Noteworthy Chemistry

April 7, 2014

Fluorinate aliphatics with a “light” touch. The increasing use of organofluorine compounds makes it important to develop selective, efficient, economical fluorination methods. Many methods for fluorinating aryl and heteroaryl rings are available, but fluorinating aliphatic compounds is challenging because it is difficult to selectively activate the C(sp3)–H bond.

C(sp3)–H bonds can be selectively cleaved to generate radical cations by one-electron oxidants such as UV-light sensitized 1,2,4,5-tetracyanobenzene (TCB, 1). Once formed, radical cations usually turn rapidly into the corresponding alkyl radicals, which can react with electrophilic fluorinating agents. These findings led S. Bloom, J. L. Knippel, and T. Lectka* at Johns Hopkins University (Baltimore) to develop a photocatalyzed method for fluorinating aliphatics with good selectivity and efficiency.

Photocatalyst 1 and electrophilic fluorinating agent 2

The researchers chose TCB as the photosensitizer and commercially available Selectfluor (2) as the electrophilic fluorine source. Using cyclododecane as the substrate, they screened reaction conditions and found that monofluorinated cyclododecane is obtained in 63% yield in 16 h in the presence of 10 mol% TCB with 302-nm UV irradiation under nitrogen.

The researchers chose TCB as the photosensitizer and commercially available Selectfluor (2) as the electrophilic fluorine source. Using cyclododecane as the substrate, they screened reaction conditions and found that monofluorinated cyclododecane is obtained in 63% yield in 16 h in the presence of 10 mol% TCB with 302-nm UV irradiation under nitrogen.

The authors applied these conditions to a variety of cyclic and linear alkanes, including natural products, with good selectivity and yields. Most notably, α-santonin, a sesquiterpene lactone that normally rearranges under UV irradiation, was monofluorinated at the α-methyl position. Photochemical rearrangement reactions were completely suppressed, and the yield of the fluorinated product was 57%. (Chem. Sci. 2014, 5, 1175–1178; Xin Su)

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Make pyrolytic fibers by incorporating aluminum nanoparticles. S. C. Kettwich, S. T. Iacono, and coauthors at the US Air Force Academy (CO) and Texas Tech University (Lubbock) describe the manufacture of energetic electrospun fibers that are composed of aluminum nanoparticles blended with a perfluoropolyether (n-Al-PFPE). A 270-kDa polystyrene was used as a carrier to promote spinnability. Unlike the smooth, uniform (80 ± 20 nm diam) surfaces of pure polystyrene electrospun fibers, the n-Al-PFPE-polystyrene nanofibers had much larger and more variable fiber diameters (5.4 ± 2.0 nm at 17 wt% loading) because of the inhomogeneity of the n-Al-PFPE particles.

Loadings of 10 wt% n-Al-PFPE produced the smallest fiber diameters; above 17 wt% n-Al-PFPE content, fibers could not be produced. Using higher amounts of n-Al-PFPE varied the assembly of the particles within the fibers.

The authors note that the decomposition temperature of the fibers remains relatively unchanged regardless of n-Al-PFPE content, with only a slight change in onset temperature at the highest loading. Measurements of flame propagation velocities showed that the n-Al-PFPE-polystyrene nanofibers burn slowly and that their combustion characteristics are not affected by n-Al-PFPE content. (ACS Appl. Mater. Interfaces 2014, 6, Article ASAP; LaShanda Korley)

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A tarantula venom peptide may be used to treat pathological pain. Predator venoms, such as those from scorpions, spiders, snakes, and other animals, are pharmacological tools that are used to investigate properties of ion channels. They are also a source of tremendous peptide diversity for drug discovery. For example, a peptide toxin extracted from a cone snail has been approved by the US Food and Drug Administration to treat intractable pain in humans.

Transient receptor potential (TRP) channels are cation channels that are involved in sensory transduction and have a central role in pain sensation. The channels have six transmembrane domains and are related to tetrameric voltage-gated ion channels; they share the same transmembrane topology and functional domain structure. The gating domain is formed by the first four transmembrane domains, S1–S4. The selectivity filter and ion-conducting pore are formed by domains S5 and S6.

TRPA1 is the only member of the TRP ankrin (TRPA) subfamily that has been identified in mammals. It is upregulated by inflammatory injury and neuropathic pain. It can be activated by foods, endogenous metabolic products, and oxidative stress–derived substances. Patients with gain-of-function TRPA1 mutations suffer debilitating pain when they fast or are under physical stress. Because TRPA1 is so important in pain signaling, it is a potential target for treating pathological pain. Some small-molecule TRPA1 antagonists have been identified, but no peptide antagonists have been isolated.

M. N. Nitabach and 13 colleagues at the Yale School of Medicine (New Haven, CT), Purdue University (West Lafayette, IN), the University of Queensland (Brisbane, Australia), and James Cook University (Cairns, Australia) developed a screen that uses the “tethered-toxin” (t-toxin) recombinant expression method to identify toxins that have high affinities for particular ion channels. They used diverse spider toxin sequences to assemble a recombinant complementary DNA library of peptide t-toxins encoded in glycosyl phosphatidyl inositol–anchored membrane-tethered form. They screened the library through functional coexpression in Xenopus oocytes with TRPA and identified the first known high-affinity TRPA1 peptide antagonist, prototoxin-I (ProTx-I).

This 35-residue peptide comes from the venom of Thrixopelma pruriens, the Peruvian green-velvet tarantula. It was previously identified as an antagonist of voltage-gated sodium channels. Further screening with ProTx-I alanine-scanning mutants showed that ProTx-I inhibits both types of channels by binding to the extracellular loops of S1–S4 gating domains.

This study suggests that ProTx-I may be valuable for the clinical treatment of pain and may establish the “toxineering” technique as a method for isolating ion-channel modifiers and designing ion-channel modifiers with altered specificity. (Curr. Biol. 2014, 24, 473–483; Abigail Druck Shudofsky)

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Make thiol–yne polymers without a catalyst. Click chemistry consists of chemical reactions that generate products quickly and reliably with high yields. The reactions are stereospecific and easy to work up. This concept is well-suited to polymer synthesis, in which modularity and ease of separation are highly desirable.

One of the best-known click reactions, azide–alkyne cycloaddition, is used to synthesize a variety of polymers; thiol–yne addition, however, is just beginning to be used for polymerization. To expand the range of alkyne hydrothiolation–based methods for polymer synthesis, A. Qin, B. Z. Tang, and colleagues at Zhejiang University (Hangzhou, China), South China University of Technology (Guangzhou), and Hong Kong University of Science & Technology developed a catalyst-free version of this reaction for making poly(vinylene sulfide)s.

The authors set out to explore Cu(I)-catalyzed thiol–yne click polymerizations. Unexpectedly, in a control experiment without a catalyst, diyne 1 and dithiol 6 reacted at 70 ºC in 12 h to give a polymer with a 17.3-kDa Mw in 55% yield. 

Diyne and dithiol monomers and their reaction to give poly(vinylene sulfide)s

The authors then optimized four reaction conditions: temperature, solvent, reaction time, and monomer concentration. The Mw and polydispersity of the polymer products decrease as reaction temperature decreases, but the yield is almost unchanged. Toluene, CHCl3, and DMF solvents lead to polymers with low Mw (5.4–10.3 kDa), whereas dioxane and THF favor products with high Mw (58.3 and 52.6 kDa, respectively). Reaction time and monomer concentration influence Mw more than yield.

Using optimized reaction conditions, the authors synthesized a library of poly(vinylene sulfide)s from diyne monomers 15 and dithiols 6 and 7. The addition-type polymerization proceeds with anti-Markovnikov–type stereochemistry, presumably via a free-radical mechanism. The polymer synthesized from 1 and 6 exhibits aggregation-induced emission enhancement similar to that of tetraphenylethylene, the core of monomer 1. (Macromolecules 2014, 47, 1325–1333; Xin Su)

[B. Z. Tang is Noteworthy Chemistry contributor Ben Zhong Tang.—Ed.]

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Suspend free-standing 2-D iron sheets in graphene pores. Theoretical studies predict that the magnetic moment of a free-standing iron monolayer is 3.1 μB, as compared with 2.2 μB measured for bulk iron. This value is important in several applications, including magnetic recording media. Materials such as graphite, BN, and MoS2 have strongly directional bonding and readily form free-standing sheet structures. Metals, however, form chemical bonds in all directions. Until now, the only examples of atomically thin metal sheets were heteroepitaxial layers attached to a substrate.

M. H. Rümmel and co-workers at the Institutes of Complex Materials, Solid State Research, and Materials Science (Dresden, Germany), the Institute for Basic Science (Daejon, Korea), the Polish Academy of Sciences (Zabrze), and Sungkyunkwan University (Suwon, Korea) formed free-standing, one-atom-thick iron sheets in the pores of graphene sheets. They used chemical vapor deposition to grow graphene on Ni–Mo substrates then detached the graphene layers by using an FeCl3 etching solution, which introduced several forms of iron.

Transmission electron microscopy (TEM) showed pure iron crystalline layers, one atom thick, suspended across perforations in the graphene sheets. Other species include body-centered cubic and hexagonal close-packed iron nanocrystals, several-atom clusters, and individual iron atoms attached to the graphene edges.

All of the monoatomic iron layers that the authors examined showed a preferential alignment of the iron (110) plane with the graphene (1–100) plane. The observed lattice constant is 2.65 Å, whereas the most stable lattice constant calculated from using density functional theory is 2.35 Å. The calculated energy difference between the two values, however, is only 0.2 eV/atom. Several factors, including spin–orbit coupling, perpendicular magnetic anisotropy, and strain produced by lattice alignment and mismatch between iron and graphene, are likely to affect the lattice constant value.

The researchers studied the modes of attachment between the iron and graphene and examined the local strain effects. They observed that iron almost always binds to open graphene edges. One iron atom generally substitutes for one carbon atom in a benzene ring, although other configurations occur as well. The researchers calculated that the largest stable crystalline monolayer is ≈12 atoms across, or 3 nm on a side. The largest crystalline monolayers that they observed were ≈10 atoms across.

When irradiated by the TEM beam, iron atoms on the graphene surface move around and collect in small holes, where they form crystalline monolayers within a few seconds. These monolayers are stable for several minutes under electron radiation; they then begin to collapse to form amorphous particles. (Science 2014, 343, 1228–1232; Nancy McGuire)

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Take an alternative biocatalytic route to pregabalin. Pregabalin (Lyrica) is a lipophilic γ-aminobutyric acid analogue that was developed to treat central nervous system disorders such as epilepsy, neuropathic pain, and anxiety. Previous biocatalytic pregabalin syntheses used a desymmetrization of a malonate derivative and the selective hydrolysis of a succinonitrile derivative.

J. W. Wong, S. Davies, and co-workers at Pfizer (Loughbeg, Ireland, and Groton, CT) describe the use of ene reductases to reduce the C=C bond of the intermediate ethyl 5-methyl-3-cyano-2-hexenoate. They investigated several routes to the cyanohexanoate; the best was a Knoevenagel reaction that uses ethyl glyoxylate hemiacetal.

All of the economically feasible routes produced the reduced intermediate as a mixture of E- and Z-isomers; the best result was an E/Z ratio of ≈3.5:1. Enzyme studies showed that enzyme OPR1 converts both isomers to (S)-pregabalin, although the E-isomer is a much better substrate for the enzyme than its Z counterpart. (Org. Process Res. Dev. 2014, 18, 109–121; Will Watson)

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Detect gaseous and aqueous hydrazine easily. Hydrazine (H2NNH2) is a widely used reagent in chemical research and in industry, but it is highly toxic and probably carcinogenic. Because of these hazards, the release of hydrazine into the environment and hydrazine exposure levels are strictly regulated. Hydrazine detection currently relies on instrumental methods such as chromatography or mass spectrometry, but these are limited in some circumstances.

In search for another detection method, L. Cui, S. Zhang, Y. Xu, and coauthors developed a fluorescence-based molecular probe that detects gaseous and aqueous hydrazine, even in living cells, with good selectivity and sensitivity.

The authors designed molecular probe 2 that detects hydrazine by using the Gabriel reaction, in which phthalimides are converted to primary amines in the presence of hydrazine. They prepared compound 2 by treating fluorescent naphthalimide 1 with phthalic anhydride, which quenches the fluorescence of 1. The reaction between 2 and hydrazine regenerates 1, along with phthalic hydrazide (3), via the Gabriel mechanism.

Fluorescence probe for hydrazine

The authors screened hydrazine and several common primary amines, anions, and metallic cations (see list) against compound 2 in aq DMSO. They found that only hydrazine significantly increases fluorescence emission by regenerating 1. TLC plates loaded with 2 can detect airborne hydrazine vapor; the emission intensity of the plate can be used to approximate the hydrazine concentration.

Molecules and ions that do not interfere with hydrazine detection

Molecules Cations Anions
n -Butylamine

Compound 2 has a linear working concentration range of 0.1−70 µM for aq hydrazine, with a limit of detection as low as 0.3 ppb. (The US Environmental Protection Agency’s threshold limit value for hydrazine is 10 ppb.) The detection limit is 111.7 mg/m3 in the gas phase. Compound 2 also rapidly images hydrazine in living HeLa cells. (Chem. Commun. 2014, 50, 1485–1487; Xin Su

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