Noteworthy Chemistry

October 31, 2011

The monomer sequence affects biopolymer degradation. The copolymer poly(lactic acid-co-glycolic acid) (PLGA) has superior biocompatibility and biodegradability. The two monomer units are randomly connected by ester linkages. The polymer hydrolyzes in biological environments to smaller chains with varying molecular weights.

The ester linkages in the glycolic acid units are more labile toward hydrolysis than the lactic acid esters. Because the PLGA structure is random, its hydrolysis rate is somewhat unpredictable, which makes it difficult to use in applications such as controlled drug delivery.

T. Y. Meyer and co-workers at the University of Pittsburgh recently synthesized nonrandom, alternating copolymers from the two monomers (J. Am. Chem. Soc. 2011, 133, 6910–6913) and found that they could control the hydrolysis of the copolymers. The degradation rate does not vary throughout the process, and the products have uniform structures (see figure).

C. M. Thomas* and J.-F. Lutz* at the National Center of Scientific Research (Paris and Strasbourg, France) discuss this discovery. They predict that poly(lactic acid-alt-glycolic acid)s will be used to improve highly regulated life science applications, especially drug-delivery systems. (Angew. Chem., Int. Ed. 2011, 50, 9244−9246; Sally Peng Li)

Calixarenes support polymetallic lanthanide clusters. Renewed interest in the synthesis of polymetallic cluster compounds that contain 4f ions is based on their uses in single-molecule magnetism and molecular cooling. Single-molecule magnets have potential applications in information storage. Cooling is important when very low-temperature local refrigeration is needed: for example, in high-resolution X-ray and γ-ray detectors in astronomy and materials science, and in security devices.

One way to increase the effective energy barrier to magnetization reversal in molecular magnets is to introduce highly anisotropic f-block ions such as Dy(III), Tb(III), Ho(III), and Er(III). Even single-ion complexes that contain these metals can display hysteresis loops in magnetization-versus-field studies. High-spin isotropic f-block ions such as Gd(III) can be used to build molecules with weak exchange interactions. These molecules are ideal candidates for enhanced magnetic cooling because their negligible anisotropy allows easy polarization of the net molecular spin and leads to large changes in magnetic entropy. The presence of degenerate or low-lying excited spin states results in extra magnetic entropy from the incremental degrees of freedom. The Gd(III) ion is thus an ideal choice for building molecular refrigerants.

The use of calix[n]arenes as ligand scaffolds for assembling this type of molecule is rare and underexploited. E. K. Brechin, S. J. Dalgarno, and coauthors at the University of Edinburgh (UK), Heriot–Watt University (Edinburgh), Lawrence Berkeley National Laboratory (CA), and the University of Zaragoza (Spain) show that simple reaction conditions can be used to isolate calix[4]arene-supported rare earth octahedra. Each calixarene group coordinates to one lanthanide at its “lower rim”; the oxygen atoms also bridge to other metal centers within the octahedron.

These authors previously showed that p-tert-butylcalix[4]arene can be used to form polynuclear transition-metal and mixed 3d–4f systems under equally simple conditions. This report demonstrates that this versatile molecule also allows access to 4f cluster motifs. (Chem. Commun. 2011, 47, Advance Article DOI: 10.1039/C1CC14603C; Gary A. Baker)

Here’s a way to resolve the enantiomers of praziquantel. Praziquantel (PZQ, 1) is the drug of choice for treating schistosomiasis, a neglected disease considered a “silent pandemic”. PZQ is produced on a large scale—300 t/year worldwide—primarily for veterinary medicinal uses. Its main use in human medicine is preventive chemotherapy against schistosomiasis in children.

PQZ is supplied as a mixture of enantiomers: The (R)-(–) isomer has the desired pharmacological affect; the (S)-(+) enantiomer is associated with side effects and the drug’s bitter taste.

An economical route to enantiopure PZQ is not available. M. H. Todd and coauthors at the University of Sydney, Syncom (Groningen, The Netherlands), and the World Health Organization (Geneva, Switzerland) report two methods for resolving PZQ enantiomers: one (A) that begins with commercially available PZQ and another (B) in which a PZQ intermediate is resolved (see figure).

In method A, rac-1 is hydrolyzed in an acidic medium to a racemic amine (rac-2), which is resolved with L-dibenzoyltartaric acid. After filtering and separating the tartaric acid from the resolved solid, (R)-2 is isolated in 99% ee and 33% overall yield. The (S)-enantiomer can be obtained from the mother liquor from the resolution process, and the resolving agent can be recycled. (R)-1 is prepared from (R)-2 by treating it with cyclohexanoyl chloride.

Method B resolves PZQ intermediate (rac)-3 with readily available L-tartaric acid to obtain (R)-3, which, after its reaction with CH2ClCOCl and hydrolysis gives (R)-2 in 94% ee and 37% yield. (R)-2 is converted to (R)-1 as in method A.

In addition to providing two routes for obtaining enantioenriched PZQ, this study is a good example of a collaborative effort for synthesizing drugs to combat neglected diseases. (PLoS Negl. Trop. Dis. 2011, 5, e1260 DOI: 10.1371/journal.pntd.0001260; JosÉ C. Barros)

Organize and stabilize block copolymers in a magnetic field. R. A. Segalman and co-workers at the University of California, Berkeley, Lawrence Berkeley National Laboratory, and Netherlands Organization for Scientific Research (Grenoble, France) explored how an applied magnetic field influences the assembly—particularly the order–disorder transition (ODT)—of rod–coil block copolymers (BCPs). The BCP used in this study was lamellar poly[2,5-di(2’-ethylhexyloxy)-1,4-phenylenevinylene]-b-polyisoprene (PPV-b-PI, Mn 12 kDa, polydispersity 1.10) with smectic liquid crystalline ordering.

The authors observed several ordering transitions in the absence of a magnetic field:

  1. melting of the semicrystalline PPV block at 60°C;
  2. simultaneous ODT and smectic-to-nematic transitions at ≈115°C; and
  3. a nematic-to-isotropic (N-I) transition at 140°C.

The BCP assembly is influenced by the interplay of the liquid crystalline segments. Applying a magnetic field aligns an initially unoriented BCP and increases its ODT. As shown by in situ, small-angle X-ray scattering studies, the ODT temperature increases with increasing field strength (e.g., a ≈30°C increase at 7 T) and is greater than the N-I transition temperature or the ODT in the absence of a magnetic field.

The authors believe that the microphase-separated, lamellar BCP morphology is stabilized when the liquid-crystal domains couple with the magnetic field. These findings offer insight into field-induced alignment and BCP self-assembly. (Macromolecules 2011, 44, 7503–7507; LaShanda Korley)

String boratabenzeneiron(II) “beads” on polymer chains. Many metal atoms and organometallic complexes have been incorporated into the backbones and substituents of polymer chains. Polymetallocenes are a class of prominent organometallic polymers that have desirable optical, electronic, magnetic, and preceramic properties. Boratabenzene is a six-membered ligand that is used to synthesize numerous organometallic complexes, but it has not been incorporated into a polymer structure until now. F. Pammer, R. A. Lalancette, and F. Jäkle* at Rutgers University–Newark (NJ) embedded boratabenzene ligands into polymetallocene backbones.

The researchers prepared a series of bis(borinato) iron (II) complexes. They used diethynyl-substituted complex 1 as a monomer for synthesizing high–molecular weight polymers 2 and 3 in high yields. To make 2, they coupled 1 with 2,5-bis (dodecyloxy)-1,4-diiodobenzene in the presence of a palladium catalyst. Polymer 3 was formed by the click polymerization of 1 with 1,4-bis (4-azidobutoxy) benzene with a copper catalyst.

The polymers are soluble and stable. Thin films are readily prepared by spin-coating THF and CH2Cl2 solutions of the polymers onto glass substrates. (Chem. Eur. J. 2011, 17, 11280–11289; Ben Zhong Tang)

Familiarize yourself with stem-cell biology. P. C. Chagastelles and N. B. Nardi* at the Federal University of Rio Grande do Sul (Porto Alegre, Brazil) and the Lutheran University of Brazil (Canoas) present a detailed introduction to and discussion of stem cells. The concept of stem cells has existed for more than a century; but now stem-cell research is a hot topic. Stem cells can self-replicate into diverse types of cells that can be used to restore damaged organs. Stem-cell research may alter current theories on therapeutics, but currently little is known about how they work.

Hematopoietic stem cells, which have been used in bone-marrow and cord-blood transplantation for more than 40 years, belong to the subgroup of adult stem cells. Every organ has its own adult stem cells, which are incapable of self-renewal. Their primary roles are to maintain and repair the tissue where they reside. Another category, embryonic stem cells (ESCs), can differentiate into different kinds of cells, but their uses are in the initial stage of development. Practical applications of embryonic stem cells are restricted because the presence of undifferentiated cells may cause cancer. Clinical trials with ESC-derived cells have been under way for only 1 year. (Kidney Inter. Suppl. 2011, 1, 63−67; Sally Peng Li)

Use polymer-supported fluoride ion to degrade nerve agent VX. Highly efficient methods for destroying chemical warfare agents (CWAs), such as the extremely toxic organophosphate-based compound VX (1), are needed to combat terrorist threats. One way to achieve this goal uses reactive sorbents to absorb and chemically convert 1 to nontoxic products.

I. Columbus, Y. Zafrani, and co-workers at the Israel Institute for Biological Research (Ness-Ziona) developed a method for decontaminating aqueous media that contain VX. They used Amberlite IRA 900 F, a styrene–divinylbenzene (SD) copolymer functionalized with quaternary ammonium fluoride groups (2). Polymer support 2 is the sorbent matrix to capture VX and the catalyst that mediates its hydrolytic destruction. In a typical degradation reaction, 1 is converted to an intermediate structure, the “G-analogue” 3, which is hydrolyzed to nontoxic ethyl methanephosphonic acid 4 as the final product.

Polymer support 2 is swollen with water to increase its volume ≈2-fold before 1 is loaded onto the resin. The process is carried out in water at pH ≈9, which completely inhibits the formation of the toxic side product desethyl-VX (5). In unbuffered water, the product contains up to 50% 5.

Under typical reaction conditions, only nontoxic 4 is present after 4 h. The authors challenged the degradation method by loading a large excess of 1 (6 equiv) onto a very small amount of resin. Even under these conditions, the degradation of 1 is complete after 6.2 days.

The authors emphasize the value of fluoride as a nucleophile in the resin; in the absence of fluoride, the catalytic process does not occur, allowing the formation of byproduct 5. Catalyst 2 is commercially available, and it is stable enough to permit its use in an aqueous environment.

This method can also degrade other CWAs such as GB (O-isopropyl methanephosphonofluoridate or sarin) or Et-G (O-ethyl methanephosphonofluoridate). The authors suggest that their degradation process is a promising candidate for active CWA barriers for use in protective clothing or air filters. (J. Org. Chem. 2011, 76, 8549–8553; W. Jerry Patterson)

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