Baeyer-Villiger Research Articles

Simple metal-free oxidative cleavage of 1,2-diols

Cleavage of 1,2-diols is easily carried out under mild conditions with the Oxone/KBr (or Oxone/NaCl) method in either acetonitrile/water or tert-butanol/water medium at room temperature. This procedure is highly efficient for the cleavage of dihydroxyfatty esters and acids. The reaction takes place through a double oxidation of the 1,2-diol, leading to the 1,2-diketone that undergoes a Baeyer-Villiger oxidation, with a final hydrolysis of the generated anhydride. The application to other diols, including simple internal and terminal diols, is also possible, but the nature of the diol substrate conditions the optimal halide/solvent system, given that important differences in reactivity are observed. These differences are ascribed to the change in the rate limiting step depending on the substrate/halide/solvent combination.

Investigation of process stability of a whole-cell biocatalyst with Baeyer–Villiger monooxygenase activity in continuous bioreactors

The stability of a whole-cell biocatalyst based on genetically modified Escherichia coli cells harboring cyclohexanone monooxygenase was investigated in a free and immobilized form in continuous bioreactors. The biotransformation of a bicyclic ketone to a racemic mixture of the corresponding lactones by an enzymatic cascade was performed in a membrane bioreactor (MBR) for free cells and in a fluidized-bed bioreactor (FBBR) for immobilized cells. Both reactors were operated at the residence time of 6.25 h with the biocatalyst concentration of 1 % w/w. Different oxygen mass transfer rates were set via the impeller speed in MBR or air flow rate in FBBR, respectively. The potential of continuous bioreactors to achieve a steady state was utilized for the analysis of different factors affecting the biocatalyst stability. An apparent steady state could be maintained in these bioreactors up to 40 h. The operation at high conversions or high oxygenation rates allowed to exclude poisoning by substrate or oxygen as causes of biocatalyst activity loss. Further experiments showed that the cells did not lose viability or plasmid. The problem in biocatalyst stability was not in the stability of cyclohexanone monooxygenase but in insufficient regeneration of cofactors. The only partially effective measure was the addition of catalase with the feed concentration of 0.025 g/L that decomposed hydrogen peroxide formed in the enzymatic cascade. However, both free and immobilized biocatalysts lost their activity completely in about a week.

Discovery and Characterization of a Baeyer-Villiger Monooxygenase using Sequence Similarity Network Analysis.

Baeyer-Villiger monooxygenases(BVMOs) are important flavin-dependent enzymes which perform oxygen insertion reactions leading to valuable products. As reported in many studies, BVMOs are usually unstable during application, preventing a wider usage in biocatalysis. Here, we discovered a novel NADPH-dependent BVMO which originates fromHalopolyspora algeriensisusing sequence similarity networks (SSNs). The enzyme is stable at temperatures between 10°C to 30°C up to five days after the purification, and yields the normal ester product. In this study,the substrate scope was investigated for a broad range of aliphatic ketones and the enzyme was biochemically characterized to identify optimum reaction conditions. The best substrate (86% conversion) was 2-dodecanone using purified enzyme. This novel BVMO could potentially be applied as part of an enzymatic cascade or in bioprocesses which utilize aliphatic alkanes as feedstock.

The Synthesis of Sn-Containing Silicates Coated with Binaphthol and Their Specific Application for Catalytic Synthesis of 6-Hydroxyhexanoic Acid and Cyclohexylformate through Baeyer-Villiger Oxidation

The Baeyer–Villiger oxidation (BVO) of ketone and aldehyde can produce ester and formate, which both have wide applications in many areas. In this work, a series of Sn-containing silicates were prepared through the sol-gel process by using structure-directing and crystallizing agents and post-synthetic coordinated modification of binaphthol. Characterizations revealed that loading of (L)-sodium lactate as the crystallizing agent decreased the crystal size of the synthesized catalyst, and there were SnO2 nanoparticles with sizes of 17–19 nm on the catalyst. Furthermore, quite differently from the 3D mesoporous structure of classical Sn-beta zeolites, the synthesized catalysts had a silt-like mesoporous structure. In the catalysis, when cyclic aliphatic ketones were used as the substrate, only BVO-type products and corresponding ring-opening products were obtained. BVO of aliphatic aldehyde produced both an aerobic oxidation product (carboxylic acid) and a BVO-type product. The presented transformation of aromatic aldehyde (benzaldehyde) only gave an aerobic oxidation product (benzoic acid). The post-synthetic coordinating attachment of (S)-binaphthol to the Sn-containing silicate backbone worsened the BVO of aliphatic ketones but improved the BVO of aliphatic aldehyde and the aerobic oxidation of aromatic aldehyde. In addition, this work also developed two new routes for the synthesis of high-value-added 6-hydroxyhexanoic acid and cyclohexylformate under catalytic BVO conditions.

Synthesis of copper(II) halide dimers with 2-amino-5-methylpyridine and serendipitous copper catalyzed synthesis of 3-bromo-2-ethyl-5-methyl-1H-pyrrolo[2,3-b]pyridine

Reaction of CuX2·nH2O (X = Cl, n = 2; X = Br, n = 0) with 2-amino-5-methylpyridine (5MAP) in acetonitrile yielded [(5MAP)2CuX2]2 (1, Cl; 2, Br). The compounds are isomorphous and crystallize in the monoclinic space group P21 /n as bihalide bridged dimers. Variable temperature magnetic measurements show very weak exchange in the two compounds (-2.1(1) K) which may correlate with previously proposed magnetostructural correlations for bihalide bridged Cu(II) dimers. In attempts to prepare 2 in 2-butanone as solvent, [(3-Br-2-Et-5-Mepyrpy)(CH3CO2)4Cu2] (3) was serendipitously isolated (3-Br-2-Et-5-Mepyrpy = 3-bromo-2-ethyl-5-methyl-7H-pyrrolido[2,3-b]pyridinium). The bicyclic ligand was synthesized in situ by condensation of 5MAP with the solvent; the acetate ions were generated by copper(II) catalyzed Baeyer-Villiger oxidation of the solvent. A mechanism for the synthesis is proposed. The resulting Cu-paddlewheel compound exhibits strong (-400 K) antiferromagnetic interactions.

Amide- and Urea-Based Solvents for Li–O2 Batteries. Part I: Experimental Evaluation

Nonaqueous Li–O2 batteries have the potential to aid in the electrification of our society due to their relatively high theoretical energy density. Unfortunately, the technology suffers from large degrees of irreversibility due to the aggressive chemical environment associated with the oxidation of the discharge product lithium peroxide. Herein, we present a study of a range of linear and cyclic amides and ureas as aprotic electrolyte solvents for the Li–O2 battery, some of which show slight increases in reversibility relative to the well-established pseudo-stable glymes, although we find that none provide reversibility necessary to enable a rechargeable system. Using quantitative differential electrochemical mass spectrometry, acid titrations, and isotopic labeling of O2 and carbon in the positive electrode, we provide insight into the degradation pathways for these solvents. In the companion article, we compare our experimental results presented here to solvent decomposition pathways including a Baeyer–Villiger oxidation mechanism.

Crosslinked Aggregates of Fusion Enzymes in Microaqueous Organic Media.

Baeyer-Villiger monooxygenases (BVMOs) are attractive for selectively oxidizing various ketones using oxygen into valuable esters and lactones. However, the application of BVMOs is restrained by cofactor dependency and enzyme instability combined with water-related downsides such as low substrate loading, low oxygen capacity, and water-induced side reactions. Herein, we described a redox-neutral linear cascade with in-situ cofactor regeneration catalyzed by fused alcohol dehydrogenase and cyclohexanone monooxygenase in aqueous and microaqueous organic media. The cascade conditions have been optimized regarding substrate concentrations as well as the amounts of enzymes and cofactors with the Design of Experiments (DoE). The carrier-free immobilization technique, crosslinked enzyme aggregates (CLEAs), was applied to fusion enzymes. The resultant fusion CLEAs were proven to function in microaqueous organic systems, in which the enzyme ratios, water contents (0.5-5 vol. %), and stability have been systematically studied. The fusion CLEAs showed promising operational (up to 5 cycles) and storage stability.

Baeyer–Villiger oxidation of cyclic ketones with H2O2 over mesoporous Sn- and Zr-BEA zeolites

Baeyer–Villiger oxidation of cyclic ketones with H2O2 over mesoporous Sn- and Zr-BEA zeolites

Amide and Urea Based Solvents for Li–O2 Batteries. Part II: Evaluation of Decomposition Pathways Using Density Functional Theory

Potential decomposition mechanisms are investigated using density functional theory (DFT) for a set of amide and urea solvents. Reaction energies and barriers are reported for proton and hydrogen abstraction, and preferred abstraction sites are identified. The N–H bond of secondary amides and the α-hydrogen atoms are more susceptible to proton abstraction than other sites in the solvent molecules. Additionally, hydrogen abstraction is more favorable at the N-alkyl substituents as well as α-hydrogen atoms that result in the formation of secondary and tertiary radicals. All proton abstraction energies are sensitive to the presence of a coordinating Li+, but the hydrogen abstraction energies do not depend on the presence of a Li+. The stabilization due to the presence of Li+ is most pronounced for sites near the carbonyl group where the Li+ interacts with the lone pair of electrons formed by proton abstraction and the carbonyl O atom. The initial steps of a Baeyer–Villiger oxidation type mechanism are also examined. Barriers for these initial steps are significantly lower if HO2– is the oxidant compared to LiO2–. A comparison to our previously reported experimental results indicates that no single reaction could be identified as the rate-limiting step that would predict the performance of this set of solvents in Li–O2 batteries.

A Cold-Active Flavin-Dependent Monooxygenase from Janthinobacterium svalbardensis Unlocks Applications of Baeyer-Villiger Monooxygenases at Low Temperature.

Cold-active enzymes maintain a large part of their optimal activity at low temperatures. Therefore, they can be used to avoid side reactions and preserve heat-sensitive compounds. Baeyer-Villiger monooxygenases (BVMO) utilize molecular oxygen as a co-substrate to catalyze reactions widely employed for steroid, agrochemical, antibiotic, and pheromone production. Oxygen has been described as the rate-limiting factor for some BVMO applications, thereby hindering their efficient utilization. Considering that oxygen solubility in water increases by 40% when the temperature is decreased from 30 to 10 °C, we set out to identify and characterize a cold-active BVMO. Using genome mining in the Antarctic organism Janthinobacterium svalbardensis, a cold-active type II flavin-dependent monooxygenase (FMO) was discovered. The enzyme shows promiscuity toward NADH and NADPH and high activity between 5 and 25 °C. The enzyme catalyzes the monooxygenation and sulfoxidation of a wide range of ketones and thioesters. The high enantioselectivity in the oxidation of norcamphor (eeS = 56%, eeP > 99%, E > 200) demonstrates that the generally higher flexibility observed in the active sites of cold-active enzymes, which compensates for the lower motion at cold temperatures, does not necessarily reduce the selectivity of these enzymes. To gain a better understanding of the unique mechanistic features of type II FMOs, we determined the structure of the dimeric enzyme at 2.5 Å resolution. While the unusual N-terminal domain has been related to the catalytic properties of type II FMOs, the structure shows a SnoaL-like N-terminal domain that is not interacting directly with the active site. The active site of the enzyme is accessible only through a tunnel, with Tyr-458, Asp-217, and His-216 as catalytic residues, a combination not observed before in FMOs and BVMOs.

Structural, textural, surface basic and catalytic properties of an aged Mg/Al layered double hydroxide and its calcination products

The influence of the length of an aging treatment on the structural and textural properties of a 2:1 Mg/Al layered double hydroxide (LDH) obtained by coprecipitation under low oversaturation conditions was examined. Increasing the aging time led to more crystalline solids consisting of increasingly large crystals; also, however, it reduced the number of macropores and decreased the specific surface area of the solids. Calcination of the LDH gave a basic mixed oxide [Mg(Al)O]. Extending the aging treatment increased the number of surface basic sites in the mixed oxide. All solids were characterized by using various instrumental techniques and used as catalysts in the Baeyer–Villiger reaction, where the calcined materials exhibited the best catalytic properties. Also, all catalysts were reusable with no appreciable loss of activity.

Effect of the different types of Sn-precursors on the properties of Sn FeMgAl-LDH samples

In this work, LDH SnFeMgAl were prepared by co-precipitation method at constant temperature and pH using different Sn precursors. Calcined and LDHs samples were then determined for their chemical, structural, acid-base, and textural properties by XRD, SEM-EDX, TGA-MS, DRIFT, N₂ physisorption, NH₃-TPD, CO₂-TPD and the Baeyer–Villiger (BV) oxidation of myrtenal. Since turbidity often occurs in tin doped LDH, the goal of this work was to find a way to use another precursor that eliminates the turbidity problem. It was found that the choice of tin precursor had a significant effect on the acid-base properties of the obtained LDH materials and thus on their catalytic activity. All prepared catalysts were active both for the BV oxidation of myrtenal itself and for the subsequent hydrolysis of the formed formate to nopinone. The best results were obtained using FeMgAl LDH in the presence of the meta-chloroperoxybenzoic acid (mCPBA) and mixed oxide FeMgAl LDH-C in the presence of H₂O₂. In terms of nopinone yield, SnFeMgAl(Cl−)-C proved to be the best catalyst, which also had the highest proportion of acid and basic active sites among all the catalysts investigated.

Isomorphous incorporation of tin ions into extra-large pore framework with high-stannum content as efficient Lewis acid catalyst

Germanium-rich *CTH zeolite without organic molecules located inside pore channels experienced only partial structural collapse and subsequently repaired to high-silica structure analogous to the original topology in a short time. The surprise acid-hydrolysis process has caused a large amount of framework Ge ions were removed, giving rise to abundant hydroxyl nests. Benefiting from the unexpected variation of framework structure and chemical composition, stannosilicates Sn-*CTH with extra-large pores and various Sn loadings (Si/Sn molar ratio in the range of 30-∞) were post-prepared depending on the reaction between the added (NH4)2SnCl6 species and the formed silanol groups in the hydroxyl nests. The resultant Sn-*CTH zeolites were able to release significantly the diffusion limitations encountered by the bulky substrates and oxidants, exhibiting promising activities to catalyze the Baeyer-Villiger (B-V) oxidation of ketones with single oxidant either hydrogen peroxide (H2O2) or large-sized tert-butyl hydroperoxide (TBHP). Especially, high ε-caprolactone product selectivity was also obtained in the B-V oxidation of cyclohexanone using H2O2 oxidant through reducing the H2O2/cyclohexanone molar ratio as well as controlling appropriate reaction time, which was more efficient than the traditional Sn-Beta-F catalyst.

The Al-Containing Silicates Modified with Organic Ligands and SnO2 Nanoparticles for Catalytic Baeyer-Villiger Oxidation and Aerobic Carboxylation of Carbonyl Compounds.

The Baeyer-Villiger Oxidation (BVO) of ketones and aldehydes produce lactones and formates, while aerobic carboxylation of aldehydes manufactures carboxylic acids, both having high added value. This work prepared a series of Al-containing silicates modified with organic ligands and SnO2 nanoparticles, which were then employed as catalyst in BVO and carboxylation. Characterizations revealed the morphology of the synthesized catalyst was changed from micron-sized thin sheets to smaller blocks, and then to uniform nanoparticles (size of 50 nm) having the doped SnO2 nanoparticles with a size of 29 nm. All catalysts showed high BET surface areas featuring silt-like mesopores. In determining the priority of BVO and carboxylation, an influence evaluation of the parameters showed the order to be substrate > oxidant > solvent > catalyst. Cyclic aliphatic ketones were suitable for BVO, but linear aliphatic and aromatic aldehydes for carboxylation. Coordination of (S)-binaphthol or doping of Sn into catalyst showed little influence on BVO under m-CPBA, but the Sn-doped catalyst largely increased BVO under (NH4)2S2O8 and H2O2. Calculations revealed that the catalyst containing both Al and Sn could give BVO intermediates lower energies than the Sn-beta zeolite model. The present system exhibited merits including wider substrate scope, innocuous catalytic metal, greener oxidant, as well as lower catalyst cost.

Catalytic Oxidation of Benzoins by Hydrogen Peroxide on Nanosized HKUST-1: Influence of Substituents on the Reaction Rates and DFT Modeling of the Reaction Path

In this research, the oxidation of a series of benzoins, R-C(=O)-CH(OH)-R, where R = phenyl, 4-methoxyphenyl, 4-bromophenyl, and 2-naphthyl, by hydrogen peroxide in the presence of nanostructured HKUST-1 (suspension in acetonitrile/water mixture) was studied. The respective benzoic acids were the only products of the reactions. The initial average reaction rates were experimentally determined at different concentrations of benzoin, H2O2 and an effective concentration of HKUST-1. The sorption of the isotherms of benzoin, dimethoxybenzoin and benzoic acid on HKUST-1, as well as their sorption kinetic curves, were measured. The increase in H2O2 concentration expectedly led to an acceleration of the reaction. The dependencies of the benzoin oxidation rates on the concentrations of both benzoin and HKUST-1 passed through the maxima. This finding could be explained by a counterplay between the increasing reaction rate and increasing benzoin sorption on the catalyst with the increase in the concentration. The electronic effect of the substituent in benzoin had a significant influence on the reaction rate, while no relation between the size of the substrate molecule and the rate of its oxidation was found. It was confirmed by DFT modeling that the reaction could pass through the Baeyer-Villiger mechanism, involving an attack by the HOO- anion on the C atom of the activated C=O group.

Highly active and stable catalysts for Baeyer–Villiger oxidation – Traditional postloading vs in situ synthesis of Fe/N/C nanoparticles

Nitrogen-doped carbon composites are prepared using simple precursors, such as glucose or urea and used as supports for Fe nanoparticles. The present work investigated two approaches for incorporating metal nanoparticles into the composite: traditional metal postloading and in situ formation of a metal/N-doped carbon catalyst. The impacts of the preparation technique on (i) the characteristics of the resulting iron oxides (Fe2O3 and Fe3O4) and (ii) the nanoparticle distribution on the support were determined. Microscopic surface characterization revealed that the postloading method promoted a uniform distribution of Fe nanoparticles (5–10 nm), which enhanced the activity and long-term stability of the catalytic system for the Baeyer–Villiger oxidation of cyclic ketones. The product yield reached 97% (5 h, 60 °C), and after the third reaction cycle, the yield remained at 96%. The proposed synthetic approach for preparing active and stable catalysts provides a new perspective for the inexpensive and sustainable synthesis of lactones.

Fe@g-C3N4: an effective photocatalyst for Baeyer–Villiger oxidation under visible light condition

We fabricated peculiar, highly cogent Fe@g-C3N4 catalysts. Under visible light conditions, Fe@g-C3N4 (1 : 1) catalyst achieved 100% cyclohexanone conversion with 99.85% 2-oxepanone selectivity in the Baeyer–Villiger oxidation reaction.

Enzymatic synthesis of pharmacologically relevant chiral sulfoxides by improved CbBVMO variants.

Baeyer-Villiger monooxygenases (BVMOs) are able to catalyse the asymmetric oxidation of sulfides. This property has made them attractive catalysts for the synthesis of chiral sulfoxide drugs. Here, we have designed and synthesised an exhaustive combinatorial mutant library of the previously identified lansoprazole sulfide monooxygenase CbBVMOV1. From this synthetic combinatorial mutant library, the best mutant, CbBVMOV3, was selected with a specific activity of approximately 1 U mg-1 for lansoprazole sulfoxides. We then optimised the reaction conditions of a two-phase system, achieving the enzymatic asymmetric synthesis of (R)-lansoprazole in a space-time yield of 213 g L-1 d-1 and an enantiomeric excess of >99% (R) with no detectable by-products. In addition, CbBVMOV3 showed higher activity towards other prazole sulfides. These results indicate the potential application of CbBVMO in the chiral sulfoxide drug industry.

Hybrid catalysis for enantioselective Baeyer–Villiger oxidation and stereoselective epoxidation: a Cp*Ir complex to fuel FMN and FAD reduction for flavoprotein monooxygenase modules

Taking advantage of the standalone capacity of the two-component flavoenzyme oxygenation module, we extended the scope of the pH and oxygen robust iridium complex, Cp*Ir(bpy-OMe)H+ to drive enzymatic reactions from a low-cost hydride source.

Alternative method to Baeyer–Villiger oxidation of cyclobutenones using I2/DMSO catalytic systems

A novel and efficient approach utilizing I2/DMSO catalytic systems for the Baeyer–Villiger oxidative rearrangement of cyclobutenones was developed.