- Development and Mechanistic Studies of the Iridium-Catalyzed C?H Alkenylation of Enamides with Vinyl Acetates: A Versatile Approach for Ketone Functionalization
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Ketone functionalization is a cornerstone of organic synthesis. Herein, we describe the development of an intermolecular C?H alkenylation of enamides with the feedstock chemical vinyl acetate to access diverse functionalized ketones. Enamides derived from various cyclic and acyclic ketones reacted efficiently, and a number of sensitive functional groups were tolerated. In this iridium-catalyzed transformation, two structurally and electronically similar alkenes—enamide and vinyl acetate—underwent selective cross-coupling through C?H activation. No reaction partner was used in large excess. The reaction is also pH- and redox-neutral with HOAc as the only stoichiometric by-product. Detailed experimental and computational studies revealed a reaction mechanism involving 1,2-Ir-C migratory insertion followed by syn-β-acetoxy elimination, which is different from that of previous vinyl acetate mediated C?H activation reactions. Finally, the alkenylation product can serve as a versatile intermediate to deliver a variety of structurally modified ketones.
- Dong, Guangbin,Liu, Peng,Qi, Xiaotian,Zhou, Bo
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supporting information
p. 20926 - 20934
(2021/08/18)
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- Bismuth subnitrate-catalyzed markovnikov-type alkyne hydrations under batch and continuous flow conditions
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Bismuth subnitrate is reported herein as a simple and efficient catalyst for the atom-economical synthesis of methyl ketones via Markovnikov-type alkyne hydration. Besides an effective batch process under reasonably mild conditions, a chemically intensified continuous flow protocol was also developed in a packed-bed system. The applicability of the methodologies was demonstrated through hydration of a diverse set of terminal acetylenes. By simply switching the reaction medium from methanol to methanol-d4, valuable trideuteromethyl ketones were also prepared. Due to the ready availability and nontoxicity of the heterogeneous catalyst, which eliminated the need for any special additives and/or harmful reagents, the presented processes display significant advances in terms of practicality and sustainability.
- ?tv?s, Sándor B.,Fül?p, Ferenc,Szécsényi, Zsanett
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- Formation of Acetals and Ketals from Carbonyl Compounds: A New and Highly Efficient Method Inspired by Cationic Palladium
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The development of a new, highly efficient, and simple method for masking carbonyl groups as acetals and ketals is described. This methodology relies on the nature of the palladium catalyst to direct the acetalization/ketalization reaction. This new protocol is mild and proceed with a very low catalyst loading at ambient temperatures. The method has been extended to a wide variety of different carbonyl compounds with various steric encumbrances to form the corresponding acetals and ketals in excellent yields.
- Green, Shawn D.,Kindoll, Tyler,Lazaro-Martinez, Brenda,Mensah, Enoch A.,West, Jesse
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p. 1810 - 1814
(2019/09/09)
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- A step forward in solvent knitting strategies: Ruthenium and gold phosphine complex polymerization results in effective heterogenized catalysts
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Porous polymers based on ruthenium and gold triphenylphosphine complexes (KPhos(Ru), KPhos(Ru)Bi, KPhos(AuCl) and KPhos(AuNTf2)) were prepared via a cost-effective solvent knitting method with [RuHClCO(PPh3)3] or AuXPPh3 (X = Cl, NTf2) as single monomers or combined with biphenyl, which represents a further approach to obtain heterogenized catalysts. The resulting materials mainly preserve the metal coordination environment of their parent complexes, are stable up to 350 °C and have reasonable surface areas (250-300 m2 g-1 for KPhos(Ru)-polymers). KPhos(Ru)s selectively catalyze the imination of alcohols in the presence of base and the results for KPhos(Au)s show they are effective for the intermolecular hydration and hydroamination of alkynes. These materials can be reused several times without significant loss of activity. This novel and simple method affords heterogenized catalysts that combine the reactivity and selectivity of their homogeneous counterparts with the stability and reusability of a heterogeneous framework.
- Valverde-González, Antonio,Marchal, Gwendoline,Maya, Eva M.,Iglesias, Marta
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p. 4552 - 4560
(2019/09/09)
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- Silver-Catalyzed Olefination of Acetals and Ketals with Diazoesters to β-Alkoxyacrylates
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The first silver-catalyzed reaction of acetals or ketals with diazoesters leading to trisubstituted or tetrasubstituted β-alkoxyacrylates is now reported. A broad range of acetals and ketals bearing different substituents is compatible with this protocol and thus provides an attractive approach for the synthesis of complex β-alkoxyacrylates. The power of this method was further demonstrated by the successful synthesis of picoxystrobin, which is one of the most popular agricultural fungicides commercialized by Dupont.
- Li, Jiawen,Qian, Bo,Huang, Hanmin
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supporting information
p. 7090 - 7094
(2018/11/23)
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- Eco-friendly synthesis and antioxidant activity of new trifluoromethyl-substituted N-(pyrimidin-2-yl)benzo[d]thiazol-2-amines and some N-derivatives
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Abstract: A convenient and environmentally benign procedure for the synthesis of a new series of trifluoromethyl-substituted N-(pyrimidin-2-yl)benzo[d]thiazol-2-amines by the cyclocondensation reaction of (benzo[d]thiazolyl)guanidine with either 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones or 2,2,2-trifluoro-1-(2-methoxycyclohexen-1-en-1-yl)ethanone is described. The main reactions were performed in refluxing water as the solvent (8–24?h), without catalysts, and the corresponding new N-(pyrimidinyl)-1H-(benzo[d]thiazolyl)amines were obtained at a 60–88?% yield. Subsequently, some di(hetero)arylamines were derivatized to the respective tertiary amines via easy N-alkylation and N-alkenylation reactions at 55–82?% yields. Finally, the Lipinski parameters and the total antioxidant activity of the new series of secondary arylamines were also evaluated. Graphical abstract: [Figure not available: see fulltext.]
- Bonacorso, Helio G.,Calheiro, Tainara P.,Rodrigues, Melissa B.,Stefanello, Sílvio T.,Soares, Félix A. A.,Zanatta, Nilo,Martins, Marcos A. P.
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p. 2185 - 2194
(2016/11/17)
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- Highly efficient acetalization of carbonyl compounds catalyzed by anilin-aldehyde resin salts
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A mild procedures for the syntheses of ethylene acetals and dimethyl acetals from the corresponding aldehydes and ketones catalyzed by 1mol% of anilinealdehyde resin salts are described. This method is also useful for the synthesis of dimethyl acetals of diaryl ketones.
- Tanemura, Kiyoshi,Suzuki, Tsuneo
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supporting information
p. 797 - 799
(2015/06/22)
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- Efficient syntheses of ethyl 2-methylthio-and ethyl 2-benzylthio-6-methyl(aryl)pyrimidine-4-carboxylates and their carboxylic acid derivatives
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A simple and efficient procedure for the synthesis of ethyl 2-methylthio-and ethyl 2-benzylthio-6-methyl(aryl)-pyrimidine-4-carboxylates and their corresponding acid derivatives is reported. The products are obtained in good yields via the cyclocondensation reaction of ethyl 4-alkoxy-2-oxo-4-methyl(aryl)-but-3-enoates with 2-methylisothiourea sulfate or 2-benzylisothiourea hydrochloride, under mild, basic, aqueous conditions.
- Zanatta, Nilo,Fortes, Andressa S.,Bencke, Carlos E.,Marangoni, Mário A.,Camargo, Adriano F.,Fantinel, Cassio A.,Bonacorso, Helio G.,Martins, Marcos A. P.
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p. 827 - 835
(2015/03/14)
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- Anodic cleavage of several ketone N-phenylsemicarbazones into methyl N-phenylcarbamate and the corresponding dimethyl acetals
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Several ketone N-phenylsemicarbazones were electrooxidized in the presence of potassium iodide and a base using methanol as the solvent to give nearly commensurate amounts of methyl N-phenylcarbamate and the corresponding dimethyl acetals. Continuous evolution of gaseous nitrogen was observed from the anolyte during the electrooxidation. The reactions were carried out under very mild reaction conditions and are presumed to proceed through a four-electron oxidation process, in which the iodide ion plays an important role as an electron carrier.
- Nishikawa, Shinnosuke,Yamamori, Haruki,Ohashi, Kousuke,Okimoto, Mitsuhiro,Hoshi, Masayuki,Yoshida, Takashi
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p. 1766 - 1771
(2013/05/21)
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- Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA
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New conjugation chemistry for polysaccharides, exemplified by dextran, was developed to enable the attachment of therapeutic or other functional moieties to the polysaccharide through cleavable acetal linkages. The acid-lability of the acetal groups allows the release of therapeutics under acidic conditions, such as that of the endocytic compartments of cells, regenerating the original free polysaccharide in the end. The physical and chemical behavior of these acetal groups can be adjusted by modifying their stereoelectronic and steric properties, thereby providing materials with tunable degradation and release rates. We have applied this conjugation chemistry in the development of water-soluble siRNA carriers, namely acetal-linked amino-dextrans, with various amine structures attached through either slow- or fast-degrading acetal linker. The carriers with the best combination of amine moieties and structural composition of acetals showed high in vitro transfection efficiency and low cytotoxicity in the delivery of siRNA.
- Cui, Lina,Cohen, Jessica L.,Chu, Crystal K.,Wich, Peter R.,Kierstead, Paul H.,Frechet, Jean M. J.
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p. 15840 - 15848,9
(2020/08/24)
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- A novel approach to the practical synthesis of sulfides: An InBr 3-Et3SiH catalytic system promoted the direct reductive sulfidation of acetais with disulfides
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We have demonstrated a facile and direct synthesis of sulfide derivatives using acetais and ketals, derived, from aromatic/ conjugated, aldehydes and aromatic ketones, with disulfides and the InBr3-Et3SiH reducing system., We also succeeded in developing an unprecedented one-pot preparation of an aliphatic sulfide from a disulfide and an aliphatic acetal. (Wiley-VCH Verlag GmbH & Co. KGaA.
- Sakai, Norio,Moritaka, Kohei,Konakahara, Takeo
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supporting information; experimental part
p. 4123 - 4127
(2009/12/09)
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- A marcus treatment of rate constants for protonation of ring-substituted α-methoxystyrenes: Intrinsic reaction barriers and the shape of the reaction coordinate
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Rate and equilibrium constants were determined for protonation of ring-substituted α-methoxystyrenes by hydronium ion and by carboxylic acids to form the corresponding ring-substituted α-methyl α-methoxybenzyl carbocations at 25°C and I = 1.0 (KCl). The thermodynamic barrier to carbocation formation increases by 14.5 kcal/mol as the phenyl ring substituent(s) is changed from 4-MeO- to 3,5-di-NO2-, and as the carboxylic acid is changed from dichloroacetic to acetic acid. The Bronsted coefficient a for protonation by carboxylic acids increases from 0.67 to 0.77 over this range of phenyl ring substituents, and the Bronsted coefficient β for proton transfer increases from 0.63 to 0.69 as the carboxylic acid is changed from dichloroacetic to acetic acid. The change in these Bronsted coefficients with changing reaction driving force, ?α/?ΔG°av = ?β/ ?ΔG°av = 1/8Λ = 0.011, is used to calculate a Marcus intrinsic reaction barrier of Λ = 11 kcal/mol which is close to the barrier of 13 kcal/mol for thermoneutral proton transfer between this series of acids and bases. The value of α = 0.66 for thermoneutral proton transfer is greater than α = 0.50 required by a reaction that follows the Marcus equation. This elevated value of β may be due to an asymmetry in the reaction coordinate that arises from the difference in the intrinsic barriers for proton transfer at the oxygen acid reactant and resonance-stabilized carbon acid product.
- Richard, John P.,Williams, Kathleen B.
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p. 6952 - 6961
(2008/02/09)
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- Antimalarial activity of 4-(5-trifluoromethyl-1H-pyrazol-1-yl)-chloroquine analogues
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The antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in the presence of the test drugs was measured by incorporation of [3H]hypoxanthine in comparison to controls with no drugs. All but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a significant activity in vitro, thus, are a promising new class of antimalarials. The three most active ones were also tested in vivo against Plasmodium berghei in mice. However, the (pyrazol-1-yl) chloroquine 3 derivatives were mostly inactive, suggesting that the aromatic functionality of the pyrazole ring was critical.
- Cunico, Wilson,Cechinel, Cleber A.,Bonacorso, Helio G.,Martins, Marcos A. P.,Zanatta, Nilo,De Souza, Marcus V.N.,Freitas, Isabela O.,Soares, Rodrigo P. P.,Krettli, Antoniana U.
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p. 649 - 653
(2007/10/03)
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- Pd(II)-catalyzed conversion of styrene derivatives to acetals: Impact of (-)-sparteine on regioselectivity
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Pd[(-)-sparteine]Cl2 catalyzes the formation of dialkyl acetals from styrene derivatives with Markovnikov regioselectivity. The substrate scope of this reaction has been investigated, and initial mechanistic studies indicate that the reaction proceeds through an enol ether intermediate and a Pd-hydride.
- Balija, Amy M.,Stowers, Kara J.,Schultz, Mitchell J.,Sigman, Matthew S.
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p. 1121 - 1124
(2007/10/03)
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- Tri-n-butylstannyl chloride-sodium cyanoborohydride mediated regioselective reductive demethoxylation of alkyl methyl ketals
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A regioselective reductive demethoxylation of alkyl methyl ketals employing sodium cyanoborohydride in the presence of a catalytic amount of tri-n-butyltin chloride as Lewis acid is described.
- Srikrishna,Viswajanani
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p. 621 - 625
(2007/10/03)
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- A mild and simple procedure for the reductive cleavage of acetals and ketals
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A convenient, mild and simple procedure, employing sodium cyanoborohydride in the presence of either catalytic or stoichiometric amount of boron trifluoride etherate in dry THF, for the reductive cleavage of the acetals and ketals is described.
- Srikrishna, Adusumilli,Viswajanani, Ranganathan
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p. 3339 - 3344
(2007/10/02)
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- Hemiacetals of Acetophenone. Aromatic Substituent Effects in the H+- and General-base-catalysed Decomposition in Aqueous Solution
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We describe a double-mixing stopped-flow technique for the study of the acid- and base-catalysed breakdown of the unstable methyl hemiacetals of aryl-substituted acetophenones in aqueous solution.The approach takes advantage of the build-up of the hemiacetal during the H+-catalysed decomposition of the corresponding dimethyl acetal.Thus, mixing a weakly basic solution of acetal with excess acid provides a solution containing unchanged acetal, the acetophenone product of the hydrolysis and the hemiacetal intermediate.After a short period of time ( +-catalysed acetal and hemiacetal breakdown are in good agreement with literature data, but our analysis suggests a larger resonance effect component than previously assumed.The corresponding set of Hammett plots for base catalysis of hemiacetal breakdown reveals a relatively weak dependence of the catalytic constants on aromatic substitution, which appears to be inconsistent with much stronger dependences on substitution in the leaving alcohol.We propose a case of non-perfect synchronization or imbalance in the transition state where, in the breakdown direction in a class n mechanism, the degree of C-O bond breakage as measured by β1g is considerable, but the change in hybridization of the central carbon (sp3 -> sp2), as measured by ρ, lags behind in the transition state so that there is less interaction with the aromatic substituents here.
- McClelland, Robert A.,Engell, Karen M.,Larsen, Truels S.,Soerensen, Poul E.
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p. 2199 - 2206
(2007/10/02)
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- The Mechanism of Termal Eliminations. Part 26. Substituent Effects at Each Carbon of Vinyl Ethers: Non-planarity of the Transition State
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A range of 1-arylethyl vinyl ethers and 1-arylvinyl isopropyl ethers, 2-phenylethyl vinyl ether, isopropenyl isopropyl ether, and isopropyl cis- and trans-phenylvinyl ether have been synthesized and their rates of termal elimination measured between 585.9-666.4 K.The Ei mechanism for vinyl ether pyrolysis has less E1 character than that for pyrolysis of the corresponding esters, so nucleophilic attack by the double bond upon the β-hydrogen is more important for the former.Electron supply to the double bond therefore increases the pyrolysis rate, so that isopropenyl isopropyl ether is more reactive than isopropyl vinyl ether (5.85-fold at 600 K), whereas acetates and formates are almost equally reactive.Likewise isopropyl 1-phenylvinyl ether is 2.2 times more reactive than isopropenyl isopropyl ether,slightly greater than the reactivity difference between the corresponding esters (benzoates and acetates).The rate-enhancing effect of a 2--phenyl substituent in ethyl vinyl ether (5.81-fold per β-hydrogen) is a little less than the corresponding effect in ethyl acetate.In the 2-phenylvinyl ethers both cis and trans phenyl groups produce slight rate acceleration, due to the combined effects of loss of conjugation on going to products, and increase in electron supply to the double bond.The trans compound is more reactive than the cis, confirming that the six-membered transition state for β-elimination is not planar.Aryl substituents in 1-arylvinyl isopropyl ethers produce only very small rate effects; the effects could not be determined for electron-supplying substituents because these induced very rapid oxidation to isopropyl benzoates, and atmospheric hydrolysis also occurs.Isopropyl 2-phenylvinyl ethers were likewise oxidized to benzaldehyde and isopropyl formate. 1-Arylethyl vinyl ethers eliminate abnormally rapidly with concurrent rearrangements to aldehydes and other products.
- Taylor, Roger
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p. 737 - 744
(2007/10/02)
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- Kinetics and Mechanism of Acid-catalysed Addition of Methanol to α-Methoxystyrenes
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A kinetic study of the complex behaviour of ring-substituted α-methoxystyrenes in acidic (HBr) methanol is reported.The reaction yields the corresponding acetals as the only kinetic products; these are subsequently partly hydrolysed into acetophenones with rates only a little lower than those of their formation.The rate-limiting step for methanol addition corresponds to proton attachement to the double bond, yielding an oxocarbenium ion which is trapped by methanol with a rate constant 10E4 higher than that of ion deprotonation.The rate constants for proton transfer from CH3OH2+ are in the same range of magnitude as those for proton transfer from H3O+ in water.The lyonium ion catalytic constants fit a good Young-Jencks equation with ρn-2.86 and ρr-1.28
- Toullec, Jean,El-Alaoui, Mohiedine,Bertrand, Roland
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p. 1517 - 1522
(2007/10/02)
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- Kinetics and Mechanism of the Acid-Catalyzed Bromination of Ring-Substituted Acetophenones in Methanol. Thermodynamics of the Ketone-Acetal-Enol Ether System in Mathanol and Water
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The kinetics of HBr-catalyzed bromination of ring-substituted acetophenones in equilibrium with acetals have been studied in methanol containing small amounts of water at very low halogen concentration (ca. 10-6 M).Under these conditions, the rate is zeroth order with respect to the halogen and first order with respect to the CH3OH2+ ion and the overall carbonyl compound concentrations.The relative concentration of acetal at equilibrium (xeq = eq/(eq + eq)) has been varied by increasing the water concentration; the lyonium ion catalytic constant depends linearly on xeq with an xeq = 0 intercept corresponding to bromination via intermediate enol formation and with an xeq = 1 intercept corresponding to bromination via enol ether.In the case of 3-nitroacetophenone (1a), these extrapolated rate constants are identical with those directly measured from the rates for bromination of 1a and of 1a dimethyl acetal, before ketone-acetal equilibration.In most cases, the enol ether path is highly predominant.Substituent effects on the constants associated with the two paths are examined.The rate constants for enol ether formation are combined with rate constants for the reverse process and with acetal formation equilibrium constants to provide acetal-to-enol ether and ketone-to-enol ether equilibrium constants in methanol.Taking into account data of Gibbs free energies of transfer from methanol to water for the different species involved, equilibrium data in water are also deduced.
- Toullec, Jean,El-Alaoui, Mohiedine
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p. 4054 - 4061
(2007/10/02)
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- Ring Substituent Effects on Acetophenone Dimethyl Acetal Formation. 2. Dual-Parameter Treatment of Kinetic Data for Acid-Catalyzed Acetal Formation and Hydrolysis in Methanol Containing Small Amounts of Water
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The rates of formation and hydrolysis of para- and meta-substituted acetophenone dimethyl acetals have been measured, by a water-concentration method, in methanol containing HBr and small amounts of water.The rate coefficients for pure anhydrous methanol have been extrapolated .Acid and water-concentration effects are consistent with the usual mechanism for acetal hydrolysis in water, but the rate-limiting step in the hydrolysis direction corresponds to water addition to the hemiacetal-yielding oxocarbenium ion.Substituent effects on both extrapolated rate coefficients fit the Young-Jencks-modified Yukawa-Tsuno equation.The validity of this equation and its usefulness for separating polar and conjugative effects are discussed.
- Toullec, Jean,El-Alaoui, Mohiedine
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p. 4928 - 4933
(2007/10/02)
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