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Immobilisation of organocatalysts onto solid supports represents a very promising solution to tackle their low productivity by enabling their reuse. Herein, the use of NMR relaxation measurements, coupled with reaction screening, was used to investigate the effect of solvent interactions with the immobilised catalyst matrix on reactivity in an asymmetric organocatalysed aldol reaction. Important insights for the further development of such complex, yet promising catalytic systems are provided.

Oxidative N-heterocyclic carbene (NHC) catalysis offers the chance to perform oxidative and oxygenative transformations which give rise to various NHC-bound intermediates, paving the way to non-umpolung processes through activation of carbon atoms and heteroatoms. The aim of this review is to discuss the developments of the literature in the field of oxidative NHC-catalysis since 2014, with particular focus to pivotal intermediates and their mechanistic involvement. More information can be found in the Review article by C. De Risi and co-workers. (DOI: 10.1002/chem.202202467).

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.

Indole-decorated glycine derivatives are prepared through an environmentally benign cross-dehydrogenative coupling between

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.

The synthesis of hydroxymethylfuroate macrocyclic oligoesters c(HMF)n promoted by an N-heterocyclic carbene (NHC) organocatalyst is herein presented together with the subsequent organocatalytic, entropically- driven ring-opening polymerization (ED-ROP) leading to the fully furan-based poly(hydroxymethylfuroate) (PHMF). The target macrocycles (mostly trimer and tetramer species) have been obtained directly from the platform chemical HMF (77% isolated yield) under high dilution conditions using a quinone as the external oxidant and the green solvent Me-THF. The ED-ROP of c(HMF)n has been optimized at 160 °C (melt condensation technique) with the couple triazabicyclodecene (TBD)/n-octanol (1 : 1) as catalyst/initiator of the polymerization process in the presence of commercial antioxidants Irganox 1010 (0.1% w/w) and Irgafos 126 (0.3% w/w) to suppress degradation side reactions. Under these conditions, the bio-based PHMF (poly-HMF) was obtained as a color-free polymer with number-average molecular weight up to 48 600 g mol−1 and dispersity between 1.5 and 1.9 as determined by NMR and GPC analyses. The thermal behavior of the novel furan-based polyester PHMF was investigated (TGA and DSC analyses) observing a good thermal stability (onset temperature of degradation ∼310 °C) and a semicrystalline structure with melting temperature above 160 °C when processed from solvent, thus making PHMF a promising material for processing as other commercial polyesters.

A series of composite CdS/TiO2 powders was obtained by nucleation of TiO2 on CdS nanoseeds. This combination presents the appropriate band edge position for photocatalytic redox reactions: visible light irradiation of CdS allows the injection of electrons into dark TiO2, increasing the lifetimes of separated charges. The electrons have been used for the quantitative photoreduction of 4-nitrobenzaldehyde to 4-aminobenzaldehyde, whose formation was pointed out by 1H NMR and ESI-MS positive ion mode. Concomitant sacrificial oxidation of 2-propanol, which was also the proton source, occurred. The use of characterization techniques (XRD, N2 adsorption-desorption) evidenced the principal factors driving the photocatalytic reaction: the nanometric size of anatase crystalline domains, the presence of dispersed CdS to form an extended active junction CdS/anatase, and the presence of mesopores as nanoreactors. The result is an efficient photocatalytic system that uses visible light. In addition, the presence of TiO2 in combination with CdS improves the stability of the photoactive material, enabling its recyclability.

2,3-dihydroxy-2-methylbutyric acid, also known as 2,3-dimethylglyceric acid, constitutes the acyl and/or the alcoholic moiety of many bioactive natural esters. Herein, we describe a chemoenzymatic methodology which gives access to all the four possible stereoisomers of the 2,3-dimethylglyceric acid ethyl ester. The racemic ethyl α-acetolactate, produced by the N-heterocycle carbene (NHC)-catalyzed coupling of ethyl pyruvate and methylacetoin was employed as the starting material. The racemic mixture was resolved through (S)-selective reductions, promoted by the acetylacetoin reductase (AAR) affording the resulting ethyl (2R,3S)-2,3-dimethylglycerate; the isolated remaining (S)-ethyl α-acetolactate was successively treated with baker’s yeast to obtain the corresponding (2S,3S) stereoisomer. syn-2,3-Dimethylgliceric acid ethyl ester afforded by reducing the rac-α-acetolactate with NaBH4 in the presence of ZnCl2 was kinetically resolved through selective acetylation with lipase B from Candida antarctica (CAL-B) and vinyl acetate to access to (2S,3R) stereoisomer. Finally, the (2R,3R) stereoisomer, was prepared by C3 epimerization of the (2R,3S) stereoisomer recovered from the above kinetic resolution, achieved through the TEMPO-mediated oxidation, followed by the reduction of the produced ketone with NaBH4. The resulting 2,3-dimethylglycertate enriched in the (2R,3R) stereoisomer was submitted to stereospecicific acetylation with vinyl acetate and CAL-B in order to separate the major stereoisomer. The entire procedure enabled conversion of the racemic α-acetolactate into the four enantiopure stereoisomers of the ethyl 2,3-dihydroxy-2-methylbutyrate with the following overall yields: 42% for the (2R,3S), 40% for the (2S,3S), 42% for the (2S,3R) and 20% for the (2R,3R).

A new 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 catalytic 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-poor 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.

Deep eutectic solvents (DESs) have emerged as an alternative to ionic liquids (ILs). DESs share with ILs some appealing features, such as low vapor pressure, capability to dissolve reagents insoluble in common organic solvents, and the possibility to tune the overall pH of the medium by replacing one of the constituents of the mixture. Furthermore, DESs can be prepared by combining molecules that come from natural sources (i.e., glycerol, glucose), making them biodegradable. DESs have already been used for a variety of reactions and protocols since they were reported for the first time by A. P. Abbott, G. Capper, D. L. Davies, R. K. Rasheed and V. Tambyrajah, Chem. Commun., 2003, 70, and among the reactions studied, organic oxidation has recently gained much attention. In particular, the recyclability of these ionic compounds makes it possible to achieve anchoring of organic oxidants, such as TEMPO and peroxydisulfate, directly onto one species of the DES mixture components. In addition, their solubility properties play a crucial role in organic oxidation since DESs have the ability to dissolve both organic lipophilic and hydrophilic species, making the oxidation of organic compounds mediated by hydrogen peroxide more efficient. Herein we report the state of the art of this developing field, focusing on the benefits of substituting common organic solvents with DESs, especially in terms of sustainability, enhancement of reactivity, and recyclability.

A strategy for the immobilization of chiral 2,3-bisaminocyclopropenium salt (pre-catalyst) onto polystyrene and silica supports is presented together with a suitable procedure for the conversion into the corresponding cyclopropenimine superbase catalysts. The activity and recyclability of polystyrene- and silica-supported cyclopropenimines were initially tested under batch conditions in a model Michael addition detecting comparable efficiencies but a superior stability of the latter heterogeneous catalyst (5 cycles, accumulated TON of 27.1). The preferred silica-supported cyclopropenimine behaved very similarly to the soluble counterpart in the reaction of glycine imine with different Michael acceptors (48-92% yield; 60-98% ee) and it could be utilized as packing material for the fabrication of fixed-bed mesoreactors (pressure-resistant stainless-steel columns). Continuous-flow experiments were performed with satisfactory long-term stability (24 h on stream) with unaltered conversion efficiency and enantioselectivity.

In-depth analysis of structure/activity relationship aids rational design of modified carbon nitride for organophotocatalysis., 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.

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.

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.

Chemistry in continuous-flow continues to attract attention from the community of synthetic organic chemists due to its now well-recognized benefits including, inter alia, quick reaction times, operational safety, rapid reaction screening/optimization, enhanced automation with possible addition of in-line reaction analysis, and easy scalability. Coupling of flow chemistry to enabling technologies (e.g. unconventional solvents, supported reagents or catalysts, microwave irradiation, photochemistry, inductive heating, microreactors) as well as to additive manufacturing (AM) technologies (i.e. 3D printing) gives additional advantages for throughput and automation, and besides this, unique opportunities are offered by compartmentalization, that allows multistep syntheses to occur reconciling incompatible reaction conditions. Based on all this, continuous-flow may itself be seen as an enabling technology which leads in the direction of process intensification meeting increasingly pressing sustainability issues (e.g. waste minimization, cost/energy reduction). As part of flow chemistry, organocatalysis represents an active research area under which there is large opportunity for re-optimizing long-standing reactions or inventing new transformations. Both homogeneous (soluble) and heterogeneous (insoluble) organic molecules have been used as catalysts for continuous-flow processing in either achiral or asymmetric fashion, any issue inherent to a homogeneous approach (high catalyst loading, difficult catalyst separation) being typically overcome with the use of heterogenized organocatalysts. This review is aimed at covering the progresses on organocatalysis in continuous-flow from 2016 to early 2020, with special attention paid to the comparison between batch and flow processes for each discussed transformation to substantiate the potential of flow technology for process intensification.

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 T 1 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 T 1 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., Solvent interactions may significantly affect homogeneous catalytic reactions. NMR relaxation and diffusion techniques can probe solvent dynamics, interactions, and aggregation in those systems, thus helping to assess their impact on the catalytic performance and rationalize solvent selection for a specific process.

The corrosion protection of coatings can be reinforced by the addition of entrapped corrosion inhibitors. &beta, cyclodextrin (&beta, CD) can form inclusion complexes with small inhibiting organic molecules that, when entrapped in coatings, allow the inhibitor release and adsorption at corrosion initiation sites. In this paper, several Nuclear Magnetic Resonance (NMR)-based experiments (e.g., Complexation-Induced Shifts (CIS), NMR titration, Diffusion-Ordered Spectroscopy (DOSY)) were performed to study the stability and geometry of a complex formed by &beta, cyclodextrin with 5-mercapto-1-phenyl-tetrazole (MPT). The complex was also detected by Electrospray Ionization (ESI) mass spectrometry and characterized by Fourier Transform Infrared (FTIR) spectra. Its influence on the protectiveness of a silane coating against bronze corrosion was evaluated in plain (AR) and concentrated (ARX10) synthetic acid rain, under different exposure conditions. In particular, the time evolution of the polarization resistance values during 20 days in ARX10 and the polarization curves recorded at the end of the immersions evidenced a higher protectiveness of the coating with the &beta, CD&ndash, MPT complex in comparison to that containing only MPT or only &beta, CD. The cyclic AR spray test carried out on coated bronze coupons with cross-cut scratches evidenced the absence of underfilm corrosion starting from the scratches only in the complex-containing coating.

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.

N-Heterocyclic carbenes (NHCs) are now well-established organocatalysts for a large number of asymmetric and non-asymmetric transformations. In the last 15 years, there has been significant interest in using NHCs in kinetic resolution (KR), dynamic kinetic resolution (DKR) and asymmetric desymmetrization reactions for the stereoselective synthesis of enantioenriched compounds, with diverse substrates and activation modes being adopted to this end. This short review brings into focus the progress made on NHC-catalyzed KR, DKR, and asymmetric desymmetrization from 2004 until December 2018. The literature discussed in this article is classified on the basis of the type of reaction involving the NHC catalyst.1 Introduction2 Acylation Strategies2.1 O-Acylation2.2 N-Acylation2.3 C-Acylation3 Aldol-Acylation Processes4 Benzoin Reactions5 Stetter Reactions6 Miscellaneous Approaches7 Conclusion

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.

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.

The design and synthesis of a set of supported azolium salt pre-catalysts is presented along with their utilization in the production of monoesters of glycerol and solketal by oxidative N-heterocyclic carbene (NHC)-catalysis through batch and continuous-flow approaches. After a propaedeutic study with soluble NHCs, the heterogeneous analogues (silica and polystyrene supports) were tested in a model monoesterification of glycerol using either the Kharasch oxidant or air (in the presence of electron transfer mediators) as the terminal oxidants. The best performing polystyrene-supported triazolium salt pre-catalyst afforded monoacylglycerols (MAGs) in high yields (up to 95%) and almost complete selectivity (monoester/diester >95 : 5) using air and the green solvent Me-THF. The synthesis of fully bio-based MAGs from furfural, 5-hydroxymethylfurfural (HMF), citronellal, and vanillin is also reported. Continuous-flow experiments have been finally performed by fabricating the corresponding packed-bed microreactor, which could be operated for ca. 120 hours with maintenance of conversion efficiency and selectivity.

A strategy for the synthesis of biologically relevant 5-hydroxy-imidazolidine-2-thione derivatives is presented. A novel class of α-sulfonylamines have been suitably prepared (46–81% yield) as precursors of formal benzylidenethiourea acceptors; these are generated in situ and intercepted by N-heterocyclic carbene (NHC)-activated aldehydes affording open-chain aza-benzoin-type adducts, which in turn undergo an intramolecular aza-acetalization reaction in a one-pot fashion. A thiazolium salt/triethylamine couple proved to be the more effective system to trigger the domino sequence giving the target heterocycles in good yields (45–97%) and diastereoselectivities (up to 99 : 1 dr). The multigram scale synthesis and elaboration of a selected 5-hydroxy-imidazolidine-2-thione compound is also described.

A strategy for the immobilization of the valuable triazolium carbene Rovis catalyst onto polystyrene and silica supports is presented. Initially, the catalyst activity and recyclability were tested under batch conditions in the model stereoselective intramolecular Stetter reaction leading to optically active chromanones. Good results in terms of yield (95%) and enantioselectivity (ee 81–95%) were detected for the polystyrene-supported catalyst (10 mol %), while poorer results were collected for the silica-supported analogue. Also, continuous-flow experiments were performed by fabricating the corresponding polystyrene monolithic microreactors (pressure-resistant stainless-steel columns) to prove the benefits of the heterogeneous catalysis and the flow regime observing a high stability of the catalytic bed (48 h) with unaltered conversion efficiency and stereoselectivity.

A convenient heterogeneous continuous-flow procedure for the polarity reversal of aromatic α-diketones is presented. Propaedeutic batch experiments have been initially performed to select the optimal supported base capable to initiate the two electron-transfer process from the carbamoyl anion of the N,N-dimethylformamide (DMF) solvent to the α-diketone and generate the corresponding enediolate active species. After having identified the 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene (PS-BEMP) as the suitable base, packed-bed microreactors (pressure-resistant stainless-steel columns) have been fabricated and operated to accomplish the chemoselective synthesis of aroylated α-hydroxy ketones and 2-benzoyl-1,4-diones (benzoin- and Stetter-like products, respectively) with a good level of efficiency and with a long-term stability of the packing material (up to five days).

The condensation of aromatic alpha-diketones (benzils) with aromatic aldehydes ( benzoin-type reaction) and chalcones ( Stetter-type reaction) in DMF in the presence of catalytic ( 25 mol%) KOtBu is reported. Both types of umpolung processes proceed with good efficiency and complete chemoselectivity. On the basis of spectroscopic evidence ( MS analysis) of plausible intermediates and literature reports, the occurrence of different ionic pathways have been evaluated to elucidate the mechanism of a model cross-benzoinlike reaction along with a radical route initiated by an electron-transfer process to benzil from the carbamoyl anion derived from DMF. This mechanistic investigation has culminated in a different proposal, supported by calculations and a trapping experiment, based on double electron-transfer to benzil with formation of the corresponding enediolate anion as the key reactive intermediate. A mechanistic comparison between the activation modes of benzils in KOtBu-DMF and KOtBu-DMSO systems is also described.