Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow.

Within the realm of organic synthesis, photocatalysis has blossomed since the beginning of the last decade. A plethora of classical reactivities, such as selective oxidation of alcohol and amines, redox radical formation of reactive species in situ, and indirect activation of an organic substrate for cycloaddition by EnT, have been revised in a milder and more sustainable fashion via photocatalysis. However, even though the spark of creativity leads scientists to explore new reactions and reactivities, the urgency of replacing the toxic and critical metals that are involved as catalysts has encouraged chemists to find alternatives in the branch of science called organocatalysis. Unfortunately, replacing metal catalysts with organic analogues can be too expensive sometimes; however, this drawback can be solved by the reutilization of the catalyst if it is heterogeneous. The aim of this review is to present the recent works in the field of heterogeneous photocatalysis, applied to organic synthesis, enabled by continuous flow. In detail, among the heterogeneous catalysts, g-CN, polymeric photoactive materials, and supported molecular catalysts have been discussed within their specific sections, rather than focusing on the types of reactions.

Heterogenised catalysts for the H-transfer reduction reaction of aldehydes: influence of solvent and solvation effects on reaction performances.

Heterogenisation of homogeneous catalysts onto solid supports represents a potential strategy to make the homogeneous catalytic function recyclable and reuseable. Yet, it is usually the case that immobilised catalysts have much lower catalytic activity than their homogeneous counterpart. In addition, the presence of a solid interface introduces a higher degree of complexity by modulating solid/fluid interactions, which can often influence adsorption properties of solvents and reactive species and, ultimately, catalytic activity. In this work, the influence of support and solvent in the H-transfer reduction of propionaldehyde over Al(OiPr)3-SiO2, Al(OiPr)3-TiO2 and Al(OiPr)3-Al2O3 heterogenised catalysts has been studied. Reaction studies are coupled with both NMR relaxation measurements as well as molecular dynamics (MD) simulations in order to unravel surface and solvation effects during the reaction. The results show that, whilst the choice of the support does not influence significantly catalytic activity, reactions carried out in solvents with high affinity for the catalyst surface, or able to hinder access to active sites due to solvation effects, have a lower activity. MD calculations provide key insights into bulk solvation effects involved in such reactions, which are thought to play an important role in determining the catalytic behaviour. The activity of the heterogenised catalysts was found to be comparable with that of the homogeneous Al(OiPr)3 catalysts for all supports used, showing that for the type of reaction studied immobilisation of the homogeneous catalyst onto solid supports is a viable, robust and effective strategy.

Modulable Photocatalyzed Strategies for the Synthesis of α-C-Glycosyl Alanine Analogues via the Giese Reaction with Dehydroalanine Derivates.

Herein, we present the α-selective Giese reaction between pyranosyl/furanosyl bromides and dehydroalanine analogues, which provides access to a library of highly valuable α-C-glycosyl alanines. The key C-glycosyl radical is generated through photocatalysis by either the new generation copper(I) complex [(DPEPhos)(bcp)Cu]PF6 or [Ru(bpy)3](BF4)2. The reactions proceed smoothly, affording the desired α-C-glycosyl alanines in up to 99% yield when diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate [Hantzsch ester (HE)] is used as an additive. N,N-Diisopropylethylamine (DIPEA) has been selected as a reductant in both protocols. A mechanistic study by means of transient absorption spectroscopy unveils a halogen-atom transfer (XAT) process in C-glycosyl radical formation.

Humin Formation on SBA-15-pr-SO3H Catalysts during the Alcoholysis of Furfuryl Alcohol to Ethyl Levulinate: Effect of Pore Size on Catalyst Stability, Transport, and Adsorption.

Herein, the alcoholysis of furfuryl alcohol in a series of SBA-15-pr-SO3H catalysts with different pore sizes is reported. Elemental analysis and NMR relaxation/diffusion methods show that changes in pore size have a significant effect on catalyst activity and durability. In particular, the decrease in catalyst activity after catalyst reuse is mainly due to carbonaceous deposition, whereas leaching of sulfonic acid groups is not significant. This effect is more pronounced in the largest-pore-size catalyst C3, which rapidly deactivates after one reaction cycle, whereas catalysts with a relatively medium and small average pore size (named, respectively, C2 and C1) deactivate after two reaction cycles and to a lesser extent. CHNS elemental analysis showed that C1 and C3 experience a similar amount of carbonaceous deposition, suggesting that the increased reusability of the small-pore-size catalyst can be attributed to the presence of SO3H groups mostly present on the external surface, as corroborated by results on pore clogging obtained by NMR relaxation measurements. The increased reusability of the C2 catalyst is attributed to a lower amount of humin being formed and, at the same time, reduced pore clogging, which helps to maintain accessible the internal pore space.

Oxidative NHC Catalysis: An Unconventional Tool for Macrocyclic Oligoesters Synthesis.

The application of N-heterocyclic carbene (NHC) catalysis under highly diluted oxidative condition to the polycondensation of dialdehydes and diols is herein presented as an alternative, atom-economical synthetic route to macrocyclic oligoesters (MCOs). The disclosed protocol paves the way to the straightforward access to MCOs, starting from commercial dialdehydes, avoiding the use of toxic diacyl chlorides, commonly employed in traditional MCOs synthetic processes. The method is totally metal-free, takes place in the green Me-THF solvent and requires the use of a fully recyclable quinone oxidant. The protocol versatility is confirmed by the employment of fossil-based and bio-based monomers such as 2,5-diformylfuran (DFF), 2,5-bis(hydroxymethyl)furan (BHMF), and isomannide, synthesizing a series of novel and known synthetically relevant macrocyclic oligoesters, fully characterized by NMR and MALDI-TOF MS analysis, with product yields (51-86 %) comparable to those obtained by traditional synthetic routes. Finally, to emphasize the synthetic relevance of the target macrocycles, an entropically-driven ring opening polymerization (ED-ROP) key study has been performed, optimizing the organocatalyzed synthesis of poly(2,5-furan-dimethylene 2,5 furandicarboxylate) (PBHMF) with number-average molecular weight up to 8200 g mol-1 and 66 % isolated yield.

Efficiency in Carbon Dioxide Fixation into Cyclic Carbonates: Operating Bifunctional Polyhydroxylated Pyridinium Organocatalysts in Segmented Flow Conditions.

Novel polyhydroxylated ammonium, imidazolium, and pyridinium salt organocatalysts were prepared through N-alkylation sequences using glycidol as the key precursor. The most active pyridinium iodide catalyst effectively promoted the carbonation of a set of terminal epoxides (80 to >95% yields) at a low catalyst loading (5 mol%), ambient pressure of CO2, and moderate temperature (75 °C) in batch operations, also demonstrating high recyclability and simple downstream separation from the reaction mixture. Moving from batch to segmented flow conditions with the operation of thermostated (75 °C) and pressurized (8.5 atm) home-made reactors significantly reduced the process time (from hours to seconds), increasing the process productivity up to 20.1 mmol(product) h-1 mmol(cat)-1, a value ~17 times higher than that in batch mode.

Oxidative N-Heterocyclic Carbene Catalysis.

N-Heterocyclic carbene (NHC) catalysis is a by now consolidated organocatalytic platform for a number of synthetic (asymmetric) transformations via diverse reaction modes/intermediates. In addition to the typical umpolung processes involving acyl anion/homoenolate equivalent species, implementation of protocols under oxidative conditions greatly expands the possibilities of this methodology. Oxidative NHC-catalysis allows for oxidative and oxygenative transformations through specific manipulations of Breslow-type species depending upon the oxidant used (external oxidant or O2 /air), the derived NHC-bound intermediates paving the way to non-umpolung processes through activation of carbon atoms and heteroatoms. This review is intended to update the state of the art in oxidative NHC-catalyzed reactions that appeared in the literature from 2014 to present, with a strong focus to crucial intermediates and their mechanistic implications.

Activity and stability studies of H-transfer reduction reactions of aldehydes and ketones over aluminium isopropoxide heterogenised catalysts.

Aluminium isopropoxide Al(OiPr)3 immobilised on various mesoporous supports (SiO2, TiO2 and γ-Al2O3) was tested for H-transfer reductions of various aldehydes and ketones in the presence of 2-propanol as a sacrificial agent. The heterogenised catalysts were characterised by N2 physisorption, XRD, SEM-EDX, FTIR and ICP-OES. The characterisation results show a successful grafting of the homogeneous aluminium isopropoxide catalyst, covalently bound to the solid surface, with high dispersion over the mesoporous supports. The heterogenised catalysts show an excellent catalytic activity with high selectivity towards the desired alcohol product, with performances that are comparable with those of the homogeneous Al(OiPr)3 catalyst. Al(OiPr)3 grafted on SiO2 shows higher activity compared to γ-Al2O3 and TiO2 supported catalysts. The catalysts remain very active after 5 cycles of reuse and no leached Al(OiPr)3 was found in the reaction mixture, hence showing an excellent stability. The work reported here shows that it is possible to effectively immobilise catalytic functions, usually working in the homogeneous phase, over solid supports, with the resulting heterogenised catalysts keeping the same catalytic activity of the homogeneous counterpart and excellent stability, and with the advantage of being able to recycle and reuse them, without loss of catalytic materials.

Synergistic Strategies in Aminocatalysis.

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.

Photoredox Cross-Dehydrogenative Coupling of N-Aryl Glycines Mediated by Mesoporous Graphitic Carbon Nitride: An Environmentally Friendly Approach to the Synthesis of Non-Proteinogenic α-Amino Acids (NPAAs) Decorated with Indoles.

Indole-decorated glycine derivatives are prepared through an environmentally benign cross-dehydrogenative coupling between N-aryl glycine analogues and indoles (yield of ≤81%). Merging heterogeneous organocatalysis and photocatalysis, C-H functionalization has been achieved by selective C-2 oxidation of N-aryl glycines to afford the electrophilic imine followed by Friedel-Crafts alkylation with indole. The sustainability of the process has been taken into account in the reaction design through the implementation of a metal-free recyclable heterogeneous photocatalyst and a green reaction medium. Scale-up of the benchmark reaction (gram scale, yield of 69%) and recycling experiments (over seven runs without a loss of efficiency) have been performed to prove the robustness of the protocol. Finally, mechanistic studies were conducted employing electron paramagnetic resonance spectroscopy to unveil the roles of the photocatalyst and oxygen in the formation of odd-electron species.

General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides and Lactams.

An iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3 + 2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using 1 mol% Vaska's complex [IrCl(CO)(PPh3)2] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent regio- and diastereoselective, inter- and intramolecular dipolar cycloaddition reactions with variously substituted electron-deficient alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures, which ultimately control the unusual selectivities observed in certain cases.

Exploring Oxidative NHC-Catalysis as Organocatalytic Polymerization Strategy towards Polyamide Oligomers.

The polycondensation of diamines and dialdehydes promoted by an N-heterocyclic carbene (NHC) catalyst in the presence of a quinone oxidant and hexafluoro-2-propanol (HFIP) is herein presented for the synthesis of oligomeric polyamides (PAs), which are obtained with a number-average molecular weight (Mn ) in the range of 1.7-3.6 kg mol-1 as determined by NMR analysis. In particular, the utilization of furanic dialdehyde monomers (2,5-diformylfuran, DFF; 5,5'-[oxybis(methylene)]bis[2-furaldehyde], OBFA) to access known and previously unreported biobased PAs is illustrated. The synthesis of higher molecular weight PAs (poly(decamethylene terephthalamide, PA10T, Mn = 62.8 kg mol-1 ; poly(decamethylene 2,5-furandicarboxylamide, PA10F, Mn = 6.5 kg mol-1 ) by a two-step polycondensation approach is also described. The thermal properties (TGA and DSC analyses) of the synthesized PAs are reported.

Light-driven, heterogeneous organocatalysts for C-C bond formation toward valuable perfluoroalkylated intermediates.

The favorable exploitation of carbon nitride (CN) materials in photocatalysis for organic synthesis requires the appropriate fine-tuning of the CN structure. Here, we present a deep investigation of the structure/activity relationship of CN in the photocatalytic perfluoroalkylation of organic compounds. Four types of CN bearing subtle structural differences were studied via conventional characterization techniques and innovative nuclear magnetic resonance (NMR) experiments, correlating the different structures with the fundamental mechanistic nexus and especially highlighting the importance of the halogen bond strength between the reagent and the catalyst surface. The optimum catalyst exhibited an excellent performance, with a very wide reaction scope, and could prominently trigger the model reaction using natural sunlight. The work lays a platform for establishing a new approach in the development of heterogeneous photocatalysts for organic synthesis related to medical, agricultural, and material chemistry.

Oxidative Coupling of Aldehydes with Alcohol for the Synthesis of Esters Promoted by Polystyrene-Supported N-Heterocyclic Carbene: Unraveling the Solvent Effect on the Catalyst Behavior Using NMR Relaxation.

Heterogeneous organocatalysts hold great potential as they offer practical advantages in terms of purification and reusability compared with the homogeneous counterpart. A puzzling aspect is the solvent effect on their catalytic performance. Here we propose a new approach whereby T1/T2 NMR relaxation measurements are used to evaluate the strength of solvent-surface interactions in the polystyrene-supported N-heterocyclic carbene-promoted oxidation of aldehydes. The results reveal that solvents with high surface affinity lead to a decrease in catalyst activity.

Solvent Effects in the Homogeneous Catalytic Reduction of Propionaldehyde with Aluminium Isopropoxide Catalyst: New Insights from PFG NMR and NMR Relaxation Studies.

Solvent effects in homogeneous catalysis are known to affect catalytic activity. Whilst these effects are often described using qualitative features, such as Kamlet-Taft parameters, experimental tools able to quantify and reveal in more depth such effects have remained unexplored. In this work, PFG NMR diffusion and T1 relaxation measurements have been carried out to probe solvent effects in the homogeneous catalytic reduction of propionaldehyde to 1-propanol in the presence of aluminium isopropoxide catalyst. Using data on diffusion coefficients it was possible to estimate trends in aggregation of different solvents. The results show that solvents with a high hydrogen-bond accepting ability, such as ethers, tend to form larger aggregates, which slow down the molecular dynamics of aldehyde molecules, as also suggested by T1 measurements, and preventing their access to the catalytic sites, which results in the observed decrease of catalytic activity. Conversely, weakly interacting solvents, such as alkanes, do not lead to the formation of such aggregates, hence allowing easy access of the aldehyde molecules to the catalytic sites, resulting in higher catalytic activity. The work reported here is a clear example on how combining traditional catalyst screening in homogeneous catalysis with NMR diffusion and relaxation time measurements can lead to new physico-chemical insights into such systems by providing data able to quantify aggregation phenomena and molecular dynamics.

Oxidative NHC-Catalysis as Organocatalytic Platform for the Synthesis of Polyester Oligomers by Step-Growth Polymerization.

The application of N-heterocyclic carbene (NHC) catalysis to the polycondensation of diols and dialdehydes under oxidative conditions is herein presented for the synthesis of polyesters using fossil-based (ethylene glycol, phthalaldehydes) and bio-based (furan derivatives, glycerol, isosorbide) monomers. The catalytic dimethyl triazolium/1,8-diazabicyclo[5.4.0]undec-7-ene couple and stoichiometric quinone oxidant afforded polyester oligomers with a number-average molecular weight (Mn ) in the range of 1.5-7.8 kg mol-1 as determined by NMR analysis. The synthesis of a higher molecular weight polyester (polyethylene terephthalate, PET) by an NHC-promoted two-step procedure via oligoester intermediates is also illustrated together with the catalyst-controlled preparation of cross-linked or linear polyesters derived from the trifunctional glycerol. The thermal properties (TGA and DSC analyses) of the synthesized oligoesters are also reported.

Enantioselective Desymmetrization of 1,4-Dihydropyridines by Oxidative NHC Catalysis.

The unprecedented desymmetrization of prochiral dialdehydes catalyzed by N-heterocyclic carbenes under oxidative conditions was applied to the highly enantioselective synthesis of 1,4-dihydropyridines (DHPs) starting from 3,5-dicarbaldehyde substrates. Synthetic elaboration of the resulting 5-formyl-1,4-DHP-3-carboxylates allowed for access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates (Hantzsch esters). DFT calculations suggested that the enantioselectivity of the process is determined by the transition state involving the oxidation of the Breslow intermediate by the external quinone oxidant.

Enzymatic synthesis of biobased aliphatic-aromatic oligoesters using 5,5'-bis(hydroxymethyl)furoin as a building block.

5,5'-Dihydroxymethyl furoin (DHMF) is a novel biobased difuranic polyol scaffold, achievable from the benzoin condensation of 5-hydroxymethylfurfural (HMF), which has recently been employed as a monomer for the preparation of cross-linked polyesters and polyurethane. Its upgrading by means of enzymatic reactions has not yet been reported. Here we demonstrated that Candida antarctica lipase B (CALB) is a suitable biocatalyst for the selective esterification of the primary hydroxyl groups of DHMF. Exploiting this enzymatic activity, DHMF has been reacted with the diethyl esters of succinic and sebacic acids obtaining fully biobased linear oligoesters with number-average molecular weight around 1000 g mol-1 and free hydroxyl groups on the polymer backbone. The structures of the DHMF-diacid ethyl ester dimers and of the oligomers were elucidated by NMR and MS analyses.

Aerobic oxidation of 5-hydroxymethylfurfural to 5-hydroxymethyl-2-furancarboxylic acid and its derivatives by heterogeneous NHC-catalysis.

The application of the oxidative system composed of a heterogeneous triazolium pre-catalyst, iron(ii) phthalocyanine and air is described for the selective conversion of 5-hydroxymethylfurfural (HMF) into the added-value 5-hydroxymethyl-2-furancarboxylic acid (HMFCA). The disclosed one-pot two-step procedure involved sequential oxidative esterifications of HMF to afford a polyester oligomer having hydroxyl and carboxyl terminal groups (Mw = 389-1258), which in turn was hydrolyzed by a supported base (Ambersep 900 OH) to yield HMFCA in 87% overall yield. The same strategy was adopted for the effective synthesis of ester and amide derivatives of HMFCA by nucleophilic depolymerization of the oligomeric intermediate with methanol and butylamine, respectively. The utilization of the disclosed oxidative system for the direct conversion of HMF and furfural into their corresponding ester, amide, and thioester derivatives is also reported.

Enantioselective Dearomatization of Alkylpyridiniums by N-Heterocyclic Carbene-Catalyzed Nucleophilic Acylation.

A chiral NHC-catalyzed dearomatizing reaction of activated N-alkylpyridinium salts with aliphatic aldehydes is described. The resulting acylated 1,4-dihydropyridines have been obtained with complete C4 regioselectivity and enantioselectivities in the range 52-78% ee. The (4R)-absolute configuration of the synthesized compounds has been determined by the TD-DFT simulation of the electronic circular dichroism spectra.