V. Van Speybroeck

Stable Amorphous Solid Dispersion of Flubendazole with High Drug Loading via Solvent Electrospinning

J. Becelaere, E. Van den Broeck, E. Schoolaert, V. Vanhoorne, J. F.R. Van Guyse, M. Vergaelen, S. Borgmans, K. Creemers, V. Van Speybroeck, C. Vervaet, R. Hoogenboom, K. De Clerck
Journal of controlled release
351, November 2022, Pages 123-126
2022
A1

Abstract 

In this work, an important step is taken towards the bioavailability improvement of poorly water-soluble drugs, such as flubendazole (Flu), posing a challenge in the current development of many novel oral-administrable therapeutics. Solvent electrospinning of a solution of the drug and poly(2-ethyl-2-oxazoline) is demonstrated to be a viable strategy to produce stable nanofibrous amorphous solid dispersions (ASDs) with ultrahigh drug-loadings (up to 55 wt% Flu) and long-term stability (at least one year). Importantly, at such high drug loadings, the concentration of the polymer in the electrospinning solution has to be lowered below the concentration where it can be spun in absence of the drug as the interactions between the polymer and the drug result in increased solution viscosity. A combination of experimental analysis and molecular dynamics simulations revealed that this formulation strategy provides strong, dominant and highly stable hydrogen bonds between the polymer and the drug, which is crucial to obtain the high drug-loadings and to preserve the long-term amorphous character of the ASDs upon storage. In vitro drug release studies confirm the remarkable potential of this electrospinning formulation strategy by significantly increased drug solubility values and dissolution rates (respectively tripled and quadrupled compared to the crystalline drug), even after storing the formulation for one year.

A general synthesis of azetidines by copper-catalysed photoinduced anti-Baldwin radical cyclization of ynamides

C. Jacob, H. Baguia, A. Dubart, S. Oger, P. Thilmany, J. Beaudelot, C. Deldaele, S. Peruško, Y. Landrain, B. Michelet, S. Neale, E. Romero, C. Moucheron, V. Van Speybroeck, C. Theunissen, G. Evano
Nature Communications
13, 560
2022
A1

Abstract 

A general anti-Baldwin radical 4-exo-dig cyclization from nitrogen-substituted alkynes is reported. Upon reaction with a heteroleptic copper complex in the presence of an amine and under visible light irradiation, a range of ynamides were shown to smoothly cyclize to the corresponding azetidines, useful building blocks in natural product synthesis and medicinal chemistry, with full control of the regioselectivity of the cyclization resulting from a unique and underrated radical 4-exo-dig pathway.

Gold Open Access

Mechanistic characterization of zeolite-catalyzed aromatic electrophilic substitution at realistic operating conditions

M. Bocus, L. Vanduyfhuys, F. De Proft, B.M. Weckhuysen, V. Van Speybroeck
JACS Au (Journal of the American Chemical Society)
2, 2, 502-514
2022
A1

Abstract 

Zeolite-catalyzed benzene ethylation is an important industrial reaction, as it is the first step in the production of styrene for polymer manufacturing. Furthermore, it is a prototypical example of aromatic electrophilic substitution, a key reaction in the synthesis of many bulk and fine chemicals. Despite extensive research, the reaction mechanism and the nature of elusive intermediates at realistic operating conditions is not properly understood. More in detail, the existence of the elusive arenium ion (better known as Wheland complex) formed upon electrophilic attack on the aromatic ring is still a matter of debate. Temperature effects and the presence of protic guest molecules such as water are expected to impact the reaction mechanism and lifetime of the reaction intermediates. Herein, we used enhanced sampling ab initio molecular dynamics simulations to investigate the complete mechanism of benzene ethylation with ethene and ethanol in the H-ZSM-5 zeolite. We show that both the stepwise and concerted mechanisms are active at reaction conditions and that the Wheland intermediate spontaneously appears as a shallow minimum in the free energy surface after the electrophilic attack on the benzene ring. Addition of water enhances the protonation kinetics by about 1 order of magnitude at coverages of one water molecule per Brønsted acidic site. In the fully solvated regime, an overstabilization of the BAS as hydronium ion occurs and the rate enhancement disappears. The obtained results give critical atomistic insights in the role of water to selectively tune the kinetics of protonation reactions in zeolites.

Gold Open Access

Acidity effect on benzene methylation kinetics over substituted H-MeAlPO-5 catalysts

M. Morten, T. Cordero-Lanzac, P. Cnudde, E. A. Redekop, S. Svelle, V. Van Speybroeck, U. Olsbye
Journal of Catalysis
404, 594-606
2021
A1

Abstract 

Methylation of aromatic compounds is a key reaction step in various industrial processes such as the aromatic cycle of methanol-to-hydrocarbons chemistry. The study of isolated methylation reactions and of the influence of catalyst acidity on their kinetics is a challenging task. Herein, we have studied unidirectional metal-substituted H-MeAlPO-5 materials to evaluate the effect of acid strength on the kinetics of benzene methylation with DME. First-principle simulations showed a direct correlation between the methylation barrier and acid site strength, which depends on the metal substituent. Three H-MeAlPO-5 catalysts with high (Me = Mg), moderate (Me = Si) and low acidity (Me = Zr) were experimentally tested, confirming a linear relationship between the methylation activation energy and acid strength. The effects of temperature and reactant partial pressure were evaluated, showing significant differences in the byproduct distribution between H-MgAlPO-5 and H-SAPO-5. Comparison with propene methylation suggested that the Mg substituted catalyst is also the most active for the selective methylation of alkenes.

Open Access version available at UGent repository
Gold Open Access

A comparative theoretical study on the solvent dependency of anthocyanin extraction profiles

K.T. Phan, E. Van den Broeck, K. Raes, K. De Clerck, V. Van Speybroeck, S. De Meester
Journal of Molecular Liquids
351
2022
A1

Abstract 

Anthocyanidins and anthocyanins are flavonoids with nutritional, antioxidative and color properties that are present in various food products and biomass, such as food waste. The large chemical diversity amongst these molecules potentially leads to different affinities or activities in food and non-food applications. In order to characterize the extraction profile, advanced analytical techniques along with optimized separation procedures are required. Alternatively, theoretical tools can be applied for predicting the solubility or binding affinity of molecules in various reaction media. In this paper, the solubility of anthocyanidins and anthocyanins was analyzed by various theoretical tools such as group contribution methods (e.g., Hansen solubility parameters and Flory-Huggins interaction parameter (χ12)) and molecular modeling (e.g., static calculations based on Density Functional Theory (DFT) and COSMO-RS). It was found that COSMO-RS was able to give quantitative information on the solubility behavior within various pure solvents and it is able to describe the main intermolecular interactions between colorant and solvent, while Hansen solubility parameters were most appropriate to find the most optimal organic solvent-water mixture ratio. In general, solvents with electron-rich aromatic rings and/or containing electron donors, acting as hydrogen bond acceptors, showed the highest solubilizing power for anthocyanidins and anthocyanins.

Gold Open Access

Porous organic polymers as metal free heterogeneous organocatalysts

M. Debruyne, V. Van Speybroeck, P. Van der Voort, C. Stevens
Green Chemistry
Volume 23, Issue 19, Page 7361-7434
2021
A1

Abstract 

Efficient catalysis is essential from a green chemistry perspective. Porous organic polymers (POPs) have recently emerged as highly effective materials for catalytic applications. POPs possess controllable compositions and functionalities, high surface areas and can be very stable. In this review we focus on the application of POPs as metal free heterogeneous organocatalysts, a booming field in green chemistry. Acid, base, combined acid-base and hydrogen bonding catalysis are addressed. In addition, chiral catalysis and CO2 utilization with POPs are discussed. The aim is to provide a comprehensive overview of the field, exploring all different types of POPs as metal free catalysts. Special attention is given to the synthesis conditions to provide the reader with more insight into the construction of these types of materials.

DOI 

10.1039/d1gc02319e

Synthesis of Nitrile-Functionalized Polydentate N-Heterocycles as Building Blocks for Covalent Triazine Frameworks

J. Everaert, M. Debruyne, F. Vandenbussche, K. Van Hecke, T.S.A Heugebaert, P. Van der Voort, V. Van Speybroeck, C. Stevens
Synthesis-Stuttgart
2021
A1

Abstract 

Covalent triazine frameworks (CTFs) based on polydentate ligands are highly promising supports to anchor catalytic metal complexes. The modular nature of CTFs allows to tailor the composition, structure, and function to its specific application. Access to a broad range of chelating building blocks is therefore essential. In this respect, we extended the current available set of CTF building blocks with new nitrile-functionalized N-heterocyclic ligands. This paper presents the synthesis of the six ligands which vary in the extent of the aromatic system and the denticity. The new building blocks may help in a rational design of enhanced support materials in catalysis.

Elucidation of the pre-nucleation phase directing metal-organic framework formation

M. Filez, C. Caratelli, M. Rivera-Torrente, F. Muniz-Miranda, M. Hoek, M. Altelaar, A.J.R. Heck, V. Van Speybroeck, B.M. Weckhuysen
Cell Reports Physical Science
2, 12, 100680
2021
A1

Abstract 

Metal-organic framework (MOF) crystallization is governed by molecular assembly processes in the pre-nucleation stage. Yet, unravelling these pre-nucleation pathways and rationalizing their impact on crystal formation poses a great challenge since probing molecular-scale assemblies and macroscopic particles simultaneously is very complex. Herein, we present a multimodal, integrated approach to monitor MOF nucleation across multiple length scales by combining in situ optical spectroscopy, mass spectrometry, and molecular simulations. This approach allows tracing initial metal-organic complexes in solution and their assembly into oligomeric nuclei and simultaneously probing particle formation. During Co-ZIF-67 nucleation, a metal-organic pool forms with a variety of complexes caused by ligand exchange and symmetry reduction reactions. We discriminate complexes capable of initiating nucleation from growth species required for oligomerization into frameworks. Co4-nuclei are observed, which grow into particles following autocatalytic kinetics. The geometric and compositional variability of metal-organic pool species clarifies long-debated amorphous zeolitic imidazolate framework (ZIF)-particle nucleation and non-classic pathways of MOF crystallization.

DOI 

dx.doi.org/10.1016/j.xcrp.2021.100680

Unexpected formation of 2,2-dichloro-N-(chloromethyl)acetamides during attempted Staudinger 2,2-dichloro-β-lactam synthesis

S. Deketelaere, E. Van den Broeck, L. Cools, D. Deturck, H. Naeyaert, K. Van Hecke, C. Stevens, V. Van Speybroeck, M. D'Hooghe
European Journal of Organic Chemistry
2021, 42, 5823-5830
2021
A1

Abstract 

In the quest for 3,3-dichloro-β-lactam building blocks, the serendipitous formation of 2,2-dichloro-N-(chloromethyl)acetamides was observed. This peculiar reactivity was investigated in detail, both experimentally and computationally by means of Density Functional Theory (DFT) calculations. 2,2-Dichloro-N-(chloromethyl)acetamides were thus shown to be formed experimentally through reaction of 2,2-dichloroacetyl chloride with glyceraldehyde-derived imines, i. e. (2,2-dimethyl-1,3-dioxolan-4-yl)methanimines, bearing aromatic N-substituents, in the presence as well as in the absence of a base. Deployment of aliphatic imines, however, resulted in complex reaction mixtures, pointing to the importance of a stabilizing aromatic substituent at nitrogen. The DFT results indicate that the substituents can alter the governing equilibria on the one hand and intrinsic barrier heights for the different routes on the other hand, showing that these are controlling the reaction outcome. Furthermore, the 2,2-dichloro-N-(chloromethyl)acetamides proved to be rather unstable in solution and thus difficult to isolate. Nonetheless, their molecular structure was confirmed by means of NMR analysis of several purified analogs and X-ray study of a 4-methoxyphenyl derivative.

Mobility and Reactivity of Cu+ Species in Cu-CHA Catalysts under NH3-SCR-NOx Reaction Conditions: Insights from AIMD Simulations

R. Millan, P. Cnudde, V. Van Speybroeck, M. Boronat
JACS Au (Journal of the American Chemical Society)
1 (10), 1778–1787
2021
A1

Abstract 

The mobility of the copper cations acting as active sites for the selective catalytic reduction of nitrogen oxides with ammonia in Cu-CHA catalysts varies with temperature and feed composition. Herein, the migration of [Cu(NH3)2]+ complexes between two adjacent cavities of the chabazite structure, including other reactant molecules (NO, O2, H2O, and NH3), in the initial and final cavities is investigated using ab initio molecular dynamics (AIMD) simulations combined with enhanced sampling techniques to describe hopping events from one cage to the other. We find that such diffusion is only significantly hindered by the presence of excess NH3 or NO in the initial cavity, since both reactants form with [Cu(NH3)2]+ stable intermediates which are too bulky to cross the 8-ring windows connecting the cavities. The presence of O2 modifies strongly the interaction of NO with Cu+. At low temperatures, we observe NO detachment from Cu+ and increased mobility of the [Cu(NH3)2]+ complex, while at high temperatures, NO reacts spontaneously with O2 to form NO2. The present simulations give evidence for recent experimental observations, namely, an NH3 inhibition effect on the SCR reaction at low temperatures, and transport limitations of NO and NH3 at high temperatures. Our first principle simulations mimicking operating conditions support the existence of two different reaction mechanisms operating at low and high temperatures, the former involving dimeric Cu(NH3)2-O2-Cu(NH3)2 species and the latter occurring by direct NO oxidation to NO2 in one single cavity.

Gold Open Access

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