occurs under thermal catalytic conditions. This enabled the detection of the key states relevant to catalysis, including solvent and alkyne complexes and their resulting transformation into manganacycles, which results from a migratory insertion reaction into the Mn-C bond. By systematic variation of the substrates (many of which are real-world structurally diverse substrates and not simple benchmark systems) and quantification of the resulting rate constants for the insertion step, a universal model for this migratory insertion process has been developed. The time-resolved spectroscopic method gave insight into fundamental mechanistic pathways underpinning other aspects of modern synthetic chemistry. The most notable was the first direct experimental observation of the concerted metalation deprotonation (CMD) mechanism through which carboxylate groups are able to mediate C-H bond activation at a metal center. This step underpins a host of important synthetic applications. This study demonstrated how the time-resolved multiple probe spectroscopy (TRMPS) method enables the observation of mechanistic process occurring on time scales from several picoseconds through to µs in a single experiment, thereby allowing the sequential observation of solvation, ligand substitution, migratory insertion, and ultimate protonation of a Mn-C bond.These studies have been complemented by an investigation of the "in reaction flask" catalyst behavior, which has provided additional insight into new pathways for precatalyst activation, including evidence that alkyne C-H bond activation may occur before heterocycle activation. Crucial insight into the fate of the catalyst species showed that excess water played a key role in deactivation to give higher-order hydroxyl-bridged manganese carbonyl clusters, which were independently found to be inactive. Traditional in situ IR and NMR spectroscopic analysis on the second time scale bridges the gap to the analysis of real catalytic reaction systems. As a whole, this work has provided unprecedented insight into the processes underpinning manganese-catalyzed reactions spanning 16 orders of magnitude in time.

A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions.

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.

Metallomimetic C-F Activation Catalysis by Simple Phosphines.

Delivering metallomimetic reactivity from simple p-block compounds is highly desirable in the search to replace expensive, scarce precious metals by cheap and abundant elements in catalysis. This contribution demonstrates that metallomimetic catalysis, involving facile redox cycling between the P(III) and P(V) oxidation states, is possible using only simple, cheap, and readily available trialkylphosphines without the need to enforce unusual geometries at phosphorus or use external oxidizing/reducing agents. Hydrodefluorination and aminodefluorination of a range of fluoroarenes was realized with good to very good yields under mild conditions. Experimental and computational mechanistic studies show that the phosphines undergo oxidative addition of the fluoroaromatic substrate via a Meisenheimer-like transition state to form a fluorophosphorane. This undergoes a pseudotransmetalation step with a silane, via initial fluoride transfer from P to Si, to give experimentally observed phosphonium ions. Hydride transfer from a hydridosilicate counterion then leads to a hydridophosphorane, which undergoes reductive elimination of the product to reform the phosphine catalyst. This behavior is analogous to many classical transition-metal-catalyzed reactions and so is a rare example of both functional and mechanistically metallomimetic behavior in catalysis by a main-group element system. Crucially, the reagents used are cheap, readily available commercially, and easy to handle, making these reactions a realistic prospect in a wide range of academic and industrial settings.

Divergent Cascade Ring-Expansion Reactions of Acryloyl Imides.

Macrocyclic and medium-sized ring ketones, lactones and lactams can all be made from common acryloyl imide starting materials through divergent, one-pot cascade ring-expansion reactions. Following either conjugate addition with an amine or nitromethane, or osmium(VIII)-catalysed dihydoxylation, rearrangement through a four-atom ring expansion takes place spontaneously to form the ring expanded products. A second ring expansion can also be performed following a second iteration of imide formation and alkene functionalisation/ring expansion. In the dihydroxylation series, three- or four-atom ring expansion can be performed selectively, depending on whether the reaction is under kinetic or thermodynamic control.

In crystallo lattice adaptivity triggered by solid-gas reactions of cationic group 7 pincer complexes.

The group 7 complexes [M(κ3-2,6-(R2PO)2C5H3N)(CO)2L][BArF4] [M = Mn, R = iPr, L = THF; M = Re, R = tBu, L = vacant site] undergo in crystallo solid-gas reactivity with CO to form the products of THF substitution or CO addition respectively. There is a large, local, adaptive change of [BArF4] anions for M = Mn, whereas for M = Re the changes are smaller and also remote to the site of reactivity.

Understanding Precatalyst Activation and Speciation in Manganese-Catalyzed C-H Bond Functionalization Reactions.

An investigation into species formed following precatalyst activation in Mn-catalyzed C-H bond functionalization reactions is reported. Time-resolved infrared spectroscopy demonstrates that light-induced CO dissociation from precatalysts [Mn(C^N)(CO)4] (C^N = cyclometalated 2-phenylpyridine (1a), cyclometalated 1,1-bis(4-methoxyphenyl)methanimine (1b)) in a toluene solution of 2-phenylpyridine (2a) or 1,1-bis(4-methoxyphenyl)methanimine (2b) results in the initial formation of solvent complexes fac-[Mn(C^N)(CO)3(toluene)]. Subsequent solvent substitution on a nanosecond time scale then yields fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)], respectively. When the experiments are performed in the presence of phenylacetylene, the initial formation of fac-[Mn(C^N)(CO)3(toluene)] is followed by a competitive substitution reaction to give fac-[Mn(C^N)(CO)3(2)] and fac-[Mn(C^N)(CO)3(η2-PhC2H)]. The fate of the reaction mixture depends on the nature of the nitrogen-containing substrate used. In the case of 2-phenylpyridine, migratory insertion of the alkyne into the Mn-C bond occurs, and fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] remains unchanged. In contrast, when 2b is used, substitution of the η2-bound phenylacetylene by 2b occurs on a microsecond time scale, and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)] is the sole product from the reaction. Calculations with density functional theory indicate that this difference in behavior may be correlated with the different affinities of 2a and 2b for the manganese. This study therefore demonstrates that speciation immediately following precatalyst activation is a kinetically controlled event. The most dominant species in the reaction mixture (the solvent) initially binds to the metal. The subsequent substitution of the metal-bound solvent is also kinetically controlled (on a ns time scale) prior to the thermodynamic distribution of products being obtained.

Ring expansion reactions of PO-containing molecules.

A series of ring expansion reactions of PO-containing molecules have been developed for the synthesis of medium-sized ring cyclic phosphonate esters and phosphonamidates. The reactivity trends initially appear to be counter-intuitive, compared with more well established ring expansion reactions of lactam derivatives, but are explained by considering the differences in heteroatom bonding to P and C respectively.

IrI(η4-diene) precatalyst activation by strong bases: formation of an anionic IrIII tetrahydride.

The reaction between [IrCl(COD)]2 and dppe in a 1 : 2 ratio was investigated in detail under three different conditions. [IrCl(COD)(dppe)], 1, is formed at room temperature in the absence of base. In the presence of a strong base at room temperature, hydride complexes that retain the carbocyclic ligand in the coordination sphere are generated. In isopropanol, 1 is converted into [IrH(1,2,5,6-η2:η2-COD)(dppe)] (2) on addition of KOtBu, with k12 = (1.11 ± 0.02) × 10-4 s-1, followed by reversible isomerisation to [IrH(1-κ-4,5,6-η3-C8H12)(dppe)] (3) with k23 = (3.4 ± 0.2) × 10-4 s-1 and k32 = (1.1 ± 0.3) × 10-5 s-1 to yield an equilibrium 5 : 95 mixture of 2 and 3. However, when no hydride source is present in the strong base (KOtBu in benzene or toluene), the COD ligand in 1 is deprotonated, followed by ß-H elimination of an IrI-C8H11 intermediate, which leads to complex [IrH(1-κ-4,5,6-η3-C8H10)(dppe)] (4) selectively. This is followed by its reversible isomerisation to 5, which features a different relative orientation of the same ligands (k45 = (3.92 ± 0.11) × 10-4 s-1; k5-4 = (1.39 ± 0.12) × 10-4 s-1 in C6D6), to yield an equilibrated 32 : 68 mixture of 4 and 5. DFT calculations assisted in the full rationalization of the selectivity and mechanism of the reactions, yielding thermodynamic (equilibrium) and kinetic (isomerization barriers) parameters in excellent agreement with the experimental values. Finally, in the presence of KOtBu and isopropanol at 80 °C, 1 is transformed selectively to K[IrH4(dppe)] (6), a salt of an anionic tetrahydride complex of IrIII. This product is also selectively generated from 2, 3, 4 and 5 and H2 at room temperature, but only when a strong base is present. These results provide an insight into the catalytic action of [IrCl(COD)(LL)] complexes in the hydrogenation of polar substrates in the presence of a base.

On the mercuration, palladation, transmetalation and direct auration of a C

The C^N^C ligand 2,6-bis(2,3-dialkoxyphenyl)pyridine forms dimercury and orthopalladated complexes, both of which may be transmetallated to gold(III) complexes; the gold complexes may also be formed directly in a Rh(III)-catalysed process, hence it is possible to circumvent the use of organomercury intermediates in the synthesis of this important class of compound.

Coumarin C-H Functionalization by Mn(I) Carbonyls: Mechanistic Insight by Ultra-Fast IR Spectroscopic Analysis.

Mn(I) C-H functionalization of coumarins provides a versatile and practical method for the rapid assembly of fused polycyclic pyridinium-containing coumarins in a regioselective manner. The synthetic strategy enables application of bench-stable organomanganese reagents in both photochemical- and thermal-promoted reactions. The cyclomanganated intermediates, and global reaction system, provide an ideal testing ground for structural characterization of the active Mn(I) carbonyl-containing species, including transient species observable by ultra-fast time-resolved spectroscopic methods. The thermodynamic reductive elimination product, solely encountered from reaction between alkynes and air-stable organometallic cyclomanganated coumarins, has enabled characterization of a critical seven-membered Mn(I) intermediate, detected by time-resolved infrared spectroscopy, enabling the elucidation of the temporal profile of key steps in the reductive elimination pathway. Quantitative data are provided. Manganated polycyclic products are readily decomplexed by AgBF4 , opening-up an efficient route to the formation of π-extended hybrid coumarin-pyridinium compounds.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides.

Two new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

Insight into ortho-boronoaldehyde conjugation via a FRET-based reporter assay.

Ortho-boronoaldehydes react with amine-based nucleophiles with dramatically increased rates and product stabilities, relative to unfunctionalised benzaldehydes, leading to exciting applications across biological and material chemistry. We have developed a novel Förster resonance energy transfer (FRET)-based assay to provide key new insights into the reactivity of these boronoaldehydes, allowing us to track conjugation with unprecedented sensitivity and accuracy under standardised conditions. Our results highlight the key role played by reaction pH, buffer additives, and boronoaldehyde structure in controlling conjugation speed and stability, providing design criteria for further innovations and applications in the field.

A comprehensive understanding of carbon-carbon bond formation by alkyne migratory insertion into manganacycles.

Migratory insertion (MI) is one of the most important processes underpinning the transition metal-catalysed formation of C-C and C-X bonds. In this work, a comprehensive model of MI is presented, based on the direct observation of the states involved in the coupling of alkynes with cyclometallated ligands, augmented with insight from computational chemistry. Time-resolved spectroscopy demonstrates that photolysis of complexes [Mn(C^N)(CO)4] (C^N = cyclometalated ligand) results in ultra-fast dissociation of a CO ligand. Performing the experiment in a toluene solution of an alkyne results in the initial formation of a solvent complex fac-[Mn(C^N)(toluene)(CO)3]. Solvent substitution gives an η2-alkyne complex fac-[Mn(C^N)(η2-R1C2R2)(CO)3] which undergoes MI of the unsaturated ligand into the Mn-C bond. These data allowed for the dependence of second order rate constants for solvent substitution and first order rate constants for C-C bond formation to be determined. A systematic investigation into the influence of the alkyne and C^N ligand on this process is reported. The experimental data enabled the development of a computational model for the MI reaction which demonstrated that a synergic interaction between the metal and the nascent C-C bond controls both the rate and regiochemical outcome of the reaction. The time-resolved spectroscopic method enabled the observation of a multi-step reaction occurring over 8 orders of magnitude in time, including the formation of solvent complexes, ligand substitution and two sequential C-C bond formation steps.

Ultrafast 2D-IR spectroscopy of [NiFe] hydrogenase from E. coli reveals the role of the protein scaffold in controlling the active site environment.

Ultrafast two-dimensional infrared (2D-IR) spectroscopy of Escherichia coli Hyd-1 (EcHyd-1) reveals the structural and dynamic influence of the protein scaffold on the Fe(CO)(CN)2 unit of the active site. Measurements on as-isolated EcHyd-1 probed a mixture of active site states including two, which we assign to Nir-SI/II, that have not been previously observed in the E. coli enzyme. Explicit assignment of carbonyl (CO) and cyanide (CN) stretching bands to each state is enabled by 2D-IR. Energies of vibrational levels up to and including two-quantum vibrationally excited states of the CO and CN modes have been determined along with the associated vibrational relaxation dynamics. The carbonyl stretching mode potential is well described by a Morse function and couples weakly to the cyanide stretching vibrations. In contrast, the two CN stretching modes exhibit extremely strong coupling, leading to the observation of formally forbidden vibrational transitions in the 2D-IR spectra. We show that the vibrational relaxation times and structural dynamics of the CO and CN ligand stretching modes of the enzyme active site differ markedly from those of a model compound K[CpFe(CO)(CN)2] in aqueous solution and conclude that the protein scaffold creates a unique biomolecular environment for the NiFe site that cannot be represented by analogy to simple models of solvation.