Approaching Unconventional Chemical Puzzles and Catalysis via Conventional Ligand Design in Amino-NHC and Carbodicarbene
J. Am. Chem. Soc. 2017, 139, 12830-12836
W.-C. Chen*, W.-C. Shih, T. Jurca, L. Zhao, D. M. Andrada, C.-J. Peng, C.-C. Chang, S.-k. Liu, Y.-P. Wang, Y.-S. Wen, G. P. A. Yap, C.-P. Hsu, G. Frenking*, and T.-G. Ong*
Angew. Chem. Int. Ed. 2015, 54, 15207–15212
W.-C. Chen, J.-S. Shen, T. Jurca, C.-J. Peng, Y.-H. Lin, Y.-P. Wang, W.-C. Shih, G. P. A. Yap, and T.-G. Ong*
Angew. Chem. Int. Ed. 2015, 54, 2420–2424
Y.-C. Hsu, J.-S. Shen, B.-C. Lin, W.-C. Chen, Y.-T. Chan, W.-M. Ching, G. P. A. Yap, C.-P. Hsu*, and T.-G. Ong*
J. Am. Chem. Soc. 2014, 136, 914–917
W.-C. Chen, C.-Y. Lee, B.-C. Lin, Y.-C. Hsu, J.-S. Shen, C.-P. Hsu*, G. P. A. Yap, and T.-G. Ong*

Ong group has been at forefront of designing a myriad of amino-nitrogen heterocyclic carbene (NHC) and carbodicarbene frameworks and investigating of their fundamental chemical reactivities, which they have made numerous significant contributions and innovations in the context of molecular catalysis, synthetic chemistry, medicinal and main group elements. The ability of catalyst to direct the green synthesis for complex molecules from simple starting materials is epitomized by the vibrant theme of the C-H bond activation. Dr. Ong has systematically established a revolutionary approach in exploiting synergistic effect between main and transition metal to promote efficient selective C-H activation. At the same time, the amazing catalytic reaction performed by enzyme has inspired Ong group to endeavor the first special acyclic pincer bis(pyridine)carbodicarbene. Such Pd metallic complex supported by this highly electron rich pincer ligand is a very active catalyst for Heck-Mizoroki and Suzuki-Miyaura coupling reactions. Finally, Ong also have discovered the formation of a hitherto unknown three-coordinate dicationic hydrido boron complex with unique bonding environment. Supporting ligand carbodicarbene gave unprecedented reaction with BH3 without using more highly electrophilic Lewis acid precursors. A reaction behavior not observed for other common NHC ligands. These results pave the way for future studies in highly electrophilic Lewis acid chemistry with interesting potential applications in organic synthesis and catalysis.

Photo-Controllable Probe Spatiotemporally Induces Neurotoxic Fibrillar Aggregates and Impairs Nucleocytoplasmic Trafficking
ACS Nano 2017, 11, 6795–6807
Ruei-Yu He, Shu-Han Chao, Yu-Ju Tsai, Chi-Chang Lee, Chu-Yi Yu, Hua-De Gao, Yung-An Huang, Eric Hwang, Hsien-Ming Lee*, and Joseph Jen-Tse Huang*

Despite hyperphosphorylated TDP-43 has been confirmed as one of the major components in the inclusion bodies of patients with Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal lobar degeneration (FTLD), the underlying disease mechanism has not yet been fully elucidated. Dr. Joseph Jen-Tse Huang, an associate research fellow at the Institute of Chemistry in Academia Sinica, Dr. Hsien-Ming Lee, an assistant research fellow at the Institute of Chemistry in Academia Sinica, and Dr. Eric Hwang, an associate professor at Department of Biological Science and Technology in National Chiao Tung University, developed a photocontrollable probe to induce TDP-43 aggregates in live cells. This platform enables researchers to spatiotemporally control the formation of the neurotoxic fibrils and directly observe the TDP-43 amyloidogenic process.

New Applications of Metal–Organic Framework (MOF) towards LED and Low-K/Low Bandgap Optoelectronic Materials
Adv. Mater. 2017, 29, 1605071
Muhammad Usman, Shruti Mendiratta, Kuang-Lieh Lu*
ACS Nano 2016, 10, 8366–8375
Golam Haider, Muhammad Usman, Tzu-Pei Chen, Packiyaraj Perumal, Kuang-Lieh Lu*, and Yang-Fang Chen*
NPG Asia Mater. 2016, 8, e333
Muhammad Usman, and Kuang-Lieh Lu*

Metal–organic frameworks (MOFs) with a low density, high porosity and easy tunability of functional and structural properties, represent potential candidates for use as opto- and microelectonic materials. A highlight published by Dr. Lu’s group in Adv. Mater. provides a perspective of recent research regarding the semiconducting properties of MOFs, bandgap studies and their potential for use in microelectronic devices. In addition, Dr. Lu, in collaboration with Prof. Yang-Fang Chen, reported on the preparation of an electrically driven WLED consisting of a Sr- based MOF, graphene, and ZnO, which generates a bright white light emission. An alkaline earth metal was used to replace the more commonly used lanthanides. The cost of production is also lower than that for current technologies. The emission spectrum of the device was close to that of natural sunlight. These findings were published in ACS Nano. A press release concerning this was distributed by ACS Nano and these results have been reported by many scientific news agencies. Furthermore, a contract dealing with the technology transfer of the white light materials and devices to a company in Taiwan has been signed.

Alkane Oxidation: Methane Monooxygenase, Related Enzymes, and Their Biomimetic Heterogeneous Formulation of the Tricopper Complex for Efficient Catalytic Conversion of Methane into Methanol at Ambient Temperature and Pressure
Chem. Rev. 2017, 117, 8574-862
Vincent C.-C. Wang, Suman Maji, Peter P.-Y. Chen, Hung Kay Lee, Steve S.-F. Yu, Sunney I. Chan
Energy Environ. Sci. 2016, 9, 1361–1374
Chih-Cheng Liu, Chung Yuan Mou, Steve S.-F. Yu, and Sunney I. Chan*

Methane monooxygenase (MMOs) mediate the facile conversion of methane to methanol in methanotrophic bacteria with high efficiency under ambient conditions. Because the selective oxidation of methane is extremely challenging, there is considerable interest in understanding how these enzymes carry out this difficult chemistry. The impetus of these efforts is to learn from the microbes to develop a biomimetic catalyst to accomplish the same chemical transformation. The discovery of a heterogeneous biomimetic artificial catalyst capable for efficient selective conversion of methane into methanol with multiple turnovers under ambient conditions is reported. The catalyst is assembled by immobilizing into mesoporous silica nanoparticles the tricopper complex that is mimic the active site of particulate methane monooxygenase (pMMO) from Methylococcus capsulatus (Bath). The heterogeneous formulation exhibits dramatically higher catalytic efficiencies and turnover numbers, with commensurate improvements in chemical yields, offering the most proficient catalyst for the selective conversion of methane into methanol at room temperature developed to date. The much higher solubility of methane within the pores of the mesoporous silica nanoparticles, as compared to the bulk solubility, led to very efficient turnover of the concentrated confined methane. This success underscores the advantages of using nanoparticles to support chemical catalysts for this difficult chemical transformation under these conditions

Landmark Progress in Porphyrin Chemistry: Synthesis of Octaluoro-Porphyrin and Cobalt Porphyrins Promoted Conversion of Nitric Oxide to Nitrous Oxide
Angew. Chem. Int. Ed. 2016, 55, 5035–5039
Chiranjeevulu Kashi, Chu-Chun Wu, Chi-Lun Mai, Chen-Yu Yeh* and Chi K. Chang*
Angew. Chem. Int. Ed. 2016, 55, 5190–5194
Chuan-Hung Chuang, Wen-Feng Liaw*, and Chen-Hsiung Hung*

Fluorinated porphyrinoids by virtue of their unique chemical robustness and reactivity are ideal systems for biomimetic applications. Yet, the most fundamental 2,3,7,8,12,13,17,18-octafluoro- porphyrin (OFP) has not been synthesized despite numerous attempts. It is now achieved by self- condensation of tetrafluoro-dipyrrylmethane-2-carboxaldehyde in the presence of MgBr2. MgOFP in solid state revealed an essentially flat structure. The fluoro-groups impart as much as 0.5 V anodic shifts for porphyrin ring oxidation/reduction, as well as hypsochromic shifts in the Uv-vis spectra. The synthetic approach paves the way to exploring the family of octahaloporphyrins (X=F, Cl, Br & I) that have been out of reach thus far. In another landmark report on porphyrin chemistry from IoC, Dr. Hung’s group reported the firstly achieved {Co(NO)}9 cobalt nitrosyl porphyrinoid complex and demonstrated that MeOH H-bonded {Co(NO)}9 cobalt-nitrosyl N-confused porphyrin induce an interaction with non-H-bonded {Co(NO)}9 species to promote a N-N bond formation. The conversion of NO-to-N2O can also be initiated by water or ethanol, and the process has been repeated as many as five cycles without significant decay of the N2O production. This result may suggest that the roles of the distal water in the native NorBC can not only shuttle protons, but also trigger N-N bond formation through H-bonding interactions.

Temporal Regulation of Lsp1 O-GlcNAcylation and Phosphorylation during Apoptosis of Activated B Cells
Nat. Commun. 2016, 7, 12526
Jung-Lin Wu, Hsin-Yi Wu, Dong-Yan Tsai, Ming-Feng Chiang, Yi-Ju Chen, Shijay Gao, Chun-Cheng Lin, Chun-Hung Lin, Kay-Hooi Khoo, Yu-Ju Chen*, and Kuo-I Lin*

Crosslinking of B-cell receptor (BCR) sets off an apoptosis programme, but the underlying pathways remain obscure. Here we decipher the molecular mechanisms bridging B-cell activation and apoptosis mediated by post-translational modification (PTM). We find that O-GlcNAcase inhibition enhances B-cell activation and apoptosis induced by BCR crosslinking. This proteome- scale analysis of the functional interplay between protein O-GlcNAcylation and phosphorylation in stimulated mouse primary B cells identifies 313 O-GlcNAcylation-dependent phosphosites on 224 phosphoproteins. Among these phosphoproteins, temporal regulation of the O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 (Lsp1) is a key switch that triggers apoptosis in activated B cells. O-GlcNAcylation at S209 of Lsp1 is a prerequisite for the recruitment of its kinase, PKC-β1, to induce S243 phosphorylation, leading to ERK activation and downregulation of BCL-2 and BCL-xL. Thus, we demonstrate the critical PTM interplay of Lsp1 that transmits signals for initiating apoptosis after BCR ligation.

Turning the Halide Switch in the Synthesis of Au-Pd Alloy and Core-Shell Nanoicosahedra with Terraced Shells: Performance in Electrochemical and Plasmon-Enhanced Catalysis
Nano Lett. 2016, 16, 5514–5520
Shih-Cheng Hsu, Yu-Chun Chuang, Brian T. Sneed, David A. Cullen, Te-Wei Chiu, and Chun-Hong Kuo*

We developed a green strategy by which highly monodispersed Au-Pd alloy and Au-Pd core-shell nanoicosahedra (IH), a shape with twenty 111 crystal faces on its surface along with thirty twin boundaries, could be aqueously prepared in one step by turning the ratio of bromide and chloride ions. Both of their particle sizes are 15-17 nm. Such small IH morphology provides not only the high surface-to-volume ratio but also the highly active surfaces due to twin-induced surface strain toward ethanol electrooxidation. The result shows both alloy and core-shell IH have at least double ECSA and Pd mass activities to those of Pd IH and commercial Pd catalysts. In addition to the advantage of the icosahedral surface, the enhancement of localized surface plasmon resonance (LSPR) is also examined and compared between the alloy and core-shell IH. It turns out that the activities of them in the reduction of 4-nitrophenol differentiate in the dark and under irradiation of visible light. The light-excited activity is always higher in each, in particular that of the core- shell IH shows higher enhanced factors than that of alloy, attributed to the higher content of Au in the cores. This work provides a green route to prepare the superior light-harvested bimetallic photocatalyst, which opens the gate to the field of aqueous nanocontrol on nanostructures

Isorecticular Synthesis of Dissectible Molecular Bamboo Tubes of Hexarhenium(I) Benzene-1,2,3,4,5,6-hexaolate Complexes
Angew. Chem. Int. Ed. 2016, 55, 8343–8347
Tien-Wen Tseng*, Tzuoo-Tsair Luo, Shi-Hao Liao, Kai-Hsiang Lu, and Kuang-Lieh Lu*

Dr. Lu’s group successfully synthesized a family of dissectible bamboo-like metal–organic nanotubes constructed of in situ generated benzenehexaolate (C6O66-)-based scaffolds, which have a doubly tri-legged geometry. These structures were assembled piece by piece. Such a nanotube is unique and unprecedented. In addition, the benzenehexaolate ligand has never been reported in any organic compounds or transition-metal complexes and is observed for the first time. This finding offers an archetypal approach to the systematic formation of dissectible molecular bamboo tubes (resembling the shape of the Taipei 101 tower).

Large-Scale Determination of Absolute Phosphorylation Stoichiometries in Human Cells by Motif-Targeting Quantitative Proteomics
Nat. Commun. 2015, 6, 6622
Chia-Feng Tsai, Yi-Ting Wang, Hsin-Yung Yen, Chih-Chiang Tsou, Wei-Chi Ku, Pei-Yi Lin, Hsuan-Yu Chen, Alexey I. Nesvizhskii, Yasushi Ishihama*, and Yu-Ju Chen*

Protein phosphorylation is one of the most critical post-translational modifications to regulate cellular function. Measuring the phosphorylation event at the proteome scale provides a system view for activated signaling pathway. To overcome the current bottleneck in accessing the stoichiometry of single-state human phosphoproteomes, we have developed a motif-targeting quantitative proteomic approach by integrating enzymatic kinase reaction and isotope-based quantitative proteomic strategy. The quantitation accuracy and sensitivity of this approach was demonstrated on the proof-of-concept experiments in lung cancer cell; phosphorylation stoichiometry of >1000 phosphorylation sites including 366 low abundant tyrosine phosphorylation sites were successfully measured with high reproducibility. To our knowledge, this approach reveals the first large-scale measurement on the basal level of phosphorylation stoichiometry in a single state human phosphoproteome. This research group further applied this developed motif targeting quantitative approach for phosphorylation stoichiometry profiling of drug resistance/sensitive lung cancer cells. On the comparison of TKI (tyrosine kinase inhibitor) sensitive (PC9) and resistance lung cancer cell (PC9/gef.), the quantitative information not only illuminated that the post-translational phosphorylation changes are significantly more dramatic than those at protein as well as mRNA levels, but also suggested potential drug-targeting proteins in the kinase-substrate network associated with acquired drug-resistance. We expected that this newly developed approach will have wide applications to provide system-wide maps of protein phosphorylation stoichiometry for either single or multiple cellular states under physiological or pathological regulation.

Programming Thermoresponsiveness of NanoVelcro Substrates Enables Effective Purification of Circulating Tumor Cells in Lung Cancer Patients
ACS Nano 2015, 9, 62–70
Zunfu Ke*, Millicent Lin, Jie-Fu Chen, Jin-sil Choi, Yang Zhang, Anna Fong, An-Jou Liang, Shang-Fu Chen, Qingyu Li, Wenfeng Fang, Pingshan Zhang, Mitch A. Garcia, Tom Lee, Min Song, Hsing-An Lin, Haichao Zhao, Shyh-Chyang Luo, Shuang Hou*, Hsiao-hua Yu*, and Hsian-Rong Tseng*

Circulating tumor cells (CTCs) are cancer cells that break away from tumors and travel in the blood, looking for places in the body to start growing new tumors called metastases. Capturing these rare cells allows doctors to detect and analyze a patient’s cancer to give insight into personalized treatment design for each patient. Scientists from the Smart Organic Materials Laboratory, Institute of Chemistry at Academia Sinica, and collaborators have developed a way to capture CTCs from blood samples – a liquid biopsy – and then release them from the surface with great cell viability using an invention called the Nano Velcro chip. This allows the scientists to examine the CTCs and analyze their genetic features. This system allows the researchers to extract CTCs much more efficient and cost-effective at a time in a patient’s life when doctors need as much information as possible and as quickly as possible. Moreover, mutational genetic analysis is successfully demonstrated to monitor the disease evolution of a sample lung cancer patient. This shows the translational value of the device in managing non-small cell lung cancer with underlying mutations.

Microwave-Assisted One-Pot Synthesis of 1,6-Anhydrosugars and Orthogonally Protected Thioglycosides
J. Am. Chem. Soc. 2014, 136(41), 14425–14431.
Yen-Chun Ko, Cheng-Fang Tsai, Cheng-Chung Wang*, Vijay M. Dhurandhare, Pu-Ling Hu, Ting-Yang Su, Larry S. Lico, Medel Manuel L. Zulueta, and Shang-Cheng Hung*

Carbohydrates are known to be involved in numerous biological processes. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. In this report, Dr. Wang and Dr. Hung describe the routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-O-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio) silane and ZnI2, respectively, under microwave irradiation. They successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages. These results have been published in J. Am. Chem. Soc. 2014.

Lithiation of a Silyl Ether; Formation on an ortho-Fries Hydroxyketone
Angew. Chem. Int. Ed. 2014, 53, 9026–9029
Hong-Jay Lo, Chin-Yin Lin, Mei-Chun Tseng, and Rong-Jie Chein*

The hydroxy-directed nucleophilic acyl alkylation of hydroxyarylamides and salicylic acid through an anionic Si→C alkyl migration was developed using a simple reagent combination of LDA and chlorosilane. The transformation involves (1) a complex-induced proximity effect (CIPE) in the deprotonation step, (2) an intramolecular Peterson type reaction of the resulting α-silyl carbanion with the amide group, and (3) fission of the final β-oxygenated silyl intermediate. This reaction giving silyl ether a new role in organic synthesis was further developed for application to an extended anionic Snieckus-Fries rearrangement. The exceptional functional group transformations achievable using a simple reagent combination of LDA and chlorosilane renders these reactions highly valuable for the synthesis of natural products and medicinally important compounds, such as the PI3K inhibitor LY294002.

Large Enhancement in Neurite Outgrowth on a Cell-Membrane-Mimicking Conducting Polymer
Nat. Commun. 2014, 5, 4523
Bo Zhu, Shyh-Chyang Luo, Haichao Zhao, Hsing-An Lin, Jun Sekine, Aiko Nakao, Chi Chen, Yoshiro Yamashita, and Hsiao-hua Yu*

Although electrically stimulated neurite outgrowth on bioelectronic devices is a promising means of nerve regeneration, immunogenic scar formation can insulate electrodes from targeted cells and tissues, thereby reducing the lifetime of the device. Ideally, an electrode material capable of electrically interfacing with neurons selectively and efficiently would be integrated without being recognized by the immune system and minimize its response. In this research article, we develop a cell membrane–mimicking conducting polymer possessing several attractive features. This polymer displays high resistance toward nonspecific enzyme/cell binding and recognizes targeted cells specifically to allow intimate electrical communication over long periods of time. Its low electrical impedance relays electrical signals efficiently. This material is capable to integrate biochemical and electrical stimulation to promote neural cellular behavior. Neurite outgrowth is enhanced greatly on this new conducting polymer; in addition, electrically stimulated secretion of proteins from primary Schwann cells can also occur upon it.

The Synthesis, Crystal Structure and Charge-transport Properties of Hexacene
Nat. Chem. 2012, 4, 574–578
Motonori Watanabe, Yuan-Jay Chang, Shun-Wei Liu, Ting-Han Chao, Kenta Goto, Md. Minarul Islam, Chih-Hsien Yuan, Yu-Tai Tao, Teruo Shinmyozu, and Tahsin J. Chow*

Acenes are a class of aromatic hydrocarbons composed of linearly fused benzene rings. They have been effectively used in a wide range of opto-electronic devices, such as organic field effect transistors (OFETs), organic photovoltaic cells (OPVs), organic light-emitting diodes (OLEDs), and organic chemosensors, etc. Dr. T. J. Chow developed new synthesis routes for higher acenes using stable and soluble precursors, which generate these structures on demand by either heating or irradiation of light (Acc. Chem. Res. 2013, 46, 1606). Using these methods, the derivatives of hexacene, pentacene (Chem. Commun. 2012, 48, 6148), and tetracene (J. Mater. Chem. 2012, 22, 13070) were successfully prepared. Many of them displayed remarkable OFET characteristics. In the Nature Chemistry article, Chow’s group used a physical vapor transport method to collect platelet-shaped crystals of hexacene from a monoketone precursor. The crystals are stable in the dark for a long period of time under an ambient condition. In crystal lattice the molecules are arranged in herringbone arrays, similar to that of pentacene. An OFET device made with a single crystal of hexacene displayed the highest hole mobility 4.28 cm2 V-1s-1 with an on/off ratio of 1 × 105 and a threshold voltage of 37 V. These devices can function under an ambient environment for more than 19 days. This result is instructive to further explorations on other higher acenes.