Noteworthy Chemistry

February 21, 2011

Glycidyl ether–based copolymers respond to thermal stimuli. Poly(ethylene glycol) (PEG) and poly(glycidyl ether)s derived from it are chemically inert, biocompatible polymers that are in great demand in biomedical fields. For example, successful research on PEG-based copolymers that respond to environmental stimuli such as temperature and pH has led to further exploration. To this end, M. Weinhart*, T. Becherer, and R. Haag at the Free University of Berlin studied the thermal responses of glycidyl methyl ether (1)–based copolymers.

The authors used glycidyl ethyl ether (2) or glycidyl 1-ethoxyethyl ether (3) as the second monomer in the copolymer chain. Copolymers 4 [prepared from poly(1-stat-2)] and 5 [prepared from poly(1-stat-3)] respond to temperature changes. Above normal body temperature (37 °C), the copolymers dehydrate in water.

To test their biocompatibility, the copolymers were immobilized on gold surfaces via self-assembled monolayer formation. At 40 °C, >50% of added fibrinogen adsorbs on the polymer surfaces as a result of polymer dehydration. When cooled to 25 °C, the copolymers rehydrate and discharge the protein from the surfaces. This reversible temperature-controlled protein adsorption–desorption behavior is not fully understood and requires further study. (Chem. Commun. 2011, 47, 1553–1555; Sally Peng Li)

New anti-inflammatory prodrugs have enhanced safety profiles. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and effectively used for treating inflammatory processes, as in osteoarthritis. These drugs inhibit cyclooxygenase-derived prostaglandin synthesis; but they can cause serious gastrointestinal problems, including irritation, ulceration, and bleeding.

One of the more effective drugs in this class is diclofenac sodium (1), which is readily converted to a prodrug by masking its carboxylate group. B. P. Bandgar and coauthors at Solapur University (India) and Swami Ramanand Teerth Marathwada University (Nanded, India) selected 1 as a scaffold for preparing prodrugs 24. Each prodrug can be enzymatically degraded to a common diclofenac metabolite. The goal was to minimize the side effects of 1 and improve its delivery characteristics.

The authors converted diclofenac sodium to prodrug esters 24 with straightforward reactions of the carboxylate anion with haloalkyl esters. They confirmed that each prodrug was >98% pure before in vitro and in vivo evaluations.

In a series of studies, they compared the bioactivity of prodrugs 24 with parent drug 1. Based on measurements of metabolic stability, enzymatic lability, aqueous solubility, lipophilicity, and acute ulcer formation, the authors state that prodrug 2 has the highest potential for an anti-inflammatory drug. This compound also has significantly lower ulcerogenic side effects than parent drug 1, which suggests that masking the carboxylate functionality of 1 decreases the potential for ulceration of the gastric mucosa. All three prodrugs have better safety profile than 1, even at higher doses.

The authors conclude that prodrug 2 is a potent alternative to 1. It produces a significant anti-inflammatory response and minimizes gastrointestinal side effects. (J. Med. Chem. 2011, 54, Article ASAP DOI: 10.1021/jm101095e; W. Jerry Patterson)

Solid-supported evaporation is an improved isolation technique. The workup after a reaction can consist of only product isolation (e.g., solvent removal) or isolation and purification. Crystallization is the preferred isolation method and usually requires an antisolvent. Solid products can also be evaporated to dryness if they are sufficiently thermally stable.

F. L. Muller and B. Whitlock* at AstraZeneca (Macclesfield, UK) developed a new isolation procedure, solid-supported evaporation (SSE), in which the reaction mass is sprayed onto adsorbent solid particles under vacuum. As the solvent evaporates, the nonvolatile substances, usually the reaction products, are deposited within the adsorbent.

The authors used a continuously fed rotary evaporator containing polypropylene beads as the adsorbent. The beads are chemically inert and accepted by regulatory authorities for pharmaceutical manufacturing processes. Maleic acid was chosen as the substrate; and MeCN, EtOH, toluene, tert-butyl methyl ether, 2-methyltetrahydrofuran, and methyl isobutyl ketone were tested as solvents.

The evaluation of polypropylene supports showed that Accurel MP1000 beads functioned better than Accurel MP100 because they have higher solvent capacity but retain less solvent after drying. The solute capacity of the beads is such that the optimum loading is 1 g product/g support. The products were recovered from the beads by washing with water, 10% EtOH in water, and then 5% water in MeCN. The authors expanded the method to thermally unstable compounds such as 3-nitrobenzaldoxime, which decomposed at a slower rate in the SSE process than evaporation to dryness because the polymer beads act as a heat sink.

The advantages of SSE are good product recovery, increased thermal stability of the product inside the beads, and avoidance of product dust. (Org. Process Res. Dev. 2011, 15, 84–90, JosÉ C. Barros).

Aggregation triggers light emission from a platinum complex. The luminescence of a “conventional” Pt(II) complex is often adversely affected by increasing its concentration: Its emission color red-shifts, and its photoluminescence quantum yield (ΦPL) decreases at high solution concentration or when it is made into a solid film. C. A. Strassert, L. De Cola, and coauthors at the Dutch Polymer Institute (Eindhoven), the University of MÜnster (Germany), National Chiao Tung University (Hsinchu, Taiwan), and the University of Cologne (Germany) synthesized an “abnormal” Pt(II) complex (1) and found that it behaves differently from its conventional congeners.

The authors prepared the complex in a simple one-pot reaction of a Pt(II) salt with mono- and tridentate ligands. Whereas dilute solutions of 1 were nonluminescent, emission switched on when the molecules self-assembled to increase the local concentration of the complex. The luminescence efficiency of the complex greatly increased (ΦPL up to 90%), but its emission spectrum changed little when its molecules aggregated, gelled, or were blended with polymer films.

Because of aggregation-induced emission, the aggregates of 1 can be used as active doping or emitting species at high doping levels in the production of organic light-emitting diodes (OLEDs). An OLED with a high doping content of 1 (10 wt%), for example, showed maximum luminance and current efficiency as high as 11,360 cd/m2 and 15.6 cd/A, respectively. (Angew. Chem., Int. Ed. 2011, 50, 946–950; Ben Zhong Tang)

Fine tune the degradation of new drug delivery carriers. H. Tan, Q. Fu, and colleagues at Sichuan University (Chengdu, China) synthesized segmented polyurethanes with pH-responsive units that facilitate biodegradation for controlled drug release. They used a biocompatible, amorphous hard domain that consisted of a functional tripeptide chain-extender and a macrodiol copolymer that consisted of poly(ε-caprolactone) (PCL) and polyethylene glycol (PEG) connected via an acid-labile hydrazine (Hyd) linker (1).

The initial materials had low molecular weights (4.2–6.2 kDa) and high polydispersities (>2.3) because they were poorly soluble, but they exhibited a degree of microphase segregation and >50% crystallinity of the PCL segments. The authors degraded the polymer chains by using enzymatic and hydrolytic pathways. Cleaving the hydrazone units could be tuned by adjusting the pH of the medium; the optimum pH varied slightly with polyurethane composition. The stability of the hydrazone linkage under physiological conditions depended on the mol ratio of the components.

The polyurethanes formed micelles, which is important for drug delivery. Micelle diameter was a function of pH-sensitive polyurethane composition. Initial studies also showed limited cytotoxicity under accelerated degradation in basic and acidic environments. (Macromolecules 2011, 44, 857–864; LaShanda Korley)

Use fluorescence from common materials as a teaching tool. Chemical phenomena observed in daily life offer a good way to introduce chemistry to students. In their recent article “Classroom Activity Connections: Lessons from Fluorescence” (J. Chem. Educ. 2010, 87, 685–686), A. MacCormac*, E. O’Brien, and R. O’Kennedy discussed ways to explain fluorescence. They suggested demonstrations of fluorescent vegetables and fruit such as peppers, tomatoes, lettuce, onions, and bananas. For example, foods that contain vitamin B12 fluoresce yellow under UV irradiation. The yellow color is brighter when a vitamin B12 tablet dissolved in vinegar is irradiated.

M. A. Muyskens* and M. S. Stewart at Calvin College (Grand Rapids, MI) report alternative ways to demonstrate fluorescence. They show that fresh green pepper fluoresces with a magenta color when a piece of yellow plastic is used to filter the light source. They also state that the yellow color described by MacCormac et al. is fluorescence from vitamin B2 (riboflavin), not B12, which fluoresces, but not in the visible spectrum.

The authors stress that students should be instructed not to look directly at the UV source and that eye protection is necessary when they get close to the light. (J. Chem. Educ. 2011, 88, 259–260; Sally Peng Li)

Add chlorobenzene to extend a hydrosiloxane reduction. Dispersing palladium in a poly(methylhydrosiloxane) (PMHS) matrix increases the metal’s catalytic activity in reduction reactions. A mixture of Pd(OAc)2 and PMHS forms polysiloxane-encapsulated palladium nanoclusters.

R. J. Rahaim, Jr., and R. E. Maleczka, Jr.,* at Michigan State University (East Lansing) previously reported that this reductive catalytic complex mediates the rapid dehydrohalogenation of chloroarenes and dehydrohalogenation–hydrogenolysis of chloroacetophenones (Tetrahedron Lett. 2002, 43, 8823–8826). This result indicated that HCl generated during the reaction affects the final product. They now show that the Pd(OAc)2–PMHS nanoclusters mediate a highly efficient deoxygenation of substrates such as acetophenone directly to ethylbenzene (PhEt, 2) when accompanied by a small amount of chlorobenzene (PhCl).

The deoxygenation stops at the alcohol product 1 in the absence of PhCl, but it proceeds quantitatively to fully deoxygenated product 2 with the addition of 10 mol% PhCl. The PhCl concentration can be reduced to 1 mol% without adverse effect; but at <1 mol%, the reaction stops at 1.

It appears that the process involves palladium nanoparticle–catalyzed hydrosilylation followed by C–O reduction. PhCl facilitates the hydrogenolysis with the slow, controlled release of HCl.

Almost no other halides affect the reaction this way. An exception is 4-chloroanisole, which allows deoxygenation of several more difficult substrates. This system results in chemo-, regio-, and stereoselective product formation to varying degrees. Increasing the steric environment around the carbonyl groups hinders the deoxygenation, whereas methyl substitution at both ortho positions completely inhibits the reaction.

The authors believe that this study represents the first example of PhCl functioning as a useful additive in palladium-mediated reductions. (Org. Lett. 2011, 13, 584–587; W. Jerry Patterson)

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