Noteworthy Chemistry

November 2, 2009

H₁ antihistamines: Potentially useful insomnia drugs
Ionic liquid preparation by anion exchange
In-chain functionalized block copolymers by hydrosilylation
Enzyme-driven self-assembly of hydrophilic block copolymers
Luminogen structure effects on emission in solutions and solids
Robust cyanation of aromatic halides
Phenylethynyl-substituted benzodithiophene-based polymers

These H₁ antihistamines are potentially useful insomnia drugs. Most drugs used for treating insomnia act on the benzodiazepine-binding site of γ-aminobutyric acid receptors in the brain. Whereas these agents promote sleep onset and maintenance, they have negative effects that include daytime sedation and cognitive and motor function impairment. As a result, the availability of these drugs is limited because of their potential for abuse or dependence; they are classified as schedule IV controlled substances.

G. Beaton and co-workers at Neuronic Biosciences (San Diego) observed that alternative classes of drugs, including first-generation H₁ antihistamines, are significant sedatives and are typically available as over-the-counter sleep aids. The authors developed a strategy for second-generation H₁-antihistamines built around a

unique first-generation indene scaffold (1) that has useful sedating properties and high selectivity for the H₁ receptor. Their synthesis of one of the most efficacious variants starts with benzothiophene substrate 2.

Palladium-catalyzed Heck coupling of 2 gives acetyl intermediate 3. Attaching a heteroaryl substituent forms target compound 4 as a chiral product. It is purified by chiral HPLC or fractional crystallization.

Compound 4 shows a pharmacological profile consistent with a useful sleep cycle, desirable clearance properties, high H₁ selectivity, and low muscarinic receptor affinity. A low value for the last property can minimize a variety of side effects including dry mouth, blurred vision, constipation, tachycardia, urinary retention, and memory deficit.

The authors used laboratory rats to assess the drug profile of 2. The encouraging results suggest that 2 may provide a similarly positive pharmacokinetic profile in humans. (J. Med. Chem. 2009, 52, 5307–5310; W. Jerry Patterson)

Use Amberlyst resins to make ionic liquids by anion exchange. Room-temperature ionic liquids (ILs) are widely known as “green” solvents and N-heterocyclic carbene precursors in organic synthesis. This class of compounds consists of a bulky cation with a variety of anions. IL properties such as viscosity and solubility can be modified by the choice of anion. Preparing the most common imidazolium ionic liquids involves the reaction of alkylimidazoles with alkyl halides followed by anion exchange with metal or ammonium salts. These anion exchange reactions, however, can result in low yields and impurities in the ILs.

I. Dinarès and co-workers at the University of Barcelona developed an IL production protocol that uses anion exchange resins. In the initial procedure, Amberlyst A-26 (hydroxide form, 1) was packed in a column and treated with a carboxylic acid solution in aqueous MeOH; carboxylate anion was retained on the resin (see figure). A methanolic solution of 1-n-butyl-3-methylimidazolium iodide ([bmim][I]) was passed through this column to obtain [bmim][OAc], [bmim][OBz], or [bmim][(S)-lactate] in quantitative yield.

The authors then applied their method to organic oxoanions (sulfonates and phosphonates) and to inorganic anions (Cl^–, NO₃^–, ClO₄^–, and BF₄^–), also in quantitative yield, as determined by NMR, electrospray ionization mass spectrometry, and Ag₂CrO₄ test analysis. The resin can be recycled by washing it with 10% aq NaOH.

To prepare weakly basic anions, ammonium salts were loaded onto the column instead of strong acids to prevent degradation of polymer matrix. This led to the preparation of bmim ILs with CF₃CO₂^–, F^–, PF₆^–, SCN^–, H₂PO₄^–, and HSO₄^– anions. Attempts to prepare ILs containing (TfO)₂N^– or MeSO₄^– (derived from their lithium or potassium salts) failed. The use of other imidazolium ionic liquids such as 1,3-di-n-butylimidazolium (bbim) and 1,3-dimethylimidazolium (mmim) salts worked as well as bmim. (Green Chem. 2009, 11, 1507–1510; José C. Barros)

Use hydrosilylation to make in-chain functionalized block copolymers. R. P. Quirk, S. Z. D. Cheng, and colleagues at the University of Akron (OH), Donghua University (Shanghai), and East China University of Science and Technology (Shanghai) have developed novel block copolymers (BCPs) that feature in-chain functionality. They combined anionic polymerization and hydrosilylation by silyl hydride–functionalized 1,1-diphenylethylene (SiH-DPE).

The authors generated polystyrene–SiH–poly(dimethylsiloxane) (PS-SiH-PDMS; 3.2 kDa, polydispersity [PDI] 1.03) by the fast addition reaction between SiH-DPE and poly(styryl)lithium (2 kDa, PDI 1.02), functionalization with ethylene oxide, and anionic ring-opening polymerization of hexamethylcyclotrisiloxane. The low PDI was maintained by terminating the room temperature reaction at ~50% conversion.

The Si–O–C bond was hydrolytically stable in solution and as a solid for months. The Si–H bond was used to incorporate polyhedral oligomeric silsesquioxanes (POSS) by hydrosilylation with allyl-functionalized POSS using a Karstedt’s catalyst (1,3-divinyltetramethyldisiloxane−platinum). The research team proposes that the resulting in-chain functionalized BCP, PS-POSS-PDMS, is an interesting material system for the future exploration of the morphological complexity of a flexible, phase-segregated BCP containing an in-chain rigid inorganic nanoparticle. (Macromolecules 2009, 42, 7258–7262; LaShanda Korley)

An enzyme initiates the self-assembly of hydrophilic block copolymers. Self-assembly is used for grouping molecules into a defined arrangement under external stimuli such as temperature, pH range, or photoinduction. R. J. Amir, C. J. Hawker, and coauthors at the University of California, Santa Barbara, and the

University of Delaware (Newark) devised a new self-assembly technique—physiological impulse–induced self-assembly—and demonstrated it with hydrophilic block copolymers.

The precursor (1) consists of two water-soluble segments, polyethylene glycol (PEG) and phosphate-grafted poly(4-hydroxystyrene). Under optimal conditions (pH 5 buffer), the acid phosphatase enzyme (APase) begins to cleave the phosphate moieties, and the grafted poly(4-hydroxystyrene) segments gradually lose their hydrophilicity. The molecules are oriented before the cleavage is completed, creating an amphiphilic core–shell structure (2). The hydrophobic poly(4-hydroxystyrene) segments aggregate to form the spherical center, and hydrophilic PEG arms surround the center as a protective “shield”. Untouched phosphate-grafted units inside the core are concealed from further attack from the enzyme. (J. Am. Chem. Soc. 2009, 131, 13949–13951; Sally Peng Li)

Manipulate light emission in solutions and solids by changing molecular structures of luminogens. Luminescence processes in solution are used to detect biological analytes; in the solid state, they are used in electroluminescence devices. It is therefore valuable to learn how the molecular structure of a luminogen affects its light emission as an isolated molecule or in a supramolecular aggregate. T. Hirose and K. Matsuda* at Kyoto University and Kyushu University (Fukuyama, Japan) synthesized amphiphilic molecules 1 and 2 and found that they show distinctly different emission behaviors in solution and aggregated states.

Compound 1 is highly emissive when dissolved in EtOAc (EA), but it becomes almost nonluminescent when supramolecularly aggregated in water. In sharp contrast, 2 is nonemissive in solution, but it becomes luminescent when aggregated; 1 and 2 exhibit aggregation-quenched and aggregation-enhanced emission (AQE and AEE), respectively. It is remarkable that the emission of the luminogens can be tuned to such large degrees by changing their molecular structures.

The amphiphilic molecules of 2 self-assemble into helical aggregates in water and show strong circular dichroism (CD). When the molecules are heated, the CD and AEE effects weaken; AEE decreases more rapidly than CD, especially at the lower critical solution temperature. This indicates that the luminescence process is more susceptible to the variations in the supramolecular packing structure than the exciton interaction and demonstrates that the AEE effect can be used to sensitively probe microscopic environmental changes. (Chem. Commun. 2009, 5832–5834; Ben Zhong Tang)

Here’s a robust cyanation of aromatic halides. Palladium-catalyzed cyanation of aromatic halides is often difficult because catalyst poisoning stalls the reaction. J. Wang and co-workers at Henan University of Science and Technology (Luoyang, China) found that adding 4.8 mol% of i-PrOH avoids this problem.

The authors used ligand-free conditions with Pd(OAc)₂ as the catalyst and K₄Fe(CN)₆ as the cyanide source in N-methylpyrrolidone or DMF as solvent. The order of addition of the reagents is important when the reaction is scaled up: the best yields are obtained when K₄Fe(CN)₆ is added last. (Org. Process Res. Dev. 2009, 13, 764–768; Will Watson)

Improve electrical properties of benzodithiophene-based polymers by using phenylethynyl substituents. Extensive research on conjugated 3-alkyl-substituted polythiophenes has resulted in processible polymers with useful electronic and photonic properties. These properties result in part from strong π-overlap in intra- and interchain delocalization as a result of ordered lamellar packing. However, M. C. Stefan, M. C. Biewer, and co-workers at the University of Texas at Dallas note that whereas the basic poly(3-hexylthiophene) polymer system exhibits attractive electronic properties, its usefulness is limited by chemists’ inability to control its molecular orbital energy levels.

The authors’ strategy was to develop benzodithiophene-type polymers with a central fused ring that contains phenylethynyl substituents that allow extended electron delocalization. The synthesis of the key monomers for this polymer system includes the reaction of known diketone 1 with an acetylide, followed by aromatization to form the fused-ring benzodithiophene skeleton 2 with the desired phenylethynyl groups.

Appropriate treatment of 2 then leads to the desired dibromo- and bis(trimethyltin)-functionalized monomers 3 and 4. Polymerizing 3 and 4 via Stille coupling gives homopolymer 5. The same type of reaction of 3 with fluorene-based dibromide 6 provides copolymer 7. A carbazole-based dibromide also can be used to form a similar copolymer (not shown).

Polymer 7 had M_n >26 kDa—significantly higher than that of parent homopolymer 5 (3.3 kDa). Polymer 5 is red-shifted by 84 nm compared with 7 and displays a strong red shift in solution that indicates long-range ordering of its polymer chains. Electrochemical measurements indicated a desirable lower band gap for these polymers, presumably the result of extended conjugation from the phenylethynyl moieties. The quantum yield for 7 is 91%, significantly higher than that of 5.

The polymers in this study apparently have adequate solubility in CHCl₃ for film formation, but the authors are currently preparing homologues with longer alkyl groups for increased solubility and thus improved processibility. (Org. Lett. 2009, 11, 4422–4425; W. Jerry Patterson)