- Comparison of the kinetic specificity of subtilisin and thiolsubtilisin toward n-alkyl p-nitrophenyl esters.
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The p-nitrophenyl esters of straight-chain fatty acids were used as substrates of the enzyme subtilisin Novo (EC 3.4.4.16) and its chemically produced artificial enzyme thiolsubtilisin. Subtilisin and thiolsubtilisin pH--activity profiles were determined, and kinetic effects of the active site O-S substitution were observed. Among the substrates tested, both enzymes show highest specificity with p-nitrophenyl butyrate. It was also found that subtilisin is more sensitive to changes in substrate chain length than is thiolsubtilisin. Second-order acylation rate constants (k2/Ks) are remarkably similar for both enzymes. However, thiolsubtilisin deacylation rate constants and Km values are lower than analogous subtilisin constants. While thiolsubtilisin deacylation rate constants give a pH profile identical with that of subtilisin, the pH profile of thiolsubtilisin acylation rate constants shows an active site pK value lowered from the subtilisin pK of 7.15 and exhibits an inflection point at pH 8.45, which is absent in subtilisin.
- Philipp,Tsai,Bender
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Read Online
- Carboxylic Acid Deoxyfluorination and One-Pot Amide Bond Formation Using Pentafluoropyridine (PFP)
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This work describes the application of pentafluoropyridine (PFP), a cheap commercially available reagent, in the deoxyfluorination of carboxylic acids to acyl fluorides. The acyl fluorides can be formed from a range of acids under mild conditions. We also demonstrate that PFP can be utilized in a one-pot amide bond formation via in situ generation of acyl fluorides. This one-pot deoxyfluorination amide bond-forming reaction gives ready access to amides in yields of ≤94%.
- Brittain, William D. G.,Cobb, Steven L.
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supporting information
p. 5793 - 5798
(2021/08/01)
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- How much does the hybridization of a carbon atom affect the transmission of the substituent effect on the chemical shift?
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1H and 13C NMR spectra of aryl esters of propionic acid, acrylic acid, and propiolic acid were systematically examined to find out the substituent effect on the chemical shift. The values of the chemical shift of the carbonyl carbon showed an inverse correlation with the Hammett ?3 values, and the magnitude of the slope was the largest with the propiolates. The ?± carbons of acrylates and propiolates also showed an inverse correlation with much smaller values of the slopes than those of the carbonyl carbons; but those of the propionates showed absolutely no correlation. However, the ?2 carbons of acrylates and propiolates showed normal correlation with larger values of the slopes. The signs and the magnitudes of the slopes may be understood by the transmission of the substituent electronic effect through bonds as well as through space. The propiolyloxy group also showed a significantly large effect on the 13C chemical shift values of the benzene ring.
- Jeong, Eun Jeong,Lee, In-Sook Han
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p. 295 - 299
(2015/03/03)
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- Organocatalytic activation of alkylacetic esters as enolate precursors to react with α,β-unsaturated imines
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Asymmetric functionalization of alkylacetic esters and their derivatives is traditionally achieved via preformed enolates with chiral auxiliaries. Catalytic versions of such transformations are attractive but challenging. A direct catalytic activation of simple alkylacetic esters via N-heterocyclic carbene organocatalysts to generate chiral enolate intermediates for highly enantioselective reactions is reported.
- Hao, Lin,Chen, Shaojin,Xu, Jianfeng,Tiwari, Bhoopendra,Fu, Zhenqian,Li, Tong,Lim, Jieyan,Chi, Yonggui Robin
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supporting information
p. 4956 - 4959
(2013/10/22)
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- Ruthenium/NHC-catalyzed tandem benzylic oxidation/oxidative esterification of benzylic alcohols with phenols
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An efficient methodology to access benzoate derivatives via tandem benzylic oxidation/oxidative esterification of benzylic alcohols with phenols catalyzed by ruthenium/NHC was developed. This operationally simple one-pot process uses O2 as the clean oxidant, producing esters in good to excellent yields.
- Zhang, Di,Pan, Changduo
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experimental part
p. 41 - 45
(2012/06/18)
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- Palladium/NHC-catalyzed tandem benzylic oxidation/oxidative esterification of benzylic alcohols with phenols
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A palladium/NHC-catalyzed tandem benzylic oxidation/oxidative esterification of benzylic alcohols with phenols to access aryl benzoate derivatives is described. The procedure tolerates a series of functional groups, such as methoxy, nitro, cyano, chloro, fluoro and bromo groups. Thus, it represents a practically alternative method to access aryl benzoate derivatives.
- Luo, Fang,Pan, Changduo,Cheng, Jiang,Chen, Fan
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supporting information; experimental part
p. 5878 - 5882
(2011/09/12)
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- The urea-dipeptides show stronger H-bonding propensity to nucleate β-sheetlike assembly than natural sequence
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In this article, we report the distinct solution behavior of a set of urea-dipeptides to that of natural sequence. The urea-dipeptides adopt β-folding conformations and form into β-sheetlike assembly in chloroform. Most surprisedly, the urea-dipeptides tend to form interpeptide H-bonding interactions even at a concentration of as low as 0.1 mM, while the natural sequence shows H-bonding propensity at a concentration of about 7 mM, indicating that the urea-dipeptides show much stronger H-bonding propensity to nucleate formation of β-sheetlike assembly than the natural sequence. CD spectra reveal that the investigated urea-dipeptides have two negative CD bands, respectively, around 217 nm and 224 nm, supporting the β-folding conformations and in turn formation of β-sheetlike assembly. The β-sheetlike assembly is also confirmed by the XRD reflections, which give two typical d-spacings of 12.7 and 4.8 A?, respectively, corresponding to stacking periodicity of the β-sheets and the spacing between peptide backbones running orthogonal to the β-sheet axis.
- Ke, Damei,Zhan, Chuanlang,Li, Xiao,Li, Alexander D.Q.,Yao, Jiannian
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experimental part
p. 8269 - 8276
(2009/12/26)
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- Erbium(III) chloride: A very active acylation catalyst
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Erbium(iii) chloride is a powerful catalyst for the acylation of alcohols and phenols. The reaction works well for a large variety of simple and functionalized substrates by using different kinds of acidic anhydrides (Ac 2O, (EtCO)2O, (PriCO)2O, (Bu tCO)2O, and (CF3CO)2), without isomerization of chiral centres. Moreover, the catalyst can be easily recycled and reused without significant loss of activity. CSIRO 2007.
- Dalpozzo, Renato,De Nino, Antonio,Maiuolo, Loredana,Oliverio, Manuela,Procopio, Antonio,Russo, Beatrice,Tocci, Amedeo
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- PEPTIDIC THROMBIN INHIBITOR COMPOUND
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The present invention relates to a novel thrombin inhibitor compound which has a good inhibitory effect against thrombosis and can be orally administered, a process for preparing the same, and to a composition for the therapeutic and/or prophylactic treatment of various diseases associated with thrombin inhibition mechanism, which comprises the same as an active ingredient.
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- Erbium(III) triflate as an extremely active acylation catalyst
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Erbium(III) triflate is a powerful catalyst for the acylation of alcohols and phenols. The reaction works well for a large variety of simple and functionalized substrates by using different kinds of acidic anhydrides {Ac 2O, (EtCO)2O, [(CH3)3CO] 2O, Bz2O, and (CF3CO)2O} without isomerisation of chiral centres. Moreover, the catalyst can be easily recycled and reused without significant loss of activity.
- Procopio, Antonio,Dalpozzo, Renato,De Nino, Antonio,Maiuolo, Loredana,Russo, Beatrice,Sindona, Giovanni
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p. 1465 - 1470
(2007/10/03)
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- Estrogenic diazenes: Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes
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Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.
- Ghosh, Usha,Ganessunker, Deshanie,Sattigeri, Viswajanani J.,Carlson, Kathryn E.,Mortensen, Deborah J.,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.
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p. 629 - 657
(2007/10/03)
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- Zn(ClO4)2·6H2O as a Powerful Catalyst for a Practical Acylation of Alcohols with Acid Anhydrides
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A new protocol for the acylation of alcohols with anhydrides in the presence of Zn(ClO4)2·6H2O as the catalyst is reported. The activity of Zn(ClO4)2· 6H2O has been proven to be superior to that exerted by dry Mg(ClO4)2 and by metal triflates. Its efficiency allows reactions between poorly reactive substrates, such as sterically hindered tertiary alcohols and aromatic anhydrides, All of the reactions were carried out at a 1:1.05 alcohol/anhydride ratio. These conditions are extremely convenient from a practical and economic point of view, since they avoid wasting reagents and allow a simple workup procedure. The catalytic action of Zn(ClO4)2·6H2O is so specific for the activation of the anhydrides, that acid-sensitive functionalities and the stereochemical configuration of the starting materials remain unaltered in the esterification process. In all cases, the acylated products are quantitatively obtained in pure form. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Bartoli, Giuseppe,Bosco, Marcella,Dalpozzo, Renato,Marcantoni, Enrico,Massaccesi, Massimo,Sambri, Letizia
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p. 4611 - 4617
(2007/10/03)
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- Fluoroboric acid adsorbed on silica gel as a new and efficient catalyst for acylation of phenols, thiols, alcohols, and amines
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Fluoroboric acid supported on silica gel efficiently catalyzes acylation of structurally diverse phenols, alcohols, thiols, and amines under solvent free conditions. Acid-sensitive alcohols are smoothly acylated without competitive side reactions.
- Chakraborti, Asit K.,Gulhane, Rajesh
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p. 3521 - 3525
(2007/10/03)
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- Studies on the mechanism of action of 2-formyl-4-pyrrolidinopyridine: Isolation and characterization of a reactive intermediate
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This paper describes the mechanism of action of 2-formyl-4- pyrrolidinopyridine (FPP, 1a) which is a catalyst for the hydroxyl-directed methanolysis of α-hydroxy esters. This species was initially designed to act as a nucleophilic catalyst; however, we have ruled out a nucleophilic mechanism by examining the activity of 6-substituted-FPP derivatives. These compounds are more hindered in the vicinity of the pyridine nitrogen than FPP itself but are also more active catalysts. Furthermore, the presence of p- nitrophenol, a mild acid, was found to accelerate the catalytic reaction. These results are inconsistent with a nucleophilic catalysis mechanism. We provide evidence that the reaction instead proceeds via dioxolanone intermediate 10. Dioxolanone 10 can be obtained by treating either the p- nitrophenyl ester or the pentafluorophenyl ester of glycolic acid with FPP in chloroform in the absence of methanol. It has been isolated, characterized, and shown to be kinetically competent when subjected to the conditions of the catalytic reaction.
- Sammakia, Tarek,Hurley, T. Brian
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p. 4652 - 4664
(2007/10/03)
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- Ozone-mediated Reaction of Anilides and Phenyl Esters with Nitrogen Dioxide: Enhanced Ortho-reactivity and Mechanistic Implications
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In the presence of ozone, anilides 1 can be nitrated rapidly with nitrogen dioxide in chloroform at 0 deg C to give a high proportion of ortho-nitro derivatives (ortho:para = 1.2-4.4) in good yields.The phenyl esters 15 can be similarly nitrated on the aromatic ring without significant cleavage of the ester bond, giving a mixture of isomeric nitro derivatives in which the ortho-isomer predominantes (ortho:para = 1.1-1.5).The oridin of the enhanced ortho reactivity is discussed in terms of an electron-transfer process involving the nitrogen trioxide as initial electrophile.
- Suzuki, Hitomi,Tatsumi, Atsuo,Ishibashi, Taro,Mori, Tadashi
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p. 339 - 344
(2007/10/02)
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- An invesigation of activities and paraoxon sensitivities of hepatic aliesterases in β-naphthoflavone-treated rats
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Aliesterases (carboxylesterases, EC 3.1.1.1) are serine esterases which may protect acetylcholinesterase during organophosphorus insecticide intoxication by providing alternative phosphorylation sites. Levels of hepatic aliesterase activity were investigated after the intraperitoneal administration of β-naphthoflavone (BNF) to female rats using nine 4-nitrophenyl esters as substrates (including straight and branched chain aliphatic and aromatic esters) and 1-naphthyl acetate. In addition, the in vitro sensitivities of aliesterases to inhibition by paraoxon, the active metabolite of the common insecticide parathion, were studied. Hepatic aliesterases from BNF-treated rats displayed lower activities than those from controls with all substrates except 4-nitrophenyl phenylbutyrate and isovalerate. The aliesterases from BNF-treated rats were more sensitive to paraoxon inhibition with 4-nitrophenyl phenylbutyrate, valerate, and butyrate. Esterases hydrolyzing 4-nitrophenyl butyrate, valerate, and branched chain esters were most sensitive to paraoxon inhibition while those hydrolyzing 4-nitrophenyl hexanoate and aromatic esters were least sensitive. The results suggested that BNF-induced changes in hepatic aliesterases could alter responses to organophosphates. Keywords: Aliesterases; β-Naphthoflavone; Paraoxon; Organophosphate
- Watson, Angela M.,Chambers, Howard,Chambers, Janice E.
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p. 217 - 226
(2007/10/03)
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- Parallel Behavior in Kinetic and NMR Effects: Secondary Deuterium Isotope Effects on the Alkaline Hydrolysis of Esters
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β-Deuterium secondary kinetic isotope effects (β-D KIEs) on the alkaline hydrolysis of the p-nitrophenyl esters of acetic, propanoic, butanoic, and pentanoic acids in pH 10.70, 0.20 M carbonate buffer at 25 deg C tend to increase with increasing chain length of the esters up to the pentanoate.The β-D KIEs are respectively 0.975 +/- 0.004, 0.960 +/- 0.002, 0.940 +/- 0.001, and 0.948 +/- 0.004.The activation energies of the esterolyses of the isotopically light esters follow a similar pattern, as do the 13C NMR nuclear shieldings in CDCl3 of the isotopically light parent carboxylic acids (20.9, 27.4, 35.9, and 33.8 (ppm)) and 13C NMR one-bond isotope shifts produced by disubstitution of deuterium for hydrogen at the α-carbons of the acids (0.45, 0.55, 0.60, and 0.59 (ppm)).Correlation of nuclear shieldings and isotope shifts is known from previous work.The possibility is considered that all of the kinetics-based and NMR relationships are linked through the operation of a common ground-state feature of the ester and acid alkyl chains.
- Matta, Michael S.,Broadway, Dale E.,Stroot, Michele K.
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p. 4916 - 4918
(2007/10/02)
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- Studies in Bile Salt Solutions. XIV. Electronic, Charge and Steric Substrate-Effects on the Esterase Activity of Bile-Salt-Stimulated Human Milk Lipase. Hydrolysis of 4-Substituted Phenyl Propionates
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The rate constants of hydrolysis of series of 4-substituted phenyl propionates, catalysed by bile-salt-stimulated human milk lipase in the absence and presence of cholate or taurocholate stimulation, have been measured at pH 7.3, 310.5 K.There is little evidence for an alkyl site electronic interaction in the rate-determining step of the esterolytic reaction.However, a negatively charged substrate or an amido-substituent caused an inhibition of unstimulated esterase activity.In the presence of the bile-salt cofactors, esterolytic activity against charged substrates may be stimulated or inhibited, depending on the proximity of the charge to the steroidal side chain and the subsequent substrate-interaction within the surrounding environment of the active site.It has been confirmed that bile-salt-stimulated lipase is not an amidase, but that an amide, of the correct geometry, may occupy the active site and restrict esterase activity.
- O'Connor, Charmian J.,Mitha, Amin S. H.
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p. 259 - 269
(2007/10/02)
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- The Stereoselective Retardation of the Alkaline Hydrolysis of Organic Esters by Binuclear Cu(II) Complexes with Cyclodextrins
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The alkaline hydrolysis of p-nitrophenyl acetate (p-NPA) in 1.0 mol dm-3 NaOH at 25 deg C was almost completely retarded by the addition of a binuclear Cu(II) complex with α-cyclodextrin Cu2α-CD).The dissociation constant for an inclusion complex of Cu2α-CD with p-NPA was determined to be 0.059 mmol dm-3, which is about one 200th that for an inclusion complex of α-CD with p-NPA.The alkaline hydrolysis of o- and m-nitrophenyl acetates was also retarded by Cu2α-CD, though the extent of retardation was much less than that for p-NPA.A binuclear Cu(II) complex with β-cyclodextrin (Cu2β-CD) also caused a stereoselective deceleration of the alkaline hydrolysis of the esters.However, the stereoselectivity of Cu2β-CD was not so remarkable as that of Cu2α-CD.Dissociation constants for inclusion complexes of Cu2α-CD with several alcohols and other organic substrates were determined by the kinetic examination of the competitive inhibition effect of the substrates on the association of Cu2α-CD with p-NPA.Cu2α-CD formed stable inclusion complexes with such disk-like molecules as cyclohexanol, cycloheptanol, and p-nitrobenzyl alcohol.The geometry of a Cu2α-CD-p-NPA inclusion complex was presumed on the basis of these results.
- Matsui, Yoshihisa,Suemitsu, Daisuke
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p. 1658 - 1662
(2007/10/02)
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- pKa VALUES OF 2- AND 2,6-DISUBSTITUTED PYRIDINE DERIVATIVES CONTAINING SULFENYL AND SULFINYL GROUPS AND ?* AND ES VALUES OF SEVERAL SULFENYL AND SULFINYL GROUPS
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pKa Values of pyridine derivatives having sulfenyl and sulfinyl groups attached to either 2- or 2,6-positions in the pyridine nuclei were measured affording the following values; 2-SCH3 (3.64), 2-S(O)CH3 (0.17), 2-CH2SCH3 (5.40), 2-CH2S(O)CH3 (3.10), 2-CH2OCH3 (4.35), 2,6-(SCH3)2 (2.37), 2,6-(CH2SCH3)2 (4.10), 2,6-(CH2S(O)CH3)2 (1.53), 2,6-(CH2OCH3)2 (3.50).These pKa values together with several other 2-substituted pyridines: 2-X-C5H4N in which X is Cl, Br, I, CN, CO2C2H5, CH3, H, OCH3, were plotted against Taft ?* values to afford a good straight line giving ρ*= -4.5.From fitting the above pKa values on this line, the ?* values of these groups were determined.Furthermore, Es values of CH3S(O)-, CH3SCH2-, CH3S(O)CH2- CH3OCH2-groups were determined and the application of the ?* values was tested by measuring both acid and alkaline hydrolyses rates of the corresponding p-nitrophenyl acetates, the modified Taft method.The additivity of these ?* values in the 2,6-positions in the pyridine nuclei was examined.The cation-transfer experiments were undertaken by using 2,6-bis(methylsulfinylmethyl)pyridine as mediator.
- Furukawa, Naomichi,Iida, Keiko,Kawai, Tsutomu,Ogawa, Satoshi,Oae, Shigeru
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p. 239 - 254
(2007/10/02)
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- Ester Aminolysis: New Reaction Series for the Quantitative Measurement of Steric Effects
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Further development of theoretical methods for computing steric effects on chemical reactivity requires a large body of new reliable quantitative data for calibration and for testing.We report here on design criteria for reaction series suitable for obtaining these data and on a successful implementation that shows promise of providing access to a particularly broad range of steric hindrance and which additionally has shown a new form of steric hindrance.The series examined in the present study is ester aminolysis in the form RCOOC6H4NO2-p + R'NH2 in acetonitrile solution.A primary purpose of the examination has been to ascertain whether aminolysis may be a useful general series or whether known or unexpected complications might render it unsuitable.We have measured rate constants for a matrix of reactions using five different R groups and four different R' groups, each reaction at a series of concentrations of amine.This is the first systematic study of the sumultaneous action of steric hindrance effects in both the acylating agent and the entering nucleophile.The reactions showed both a second-order term k2 and a relatively less important third-order term k32.The Taft equation was applied to subsets of the rate constants.For each amine there were data for a set of esters for which the R group was the variable.The slopes ρs for these sets were nearly unity.For each ester there were corresponding data for a series of amine reactions in which R' was the variable.These sets also gave good correlations, but the slopes ρs' were considerably larger, about 2.3.This unusually large difference in response to structural effects in the acylating agent and in the nucleophile is unexpected and appears to arise from a new type of steric hindrance.An obvious explanation based on bond lengths proves to be quantitatively insufficient; that explanation postulates that there is greater hindrance for the amine because the C-N bond is short in comparison with the C-C bond.The difference may be due instead to a requirement for special orientation within the transition state, a matter currently under theoretical investigation.The k2 and the k3 sets gave similar correlations, an important finding in at least two respects.It means that steric effects are well-defined in this example of ester aminolysis, and it means also that the extra molecule of amine is far enough from the reaction center so that no additional steric hindrance results.The reactions observed in the present study cover a range of 5 powers of 10 in relative rate constants.Preliminary studies with other examples of aminolysis suggest that a range of relative rate constants covering well in excess of 12 powers of 10 should be observable.
- DeTar, DeLos F.,Delahunty, Claire
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p. 2734 - 2739
(2007/10/02)
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