May 15, 2013
- Activate the β-position of saturated carbonyls with light
- Make polymer nanofibers from melt-blown fiber blends
- Couple ThFFF and NMR to analyze macromolecules
- Use chemiluminescence to assay proteases
- Oxidize benzene to phenol with visible light
- Optimizing lab yields is just the start for an industrial process
Activate the β-position of saturated carbonyls with visible light. Activating the β-position of saturated carbonyl compounds is a challenge that receives significant attention. Although several direct and indirect β-functionalization methods are available, they are limited by narrow substrate scopes or complicated pretreatments. D. W. C. MacMillan and co-workers at Princeton University (NJ) devised a pathway to carbonyl β-arylation that combines visible-light–induced photoredox catalysis and amine catalysis. Their method encompasses a broad range of substrates.
The authors note that excited state Ir(ppy)3*, produced by irradiating photoredox catalyst Ir(ppy)3 with visible light, can reduce the arene coupling partner dicyanobenzene (1) via single-electron transfer (SET) to radical anion 2. In the process, Ir(ppy)3* is oxidized to [Ir(ppy)3]+. The ligand ppy is tris(2-phenylpyridinato-C2,N).
In conjunction with this cycle, enamine 5, formed from aldehyde 3 and amine catalyst 4, can be oxidized by [Ir(ppy)3]+ in another SET to yield radical cation 6. When 6 deprotonates, it converts to the key five π-electron β-activated intermediate 7. Subsequent radical–radical coupling between 7 and 2 yields cyclohexadienyl anion 8 through sp3–sp3 C–C bond formation. Hydrolyzing 8 gives β-arylated product 9 and regenerates catalyst 4.
The authors validated the proposed pathway by irradiating octanal and 1 in the presence of Ir(ppy)3, N-isopropylbenzylamine, and 1,4-diazobicyclo[2.2.2]nonane (DABCO) with a 26-W fluorescent light bulb. The product formed in 86% yield.
[For another reaction that uses visible-light catalysis, see below.—Ed.]
Make polymer nanofibers from melt-blown fiber blends. C. W. Macasko, F. S. Bates, and coauthors at the University of Minnesota (Minneapolis) and Cummins Filtration (Cookeville, TN) prepared nanometer-scale polymer fibers by melt-blowing an immiscible 1:3 v/v blend of poly(ethylene-co-chlorotrifluoroethylene) (PECTFE) and poly(butylene terephthalate) (PBT). Their method produces a nanofiber-in-fiber array that can be separated by selective solvent etching.
Etching the array with CF3CO2H yields long single PBT nanofibers (≈70 nm diam) from the ≈3-μm PECTFE-PBT fiber assembly. The authors applied this procedure to other blend systems (e.g., polystyrene [PS]-PBT and PS-PECTFE) to make uniform nanoscale fibers. The method has potential uses in the filtration industry. (ACS Macro Lett. 2013, 2, 301–305; LaShanda Korley)
Couple ThFFF and NMR to analyze macromolecules thoroughly. Field-flow fractionation (FFF) is a macromolecule separation technique that uses external fields to enrich analytes in the flow channel. Thermal field-flow fractionation (ThFFF), in particular, relies on a temperature gradient to separate polymers. FFF significantly reduces shear forces to help avoid the shear degradation that occurs in chromatography.
W. Hiller and coauthors at the Technical University of Dortmund (Germany) and the University of Stellenbosch (Matieland, South Africa) developed an online ThFFF-NMR detector that can be used to determine the chemical compositions and molar masses of a variety of polymer materials.
The authors’ setup consists of a ThFFF system, a UV detector, a loop collector, and an NMR spectrometer (see figure). A sample injected into the ThFFF instrument is separated, then driven through the loop collector to the NMR flow probe to acquire NMR spectra in real time. The authors selected HPLC-grade THF as the eluent; the WET technique can be used to suppress its NMR signal. (WET is an acronym for water suppression enhanced through T1 effects.)
When the authors analyzed samples of homopolymers and block copolymers with the ThFFF-NMR system, they found that the techniques give excellent separation in the high molar-mass region. The technique works better than size-exclusion chromatography (SEC)-NMR, which is more appropriate for polymers with molar masses <10 kDa.
ThFFF-NMR also separates polystyrene (PS), poly(methyl methacrylate) (PMMA), and polyisoprene (PI) samples that have similar hydrodynamic sizes, whereas SEC-NMR fails to do so. Significantly, ThFFF-NMR separates block copolymers such as PS-b-PMMA, PI-b-PMMA, and PS-b-PI, on the basis not only of their molar masses and structures, but also of their microstructures and chemical compositions. (Macromolecules 2013, 46, 2544–2552; Xin Su)
Current methods for measuring protease activity are electrophoresis, high-performance liquid chromatography, the enzyme-linked immunosorbent assay, and colorimetry and fluorometry that require specific, complex, expensive probes.
C. Yu and colleagues at the Changchun Institute of Applied Chemistry (China) and the University of the Chinese Academy of Sciences (Beijing) developed a protease turn-on assay method based on chemiluminescence (CL). They devised a flow-injection system to monitor CL produced by the luminol–H2O2 reaction.
The method uses cytochrome c (cyt c) as the substrate. Cyt c contains an Fe(II) porphyrin heme cofactor that poorly catalyzes luminol–H2O2 CL. When the protease trypsin is added to cyt c, it liberates a heme–peptide conjugate, which catalyzes the luminol–H2O2 reaction that emits a CL signal.
Substituting cyt c with bovine serum albumin, lysozyme, or collagenase fails to produce the same result because these proteins do not contain heme cofactors. MALDI-TOF MS analysis showed that the heme cofactor must be conjugated to a peptide to prevent heme self-aggregation, which nullifies the CL reaction. (MALDI-TOF MS is matrix-assisted laser desorption ionization time-of-flight mass spectrometry.) UV–vis spectroscopy showed that Fe(II) is oxidized to Fe(III) in the heme–peptide conjugate.
The authors’ method is simple, fast, inexpensive, and highly sensitive; and it does not require special equipment. The heme-cofactor requirement ensures that protein contaminants do not interfere with the analysis. The method can be expanded to other proteases, such as papain, proteinase K, and chymotrypsin.
Oxidize benzene to phenol with visible light. Phenol and its derivatives are essential building blocks for many laboratory compounds, pharmaceuticals, and industrial products. A one-step conversion of benzene to phenol is desirable, but existing methods use harsh conditions and give low yields and poor selectivity.
K. Ohkubo, A. Fujimoto, and S. Fukuzumi* at Osaka University, Japan Science and Technology (Osaka), and Ewha Womans University (Seoul) produced phenol in high yields under mild conditions by catalytically oxygenating benzene under visible light in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 1) and tert-butyl nitrite (TBN).
Singlet excited DDQ is too weak an oxidant to oxidize benzene by electron transfer, but triplet excited DDQ is a stronger oxidant. The authors first showed that benzene is converted into phenol under visible light (390–600 nm) in oxygen-saturated MeCN with excess DDQ in the presence of H2O (first reaction in the figure). The reaction is complete in 24 h with 99% yield and >99% selectivity. DDQ is reduced to 2,3-dichloro-5,6-dicyanohydroquinone (DDQH2, 2). Adding the oxidant TBN in the presence of oxygen regenerates all of the DDQ (Shen, Z., et al. Adv. Synth. Catal. 2011, 353, 3031–3038).
When the authors reduced DDQ from excess to catalytic amounts, they obtained a 93% yield of phenol with 98% benzene conversion in 30 h (second reaction). A labeling study showed that the oxygen atom in phenol originates from water rather than oxygen.
Mechanistic studies showed that the benzene radical cation produced by the electron-transfer reaction between triplet excited DDQ and benzene reacts with water to give an OH-adduct radical. The radical reacts with a DDQ radical anion to yield phenol and DDQH2. The quantum yield of phenol formation is as high as 0.45, the highest reported value for the direct photooxygenation of benzene to phenol. (J. Am. Chem. Soc. 2013, 135, 5368–5371; Xin Su)
[For another reaction that uses visible-light catalysis, see above.—Ed.]
Optimizing lab yields is just the start for an industrial process. U. LÉtinois and co-workers at DSM Nutritional Products (Basel, Switzerland) developed a process for making 4-aminopyrimidines. In the key reaction, the enolate derived from N,2-diformyl-2-aminoacetonitrile is coupled with an amidine hydrochloride (initially acetamidine·HCl).
Catalyst and solvent screening led to a process that uses CuCl or ZnCl2 as the catalyst in toluene solvent to give yields of 80–87%. In all cases, however, the reaction mixture was a sticky slurry, which is undesirable for scale-up. Additional screening showed that the starting materials decompose in dipolar aprotic solvents such as DMF, N-methylpyrrolidone, and DMSO; but an i-PrOH–toluene mixture works well.
The authors used design-of-experiments optimization to determine the effects of solvent ratio, catalyst loading, and amidine·HCl stoichiometry on the ease of stirring the reaction mixture. The optimized procedure can be used to prepare a variety of 4-amino-5-aminomethylpyrimidines in good yields. (Org. Process Res. Dev. 2013, 17, 427–431; Will Watson)
What do you think of Noteworthy Chemistry? Let us know.