- Synthesis of honokiol analogues and evaluation of their modulating action on VEGF protein secretion and telomerase-related gene expressions
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A group of 36 biphenyl derivatives structurally related to honokiol were synthesized by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT, and c-Myc genes; the two latter involved in the activation of telomerase in tumoral cells. Some of the synthetized derivatives showed promising pharmacological features as they exhibited IC50 values in low micromolar range, good therapeutic margins, and a multiple mode of action on tumor cells based on the inhibition of VEGF and, at the same time, of the expression of genes related to the activation of telomerase.
- Sánchez-Peris, María,Murga, Juan,Falomir, Eva,Carda, Miguel,Marco, Juan Alberto
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Read Online
- Palladium-catalyzed anti-Markovnikov oxidative acetalization of activated olefins with iron(iii) sulphate as the reoxidant
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This paper discloses the efficient palladium-catalyzed anti-Markovnikov oxidative acetalization of activated terminal olefins with iron(iii) sulfate as the reoxidant. This methodology requires mild reaction conditions and shows high regioselectivity toward anti-Markovnikov products and compatibility with a wide range of functional groups. Iron(iii) sulphate was the sole reoxidant used in this method. Various olefins like vinylarenes, aryl-allylethers, aryl or benzyl acrylates and homoallylic alcohols all reacted well providing anti-Markovnikov acetals, some of which represent orthogonally functionalized 1,3- and 1,4-dioxygenated compounds.
- Fernandes, Rodney A.,Kumar, Praveen,Yadav, Sandhya S.
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p. 427 - 443
(2022/01/20)
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- Metal-free Photochemical Atom Transfer Radical Addition (ATRA) of BrCCl3 to Alkenes
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A simple, photochemical, and metal-free protocol for the atom transfer radical addition (ATRA) of bromotrichloromethane onto various alkenes is described. Among a range of organic molecules, phenylglyoxylic acid proved to be the most suitable photoinitiator to promote a sustainable process for the addition of bromotrichloromethane to olefins. This photochemical atom transfer radical protocol can be expanded into a wide substrate scope of aliphatic olefins bearing various functional groups, leading to the corresponding products in good to excellent yields.
- Nikitas, Nikolaos F.,Voutyritsa, Errika,Gkizis, Petros L.,Kokotos, Christoforos G.
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supporting information
p. 96 - 101
(2021/01/04)
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- Nickel Hydride Catalyzed Cleavage of Allyl Ethers Induced by Isomerization
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This report discloses the deallylation of O - and N -allyl functional groups by using a combination of a Ni-H precatalyst and excess Bronsted acid. Key steps are the isomerization of the O - or N -allyl group through Ni-catalyzed double-bond migration followed by Bronsted acid induced O/N-C bond hydrolysis. A variety of functional groups are tolerated in this protocol, highlighting its synthetic value.
- Kathe, Prasad M.,Berkefeld, Andreas,Fleischer, Ivana
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supporting information
p. 1629 - 1632
(2021/02/09)
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- Nickel-catalyzed deallylation of aryl allyl ethers with hydrosilanes
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An efficient and mild catalytic deallylation method of aryl allyl ethers is developed, with commercially available Ni(COD)2 as catalyst precursor, simple substituted bipyridine as ligand and air-stable hydrosilanes. The process is compatible with a variety of functional groups and the desired phenol products can be obtained with excellent yields and selectivity. Besides, by detection or isolation of key intermediates, mechanism studies confirm that the deallylation undergoes η3-allylnickel intermediate pathway.
- Wang, Jingyang,Wang, Yu,Ding, Guangni,Wu, Xiaoyu,Yang, Liqun,Fan, Sijie,Zhang, Zhaoguo,Xie, Xiaomin
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supporting information
(2021/09/28)
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- Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands – Functional characterization and modeling studies on H3 and H4 receptors
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Histamine acts through four different receptors (H1R-H4R), the H3R and H4R being the most explored in the last years as drug targets. The H3R is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while H4R blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human H3R/H4R ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hH3R affinity (pKi > 7), compound 1h being the most potent (pKi 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gαi activity indicated that the compounds are potent antagonists. Only one compound (2c, pKi 7.1) presented high affinity for hH4R. In contrast to what was observed for hH3R, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hH3R, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hH3R. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hH4R was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hH3R and hH4R.
- Corrêa, Michelle F.,Balico-Silva, André L.,Kiss, Dóra J.,Fernandes, Gustavo A.B.,Maraschin, Jhonatan C.,Parreiras-e-Silva, Lucas T.,Varela, Marina T.,Sim?es, Sarah C.,Bouvier, Michel,Keser?, Gy?rgy M.,Costa-Neto, Claudio M.,Fernandes, Jo?o Paulo S.
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- Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta
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Cardiovascular diseases (CVDs) present high prevalence rates in the current world. It is estimated that approximately one-third of the global deaths are related to CVDs, and thus there is still a need for novel drugs to treat these disorders. We serendipitously discovered that LINS01005 (5a) is a potent vasodilating agent in rat aorta, and therefore a set of analogues were evaluated for the vasodilating potency in Wistar and SHR rat thoracic aorta precontracted with norepinephrine, with endothelium intact (E+) or denuded (E–) aortic rings. Compounds 5a and 5b were the most potent, showing submicromolar potency for endothelium intact vessels (EC50 853 and 941 nM, respectively) and micromolar values for E– vessels (EC50 2.4 and 7.1 μM, respectively). These compounds were indeed significantly more potent vasodilating agents in SHR-derived aortic rings (p 50 2.4 nM (E+) 9.0 nM (E–)] and 5b [EC50 20 nM (E+) 2.1 μM (E–)]. SAR analysis though PCA and HCA were performed, suggesting that N-phenylpiperazine is essential to the activity, while increasing volume in the substituted aromatic moiety is detrimental to the potency. This is the first report of the vasodilating properties of such compounds, and studies regarding the mechanism of action are in progress in our group.
- Ginoza, Milton,Fernandes, Gustavo A.B.,Corrêa, Michelle F.,Fernandes, Jo?o Paulo S.
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- Profiling of LINS01 compounds at human dopamine D2 and D3 receptors
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Abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H3 receptor (H3R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D2 receptor (D2R) and dopamine D3 receptor (D3R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using [3H]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D2R and D3R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D3R (Ki 0.3–1.5 μM), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D2R (Ki 1.3–5.5 μM). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H3R and D2R/D3R-ligands are provided. Graphic abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, and thus LINS01 compounds previously reported as histamine H3 receptor antagonists were evaluated as dopamine D2R and D3R ligands. The compounds showed micromolar affinities to both receptors[Figure not available: see fulltext.].
- Corrêa, Michelle F,Reiner, David,Fernandes, Gustavo A B,Varela, Marina T,Aranha, Cecília M S Q,Stark, Holger,Fernandes, Jo?o Paulo S
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- Small Molecule NF-κB Inhibitors as Immune Potentiators for Enhancement of Vaccine Adjuvants
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Adjuvants are added to vaccines to enhance the immune response and provide increased protection against disease. In the last decade, hundreds of synthetic immune adjuvants have been created, but many induce undesirable levels of proinflammatory cytokines including TNF-α and IL-6. Here we present small molecule NF-κB inhibitors that can be used in combination with an immune adjuvant to both decrease markers associated with poor tolerability and improve the protective response of vaccination. Additionally, we synthesize a library of honokiol derivatives identifying several promising candidates for use in vaccine formulations.
- Moser, Brittany A.,Escalante-Buendia, Yoseline,Steinhardt, Rachel C.,Rosenberger, Matthew G.,Cassaidy, Britteny J.,Naorem, Nihesh,Chon, Alfred C.,Nguyen, Minh H.,Tran, Ngoctran T.,Esser-Kahn, Aaron P.
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- Enantioselective Construction of Si-Stereogenic Center via Rhodium-Catalyzed Intermolecular Hydrosilylation of Alkene
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Catalytic, enantioselective synthesis of stereogenic silicon compounds remains a challenge. Herein, we report a rhodium-catalyzed regio- and enantio-selective intermolecular hydrosilylation of alkene with prochiral dihydrosilane. This new method features a simple catalytic system, mild reaction conditions and a wide functional group tolerance.
- He, Tao,Liu, Li-Chuan,Ma, Wen-Peng,Li, Bin,Zhang, Qing-Wei,He, Wei
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supporting information
p. 17011 - 17015
(2020/11/30)
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- Synthesis of Benzofuran and Indole Derivatives Catalyzed by Palladium on Carbon
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Benzofurans and indoles are key moieties in many natural products and pharmaceuticals. Herein, we describe a cheap and easy-to-execute strategy for the synthesis of benzofurans and indoles, employing Pd/C as the promoter. A variety of substituted allyl-anilines and allyl-phenols were converted into the desired products in good to excellent yields. Recycling of Pd/C was possible up to five cycles, keeping similar levels of reactivity.
- Savvidou, Anatoli,IoannisTzaras, Dimitrios,Koutoulogenis, Giorgos S.,Theodorou, Alexis,Kokotos, Christoforos G.
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supporting information
p. 3890 - 3897
(2019/06/27)
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- Green Organocatalytic Synthesis of Dihydrobenzofurans by Oxidation-Cyclization of Allylphenols
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A green and cheap protocol for the synthesis of dihydrobenzofurans via an organocatalytic oxidation of o -allylphenols is presented. The use of 2,2,2-trifluoroacetophenone and H 2 O 2 as the oxidation system, leads to a highly useful synthetic method, where a variety of substituted o -allylphenols were cyclized in high yields..
- Triandafillidi, Ierasia,Sideri, Ioanna K.,Tzaras, Dimitrios Ioannis,Spiliopoulou, Nikoleta,Kokotos, Christoforos G.
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supporting information
p. 4254 - 4260
(2017/09/12)
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- Regioselective Alkoxycarbonylation of Allyl Phenyl Ethers Catalyzed by Pd/dppb under Syngas Conditions
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A simple and regioselective synthesis of phenoxy esters and phenylthio esters is reported. The products are obtained by selective alkoxycarbonylation catalyzed by Pd2(dba)3, 1,4-bis(diphenylphisphino)butane (dppb), and syngas (CO/H2) in chloroform/alcohol. This methodology affords bifunctional products in good yield with excellent n-selectivity and without the need to use additives.
- Amézquita-Valencia, Manuel,Alper, Howard
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p. 3860 - 3867
(2016/05/24)
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- Reduction of C,O-chelated organotin(IV) dichlorides and dihydrides leading to protected polystannanes
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A series of aryloxy organotin compounds Ph3Sn(CH2)3OC6H4R (5: R = H; 6: R = Ph; 7: R = OCH3, 8: R = CF3), Ph2ClSn(CH2)3OC6H4R (9: R = H; 10: R = Ph) and PhCl2Sn(CH2)3OC6H4R (12: R = H; 13: R = Ph) have been synthesized and characterised by NMR (1H, 13C, 119Sn) spectroscopy. X-ray structure determinations of 9, 10, 12 and 13 reveal a distorted trigonal bipyramidal geometry at Sn with Cl trans to the datively bonded O whereas 8 possesses tetrahedral geometry and a Sn? dative interaction is absent. Triorganotin hydrides Ph2HSn(CH2)3OC6H4R (14: RH; 15: RPh) and diorganotin dihydrides PhH2Sn(CH2)3OC6H4R (16: RH; 17: RPh) were prepared by reduction of the corresponding dihalides with LiAlH4. Catalytic dehydrocoupling of dihydrides 16 or 17 with a late transition metal catalyst afforded asymmetrical hypercoordinated polystannanes [PhSn(CH2)3OC6H4R]n (18: RH; 19: RPh) with relatively high molecular weights (Mw 1.3 104 e 2.5 105 Da) and narrow polydispersities (PDI's 1.3e3.3). NMR and UVeVis spectroscopy studies indicate that the new polymers display dramatically improved light stability, but remain sensitive to moisture.
- Khan, Aman,Komejan, Sarah,Patel, Aagam,Lombardi, Christopher,Lough, Alan J.,Foucher, Daniel A.
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p. 180 - 191
(2015/02/19)
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- Enantioselective synthesis of benzofurans and benzoxazines via an olefin cross-metathesis-intramolecular oxo-Michael reaction
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Chiral phosphoric acid and Hoveyda-Grubbs II were found to catalyze an olefin cross-metathesis-intramolecular oxo-Michael cascade reaction of the ortho-allylphenols and enones to provide a variety of benzofuran and benzoxazine derivatives in moderate to good yields and enantioselectivity.
- Zhang, Jun-Wei,Cai, Quan,Gu, Qing,Shi, Xiao-Xin,You, Shu-Li
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supporting information
p. 7750 - 7752
(2013/09/02)
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- Design, synthesis, and anti-proliferative evaluation of [1,1′-biphenyl]-4-ols as inhibitor of HUVEC migration and tube formation
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Allylated biphenol neolignans contain a variety of chemopreventive entities that have been used as anti-tumor drug leads. Herein, 37 allylated biphenols were evaluated for anti-proliferative activity by the MTT assay and inhibitory effect on the migration and tube formation of HUVECs featuring anti-angiogenic properties. 3-(2-Methylbut-3-en-2-yl)-3′,5′-bis(trifluoromethyl)-[1, 1′-biphenyl]-4-ol (5c) exerted an inhibitory effect on HUVECs compared to honokiol (IC50 = 47.0 vs. 52.6 μM) and showed significant blocking effects on the proliferation of C26, Hela, K562, A549, and HepG2 (IC 50 = 15.0, 25.0, 21.2, 29.5, and 13.0 μM, respectively), superior to those of honokiol (IC50 = 65.1, 62.0, 42.0, 75.0, and 55.4 μM, respectively). Importantly, compound 5c inhibited the migration and capillary-like tube formation of HUVECs in vitro.
- Ran, Yan,Ma, Liang,Wang, Xuewei,Chen, Jinying,Wang, Guangcheng,Peng, Aihua,Chen, Lijuan
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experimental part
p. 8091 - 8104
(2012/10/07)
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- A domino amidation route to indolines and indoles: Rapid syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine
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(Chemical Equation Presented) When subjected to palladium-catalyzed amidation conditions, 2-triflyloxy phenethyl carbonates undergo, in addition to the expected aryl cross-coupling, an additional amidation with net displacement of the carbonate. The result is a one-step synthesis of indolines which may be oxidized to indoles. The utility of the procedure is illustrated by the two- or three-step syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine.
- Ganton, Michael D.,Kerr, Michael A.
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p. 4777 - 4779
(2007/10/03)
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- Organotin compounds bearing mesogenic sidechains: synthesis, X-ray structures and polymerisation chemistry
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Organotin compounds R3Sn(CH2)n+2OC6H4C6H4Y (R3 = Ph3, Ph2Bu, Y = H, CN; n = 1-3) and RX2Sn(CH2)n+2OC6H4Y (R = Ph, Bu; Y = H, X = Br, I; n = 1-3) have been synthesised and characterised by 1H-, 13C-, 119Sn-NMR and Moessbauer spectroscopies. X-ray crystallography reveals tetrahedral geometries for Ph3Sn(CH2)4OC6H4C6H5 and Ph3Sn(CH2)3OC6H4C6H4CN, a six-coordinated, bromine-bridged dimeric structure for PhBr2Sn(CH2)3OC6H4C6H5 containing a mer-Br3C2OSn coordination sphere about tin and five-coordinated monomeric structure for PhBr2Sn(CH2)3OC6H4C6H4CN. In all cases there is strong alignment of mesogenic groups in the solid-state but only PhBr2(CH2)3OC6H4C6H4CN shows any indication of liquid-crystal behaviour. Wurtz polymerisation of RBr2Sn(CH2)5OC6H4C6H5 (R = Ph, Bu), both of which contain non-chelating ether functions, generated polystannanes (RR'Sn)n with Mn 2.3*105; Mw 3.0*105; Mw/Mn 1.30 and Mn 1.3*105; Mw 2.5*105; Mw/Mn 1.96, respectively, while no polymer was obtained from chelated PhBr2Sn(CH2)3OC6H4C6H5.
- Deacon, P.R.,Devylder, N.,Hill, M.S.,Mahon, M.F.,Molloy, K.C.,Price, G.J.
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- Aryloxazolidinediones: Identification of potent orally active PPAR dual α/γ agonists
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A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual α/γ agonists. Based on the results of efficacy studies in the db/db mice
- Desai, Ranjit C.,Gratale, Dominick F.,Han, Wei,Koyama, Hiroo,Metzger, Edward,Lombardo, Victoria K.,MacNaul, Karen L.,Doebber, Thomas W.,Berger, Joel P.,Leung, Kwan,Franklin, Ronald,Moller, David E.,Heck, James V.,Sahoo, Soumya P.
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p. 3541 - 3544
(2007/10/03)
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- Carboxylic acid derivatives as IP antagonists
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This invention relates to compounds which are generally IP receptor antagonists and which are represented by Formula I: wherein: R1, R2, and R3 are each independently in each occurrence aryl or heteroaryl; R4 is
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- Intramolecular triplet energy transfer in flexible molecules: Electronic, dynamic, and structural aspects
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Exothermic intramolecular triplet energy transfer (TET) rate constants in various flexible bichromophoric systems D-(CH2)n-O-A (D = benzoyl, 4-methylbenzoyl; A = 2-naphthyl, 4-, 3-, 2-biphenyl; n = 3-14) have been determined from steady-state quenching and quantum yield measurements. The magnitude of the rate constants in molecules where n = 3 is comparable to those in molecules with a rigid spacer between chromophores, so that a through-bond mechanism is presumed to remain important. A very gradual drop in TET rate constants as the connecting polymethylene chain becomes longer indicates that through-space interactions compete and apparently provide the only mechanism responsible for transfer when n ≥ 5. Rate constants in long molecules (n = 11-14) remain remarkably high (~108 s-1) - lower than in those with four-atom tethers by only 1 order of magnitude. This effect is explained on the basis of rapid conformational equilibria always keeping a sufficient fraction of the molecules coiled so that the two chromophores are close enough to interact within 10 ns, the time required for the competing γ-hydrogen abstraction used to monitor triplet lifetimes. Energy transfer accounts for 40-75% of triplet decay for the longer molecules. This high efficiency indicates that only a small fraction involves static quenching in ground-state conformers with the two ends within 4 A. The majority must represent a combination of rate-determining bond rotations to such geometries and equilibrated conformations with their ends farther apart but still able to undergo energy transfer within 10 ns. Thus, the measured rate constants are, in fact, a weighted average of three different conformational mechanisms. The decrease in rate constant with tether length is not monotonic: a relative increase in rate for medium-chain-length molecules is explained by a larger number of favorable conformers and further, in biphenyl derivatives, by a rotation along the terminal O-C bond between the tether and the aromatic ring. As was expected, replacement of the polymethylene tether with poly(ethylene oxide) promotes better flexibility and thus higher transfer rates. Rate constants were found to be lower by a factor of ~2 when biphenyl rather than naphthyl is the acceptor, in agreement with earlier bimolecular measurements. With the 4-methylbenzoyl group (π,π* lowest triplet) as donor instead of benzoyl (n,π* lowest triplet), a small (~1.5x) but consistent rate increase occurred for all tether lengths.
- Wagner, Peter J.,Klan, Petr
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p. 9626 - 9635
(2007/10/03)
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- Improved Cs2CO3 promoted O-alkylation of phenols
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Cesium carbonate mediated O-alkylation of phenols was carried out under mild conditions to give the corresponding phenol ethers exclusively. The methodology is more efficient than previous methods since harsh conditions such as higher temperatures and lon
- Parrish, Jay P.,Sudaresan, Bhuvana,Jung, Kyung Woon
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p. 4423 - 4431
(2007/10/03)
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- Convenient criterion for the distinction between electrophilic and electron transfer reactions of electron-rich alkenes
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Both experimental and theoretical studies confirm that the formation of aryl vinyl ether and aryl vinyl sulfide cation radicals from the corresponding neutral substrates correlates with the Brown σ+ parameters as opposed to Hammett σ values. Peak oxidation potentials for both classes of substrates correlate preferentially with σ+, as do gas-phase ionization energies calculated by both semi-empirical and ab initio methods. In contrast, the protonation energies of the same substrates, which relate to carbocation formation, correlate preferentially with σ values, as do rates of protonation and other electrophilic additions. These observations permit a sharp distinction between electrophilic and electron transfer reactions of these two common classes of electron-rich substrates. Using this criterion, the cycloadditions of tetracyanoethylene to these substrates are found to proceed via an electrophilic mechanism, rather than by a previously proposed electron transfer mechanism.
- Bauld, Nathan L.,Aplin, J. Todd,Yueh, Wang,Endo, Stephanie,Loving, Angie
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