Noteworthy Chemistry

January 10, 2011

A macrotricyclic superbase makes an excellent catalyst. Much research has focused on developing neutral organic superbases, whose strongly basic properties allow them to mediate reactions previously restricted to inorganic ionic bases. The three pyridine nitrogen atoms in previously reported macrotricyclic aminopyridine 1 form a cavity for capturing a single proton (Kanbara, T.; Suzuki, Y.; Yamamoto, T. Eur. J. Org. Chem. 2006, 3314–3316). The high proton affinity of this cavity makes the compound strongly basic with an estimated pKBH+ of ~23.1.

T. Kanbara and coauthors at the University of Tsukuba (Japan) and Tosoh Corp. (Yokkaichi, Japan) increased the basicity of this tricyclic scaffold by using 4-pyrrolidinopyridine moieties in place of the pyridine rings to form compound 2. This macrocycle is synthesized in a four-step procedure that starts with 2,6-dibromo-4-pyrrolidinopyridine (3).

The palladium-catalyzed aryl amination of 3 with different proportions of p-toluidine forms 4 and 5, which lead to the macrotricyclic target. (Xantphos is a xanthene-based phosphine ligand.) In the final step, copper-catalyzed aryl amination of 4 with 5 produces the desired pyrrolidine-substituted macrocyclic ring 2. The product first forms as the inner protonated form and subsequently is converted to free 2 with an estimated pKBH+ of 28.1—a dramatic 104–105-fold increase in basicity compared with that of 1.

The authors used the same method to prepare a similar tricyclic structure, with piperidine groups replacing the pyrrolidine groups. The pKBH+ of this base, however, was slightly less than that of 2.

The authors assessed the catalytic properties of 2 by using it to mediate a typical Michael addition, with 2-cyclohexenone as the Michael acceptor. This resulted in a 97% yield of adduct 6. No product was formed using 1 as the catalyst. These results confirm the performance of 2 as a superbase that efficiently deprotonates the MeNO2 reactant. (Org. Lett. 2010, 12, 5242–5245; W. Jerry Patterson)


Compare ultrasonic distillation with sparging for purifying liquids. Distillation, a traditional separation method for liquid mixtures, is based on the differences in the boiling points of the components. Ultrasonic distillation is a recently developed technique in which evaporation is triggered by ultrasound irradiation rather than heat.

When a liquid mixture is irradiated with ultrasound, a mixture of vapor and droplets of the lower-boiling liquid is generated above the surface (see figure). An inert gas such as nitrogen is used to sweep the lower-boiling liquid through an outlet. The higher-boiling liquid stays in the chamber.

Sparging is another way to purify liquids. An inert gas is bubbled through the liquid mixture to remove the low-boiling liquids from the solution. Sparging does not require heating or irradiating the solution to the boiling point of any of the components. Which pathway is more efficient for liquid separation?

G. J. Diebold and co-workers at Brown University (Providence, RI) investigated the efficiency of the two techniques for separating EtOH–H2O mixtures. They tested a series of solutions with different ratios of the components. At ambient temperature, more EtOH is released as a vapor by sparging than by ultrasonic distillation at all concentrations. The results were the same for EtOH–EtOAc solutions. The authors state that despite these results ultrasonic distillation warrants further study. (Anal. Chem. 2010, 82, 10090–10094; Sally Peng Li)


Incorporate photolabile units into amphiphilic block copolymers. Led by H. Yang and P. Keller, researchers at Southeast University (Nanjing, China), Pierre and Marie Curie University (Paris), the Curie Institute (Paris), and the University of Colorado (Boulder) incorporated the photocleavable α-truxillic acid (2,4-diphenyl-1,3-cyclobutanedicarboxylic acid) moiety as a strategy for disassembling micelles and vesicles derived from amphiphilic block copolymers (BCPs). The authors used a multistep synthesis to generate the truxillic acid–derived BCPs that contained poly(ethylene glycol) and polyacrylates [poly(butyl acrylate) or poly(cyclohexyl acrylate)] by using macroinitiator-based atom transfer radical polymerization.

The authors varied the degree of polymerization of the acrylate block, which affected the photocleaving process (because of concentration-dependent UV-generated ozone susceptibility) and the assembled morphologies in aqueous environments. With the more rigid poly(cyclohexyl acrylate), a combination of self-assembled vesicles and micelles formed in H2O–cosolvent mixtures. Photoexposure of these assemblies resulted in complete cleavage of the BCPs after 24 h, and an exposure-dependent evolution of the BCP self-assembled structures was observed. (Macromolecules 2010, 43, Article ASAP DOI: 10.1021/ma1016264; LaShanda Korley)


Synthesize vitamin D3 in a microreactor. The conversion of provitamin D3 (1) to vitamin D3 (3) is a two-step procedure that includes a photochemical reaction to form previtamin D3 (2) and a thermal reaction to give the target molecule. The photochemical reaction, however, is often nonselective because of similar absorption wavelengths, and the yield on the industrial scale is usually 20%.

T. Takahashi and coauthors at the Tokyo Institute of Technology and Tohoku University (Sendai, Japan) envisaged combining the photochemical and thermal reactions in a microreactor operating in continuous-flow mode. The microreactor has thin walls that improve light penetration.

The two-stage irradiation method was developed using an economical, high-intensity mercury lamp. In the first stage, 313–578 nm light is used to convert 1 to a mixture of 2 and tachysterol (4) in >80% combined yield. The yield of byproduct lumisterol (5) is <10%. The second step, irradiating the reaction mixture at 360 nm and 100 °C, produces vitamin D3. Solvent screening showed 1,4-dioxane to be best, and concentrations can be greater than in traditional photochemical processes.

The isolated yield of 3 is 32%, higher than any other transformations that do not use a laser, sensitizer, or filter compound. The process does not require purification or isolation of intermediates and can be scaled up with continuous operation or by adding more microreactors. (Chem. Commun. 2010, 46, 8722–8724; JosÉ C. Barros)


Suzuki polycoupling gives hyperbranched poly(m-phenylene)s with excellent processibility. Polyphenylenes are a family of aromatic polymers with unique properties such as high thermal stability. Hyperbranched poly(m-phenylene)s (HBPmPs) have been prepared by Suzuki polycoupling (SPC) of AB2 monomers such as 3,5-dibromophenylboronate esters, but the products are often oligomers with low molecular weights and poor solubility.

Z. Xue, A. D. Finke, and J. S. Moore* of the University of Illinois at Urbana–Champaign developed an efficient SPC reaction that allows HBPmPs to be synthesized with high molecular weights and excellent macroscopic processibility.

The researchers designed and synthesized an m-terphenyl-based AB2 monomer (1) that undergoes efficient SPC in the presence of a catalyst system that consists of Pd(OAc)2 and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos). The product HBPmPs (2) have high molecular weights (Mn up to ~60 kDa), low polydispersity indices (Mw/Mn as low as 1.3:1), and high solubility in common organic solvents.

The experimental data suggest that the SPC of 1 proceeds by a pseudo–chain-growth mechanism. The researchers showed that the end groups of the HBPmPs can be readily transformed by in situ Suzuki–Miyaura cross-coupling reactions to yield new HBPmPs with various peripheral functionalities. (Macromolecules 2010, 43, 9277–9282; Ben Zhong Tang)


Does drinking tap water cause iodine deficiency? Iodine in the form of iodide ion is essential for the biosynthesis of thyroid hormones, which assist in managing metabolism in adults and promoting proper growth in children. Certain chemicals interfere with iodide intake by the thyroid gland, possibly causing a deficiency. Iodine deficiency is a significant public health problem: In 2007, the World Health Organization reported that ~31% of the world’s population has this condition (see Assessment of iodine deficiency disorders and monitoring their elimination: A Guide for Programme Managers).

Iodide intake is closely related to daily food and beverage consumption. Tap water can contain perchlorate and nitrate ions, which interrupt iodide intake by the thyroid. However, it is uncertain whether the consumption of tap water contributes to the development of iodide deficiency. B. C. Blount and coauthors at the Centers for Disease Control and Prevention (Atlanta) and Texas Tech University (Lubbock) surveyed >3000 US residents to determine whether the levels of perchlorates and nitrates in tap water are sufficient to cause deficiencies.

The results showed that the median perchlorate intake from tap water accounts for ~10% of perchlorate consumption and <5% of nitrate consumption. Tap water is also not a significant source of iodide. The authors conclude that it constitutes an insignificant percentage of perchlorate and nitrate intake and food is the major source of these ions. (Environ. Sci. Technol. 2010, 44, 9564–9570; Sally Peng Li)


The asymmetric trifluoromethylation of alkynyl ketones uses trimethylsilyltrifluoromethane. The catalytic enantioselective preparation of trifluoromethyl-substituted tertiary propargyl alcohols leads to important chiral building blocks for pharmaceuticals; for example, this stereocenter can be incorporated in efavirenz, a non-nucleoside reverse transcriptase inhibitor that forms part of a highly active antiretroviral therapy for treating HIV-1.

N. Shibata and coauthors at Nagoya Institute of Technology (Japan) and Rigaku Corp. (Tokyo) report the first catalytic, asymmetric, direct trifluoromethylation of propargyl ketones such as 1 that uses trimethylsilyltrifluoromethane (Me3SiCF3) to form the corresponding propargyl alcohols (3) with the desired quaternary carbon stereocenter in up to 96% ee. In all cases, an initial trimethylsilyl ether adduct forms, and n-Bu4NF is added to remove the trimethylsilyl protecting group and release the free alcohol.

The catalyst combination for this procedure consists of chiral cinchona alkaloid quaternary nitrogen salt 2 and Me4NF. All reactions proceed in essentially quantitative yield (according to TLC analysis), although isolated yields of 3 are typically lower after the protecting group is removed.

The reaction is based primarily on tert-butyl-substituted ethynyl ketone reactants, but the authors expanded it to other sterically demanding ethynyl substituents. In a key example, (triisopropylsilyl)ethynyl aryl ketone 4 leads to trifluoromethylated adduct 5 with 86% ee. In this case, the triisopropylsilyl group at the ethynyl position and the O-trimethylsilyl protecting group are simultaneously removed with n-Bu4NF to form nonsilylated propargyl alcohols. A variant of this method gives biologically attractive aryl heteroaryl trifluoromethyl carbinols with no loss of enantiomeric purity. (Org. Lett. 2010, 12, 5104–5107; W. Jerry Patterson)


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