Achim Stolle

Fast, Ligand‐ and Solvent‐Free Synthesis of 1,4‐Substituted Buta‐1,3‐diynes by Cu‐Catalyzed Homocoupling of Terminal Alkynes in a Ball Mill

A method for the Glaser coupling reaction of alkynes by using a vibration ball mill has been developed. The procedure avoids the use of ligands and solvents during the reaction. Aryl- and alkyl-substituted terminal alkynes undergo homocoupling if coground with KF-Al(2)O(3) and CuI as a milling auxiliary and catalyst. Furthermore, an alternative protocol has been developed incorporating 1,4-diazabicyclo[2.2.2]octane (DABCO) as an additional base allowing the use of KF-Al(2)O(3) with a lower KF loading. Besides Cu salts, the homocoupling of phenylacetylene is also catalyzed by Ni or Co salts, as well as by PdCl(2). TMS-protected phenylacetylene could be directly converted into the homocoupling product after in situ deprotection of the alkyne by fluoride-initiated removal of the trimethylsilyl group.

Energetic assessment of the Suzuki–Miyaura reaction: a curtate life cycle assessment as an easily understandable and applicable tool for reaction optimization

The solvent-less Pd-catalyzed Suzuki–Miyaura cross coupling of different aryl halides with phenylboronic acid and an in situ generated solid base was investigated in order to study the influence of different modes of energy entry. For this reason reactions were performed in two different ball-milling set-ups and also different techniques of microwave irradiation have been applied. Combination of reaction data (yield, selectivity, batch size) with energetic data (line power consumption) was used to generalize the results as a curtate life cycle assessment (cLCA), breaking down the reaction to the reaction step, neglecting up- and downstream processes. Thus cLCA was applied for early-level reaction optimization and as decision guidance for constitutive experiments. Under the applied reaction and boundary conditions applied for the solvent-free Suzuki–Miyaura reaction ball milling is proven to be a more effective tool for energy entry than microwave irradiation.

Degradation of carbamazepine in environmentally relevant concentrations in water by Hydrodynamic-Acoustic-Cavitation (HAC)

The antiepileptic drug carbamazepine is one of the most abundant pharmaceuticals in the German aquatic environment. The effect of low carbamazepine concentrations (1-50 μg L(-1)) is discussed controversially, but ecotoxicological studies revealed reproduction toxicity, decreased enzymatic activity and bioaccumulation in different test organisms. Therefore, as a preventive step, an efficient and cost-effective technique for wastewater treatment plants is needed to stop the entry of pharmaceuticals into the aquatic environment. Cavitation, the formation, growth, and subsequent collapse of gas- or vapor-filled bubbles in fluids, was applied to solve this problem. The technique of Hydrodynamic-Acoustic-Cavitation was used showing high synergistic effect. Under optimized conditions carbamazepine (5 μg L(-1)) was transformed by pseudo-first order kinetics to an extent of >96% within 15 min (27% by hydrodynamic cavitation, 33% by acoustic cavitation). A synergistic effect of 63% based on the sum of the single methods was calculated. Carbamazepine concentrations were monitored by a sensitive and selective immunoassay and after 60 min no known metabolites were detectable by LC-MS/MS.

Switchable Selectivity during Oxidation of Anilines in a Ball Mill

A solvent-free method for the direct oxidation of anilines to the corresponding azo and azoxy homocoupling products by using a planetary ball mill was developed. Various oxidants and grinding auxiliaries were tested and a variety of substituted anilines were investigated. It was possible to form chemoselectively either azo, azoxy, or the nitro compounds from reaction of aromatic anilines. The selectivity of the solvent-free reaction is switchable by applying a combination of oxidant and grinding auxiliary. Furthermore, a comparison with other methods of energy input (microwave, classical heating, and ultrasound) highlighted the advantages of the ball mill approach and its high energy efficiency.

Solvent-free dehydrogenation of γ-terpinene in a ball mill: investigation of reaction parameters

The present article reports on the solvent-free dehydrogenation of γ-terpinene (1) in a planetary ball mill affording p-cymene (2) as the predominant reaction product. The influence of various reaction parameters and technical variables on the transformation of 1 has been assessed. Thus, it is shown that KMnO4 can be substituted by other, less-toxic and environmentally-benign oxidation agents (Oxone®, NaIO4, I2). In most cases the reaction yielded 2 with high selectivities, whereby conversion can be fine-tuned by variation of the oxidant-to-substrate ratio, the rotation frequency νrot, the number of milling balls nball or the type of grinding auxiliary employed. Contrary to particle refinement processes, the size of the milling balls d (constant mass) has no influence on the conversion and chemical yield.

Aromatic substitution in ball mills: formation of aryl chlorides and bromides using potassium peroxomonosulfate and NaX

Aryl chlorides and bromides are formed from arenes in a ball mill using KHSO5 and NaX (X = Cl, Br) as oxidant and halogen source, respectively. Investigation of the reaction parameters identified operating frequency, milling time, and the number of milling balls as the main influencing variables, as these determine the amount of energy provided to the reaction system. Assessment of liquid-assisted grinding conditions revealed, that the addition of solvents has no advantageous effect in this special case. Preferably activated arenes are halogenated, whereby bromination afforded higher product yields than chlorination. Most often reactions are regio- and chemoselective, since p-substitution was preferred and concurring side-chain oxidation of alkylated arenes by KHSO5 was not observed.

Hydrogenation of citral: a wide-spread model reaction for selective reduction of α,β-unsaturated aldehydes

Citral (1) is an α,β-unsaturated aldehyde classified as a monoterpenoid compound from the 3,6-dimethyloctane series, characterized by a head-to-tail linkage of two isoprenoid subunits. The “citrus effect” in many consumer goods can be traced back to the odor of 1, which is also an important building block in the fine chemical industry for production of carotenoids, vitamins, and other flavors and fragrances. The presence of three unsaturated sites in the molecule, i.e. a carbonyl group, a conjugated and an isolated CC bond, makes 1 an interesting model compound for catalytic tests in the field of selective hydrogenation of α,β-unsaturated carbonyl compounds. Several types of catalysts have been described so far for this reaction. The choice of active metal as well as the manipulation of the electronic and steric conditions of the active metal sites in heterogeneous but also homogeneous catalysts allowed the discrimination of distinct reaction pathways affording partially hydrogenated products. Thus, industrially important products like citronellal (2), geraniol (E-3), nerol (Z-3), or citronellol (5) are available from 1 by addition of hydrogen to one of the unsaturated sites. The present review discusses the various possibilities of catalyst design leading to selective but also active catalyst systems for hydrogenation of 1 covering the literature from 1990–2012. Beside supported catalysts with one or two transition metals containing active sites for surface hydrogen splitting, the fields of enzymatic and catalytic transfer hydrogenation are highlighted. In addition scope and limitation of advanced reaction technologies with respect to hydrogenation of 1 are presented, i.e. continuous processing, reduction in supercritical CO2, or the effect of ionic liquids as solvents or reaction modifiers.

An Alternative Solvent‐Free Synthesis of Nopinone under Ball‐Milling Conditions: Investigation of Reaction Parameters

A new method for the oxidative cleavage of β-pinene (1) yielding nopinone (2) with potassium permanganate as oxidant under solvent-free conditions was established. The reaction was performed in a conventional ball mill with use of a grinding auxiliary. The auxiliary has the ability to sorb liquid reactants such as 1 on its surface to make liquid(s) accessible for mechanical impact. Different reaction parameters and technical variables were assessed concerning their influence on yield and selectivity of 2. Different chemical parameters such as oxidants, grinding auxiliaries, and quantities were investigated. Also tuning parameters including milling time, rotation frequency, and number of milling balls were explored.

Solvent-free reactions of alkynes in ball mills: It is definitely more than mixing

This contribution presents two solvent-free reactions of terminal alkynes in ball mills: Pd-catalyzed Sonogashira cross-coupling and Cu-catalyzed homo-coupling (Glaser reaction). The results are compared to other solvent-free reaction protocols, which have been published up to date for those types of reactions. Reactions are assessed on the basis of reaction variables like type of catalyst and base or reaction time. Furthermore, performance-based parameters (yield, selectivity, turnover number, TON, and turnover frequency, TOF) are considered and evaluated. Findings from ball-milling experiments indicate that those processes are comparable to the energy entry by microwave irradiation with respect to reaction time and TOF.

Pd on Porous Glass: A Versatile and Easily Recyclable Catalyst for Suzuki and Heck Reactions

The catalytic activity of Pd supported on porous glass was studied for both Suzuki and Heck reactions under aerobic conditions, with particular focus on the Suzuki coupling. The reactions were carried out in water under microwave irradiation. The effects of the catalyst preparation process (calcination time and temperature), as well as the base, substrate, and boron compound used on the coupling reaction were investigated in relation to the reusability of the catalyst. Various bases promote the Suzuki coupling of phenylboronic acid with bromophenol very effectively resulting in quantitative conversion and excellent selectivity for the coupling product. However, most bases lead to deactivation of the catalyst after the first reaction cycle and the catalyst must be reactivated before reuse. Therefore, excellent conversions and selectivities for individual reactions are not sufficient to conclude if the chosen conditions are suitable for a given reaction, but resuits from recycling studies have to be considered also.