Towards the Industrial Implementation of Mn-based Catalyst for the Hydrogenation of Ketones and Carboxylic Esters.

There is a constant pressure in industry to move away from platinum group metals (PGM) and achieve more environmentally friendly and sustainable production processes in the future. Recently developed Mn-based catalysts offer an interesting opportunity to complement established catalysts based on Ru. In this article, recent achievements in the field are highlighted and recent achievements in the collaboration of Solvias AG with the group of Prof. M. Clarke towards the implementation of these catalysts on industrial scale are outlined.

Ligand Hydrogenation during Hydroformylation Catalysis Detected by In Situ High-Pressure Infra-Red Spectroscopic Analysis of a Rhodium/Phospholene-Phosphite Catalyst.

Phospholane-phosphites are known to show highly unusual selectivity towards branched aldehydes in the hydroformylation of terminal alkenes. This paper describes the synthesis of hitherto unknown unsaturated phospholene borane precursors and their conversion to the corresponding phospholene-phosphites. The relative stereochemistry of one of these ligands and its Pd complex was assigned with the aid of X-ray crystal structure determinations. These ligands were able to approach the level of selectivity observed for phospholane-phosphites in the rhodium-catalysed hydroformylation of propene. High-pressure infra-red (HPIR) spectroscopic monitoring of the catalyst formation revealed that whilst the catalysts showed good thermal stability with respect to fragmentation, the C=C bond in the phospholene moiety was slowly hydrogenated in the presence of rhodium and syngas. The ability of this spectroscopic tool to detect even subtle changes in structure, remotely from the carbonyl ligands, underlines the usefulness of HPIR spectroscopy in hydroformylation catalyst development.

Manganese-Catalyzed Hydrogenation of Amides and Polyurethanes: Is Catalyst Inhibition an Additional Barrier to the Efficient Hydrogenation of Amides and Their Derivatives?

The hydrogenation of amides and other less electrophilic carbonyl derivatives with an N-C=O functionality requires significant improvements in scope and catalytic activity to be a genuinely useful reaction in industry. Here, we report the results of a study that examined whether such reactions are further disadvantaged by nitrogen-containing compounds such as aliphatic amines acting as inhibitors on the catalysts. In this case, an enantiomerically pure manganese catalyst previously established to be efficient in the hydrogenation of ketones, N-aryl-imines, and esters was used as a prototype of a manganese catalyst. This was accomplished by doping a model ester hydrogenation with various nitrogen-containing compounds and monitoring progress. Following from this, a protocol for the catalytic hydrogenation of amides and polyurethanes is described, including the catalytic hydrogenation of an axially chiral amide that resulted in low levels of kinetic resolution. The hypothesis of nitrogen-containing compounds acting as an inhibitor in the catalytic hydrogenation process has also been rationalized by using spectroscopy (high-pressure infrared (IR), nuclear magnetic resonance (NMR)) and mass spectrometry studies.

Rational Design of a Facially Coordinating P,N,N Ligand for Manganese-Catalysed Enantioselective Hydrogenation of Cyclic Ketones.

DFT calculations on the full catalytic cycle for manganese catalysed enantioselective hydrogenation of a selection of ketones have been carried out at the PBE0-D3PCM //RI-BP86PCM level. Mn complexes of an enantiomerically pure chiral P,N,N ligand have been found to be most reactive when adopting a facial coordination mode. The use of a new ligand with an ortho-substituted dimethylamino-pyridine motif has been calculated to completely transform the levels of enantioselectivity possible for the hydrogenation of cyclic ketones relative to the first-generation Mn catalysts. In silico evaluation of substrates has been used to identify those likely to be reduced with high enantiomer ratios (er), and others that would exhibit less selectivity; good agreements were then found in experiments. Various cyclic ketones and some acetophenone derivatives were hydrogenated with er's up to 99 : 1.

Manganese-catalysed transfer hydrogenation of esters.

Manganese catalysed ester reduction using ethanol as a hydrogen transfer agent in place of dihydrogen is reported. High yields can be achieved for a range of substrates using 1 mol% of a Mn(i) catalyst, with an alkoxide promoter. The catalyst is derived from a tridentate P,N,N ligand.

A consecutive process for C-C and C-N bond formation with high enantio-and diastereo-control: direct reductive amination of chiral ketones using hydrogenation catalysts.

High diastereoselectivity was observed in the Rh-catalysed reductive amination of 3-arylcyclohexanones to form tertiary amines. This was incorporated into a one-pot enantioselective conjugate addition and diastereoselective reductive amination, including an example of assisted tandem catalysis.

High iso Aldehyde Selectivity in the Hydroformylation of Short-Chain Alkenes.

The hydroformylation of propene to give predominantly iso-butanal has been achieved; class-leading selectivity is possible even at higher temperatures that deliver fast conversion. Racemic rhodium complexes of bidentate phospholane phosphites derived from tropos-biphenols and unusual solvent systems are the key to the selectivity observed.

A Bifunctional MOF Catalyst Containing Metal-Phosphine and Lewis Acidic Active Sites.

Post-synthetic modification of the hafnium metal-organic framework MOF-808(Hf) to include triarylphosphine ligands is reported. Sulfonated phenylphosphines are incorporated without oxidation to give a "MOF ligand" that can complex late transition metals such as Ir and Rh to give a bifunctional catalyst containing both metal-phosphine complexes and the Lewis acidic framework hafnium metal sites. The metallated phosphine-bearing MOFs act as fully heterogeneous bifunctional catalysts for tandem reductive amination and hydroaminomethylation reactions.

Manganese Catalyzed Hydrogenation of Enantiomerically Pure Esters.

A manganese-catalyzed hydrogenation of esters has been accomplished with TONs up to 1000, using cheap, environmentally benign, potassium carbonate and simple alcohols as activator and solvent, respectively. The weakly basic conditions lead to good functional group tolerance and enable the hydrogenation of enantiomerically enriched α-chiral esters with essentially no loss of stereochemical integrity.

Understanding a Hydroformylation Catalyst that Produces Branched Aldehydes from Alkyl Alkenes.

This paper reports experimental and computational studies on the mechanism of a rhodium-catalyzed hydroformylation that is selective for branched aldehyde products from unbiased alkene substrates. This highly unusual selectivity relies on a phospholane-phosphite ligand prosaically called BOBPHOS. Kinetic studies using in situ high pressure IR (HPIR) and the reaction progress kinetic analysis methodology suggested two steps in the catalytic cycle were involved as turnover determining. Negative order in CO and positive orders in alkene and H2 were found and the effect of hydrogen and carbon monoxide partial pressures on selectivity were measured. Labeling studies found rhodium hydride addition to the alkene to be largely irreversible. Detailed spectroscopic HPIR and NMR characterization of activated rhodium-hydrido dicarbonyl species were carried out. In the absence of H2, reaction of the rhodium-hydrido dicarbonyl with allylbenzene allowed further detailed spectroscopic characterization of four- and five-coordinate rhodium-acyl species. Under single-turnover conditions, the ratios of branched to linear acyl species were preserved in the final ratios of aldehyde products. Theoretical investigations uncovered unexpected stabilizing CH-π interactions between the ligand and substrate which influenced the high branched selectivity by causing potentially low energy pathways to become unproductive. Energy span and degree of TOF control analysis strongly support experimental observations and mechanistic rationale. A three-dimensional quadrant model was built to represent the structural origins of regio- and enantioselectivity.

Diastereoselective and Branched-Aldehyde-Selective Tandem Hydroformylation-Hemiaminal Formation: Synthesis of Functionalized Piperidines and Amino Alcohols.

Starting from readily available allylglycine, a tandem hydroformylation-hemiaminal formation reaction has been developed for the synthesis of chiral functionalized piperidines, with very good diastereoselectivity and branched regioselectivity using Rh/(S,S,S)-BOBPHOS catalysts. Tandem hydroformylation-hemiacetal formation also proceeds with good diastereoselectivity (88:12), with the hemiacetal product being hydrogenated with retention of stereochemistry to give a chiral intermediate used in the synthesis of the new antibiotic nemonoxacin.

A Highly Active Manganese Catalyst for Enantioselective Ketone and Ester Hydrogenation.

A new hydrogenation catalyst based on a manganese complex of a chiral P,N,N ligand has been found to be especially active for the hydrogenation of esters down to 0.1 mol % catalyst loading, and gives up to 97 % ee in the hydrogenation of pro-chiral deactivated ketones at 30-50 °C.

Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity.

In the hydrogenation of sluggish unactivated enamine substrates, Rh complexes of electron-deficient phosphines are demonstrated to be far more reactive catalysts than those derived from triphenylphosphine. These operate at low catalyst loadings (down to 0.01 mol %) and are able to reduce tetrasubstituted enamines. The use of the sustainable and environmentally benign solvent (R)-limonene for the reaction is also reported with the amine isolated by acid extraction.

On the Functional Group Tolerance of Ester Hydrogenation and Polyester Depolymerisation Catalysed by Ruthenium Complexes of Tridentate Aminophosphine Ligands.

The synthesis of a range of phosphine-diamine, phosphine-amino-alcohol, and phosphine-amino-amide ligands and their ruthenium(II) complexes are reported. Five of these were characterised by X-ray crystallography. The activities of this collection of catalysts were initially compared for the hydrogenation of two model ester hydrogenations. Catalyst turnover frequencies up to 2400 h(-1) were observed at 85 °C. However, turnover is slow at near ambient temperatures. By using a phosphine-diamine Ru(II) complex, identified as the most active catalyst, a range of aromatic esters were reduced in high yield. The hydrogenation of alkene-, diene-, and alkyne-functionalised esters was also studied. Substrates with a remote, but reactive terminal alkene substituent could be reduced chemoselectively in the presence of 4-dimethylaminopyridine (DMAP) co-catalyst. The chemoselective reduction of the ester function in conjugated dienoate ethyl sorbate could deliver (2E,4E)-hexa-2,4-dien-1-ol, a precursor to leaf alcohol. The monounsaturated alcohol (E)-hex-4-en-1-ol was produced with reasonable selectivity, but complete chemoselectivity of C=O over the diene is elusive. High chemoselectivity for the reduction of an ester over an alkyne group was observed in the hydrogenation of an alkynoate for the first time. The catalysts were also active in the depolymerisation reduction of samples of waste poly(ethylene terephthalate) (PET) to produce benzene dimethanol. These depolymerisations were found to be poisoned by the ethylene glycol side product, although good yields could still be achieved.

Rapid Asymmetric Transfer Hydroformylation (ATHF) of Disubstituted Alkenes Using Paraformaldehyde as a Syngas Surrogate.

As an alternative to conventional asymmetric hydroformylation (AHF), asymmetric transfer hydroformylation (ATHF) by using formaldehyde as a surrogate for syngas is reported. A catalyst derived from commercially available [Rh(acac)(CO)2 ] (acac=acetylacetonate) and 1,2-bis[(2S,5S)-2,5-diphenylphospholano]ethane(1,5-cyclooctadiene) (Ph-BPE) stands out in terms of both activity and enantioselectivity. Remarkably, not only are high selectivities achievable, the reactions are very simple to perform, and higher enantioselectivity (up to 96 % ee) and/or turnover frequencies than those achievable by using the same catalyst (or other leading catalysts) can be obtained by using typical conditions for AHF.

Mixed-metal MIL-100(Sc,M) (M=Al, Cr, Fe) for Lewis acid catalysis and tandem C-C bond formation and alcohol oxidation.

The trivalent metal cations Al(3+) , Cr(3+) , and Fe(3+) were each introduced, together with Sc(3+) , into MIL-100(Sc,M) solid solutions (M=Al, Cr, Fe) by direct synthesis. The substitution has been confirmed by powder X-ray diffraction (PXRD) and solid-state NMR, UV/Vis, and X-ray absorption (XAS) spectroscopy. Mixed Sc/Fe MIL-100 samples were prepared in which part of the Fe is present as α-Fe2 O3 nanoparticles within the mesoporous cages of the MOF, as shown by XAS, TGA, and PXRD. The catalytic activity of the mixed-metal catalysts in Lewis acid catalysed Friedel-Crafts additions increases with the amount of Sc present, with the attenuating effect of the second metal decreasing in the order Al>Fe>Cr. Mixed-metal Sc,Fe materials give acceptable activity: 40 % Fe incorporation only results in a 20 % decrease in activity over the same reaction time and pure product can still be obtained and filtered off after extended reaction times. Supported α-Fe2 O3 nanoparticles were also active Lewis acid species, although less active than Sc(3+) in trimer sites. The incorporation of Fe(3+) into MIL-100(Sc) imparts activity for oxidation catalysis and tandem catalytic processes (Lewis acid+oxidation) that make use of both catalytically active framework Sc(3+) and Fe(3+) . A procedure for using these mixed-metal heterogeneous catalysts has been developed for making ketones from (hetero)aromatics and a hemiacetal.

Catalytic constructive deoxygenation of lignin-derived phenols: new C-C bond formation processes from imidazole-sulfonates and ether cleavage reactions.

As part of a programme aimed at exploiting lignin as a chemical feedstock for less oxygenated fine chemicals, several catalytic C-C bond forming reactions utilising guaiacol imidazole sulfonate are demonstrated. These include the cross-coupling of a Grignard, a non-toxic cyanide source, a benzoxazole, and nitromethane. A modified Meyers reaction is used to accomplish a second constructive deoxygenation on a benzoxazole functionalised anisole.

Rhodium/phospholane-phosphite catalysts give unusually high regioselectivity in the enantioselective hydroformylation of vinyl arenes.

Using the phospholane-phosphite ligand, BOBPHOS, almost perfect regioselectivities and high enantioselectivities (up to 92% ee) are observed in Rh catalysed enantioselective hydroformylation of vinyl arenes. This can be achieved under solvent-free conditions.

Highly enantioselective hydrogenation and transfer hydrogenation of cycloalkyl and heterocyclic ketones catalysed by an iridium complex of a tridentate phosphine-diamine ligand.

Ir complexes of chiral phosphine-diamine ligands catalyse the hydrogenation and transfer hydrogenation of aryl-piperidin-4-yl methanones, and ketones bearing both an aryl group and secondary alkyl substituent with up to 98% e.e., and with substrate to catalyst ratios of up to 4000.