Toward a greener world—cyclodextrin derivatization by mechanochemistry

Cyclodextrin (CD) derivatives are a challenge, mainly due to solubility problems. In many cases, the synthesis of CD derivatives requires high-boiling solvents, whereas the product isolation from the aqueous methods often requires energy-intensive processes. Complex formation faces similar challenges in that it involves interacting materials with conflicting properties. However, many authors also refer to the formation of non-covalent bonds, such as the formation of inclusion complexes or metal–organic networks, as reactions or synthesis, which makes it difficult to classify the technical papers. In many cases, the solubility of both the starting material and the product in the same solvent differs significantly. The sweetest point of mechanochemistry is the reduced demand or complete elimination of solvents from the synthesis. The lack of solvents can make syntheses more economical and greener. The limited molecular movements in solid-state allow the preparation of CD derivatives, which are difficult to produce under solvent reaction conditions. A mechanochemical reaction generally has a higher reagent utilization rate. When the reaction yields a good guest co-product, solvent-free conditions can be slower than in solution conditions. Regioselective syntheses of per-6-amino and alkylthio-CD derivatives or insoluble cyclodextrin polymers and nanosponges are good examples of what a greener technology can offer through solvent-free reaction conditions. In the case of thiolated CD derivatives, the absence of solvents results in significant suppression of the thiol group oxidation, too. The insoluble polymer synthesis is also more efficient when using the same molar ratio of the reagents as the solution reaction. Solid reactants not only reduce the chance of hydrolysis of multifunctional reactants or side reactions, but the spatial proximity of macrocycles also reduces the length of the spacing formed by the crosslinker. The structure of insoluble polymers of the mechanochemical reactions generally is more compact, with fewer and shorter hydrophilic arms than the products of the solution reactions

Enabling technologies and green processes in cyclodextrin chemistry

The design of efficient synthetic green strategies for the selective modification of cyclodextrins (CDs) is still a challenging task. Outstanding results have been achieved in recent years by means of so-called enabling technologies, such as microwaves, ultrasound and ball mills, that have become irreplaceable tools in the synthesis of CD derivatives. Several examples of sonochemical selective modification of native α-, β- and γ-CDs have been reported including heterogeneous phase Pd- and Cu-catalysed hydrogenations and couplings. Microwave irradiation has emerged as the technique of choice for the production of highly substituted CD derivatives, CD grafted materials and polymers. Mechanochemical methods have successfully furnished greener, solvent-free syntheses and efficient complexation, while flow microreactors may well improve the repeatability and optimization of critical synthetic protocols

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

A number of per-6-substituted cyclodextrin derivative syntheses have been effectively carried out in a planetary ball mill under solvent-free conditions. The preparation of Bridion® and important per-6-amino/thiocyclodextrin intermediates without polar aprotic solvents, a source of byproducts and persistent impurities, could be performed. Isolation and purification processes could also be simplified. Considerably lower alkylthiol/halide ratio were necessary to reach the complete reaction in comparison with thiourea or azide reactions. While the presented mechanochemical syntheses were carried out on the millimolar scale, they are easily scalable

Medium-high frequency sonication dominates spherical-SiO2 nanoparticle size

Spherical SiO(2) nanoparticles (SSNs) have been inventively synthesized using the Stöber method with sonication at medium–high frequencies (80, 120, and 500 kHz), aiming to control SSN size and shorten reaction time. Compared to the conventional method, such sonication allowed the Stöber reaction complete in 20–60 min with a low molar ratio of NH(4)OH/tetraethyl orthosilicate (0.84). The hydrodynamic diameters of 63–117 nm of SSNs were obtained under sonication with 80, 120, and 500 kHz of ultrasonic frequencies. Moreover, the SSNs obtained were smaller at 120 kHz than at 80 kHz in a multi-frequencies ultrasonic reactor, and the SSN size decreased with increasing ultrasonic power at 20 °C, designating the sonochemical unique character, namely, the SSN-size control is associated with the number of microbubbles originated by sonication. With another 500 kHz ultrasonic bath, the optimal system temperature for producing smaller SSNs was proven to be 20 °C. Also, the SSN size decreased with increasing ultrasonic power. The smallest SSNs (63 nm, hydrodynamic diameter by QELS, or 21 nm by FESEM) were obtained by sonication at 207 W for 20 min at 20 °C. Furthermore, the SSN size increased slightly with increasing sonication time and volume, favoring the scale-up of SSNs preparation. The mechanisms of controlling the SSN size were further discussed by the radical’s role and effects of ammonia and ethanol concentration

Complexes of peracetylated cyclodextrin in a non-aqueous aprotic medium: the role of residual water

This paper describes the interaction between aromatic esters and peracetylated cyclodextrins (CDs) studied by NMR spectroscopy in deuterochloroform (CDCl3). The observed chemical shift changes highlight the existence of interactions between an aromatic alkyl ester, water and peracetylated CDs. In some cases, substituent chemical shift determination was influenced by the low water content of CDCl3 and/or the host molecule. Higher CD concentrations resulted in water signal drifts in all studied cases. It was not possible to obtain a completely dry sample of peracetyl γCD: ∼1 mol of water remained and the water signal showed reversed movement, with respect to the other two CD analogues, upon increasing host concentration. The estimated 1 : 1 stability constants for the water : peracetyl CD complexes are in the 50–150 M−1 range in CDCl3, but show a relatively large calculation error. The calculated 1 : 1 stability constants for the peracetyl CD : ester complexes are also in this range, but 1 : 2 and 2 : 1 complex compositions are also possible. Overall, our results highlight dynamic aspects of water nanoconfined in a highly hydrophobic environment, thus mimicking biological recognition where a few water molecules often play a pivotal role.Trabajo financiado por: Ministerio de Economía y Competitividad. Proyecto CTQ2013-44787-P, para Pedro Cintas Moreno Junta de Extremadura y Fondos FEDER. Ayuda GR15022, para Pedro Cintas Moreno Samarate Resilia srl (Italia). Ayuda financierapeerReviewe

Synthesis of randomly substituted anionic cyclodextrins in ball milling

A number of influencing factors mean that the random substitution of cyclodextrins (CD) in solution is difficult to reproduce. Reaction assembly in mechanochemistry reduces the number of these factors. However, lack of water can improve the reaction outcomes by minimizing the reagent’s hydrolysis. High-energy ball milling is an efficient, green and simple method for one-step reactions and usually reduces degradation and byproduct formation. Anionic CD derivatives have successfully been synthesized in the solid state, using a planetary ball mill. Comparison with solution reactions, the solvent-free conditions strongly reduced the reagent hydrolysis and resulted in products of higher degree of substitution (DS) with more homogeneous DS distribution. The synthesis of anionic CD derivatives can be effectively performed under mechanochemical activation without significant changes to the substitution pattern but the DS distributions were considerably different from the products of solution syntheses