February 16, 2009
Take a mechanochemical approach to the Suzuki–Miyaura reaction. The Suzuki–Miyaura reaction is one of the most studied C–C coupling reactions for industrial applications. The procedure involves a halide, a boronic acid, an inorganic base, and a palladium source; it requires a solvent and sometimes elevated temperature. B. Ondruschka and coauthors at Friedrich-Schiller University Jena and the Technical University of Braunschweig (both in Germany) report a mechanochemical approach to this reaction that uses ball milling.
The authors chose the reaction between 4-bromoacetophenone and phenylboronic acid in the presence of KF–Al2O3 and Pd(OAc)2 as their model. They selected grinding materials (type, size, and number of milling balls), beaker material, revolutions per minute (rpm), and milling time as the parameters to be optimized (see figure).
The authors first evaluated rpm and grinding material; they found that both variables influence reaction yields and that the influence of grinding material is greater at lower rpm than at higher rpm. Milling time is also more critical at lower rpm. Long reaction times cause the product to decompose. The combination of balls and beakers of the same material is advantageous in terms of product yield. The maximum relative velocity of the grinding material contributes most to the kinetic energy of the process—more so than the number of balls (which reflects the active surface area).
The authors note that this technique allows Suzuki–Miyaura reactions to be run under solvent-free mechanochemical conditions. The method is environmentally friendly with simple workup procedures and has a better energy balance than thermal- and microwave-mediated processes. (Org. Process Res. Dev. 2009, 13, 44–48; José C. Barros)
A new twist on miniemulsions generates functional nanoparticles. R. Haag and colleagues at the Free University of Berlin and the Max Planck Institute for Polymer Research (Mainz, Germany) detail the synthesis of hydrophilic and hydrophobic functional nanoparticles derived from hyperbranched polyglycerol (HPG) macromonomers. They use a miniemulsion polymerization scheme and Huisgen alkyne–azide “click” chemistry.
In the presence of a surfactant and catalyst system, aqueous miniemulsification of HPG (5 kDa, 60% degree of branching [DB], and 80% propargyl bromide–functionalized) with decane diazide cross-linker in CHCl3 yielded hydrophobic nanoparticles. By varying the amount of surfactant to CHCl3, the researchers could tune the diameter of the monodisperse, hydrophobic nanoparticles between 25 and 85 nm.
Hydrophilic nanoparticles were synthesized by using a surfactant-stabilized inverse miniemulsion of HPG (5 kDa, 60% DB, and 30% azido or propargyl bromide functionality) in DMF suspended in cyclohexane via catalyst-free, thermally activated cycloaddition. As in the hydrophobic scheme, hydrophilic HPG-based nanoparticles were monodisperse with diameters between 45 and 90 nm as function of surfactant content. In both strategies, the yield was lower for larger diameter nanoparticles. The authors also covalently incorporated a dye molecule into the core of the hydrophilic nanoparticles in a preliminary study of the development of functional nanoparticles with a view toward drug delivery applications. (Macromolecules 2009, 42, 556–559; LaShanda Korley)
Use macrocycles as reactants to form bi-and tricyclic lactam scaffolds. J. A. Porco, Jr., and coauthors at Boston University and the University of New Hampshire (Durham) report a simple and innovative synthesis of macrocyclic bislactams (1) by cyclodimerizing homoallylic amine esters. They then used 1 as a reactant to form bicyclic (2) and tricyclic (3) bislactams.
The synthesis of 1 is mediated by a zirconium complex (HYP is 2-hydroxypyridine) and proceeds with yields as high as 80%—exceptionally high for a 14-membered macrocycle. The optimum concentration of the amine ester for formation of 1 is 0.6 M.
Compound 1 is treated with base to provide varying ratios of products 2 and 3; the ratio depends strongly on the type of aryl substitution and the reaction solvent. When Ar is 3-MeOC6H4 and the solvent is N,N-dimethylacetamide (DMAc), a ~1:1 mixture of 2 and 3 form, whereas the ratio is 1:4 when Ar is 2-naphthyl. When the solvent is changed to DMF, 2 is formed exclusively with both aromatic substituents.
The authors further functionalized three tricyclic structures illustrated by 3 via diastereoselective alkylation using lithium hexamethyldisilazide (LiHMDS) followed by quenching with alkyl halides. Surprisingly, the resulting bisalkylated products (e.g., 4) formed as single diastereomers.
Mechanistic studies of the reaction leading to the bislactams support an olefin isomerization–intramolecular conjugate addition pathway. Considering the frequent occurrence of macrocyclic rings in natural products, these densely functionalized structures could have potential value for making bioactive compounds. (Org. Lett. 2009, 11, 413–416; W. Jerry Patterson)
Surface roughness enhances sorption probability of aromatics on zeolite crystals. H-ZSM-5 zeolite is an important material in the petrochemical processes such as toluene alkylation, disproportionation, xylene isomerization, and hydrocarbon separation because of its selective micropore channels. Adsorption is one of the fundamental steps in these processes. Studies have shown that the sticking probability of aromatic molecules on zeolites is relatively low and highly sensitive to the number of statistically favorable orientations of the molecules during the collision with the external surface of the zeolite particles. Therefore, enhancing this number should enhance trapping of the molecules.
J. A. Lercher and co-workers at the Technical University of Munich (Germany) show that surface modification of H-ZSM-5 with a thin layer of amorphous porous silica can greatly enhance the sorption probability of aromatic molecules. In time-resolved benzene sorption profiles, the initial adsorption rate on modified H-ZSM-5 is significantly faster than that on the unmodified material. The authors believe that the improved sorption rate is a result of the enhanced surface roughness of the modified zeolite, which increases the molecules’ sticking probability. (Angew. Chem., Int. Ed. 2009, 48, 533–538; George Xiu Song Zhao)
Here’s an unusually simple aryl–alkyl cross-coupling reaction. Cross-coupling reactions have evolved in into extremely valuable methods for organic synthesis. They are based primarily on mediation by palladium or nickel complexes. Because of the high costs of these catalysts and concerns about the toxicity of their residues, W. M. Czaplik, M. Mayer, and A. J. von Vangelin* at the University of Cologne (Germany) sought economical and safe alternatives for the cross-coupling process.
They developed a mild, easy method for aryl-alkyl cross-coupling that features “domino” iron catalysis, in which inexpensive FeCl3 serves as a precatalyst that leads to Grignard agent formation and subsequent cross-coupling. Their work includes the formation of aryl–alkyl (1) and 2-alkenyl–alkyl (2) cross-coupling products under one-pot conditions.
TMEDA is tetramethylethylenediamine; it is critical to the success of these reactions, likely by stabilizing the iron and magnesium complexes. When TMEDA is absent, the reaction fails.
The scope of this process includes the reaction of substituted (alkyl, alkoxy, fluoro, and amino) aryl bromides and heteroaryl bromides with primary and secondary alkyl bromides. When alkenyl bromides are used as the coreactant with alkyl bromides, the reaction efficiency is a function of olefinic structure. Vinyl bromide gives only a complex product mixture, but dimethylvinyl bromide gives the corresponding olefinic cross-coupling product in moderate yields.
The authors note that, despite the expected thermodynamic preference in this reaction for homocoupling to give the biaryl, the process displays high selectivity for the desired cross-coupling product with <9% biaryls formed in all cases. This one-pot reaction features a novel sequence of iron-catalyzed Grignard formation and iron-catalyzed cross-coupling and constitutes the first example of domino iron catalysis for cross-coupling reactions. (Angew. Chem., Int. Ed. 2009, 48, 607–610; W. Jerry Patterson)
Directly substitute nitropyridones by in situ silylation. 3-Nitro-4-pyridones cannot be substituted directly but require conversion of the hydroxy group to a chloride or methoxy group, which can then be displaced by a variety of nucleophiles. R. A. Singer* and M. Doré at Pfizer (Groton, CT) describe a direct substitution method that uses in situ silylation with hexamethyldisilazane (HMDS).
The reaction is operationally simple and does not need to be carried out in a stepwise manner. An amine, HMDS, and the nitropyridone are heated at 60–75 °C in MeCN for 8–24 h to give a >80% yield of an aminonitropyridine. (Org. Process Res. Dev. 2008, 12, 1261–1264; Will Watson)
Use stereolithography to create biocompatible porous networks. D. W. Grijpma and coauthors at the University of Twente (Enschede, The Netherlands) and the University of Groningen (The Netherlands) designed biocompatible resin materials that are suitable for making tissue engineering scaffolds by stereolithography. They developed porous networks (see image) based on oligomeric fumaric acid monoethyl ester (FAME)–functionalized (86–97%) poly(D,L-lactide) (PDLLA, ~3000 Da) photo-cross-linked in the presence of hydrophilic N-vinyl-2-pyrrolidone (NVP) comonomer (20–50 wt%).
The authors’ comonomer strategy enhances photopolymerization and cross-linking kinetics and provides suitable mechanical integrity and cell adhesion characteristics necessary for tissue engineering applications. For example, gelation (~90%) is achieved within 15 min for the PDLLA–FAME macromonomer–NVP system compared with an irradiation time of 3 h (~81% gel) without NVP. Increasing the NVP content from 0 to 50% results in an increase in Tg from ~39 to 96 °C and produces high water uptake values and lower contact angles compared with the high–molecular weight PDLLA control. The contact angle measurements are less sensitive when >20% NVP is incorporated because of the optimal concentration of hydrophilic NVP segments at the network surface. The ability to attenuate the degree of hydrophilicity by NVP incorporation is a crucial step toward tailoring cell-seeding phenomena.
As expected, the Young’s modulus decreases with increasing amounts of NVP in the hydrated state, whereas the converse is observed in the dry state. The extensibility is unaffected in the wet or dry state as a function of NVP level. The tensile strength of hydrated PDLLA–FAME–NVP networks, however, is dramatically affected, decreasing from ~42 MPa to ~7 MPa as the NVP content increases from 0 to 50%.
The NVP also serves to enhance the number of elastically effective chains in the network. Desirable spread morphology was obtained in cell adhesion studies on PDLLA–FAME–NVP networks with adherence behavior similar to PDLLA and tissue culture polystyrene controls. The authors formed 3-D scaffolds in the PDLLA–FAME–NVP resin systems via stereolithography, producing homogeneous and interconnected gyroid morphology with a porosity of 80% and interconnected pore diameter of ~256 μm. (Biomacromolecules 2009, 10, ASAP Article DOI: 10.1021/bm801001r; LaShanda Korley)
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