Aqueous Aldol Reaction Research Articles

A Pyrrolidine Functionalized Poly[(Ethylene Glycol) Methacrylate] Resin as a Heterogeneous Catalyst for Aqueous Aldol Reactions

The development of a performant aminated catalyst for aldol condensations requires the combined tuning of the active site, support and solvent system. For this purpose, a pyrrolidine group was immobilized on a swellable polymer resin. Favorable interactions between the support and water (in its role as solvent) resulted in a turnover frequency (TOF) amounting to 3.0 ± 1.5 × 10−3 s−1, despite potential inhibition of the active sites by formation of iminium species. The affinity of the solvent for the poly[(ethylene glycol) methacrylate] support resulted in efficient swelling of the catalytic material, which was shown to be key to the observed catalytic performance.

Biomass waste-derived recyclable heterogeneous catalyst for aqueous aldol reaction and depolymerization of PET waste

Eco-friendly biomass waste-derived recyclable heterogeneous catalyst for aldol reaction in water and for methanolysis of PET waste.

Aminated poly(ethylene glycol) methacrylate resins as stable heterogeneous catalysts for the aldol reaction in water

Amine functionalized silicas have frequently been investigated as potential aldol reaction catalysts. However, active site leaching due to hydrolysis cannot be avoided, limiting the long-term stability of these catalysts in aqueous aldol reactions. Therefore, novel catalysts based on an organic resin have been developed starting from a suspension polymerized poly(ethylene glycol) methacrylate (PEGMA) hydrogel with poly(ethylene glycol) dimethacrylate (PEGDMA) as cross-linker. Amine functionalization was performed by chlorination of the terminal hydroxyl groups in the resulting PEGMA resin and subsequent nucleophilic substitution with an amine precursor, i.e., ethylenediamine (EDA), N,N′-dimethylethylenediamine (DED), or methylamine (MA). The successful synthesis of the catalysts was confirmed by 13C NMR, FT-IR, and elemental CHN analysis. Performance evaluation in a batch reactor for the aqueous aldol reaction of acetone with 4-nitrobenzaldehyde resulted in a turnover frequency (TOF) of the PEGMA-EDA catalyst amounting to 6.3 ± 0.4 · 10−4 s−1, which is of the same order of magnitude as that of the corresponding state-of-the-art amine functionalized silica evaluated using hexane as solvent. The PEGMA-DED catalyst exhibited a somewhat lower TOF of 3.1 ± 0.2 · 10−4 s−1, while the PEGMA-MA catalyst did not exhibit any turnover, indicating that the secondary amine in the backbone of the active site in the PEGMA-EDA catalyst is inactive. Continuous-flow evaluation of the PEGMA-EDA catalyst in a packed-bed reactor indicated that, as opposed to a primary amine functionalized silica catalyst, a stable catalytic activity as a function of time on stream could be achieved for at least 8 h and, hence, that no deactivation has occurred in this timeframe.

Novel amphiphilic poly(2-oxazoline)s bearing l-prolinamide moieties as the pendants: Synthesis, micellization and catalytic activity in aqueous aldol reaction

Abstract Novel amphiphilic poly(2-oxazoline)s bearing l -prolinamide moieties at the alkyl side-chain termini were designed and synthesized by a bottom-up protocol. These polymers formed micelle-type assemblies with a size of 10–30 nm in water, in which the majority of prolinamide active groups was tucked into the hydrophobic inner core. As a nanoreactor, the micellar systems were successfully applied to the direct asymmetric aldol reaction in aqueous media. The results demonstrated that the polymer-bound prolinamide catalysts show a significant improvement in catalytic efficiency when compared with their monomeric counterpart and non-amphiphilic reference polymer, affording the anti-product with a moderate stereoselectivity in the representative aldol addition of cyclohexanone to p -nitrobenzaldehyde. Additionally, the poly(2-oxazoline) derivatives can also promote effectively the reactions of tetrahydro-4 H -pyran-4-one or cyclopentanone donors to give the corresponding aldol adducts in high yield and with good diastereo- and enantioselectivities.

Aqueous asymmetric aldol reactions in polymersome membranes

A high-yielding enantioselective aqueous aldol reaction is carried out in the membrane of polymersome nanoreactors.

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio­selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

N-Tosyl-(S a)-binam- l -prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo- and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.

ChemInform Abstract: Neighboring Heteroatom Effect Unique to Aqueous Aldol Reactions of Water‐Insoluble Substrates.

AbstractThis describes a series of high‐yielding aqueous aldol reactions, some of them unachievable in organic solvents.

Neighboring Heteroatom Effect Unique to Aqueous Aldol Reactions of Water-Insoluble Substrates

The reactions of ketones and aldehydes in the presence of Li(+) and in the presence or absence of PTC mediated by water were performed to produce aldol products. Several advantages of the aqueous reactions over organic solvent-mediated ones have been demonstrated including higher yields, shorter reaction times, simpler purifications, and better functional group tolerance. Some reactions that do not take place in organic solvents have been realized in water. The successes are attributed to the neighboring heteroatom effect. In the aqueous aldol condensations, Li2CO3 was an efficient catalyst, and therefore base-liable groups such as epoxides, esters, and silyl groups could survive. For heteroaromatic ethanones, the aqueous aldol reactions were accomplished without PTC to give β-hydroxyketones in good yields. The water-mediated condensations of aldosyl hemiacetals with aromatic ketones led to a new carbohydrate-derived skeleton in quantitative yields. To some extent, this research has expanded the applicablities of aldol condensations and reactions.

Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids

N-Tosyl-(Sa)-binam-L-prolinamide is an efficient catalyst for the aqueous aldol reaction, between glyoxylic acid, as monohydrate or aqueous solution, and ketones. This reaction led to the formation of chiral α-hydroxy-γ-keto carboxylic acids in high levels of diastereo- and enantioselectivities achieving mainly anti aldol products.

A DFT study of the origins of the stereoselectivity in the aldol reaction of bicyclic amino ketones in the presence of water

Experimental diastereoselectivities of the direct solvent-less (neat) aldol reactions of tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) and granatanone (pseudopelletierine, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one) in the presence of catalytic amounts of water are most accurately reproduced by thermodynamic distributions of isomeric products calculated in the gas phase at the B3LYP/6-31g(d) level of theory. Less than 30% systematic errors, on average, exist in the predicted anti/syn-diastereomeric ratio (dr) for the solvent-less reaction of tropinone with several aromatic aldehydes. The CPCM-B3LYP/6-31g(d) method reproduces the anti/syn-diastereomeric ratio of the aqueous aldol reaction of tropinone with several aromatic aldehydes with reasonable deviation (0–88%), excellent (0–10)% agreement was found for the reactions of tropinone and granatanone with benzaldehyde. Qualitatively satisfactory agreement was also found for dr values in different solvents (DMF, THF, and Et3N). The density functional theory (DFT) results support the notion of the thermodynamic control of the reaction.

Investigating Ionic Effects Applied to Water Based Organocatalysed Aldol Reactions

Saturated aqueous solutions of various common salts were examined for their effect on aqueous aldol reactions catalysted by a highly active C2-symmetric diprolinamide organocatalyst developed in our laboratory. With respect to the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, deionised water was always a superior medium to salt solutions though some correlation to increasing anion size and depression in enantiomeric excess could be observed. Additionally, the complete inhibition of catalyst activity observed when employing tap water could be alleviated by the inclusion of ethylenediaminetetraacetate (EDTA) into the aqueous media prior to reaction initiation. Extension of these reaction conditions demonstrated that these ionic effects vary on a case-to-case basis depending on the ketone/aldehyde combination.

Spontaneous and diastereoselective aldol reactions of cyclic β-amino ketones in the presence of water

Direct aldol reactions of 4-methyl-1-piperidone, tropinone and granatanone (pseudopelletierine) take place spontaneously in the presence of water without any catalyst or additional reagents. The anti/ syn-diastereoselectivity of the aqueous aldol reaction depends on the amount of water used. The syn-selectivity of the reaction is probably due to the thermodynamic control. Excellent atom economy and low E factors together with anti-selectivity as high as 98:2 for the tropinone aldol were obtained.

Picolylamine as an organocatalyst template for highly diastereo- and enantioselective aqueous aldol reactions

A pyridine based 1,2-diamine containing only one stereogenic center has been identified for fast aldol reactions (16-48 h). Using 2-5 mol% of (R)- or (S)-PicAm-2, cyclohexanone (3.3 equiv) readily undergoes aldol reactions with o-, m-, and p-substituted aromatic aldehyde partners (limiting reagent), including the poor electrophile 4-methylbenzaldehyde (95-99% ee). Furthermore, functionalized cyclic ketone substrates have been converted into four aldol products 9-12 using the lowest catalyst loading (5.0 mol%) to date with the highest yield and enantioselectivity.

Novel enantiocontrol system with aminoacyl derivatives of glucoside as enamine-based organocatalysts for aldol reaction in aqueous media

Introduction of carbohydrate auxiliary into enanine-based catalyst provided a novel enantiocontrol for aqueous aldol reaction. Methyl 2-( l-prolyl)amido-2-deoxy-α- d-glucopyranosides led to the enantiocontrol as parent amino acids did in the reaction of acetone with 4-nitrobenzaldehyde, and provided R-aldol in an improved efficiency compared with that of l-proline in aqueous media. The enantioreversal control of that with parent amino acid was observed in the reaction with methyl 2-( l- tert-leucyloxy)-α- d-glucopyranoside, which provided S-aldol predominantly in moderate efficiency. The novel enantiocontrol system was proposed to occur as a result of the generation of the transition state through the reaction of enamine with hydroxyl group on glucoside auxiliary.

Kinetic isotope and thermodynamic analysis of the nornicotine-catalyzed aqueous aldol reaction

A series of kinetic isotope effects and thermodynamic studies were performed to test key predictions of a computationally derived model for a nornicotine-catalyzed aqueous aldol reaction. The relative energies of the two computationally-derived transition states were challenged using the proton inventory, which demonstrated that a single water molecule from the solvent is involved in, or before, the rate-limiting step. These results suggest the importance of proton transfer in the aqueous aldol reaction and may assist the development of other aqueous organocatalytic processes.

Hammett Correlation of Nornicotine Analogues in the Aqueous Aldol Reaction: Implications for Green Organocatalysis

[reaction: see text] A series of meta- and para-substituted 2-arylpyrrolidines were synthesized and examined for their ability to catalyze an aqueous aldol reaction under buffered conditions. Kinetic analysis of arylpyrrolidine-catalyzed reactions displayed a linear Hammett correlation with rho = 1.14 (R(2) = 0.996), indicating that the reaction is accelerated by electron-withdrawing aryl rings. These results show promise for the development of a synthetically viable aqueous organo-catalyst.

Prebiotic carbohydrate synthesis: zinc–proline catalyzes direct aqueous aldol reactions of α-hydroxy aldehydes and ketones

Zn-proline catalyzed aldolisation of glycoladehyde gave mainly tetroses whereas in the cross-aldolisation of glycoladehyde and rac-glyceraldehyde, pentoses accounted for 60% of the sugars formed with 20% of ribose.

Nornicotine aqueous aldol reactions: synthetic and theoretical investigations into the origins of catalysis.

The recent discovery that nornicotine 1, a minor nicotine metabolite, can catalyze the aldol reaction under physiologically relevant conditions has initiated research efforts into the potential chemical roles of nicotine metabolites. Herein, we disclose studies aimed at determining the origin and thus mechanism of the nornicotine-catalyzed aqueous aldol reaction. Conformationally constrained compounds designed to mimic the low-energy conformations of nornicotine were synthesized and tested for aldol catalysis; however, none showed rate enhancements on par with nornicotine. To further explore the mechanism of this process, a density functional theory (DFT) study was performed by using a variety of compounds previously tested for catalysis. These in silico studies have uncovered an unprecedented mechanistic subtlety of aqueous aldol reactions. Unlike the single transition state model observed for aldol reactions in organic solvent, the nornicotine-catalyzed reaction in water proceeds via a two-step mechanism in which a water molecule is utilized in both steps and a stable intermediate is generated. In total, these studies validate the proposed enamine-based mechanism of nornicotine-catalyzed aqueous aldol reactions and also provide the basis for future studies into the stereoelectronic nature of individual catalyst structures.

Towards peptide isostere libraries: aqueous aldol reactions on hydrophilic solid supports

Polar polyoxyethylene-polyoxypropylene (POEPOP) resin was derivatised with a 4-hydroxymethyl phenoxy linker and used as a solid support for lanthanide triflate catalysed Mukaiyama type solid phase aldol reactions. The conditions were optimised using resin bound 4-alkoxybenzaldehyde and it was shown that use of an aqueous solvent was crucial. Also, the reactions were performed with an N-terminal peptide aldehyde substrate in very high yields. POEPOP resins prepared with different monomer chain lengths and commercially available PEG-grafted NovaSyn TG resin were compared in the reactions.

ChemInform Abstract: Lewis Acid Catalysis in Micellar Systems. Sc(OTf)3‐Catalyzed Aqueous Aldol Reactions of Silyl Enol Ethers with Aldehydes in the Presence of a Surfactant.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.