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Noteworthy Chemistry

April 20, 2015

 

The pharmaceutical process chemistry lab has changed a lot. The environment of the pharmaceutical process development laboratory has changed over the past 20 years to better reproduce industrial-scale conditions for scaling up products for manufacture. By using several examples of process chemistry, S. Caron* and N. M. Thomson at Pfizer (Groton, CT) describe how industrial labs for organic synthesis differ from their academic counterparts for making active pharmaceutical ingredients (APIs).

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The authors first discuss route selection, emphasizing screening and purification methods that are reliable for industrial production; definition of starting materials, intermediates, and impurities; and the choice of the final form of the API. They next discuss process optimization, such as the relationship between API purity and process parameters, the understanding of starting material solubility to aid design, reaction kinetics, process modeling, comparison of batch and flow conditions, and design of experiments.

Finally, issues related to technology transfer and scale-up, such as process safety, process fit (the equipment configuration), and data management are considered. Developing modern API production processes, from laboratory to industrial scale, is a multidisciplinary task that requires several tools to predict, analyze, and assess safety and reproducibility. The laboratory has changed so that the entire workforce operates collaboratively in a data-rich environment. (J. Org. Chem. DOI: 10.1021/jo502879m, José C. Barros)

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Use MOFs to destroy chemical warfare agents. Chemical warfare agents are among the most notorious weapons of mass destruction. With increased terrorist activities and regional military conflicts worldwide, there is an urgent need to mitigate the risk from chemical warfare agents, especially organophosphorus-based nerve agents such as sarin and soman. Bulk destruction of chemical weapon stockpiles is highly desirable, but few materials can break them down efficiently and rapidly.

By using a highly porous and chemically stable metal–organic framework (MOF), J. T. Hupp and O. K. Farha at Northwestern University (Evanston, IL) and colleagues in the United States and Saudi Arabia demonstrated the degradation of phosphonate ester–based nerve agents and their simulants.

The researchers used an MOF material called NU-1000 that features eight connected Zr63-O)43-OH)4(H2O)4(OH)4 nodes and tetratopic 1,3,6,8-(p-benzoate)pyrene linkers with wide channels “decorated” in their interiors by terminal-zirconium–ligated aquo and hydroxo groups. NU-1000 was highly efficient for catalyzing the hydrolysis of the nerve agent simulant dimethyl 4-nitrophenyl phosphate, among others.

More importantly, NU-1000 degraded soman via catalytic hydrolysis with high turnover frequencies in buffer solutions under 50% RH. NU-1000 is one of the most active heterogeneous catalysts for soman hydrolysis, and the authors attribute its performance to uniquely configured nodes that allow easy access to catalytically active sites within the MOF.

NU-1000 should be useful as a material for the bulk destruction of nerve agents. Given its flexible structure, it may be developed into materials that target other hazardous chemicals. (Nat. Mater. DOI: 10.1038/nmat4238; Xin Su)

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Hybrid cage complexes fluoresce in solution and as solids. Many fluorophores emit brightly as dissolved molecules but become dark when they aggregate. Other fluorogens behave in the opposite way. These phenomena often are referred to as aggregation-caused quenching and aggregation-induced emission (AIE).

F. Huang, P. J. Stang, and coauthors at Zhejiang University (Hangzhou, China), the University at Buffalo (NY), and the University of Utah (Salt Lake City) developed two supramolecular coordination complexes (SCCs), both of whose individual molecules and aggregates are emissive.

Simply stirring mixtures of AIE ligand 1, dicarboxylate ligand 2 or 3, and platinum(II) acceptor 4 under appropriate conditions readily yields tetragonal metallacages 5 or 6 (see figure). Unlike their insoluble counterparts, metal–organic frameworks (MOFs), the discrete SCCs are soluble, and their solutions photoluminesce in various colors. Although solutions of 1 are nonemissive, the SCC solutions luminesce because the immobilization of the tetraarylethylene units inside the metallacages restricts the intramolecular rotation of the aryl rotors.

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Synthesis of SCCs that photoluminesce in solution and as aggregates

The emission of the SCC solutions changes with the type and composition of the solvents. This solvatochromic effect allows their fluorescence color to be tuned over a wide spectral range and with varying efficiency. The photoluminescence color of poly(ethylene glycol)–functionalized SCC 6 is sensitive to structurally similar ester solvents, a property that may be the basis of a fluorescent chemosensor for detecting difficult-to-differentiate molecules.

The SCCs’ emissions intensify with aggregation. The nonplanar cage structures of the SCCs weaken intercage interactions, and aggregate formation further restricts the rotation of the aryl rotors, making the SCCs AIE-active.

Partial aggregates of molecules of 6 in tetrahydrofuran emit white light. The aggregation-induced white-light emission from an SCC in a single solvent at room temperature makes the metallacage a promising candidate for advanced optoelectronic materials. It is an excellent complement to conventional white-light emission materials that often require a mixture of two or more components and/or solvents. (Nat. Chem. DOI: 10.1038/nchem.2201; Ben Zhong Tang)

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Precipitate salts from a water-soluble amidation product. Q. Tian and coauthors at Genentech (South San Francisco, CA) and F. Hoffmann-La Roche (Basel, Switzerland) developed a second-generation, protecting-group–free synthesis of a P13K/mTOR inhibitor. Pathways of the P13K and mTOR kinases are frequently activated in human tumors.

One required building block for the inhibitor is a piperazine lactamide, which the authors prepared directly from piperazine and ethyl (S)-lactate with sodium methoxide in methanol. Optimal conditions to achieve a 70% assay yield required a 1.3:1 ethyl (S)-lactate/piperidine mol ratio.

The reaction was followed by the addition of 3 equiv of water. The water-soluble product was isolated by first adding 0.25 equiv oxalic acid to precipitate the sodium as its oxalate salt. Then more oxalic acid was added to pH 7.0–7.5, which precipitated piperazine oxalate.

After filtration removed the salts, the mother liquors that contained the product were treated with yet more oxalic acid (1.12 equiv) to give the desired product as the oxalate salt in 59% yield and >99% purity. (Org. Process Res. Dev. DOI: 10.1021/op500366s; Will Watson)

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Modern-day knights might wear shining cardigans. Light-emitting fibers that can be woven or knitted into fabrics may potentially be used for many things, from safety clothing for night-time walkers and cyclists to medical devices. H. Peng and coauthors at Fudan University (Shanghai), Shanghai University, and the University of California, Los Angeles, developed fibers that function as polymer light-emitting electrochemical cells (PLECs). These fibers efficiently produce light and require very little power.

The researchers dip-coated a thin stainless steel wire, the cathode, with a layer of zinc oxide (ZnO) nanoparticles. A second dip-coating deposited an electroluminescent polymer layer. They then wrapped an outer layer of aligned carbon nanotubes, which served as a transparent anode, around the outside of the polymer coating.

The ZnO layer reduces current leakage and prevents the metal from fluorescence-quenching the polymer layer. The polymer layer contains the blue-light–emitting polyfluorene copolymer PF-B, the ethoxylated trimethylolpropane triacrylate electrolyte ETT-15, and the salt lithium trifluoromethanesulfonate.

The resulting ≈1 mm-thick fibers can be twisted or woven into textiles. When a potential of a few volts is applied between the metal wire and the carbon nanotube layer, the entire fiber surface emits light. Coating fibers with polymers that emit different colors and connecting them to independently variable external current sources allowed the resulting colors to be tuned continuously and independently over a wide range (see figure).

Fiber-shaped PLECs with tunable colors twisted together to generate colorful lights
Courtesy of H. Peng

Previous attempts at making LECs were limited by the contact arrangement of the electrodes or the small scale of the fibers. This study overcomes these limitations, although the fibers require ≈21 min to achieve maximum luminescence. The intensity decreases slowly over the next 4 h. Repeated bending of the fibers does not decrease their performance, which the authors demonstrated by weaving light-emitting fabrics.

Future development work will concentrate on increasing operating stability. Other improvements could include generating other colors, scaling up production, and developing an outer protective coating material for the fibers. (Nat. Photonics DOI: 10.1038/nphoton.2015.37; Nancy McGuire

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