- A model reaction assesses contribution of H-tunneling and coupled motions to enzyme catalysis
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To assess the contribution of physical features to enzyme catalysis, the enzymatic reaction has to be compared to a relevant uncatalyzed reaction. While such comparisons have been conducted for some hydrolytic and radical reactions, it is most challenging for biological hydride transfer and redox reactions in general. Here, the same experimental tools used to study the H-tunneling and coupled motions for enzymatic hydride transfer between two carbons were used in the study of an uncatalyzed model reaction. The enzymatic oxidations of benzyl alcohol and its substituted analogues mediated by alcohol dehydrogenases were compared to the oxidations by 9-phenylxanthylium cation (PhXn+). The PhXn+serves as an NAD+ model, while the solvent, acetonitrile, models the protein environment. Experimental comparisons included linear free energy relations with Hammett reaction constant (ρ) of zero versus -2.7; temperature-independent versus temperature-dependent primary KIEs; deflated secondary KIEs with deuteride transfer (i.e., primary-secondary coupled motion) versus no coupling between secondary KIEs and H- or D-transfer; and large versus small secondary KIEs for the enzymatic versus uncatalyzed alcohol oxidation. Some of the differences may come from differences in the order of microscopic steps between the catalyzed versus uncatalyzed reactions. However, several of these comparative experiments indicate that in contrast to the uncatalyzed reaction the transition state of the enzymatic reaction is better reorganized for H-tunneling and its H-donor is better rehybridized prior to the C-H→C transfer. These findings suggest an important role for these physical features in enzyme catalysis.
- Liu, Qi,Zhao, Yu,Hammann, Blake,Eilers, James,Lu, Yun,Kohen, Amnon
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- Palladium-Catalyzed Three-Component Silylalkoxylation of 1,3-Diene with Alcohol and Disilane via Oxidative Coupling
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A regioselective and Z-selective three-component silylalkoxylation of 1,3-diene using various alcohols, disilane, and a catalytic Pd/Cu/1,4-benzoquinone/O2 system is established in this Letter. The reaction generates tetra-substituted allyl silanes containing allyl ether moieties in up to 80% isolated yield and on a 1-10 mmol scale via oxidative coupling. A wide variety of substrates, including benzyl alcohol derivates, aliphatic alcohols, and bioactive compounds such as cholesterol, are suitable for use in the developed reaction system.
- Torii, Kazuyuki,Tabaru, Kazuki,Obora, Yasushi
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- Electron and Hydrogen Atom Transfer Mechanisms for the Photoreduction of o-Quinones. Visible Light Induced Photoreaction of β-Lapachone with Amines, Alcohols, and Amino Alcohols
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β-Lapachone (1), a substituted o-naphthoquinone absorbing into the visible (λmax=424 nm in benzene), is cleanly and efficiently reduced to the corresponding semiquinone radical upon photolysis in degassed solutions with alcohols, amines, and β-amino alcohols.The course and products of these photoreactions have been followed by NMR, ESR, fluorescence, and absorption spectroscopy.For all three types of reductant the overall reaction involves 2e- oxidation of the donor, and the quantum efficiencies show a dependence upon quinone concentration indicative of therole of a second dark reduction of 1 by products of the primary photolysis.For amines and amino alcohols the reaction is initiated by single electron transfer quenching of triplet 1.For triethylamine the mechanism is indicated to be a sequence of two electron transfer-proton transfer steps culminating in two semiquinone radicals and the enamine Et2NCH=CH2.For amino alcohols a C-C cleavage concurrent with deprotonation of the alcohol (oxidative photofragmentation) occurs, in competition with reverse electron transfer, following the quenching step.For both amines and amino alcohols, limiting efficiencies of reaction approach 2 (for QH. formation).In contrast, both 2-propanol and benzyl alcohol are oxidized by excited states of 1 with much lower efficiency.The probable mechanism for photooxidation of the alcohols involves a H atom abstraction quenching of the excited state followed by an electron transfer-proton transfer sequence in which a ground-state 1 is reduced.Lower limiting efficiencies for photoreduction of 1 by the alcohols are attributed to inefficiencies of net H-atom transfer in the quenching step.
- Ci, Xiaohong,Silva, Rosaly Silveira da,Nicodem, David,Whitten, David G.
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- Are carboxyl groups the most acidic sites in amino acids? Gas-phase acidity, H/D exchange experiments, and computations on cysteine and its conjugate base
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Hydrogen-deuterium exchange experiments were carried out on the conjugate base of cysteine with four different deuterated alcohols. Three H/D exchanges are observed to take place in each case, and a relay mechanism which requires the SH and CO2
- Tian, Zhixin,Pawlow, Anna,Poutsma, John C.,Kass, Steven R.
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Read Online
- Cross β-arylmethylation of alcohols catalysed by recyclable Ti-Pd alloys not requiring pre-activation
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Ti-Pd alloy catalysts were developed for the cross β-arylmethylation between arylmethylalcohols and different primary alcohols via a hydrogen autotransfer mechanism. The alloy catalysts could be reused multiple times without the need for pre-activation. Analysis of the reaction solution by inductively coupled plasma atomic absorption spectroscopy indicated that only a minimal amount of Ti and no Pd was leached from the catalyst.
- Utsunomiya, Masayoshi,Kondo, Ryota,Oshima, Toshinori,Safumi, Masatoshi,Suzuki, Takeyuki,Obora, Yasushi
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supporting information
p. 5139 - 5142
(2021/05/31)
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- A Water/Toluene Biphasic Medium Improves Yields and Deuterium Incorporation into Alcohols in the Transfer Hydrogenation of Aldehydes
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Deuterium labeling is an interesting process that leads to compounds of use in different fields. We describe the transfer hydrogenation of aldehydes and the selective C1 deuteration of the obtained alcohols in D2O, as the only deuterium source. Different aromatic, alkylic and α,β-unsaturated aldehydes were reduced in the presence of [RuCl(p-cymene)(dmbpy)]BF4, (dmbpy=4,4′-dimethyl-2,2′-bipyridine) as the pre-catalyst and HCO2Na/HCO2H as the hydrogen source. Moreover, furfural and glucose, were selectively reduced to the valuable alcohols, furfuryl alcohol and sorbitol. The processes were carried out in neat water or in a biphasic water/toluene system. The biphasic system allowed easy recycling, higher yields, and higher selective D incorporation (using D2O/toluene). The deuteration took place due to an efficient effective M–H/D+ exchange from D2O that allows the inversion of polarity of D+ (umpolung). DFT calculations that explain the catalytic behavior in water are also included.
- Ruiz-Casta?eda, Margarita,Santos, Lucía,Manzano, Blanca R.,Espino, Gustavo,Jalón, Félix A.
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supporting information
p. 1358 - 1372
(2021/03/16)
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- Critical role of solvent-modulated hydrogen-binding strength in the catalytic hydrogenation of benzaldehyde on palladium
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Solvents not only disperse reactants to enhance mass transport in catalytic reactions but also alter the reaction kinetically. Here, we show that the rate of benzaldehyde hydrogenation on palladium differs by up to one order of magnitude in different solv
- Cheng, Guanhua,Chin, Ya-Huei (Cathy),Gutiérrez, Oliver Y.,Jentys, Andreas,Lercher, Johannes A.,Liu, Yue
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p. 976 - 985
(2021/11/24)
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- Selective oxidation of exogenous substrates by a bis-Cu(III) bis-oxide complex: Mechanism and scope
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Cu(III)2(μ-O)2 bis-oxides (O) form spontaneously by direct oxygenation of nitrogen-chelated Cu(I) species and constitute a diverse class of versatile 2e?/2H+ oxidants, but while these species have attracted attention as biomimetic models for dinuclear Cu enzymes, reactivity is typically limited to intramolecular ligand oxidation, and systems exhibiting synthetically useful reactivity with exogenous substrates are limited. OTMPD (TMPD = N1, N1, N3, N3-tetramethylpropane-1,3-diamine) presents an exception, readily oxidizing a diverse array of exogenous substrates, including primary alcohols and amines selectively over their secondary counterparts in good yields. Mechanistic and DFT analyses suggest substrate oxidation proceeds through initial axial coordination, followed by rate-limiting rotation to position the substrate in the Cu(III) equatorial plane, whereupon rapid deprotonation and oxidation by net hydride transfer occurs. Together, the results suggest the selectivity and broad substrate scope unique to OTMPD are best attributed to the combination of ligand flexibility, limited steric demands, and ligand oxidative stability. In keeping with the absence of rate-limiting C–H scission, OTMPD exhibits a marked insensitivity to the strength of the substrate Cα–H bond, readily oxidizing benzyl alcohol and 1-octanol at near identical rates.
- Large, Tao A.G.,Mahadevan, Viswanath,Keown, William,Stack, T. Daniel P.
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p. 782 - 792
(2019/01/03)
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- Iron-Catalyzed Ligand Free α-Alkylation of Methylene Ketones and β-Alkylation of Secondary Alcohols Using Primary Alcohols
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Herein, we demonstrate a general and broadly applicable catalytic cross coupling of methylene ketones and secondary alcohols with a series of primary alcohols to disubstituted branched ketones. A simple and nonprecious Fe2(CO)9 catalyst enables one-pot oxidations of both primary and secondary alcohols to a range of branched gem-bis(alkyl) ketones. A number of bond activations and formations selectively occurred in one pot to provide the ketone products. Coupling reactions can be performed in gram scale and successfully applied in the synthesis of an Alzehimer's drug. Alkylation of a steroid hormone can be achieved. A single catalyst enables sequential one-pot double alkylation to bis-hetero aryl ketones using two different alcohols. Preliminary mechanistic studies using an IR probe, deuterium labeling, and kinetic experiments established the participation of a borrowing-hydrogen process using Fe catalyst, and the reaction produces H2 and H2O as byproducts.
- Alanthadka, Anitha,Bera, Sourajit,Banerjee, Debasis
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p. 11676 - 11686
(2019/10/02)
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- Dehydrogenative Coupling of Aldehydes with Alcohols Catalyzed by a Nickel Hydride Complex
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A nickel hydride complex, {2,6-(iPr2PO)2C6H3}NiH, has been shown to catalyze the coupling of RCHO and R′OH to yield RCO2R′ and RCH2OH, where the aldehyde also acts as a hydrogen acceptor and the alcohol also serves as the solvent. Functional groups tolerated by this catalytic system include CF3, NO2, Cl, Br, NHCOMe, and NMe2, whereas phenol-containing compounds are not viable substrates or solvents. The dehydrogenative coupling reaction can alternatively be catalyzed by an air-stable nickel chloride complex, {2,6-(iPr2PO)2C6H3}NiCl, in conjunction with NaOMe. Acids in unpurified aldehydes react with the hydride to form nickel carboxylate complexes, which are catalytically inactive. Water, if present in a significant quantity, decreases the catalytic efficiency by forming {2,6-(iPr2PO)2C6H3}NiOH, which causes catalyst degradation. On the other hand, in the presence of a drying agent, {2,6-(iPr2PO)2C6H3}NiOH generated in situ from {2,6-(iPr2PO)2C6H3}NiCl and NaOH can be converted to an alkoxide species, becoming catalytically competent. The proposed catalytic mechanism features aldehyde insertion into the nickel hydride as well as into a nickel alkoxide intermediate, both of which have been experimentally observed. Several mechanistically relevant nickel species including {2,6-(iPr2PO)2C6H3}NiOC(O)Ph, {2,6-(iPr2PO)2C6H3}NiOPh, and {2,6-(iPr2PO)2C6H3}NiOPh·HOPh have been independently synthesized, crystallographically characterized, and tested for the catalytic reaction. While phenol-containing molecules cannot be used as substrates or solvents, both {2,6-(iPr2PO)2C6H3}NiOPh and {2,6-(iPr2PO)2C6H3}NiOPh·HOPh are efficient in catalyzing the dehydrogenative coupling of PhCHO with EtOH.
- Eberhardt, Nathan A.,Wellala, Nadeesha P. N.,Li, Yingze,Krause, Jeanette A.,Guan, Hairong
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p. 1468 - 1478
(2019/04/17)
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- Mechanism of Copper/Azodicarboxylate-Catalyzed Aerobic Alcohol Oxidation: Evidence for Uncooperative Catalysis
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Cooperative catalysis between CuII and redox-active organic cocatalysts is a key feature of important chemical and enzymatic aerobic oxidation reactions, such as alcohol oxidation mediated by Cu/TEMPO and galactose oxidase. Nearly 20 years ago, Markó and co-workers reported that azodicarboxylates, such as di-tert-butyl azodicarboxylate (DBAD), are effective redox-active cocatalysts in Cu-catalyzed aerobic alcohol oxidation reactions [ Markó, I. E., et al. Science 1996, 274, 2044 ], but the nature of the cooperativity between Cu and azodicarboxylates is not well understood. Here, we report a mechanistic study of Cu/DBAD-catalyzed aerobic alcohol oxidation. In situ infrared spectroscopic studies reveal a burst of product formation prior to steady-state catalysis, and gas-uptake measurements show that no O2 is consumed during the burst. Kinetic studies reveal that the anaerobic burst and steady-state turnover have different rate laws. The steady-state rate does not depend on [O2] or [DBAD]. These results, together with other EPR and in situ IR spectroscopic and kinetic isotope effect studies, reveal that the steady-state mechanism consists of two interdependent catalytic cycles that operate in sequence: a fast CuII/DBAD pathway, in which DBAD serves as the oxidant, and a slow CuII-only pathway, in which CuII is the oxidant. This study provides significant insight into the redox cooperativity, or lack thereof, between Cu and redox-active organic cocatalysts in aerobic oxidation reactions.
- McCann, Scott D.,Stahl, Shannon S.
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supporting information
p. 199 - 206
(2016/01/25)
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- Activation of Benzyl Aryl Carbonates: The Role of Cation-π Interactions
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Benzyl aryl carbonates can react with a nucleophile to yield an activated electrophile and an aryloxide anion. Previously, we had utilized this in the synthesis of α-nitro esters from nitroalkanes. To further understand the process of activation of these carbonates by nucleophiles, we have performed kinetic studies on the hydrolysis of carbonates using nucleophiles. Rate constants for the hydrolysis were obtained under pseudo-first-order conditions with DABCO as the nucleophile. A comparison of rate constant for hydrolysis of isobutyl phenyl carbonate with benzyl phenyl carbonate shows that the presence of benzyl group results in a 16-fold acceleration of hydrolysis rate. This indicates that the transition state for activation of carbonate is stabilized by cation-π interactions. A comparison of the rate constant for various aromatic rings indicates that electron-donating substituents on the benzyl groups accelerate the rate of hydrolysis. Studies were also carried out with DMAP as nucleophile and the results are presented. Our studies show that stable carbonates can be activated using nucleophiles. Activated acyl groups generated from acid anhydrides have been used in several enantioselective reactions. Our studies show that carbonates can be stable alternatives to acid anhydrides.
- Reddy, Golipalli Ramana,Avadhani, Anusha S.,Rajaram, Sridhar
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p. 4134 - 4141
(2016/06/09)
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- Highly efficient reduction of aldehydes with silanes in water catalyzed by silver
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A highly efficient silver-catalyzed chemoselective method for the reduction of aldehydes to their corresponding alcohols in water was developed by using hydrosilanes as reducing agents. The ketones remained essentially inert under the same reaction conditions, thereby providing an additional synthetically useful chemoselectivity. Georg Thieme Verlag Stuttgart, New York.
- Jia, Zhenhua,Liu, Mingxin,Li, Xingshu,Chan, Alberts. C.,Li, Chao-Jun
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p. 2049 - 2056
(2013/10/21)
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- Comparative study on reducing aromatic aldehydes by using ammonia borane and lithium amidoborane as reducing reagents
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Lithium amidoborane (LiNH2BH3) and ammonia borane (NH3BH3) reduce aromatic aldehydes in tetrahydrofuran (THF) through two different pathways. LiNH2BH3 only transfers hydridic hydrogen on boron to aldehydes through a hydroboration process to achieve lithium aminoborate; ammonia borane, on the other hand, transfers both protic and hydridic hydrogens on N and B, respectively, to aldehydes to directly achieve corresponding alcohols. Mechanistic investigations confirm that protic H(N) and hydridic H(B) of ammonia borane participate in the reduction, in which the dissociation of both B-H and N-H bonds is likely to be involved in the rate-determining step. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2012.
- Xu, Weiliang,Fan, Hongjun,Wu, Guotao,Chen, Ping
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scheme or table
p. 1496 - 1501
(2012/07/31)
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- Versatile zirconium reductants and carbon-carbon coupling agents selectively accessible from the 2:1 molar aggregate of n-butyllithium and zirconium(IV) salts
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In previous studies of transition metal alkyls the 2:1 molar aggregate of n-butyllithium and zirconium(IV) salts has been found to react both with benzylic hydrocarbons and aromatic carbonyl derivatives in diverse and useful ways. In the present study the reactions of the aggregates, 2nBuLi· ZrE4 (E = Cl, OEt), with benzaldehyde have involved carbometallation, hydrometallation and reductive dimerization (paths 1-3) in THF and were selectively achievable by temperature control alone. First, at -78 °C benzaldehyde underwent carbolithiation to give upon hydrolysis 1-phenyl-1-pentanol. However, short-term reaction times and prompt D 2O quenching revealed that with Zr(OEt)4 both benzaldehyde and 1-phenyl-1-pentanol were deuteriated, consistent with the presence of a phenyl(lithioxy)carbene intermediate. The observed dimerization of benzaldehyde to benzyl benzoate by lithium 2,2,6,6-tetramethylpiperidide is also consistent with such a phenyl(lithioxy)carbene intermediate. Second, at 25 °C the 2nBuLi·ZrE4 aggregate reduced benzaldehyde exclusively to benzyl alcohol, which observation is consistent with the formation of the hydrozirconating agent, H2ZrE2. Third, heating the aggregate at reflux and subsequent reaction with benzaldehyde produced solely the reduced dimer, 1,2-diphenyl-1,2-ethanediol with high stereoselectivity: E = Cl, rac/meso of 93:7 and E = OEt, rac/meso of 100:0. The proposed mechanism involves the formation of ZrE2, the epizirconation of benzaldehyde and the insertion of the second benzaldehyde into the zirconaoxacyclopropane under steric control. Finally, the high selectivity in hydrozirconation and reductive dimerization shown by 2nBuLi·ZrE4 appears at this time to be superior to that attainable with analogous titanium or hafnium aggregates. The aggregate 2 nBuLi·ZrE4 (E = Cl, OEt) in THF undergoes highly selective reactions with benzaldehyde controllable by temperature: 1) at -78 °C carbolithiation gives 1-phenyl-1-pentanol; 2) at 25 °C benzyl alcohol is exclusively formed; and 3) after reflux reductive dimerization to the glycol by ZrE2 takes place with high selectivity (rac/meso ≈ 95:5). Copyright
- Eisch, John J.,Gitua, John N.,Yu, Kun
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experimental part
p. 3523 - 3530
(2011/09/15)
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- Ammonia borane as a metal free reductant for ketones and aldehydes: A mechanistic study
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Without a catalyst ketones and aldehydes were reacted in THF with ammonia borane (AB) to proceed hydroboration forming alkyl borates. Mechanistic studies revealed that dissociation of ammonia from AB occurred before the hydroboration step. When methanol was used as the solvent, metal free methanolysis of AB would take place with the ketone/aldehyde being directly hydrogenated by the MeOH·BH3 complex.
- Yang, Xianghua,Fox, Thomas,Berke, Heinz
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experimental part
p. 7121 - 7127
(2011/10/05)
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- Bis(μ-oxo) dicopper(III) species of the simplest peralkylated diamine: Enhanced reactivity toward exogenous substrates
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N,N,N′,N′-tetramethylethylenediamine (TMED), the simplest and most extensively used peralkylated diamine ligand, is conspicuously absent from those known to form a bis(μ-oxo)dicopper(III) (O) species, [(TMED) 2Cu(III)2(μ2-O)2]2+, upon oxygenation of its Cu(I) complex. Presented here is the characterization of this O species and its reactivity toward exogenous substrates. Its formation is complicated both by the instability of the [(TMED)Cu(I)]1+ precursor and by competitive formation of a presumed mixed-valent trinuclear [(TMED) 3Cu(III)Cu(II)2(μ3-O)2] 3+ (T) species. Under most reaction conditions, the T species dominates, yet, the O species can be formed preferentially (>80%) upon oxygenation of acetone solutions, if the copper concentration is low (1+ is prepared immediately before use. The experimental data of this simplest O species provide a benchmark by which to evaluate density functional theory (DFT) computational methods for geometry optimization and spectroscopic predictions. The enhanced thermal stability of [(TMED)2Cu(III)2(μ2-O)2] 2+ and its limited steric demands compared to other O species allows more efficient oxidation of exogenous substrates, including benzyl alcohol to benzaldehyde (80% yield), highlighting the importance of ligand structure to not only enhance the oxidant stability but also maintain accessibility to the nascent metal/O2 oxidant.
- Kang, Peng,Bobyr, Elena,Dustman, John,Hodgson, Keith O.,Hedman, Britt,Solomon, Edward I.,Stack, T. Daniel P.
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experimental part
p. 11030 - 11038
(2011/02/22)
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- Alkoxyallylsilanes: Functional protecting groups
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Allyl-t-butylmethylsilyl groups were shown to function as alcohol protecting groups whose hydrolytic stability was greater than t- butyldimethylsilyl (TBS) and Si(SiMe3)3 (sisyl) groups. Pseudo-first-order rate constants for the acid
- Balduzzi, Sonya,Brook, Michael A.
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p. 1617 - 1622
(2007/10/03)
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- Hydrogen isotope fractionation factors for N,N-dimethylbenzyl-ammonium ion and some related species: An unusually strong preference for deuterium over protium
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Deuterium fractionation factors were determined by the 1H and 13C NMR methods in aqueous solution for PhCH2NLMe2+ (φ = 1.47 ± 0.05), PhCH2OL (φ = 1.04 ± 0.06), PhCO2L (φ = 1.04 ± 0.08), and CH3CO2L (φ = 0.99 ± 0.02). The medium effect for transferring PhCH2NMe2 from H2O to D2O, Φ = 1.025 ± 0.003, was also determined by partitioning this substance between water and immiscible organic solvents, and a UV spectroscopic method was used to measure the solvent isotope effect on the acid ionization of PhCH2NLMe2+, (Qa)H/(Qa)D = 4.88 ± 0.16. This solvent isotope effect agrees well with the value predicted using the relevant fractionation factors, (Qa)H/(Qa)D = 4.38 ± 0.28. The unusually large value of φ for PhCH2NLMe2+ is attributed to stiffened bending vibrations of its N-L bond imposed by the tetrahedral structure of the ion and the bulk of its methyl groups.
- Guo, Hong-Xun,Kresge, A. Jerry
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p. 295 - 298
(2007/10/03)
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