84 research outputs found
Carbanion and enol intermediates in c-nitrosation and halogenation
No full textA kinetic study of the mtrosation of ethyl cyanoacetate, diethyl malonate and malononitrile, in acidic water/dioxan solution, by nitrous acid, at 25ºC, was under taken. Catalysis of this reaction was obtained by the addition of nucleophilic catalysts; chloride ion, bromide ion, thiocyanate ion and thiourea. The results were consistent with a mechanism where malononitrile reacted exclusively via the carbanion intermediate. Within the pH range used, pH 0∙7 to pH 3∙3, ethyl cyano acetate and diethyl malonate reacted either through a carbanion intermediate, at higher acidity, or an enol intermediate, at lower acidity. Values of the second order rate constant for the attack of the nitrosating species upon the carbanions were obtained. The carbanions of malononitrile and diethyl malonate reacted at the diffusion limit, in the presence of catalysts. Nitrosation of ethyl cyanoacetate, via its carbanion, showed an already established trend in the reactivity of the nitro sating species, NOSC(NH(_2))(_2) < NOSCN < NOBr < NOCl. A kinetic study of the nitrosation of malonic and methylmalonic acids, and of the iodination and bromination of these two acids as well as ethylmalonic and phenylmalonic acids, in aqueous acidic solutions, at 25ºC, was also undertaken. At high acidity nitrosation was shown to proceed via an enol intermediate and at lower acidities via a carbanion. Nitrosation of the intermediate was rate determining. Under certain conditions, in nitrosation, it was possible to make the enolisation rate limiting. lodination and bromination, by the halogen molecules, involved rate determining enol formation. lodination by triiodide ion involved rate determining iodination of the enol. Values of the enolisation rate constant, kg, were obtained for all four of the acid substrates, these were in reasonable agreement for the different electrophilic processes. Between pH 0 and pH 2 the results fitted an intramolecular acid catalysed enolisation mechanism. At higher pH values (2 to 4) the results fitted a change in mechanism to include, additionally, base catalysed enolisation and enol carboxylate formation pathways
Halo enol lactone and protio enol lactone inhibitors of alpha-chymotrypsin: Mechanism and stereospecific behavior of inhibition
No full textA kinetic study of inactivation of -chymotrypsin by enol lactones was performed. Halo enol lactones, 3-(1-naphthyl)-6(E)-(iodomethylene)tetrahydro-2-pyranone (Np6I) and 3-phenyl-6(E)-(bromomethylene)tetrahydro-2-pyranone (Ph6Br), showed burst kinetics in the inactivation of the enzyme, which requires a complicated kinetic scheme including partitioning of the first acyl enzyme between the covalent derivatization of the enzyme by the revealed halomethyl ketone reactive group (permanent inactivation) and formation of the second acyl enzyme by the hydrolysis of the halomethyl ketone of the first acyl enzyme to the non-reactive hydroxymethyl ketone group (transient inhibition). Deacylation of the second acyl enzyme leads to reactivation to free enzyme, which will be available for inactivation again. From the rate of the time-dependent irreversible inactivation and the rate of deacylation, a partition ratio between transient inhibition and permanent inactivation was calculated. A halo enol lactone with a small partition ratio showed a large burst. The efficiency of halo enol lactones as suicide inactivators is thus limited by the hydrolysis of the halomethyl reactive group.The corresponding protio enol lactones showed only transient inhibition (not inactivation) due to the lack of halogen in the lactone molecule, but deacylation rates of 4-phenyl-6-methylenetetrahydro-2-pyranone (Ph6H) and 3-(1-naphthyl)-6-methylenetetrahydro-2-pyranone (Np6H) were very slow, and they are thus still effective inhibitors by formation of stable acyl enzymes. In order to understand this slow deacylation and stereospecific behavior of inhibition, protio enol lactones were resolved into their two enantiomers, and the effects of the structure variation of the lactones on the inhibition kinetics were studied. This study shows that S enantiomer binds more strongly to the active site of the enzyme than R enantiomer, and the deacylation rates of the R enantiomers of Ph6H and Np6H are very slow, with the half-lives of 4.0 h and 12.6 h at pH 7.2, respectively. The enantioselectivity of deacylation of these lactones is very large, with the R enantiomers having 60-70 fold slower deacylation rates than the S enantiomers. This slow deacylation could be explained by a twisted acyl enzyme model. Since deacylation is the rate-determining step, these lactones with very slow deacylation rates act as alternate substrate inhibitors.Made available in DSpace on 2011-05-07T13:42:12Z (GMT). No. of bitstreams: 2
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The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors
No full textHuman neutrophil elastase (HNE) has been found to be responsible for the destruction of lung tissue in emphysema. Based on the primary substrate selectivity of HNE, a series of valine mimic protio and bromo enol lactones were designed as HNE inhibitors. General methods were developed for the preparation of - and -alkyl-substituted 5-alkynoic acids by the bromoform reaction of the corresponding alkynoic methyl ketone, prepared by the Eschenmoser-Tanabe fragmentation. -Methyl- and -dimethyl-5-hexynoic acids were synthesized from commercially available isophorone and 3,5-dimethyl-2-cyclohexen-2-one, respectively. -Substituted 5-hexynoic acids were prepared from 3-ethoxy-2-cyclohexen-1-one, using a novel ZnCl\sb2-mediated alkylation of 3-ethoxy-2-cyclohexen-1-one. The most efficient method for preparation of -substituted-5-hexynoic acids involved a four reaction sequence--alkylation of the corresponding -substituted ester with 1,4-dibromobutane, elimination, bromination and bis-dehydrobromination--with an overall yield of 40%. Protio enol lactonizations were performed with mercury(II) catalysis in CH\sb2Cl\sb2 or CH\sb2Cl\sb2-H\sb2O. Stereoselective Z-bromo enol lactonization was carried out by Br\sp+-induced lactonization in the presence of Ag\sp+. E-Bromo enol lactones were stereoselectively prepared by an improved method with NBS in CH\sb2Cl\sb2-H\sb2O.The inhibition of HNE by valine mimic enol lactones was studied in terms of inhibitory potency, efficiency, and nature of the inhibition. The enzyme-inhibitor binding constant and first-order and second-order acylation rate constants were determined for HNE and porcine pancreatic elastase (PPE). The structure-activity relationships show that -substituted enol lactones are more effective inhibitors than -substituted ones for HNE. The protio enol lactones with longer -substituted carbon chains (3 carbons) are better inhibitors than those with shorter carbon chains (2 carbons). The -isopropyl bromo enol lactone with a 6-methyl substituent is a less effective k\sb{\rm cat} inhibitor than the 6-unsubstituted one. The enantiomeric selectivity of -iPr6Br may be small due to its low turnover number. No olefinic geometry stereoselectivity, i.e., -iPr6(Z)Br vs -iPr6(E)Br is evident in the inhibition.Made available in DSpace on 2011-05-07T12:22:05Z (GMT). No. of bitstreams: 2
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Previous issue date: 1991Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding ([email protected]) on 2011-05-07T14:40:09Z
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Reactions of fluoroalkanesulfonyl azides with trimethylsilyl enol ethers
No full textReactions of per(poly)-fluoroalkanesulfonyl azides RfSO2N3 with trimethylsilyl enol ethers RCH=C(H)OSiMe3 (R-t=t-Bu, Ph) afforded alpha-[N-(fluoroalkanesulfonyl)]amino ketones RC(O)CH2NHSO2Rf in good yields. The cycloanalog 1-cyclohexenyl trimethylsilyl ether reacted with the azides to give one-carbon ring-contracted product N-fluoroalkanesulfonyl cyclopentanecarboxamides, c-C5H11CONHSO2Rf In the case of 1-cyclooctenyl trimethylsilyl ether, however, two products alpha-[N-(fluoroalkane sulfonyl)amine cyclooctanones and c-C7H13CONHSO2Rf were obtained. (C) 1999 Elsevier Science S.A. All rights reserved.Chemistry, Inorganic & NuclearChemistry, OrganicSCI(E)CPCI-S(ISTP)1
LOWERING OF KETO-ENOL TAUTOMERIZATION BARRIER OF CYCLIC DIKETONES VIA CHO INTERACTION
No full textAuthor Institution: Department of Physical Chemistry, Indian Association for the cultivation of science, Calcutta 700032, India. E-mail: [email protected] association and keto-enol tautomerization of -cyclohexanedione (-CHD) and analogues have been investigated in argon matrix and also in a thin solid film prepared by depositing pure -CHD vapour on a cold (8 K) KBr window. Infrared spectra reveal that in low-pressure vapour and argon matrix, the molecules are exclusively in diketo tautomeric form. The CHO hydrogen bonded dimers of the diketo tautomer are produced by annealing the matrix at 28 K. No indication is found for keto-enol tautomerization of -CHD in dimeric complexes in argon matrix within the temperature range of 8-28 K. On the other hand, in the thin film of pure diketo tautomer, the conversion initiates when the film is heated at temperatures above 165 K. The observed threshold appears to be associated with excitation of the intermolecular modes in the solid, and the IR spectra recorded at high temperatures display narrowing of vibrational bandwidths, which has been associated to re-orientations of the molecules in solid. The non-occurrence of tautomerization in the dimer is consistent with the prediction of electronic structure calculations at B3LYP/6-311++G**, M05-2X/6-311++G** and MP2/6-311++G** levels. The transition state calculation predicts that CHO interaction has a dramatic effect on lowering of the tautomerization barrier, from more than 60 kcal/mol of bare molecule to 35-40 kcal/mol in dimers. Details of the results on analogous systems will be discussed in the talk. \section*{{\small Reference}} "CHO Interaction Lowers Hydrogen Transfer Barrier to Keto-Enol Tautomerization of -Cyclohexanedione: Combined Infrared Spectroscopic and Electronic Structure Calculation Study", B. Bandyopadhyay, P. Pandey, P. Banerjee, A. K. Samanta, and T. Chakraborty, J. Phys. Chem A. 116,3836-3845 (2012)
The synthesis and evaluation of halo and protio enol lactone Pro-Val pseudodipeptides as potential inhibitors of human leukocyte elastase
No full textMechanism-based inhibitors of the serine protease -chymotrypsin have previously been prepared from aryl-substituted halo and protio enol lactones. In this study, the enantiomerically pure disubstituted protio and halo enol lactones 11a-c and 12a-b were prepared as potential inhibitors of the serine protease human leukocyte elastase (HLE). These lactones are incorporated into a Pro-Val pseudodipeptide in order to enhance binding and specificity towards HLE. The synthesis of these compounds proceeded by the cyclization of N-protected forms of the acetylenic amino acid epimers 13a and 13b. The amino acids were obtained by amide bond hydrolysis of the bicyclic oxa lactams 19a and 19b, prepared in six steps from Boc-(L)-proline.One of the target lactones, the trans bromo enol lactone 12a, is a potent inhibitor of HLE and -chymotrypsin, but a much poorer inhibitor of serine proteases of different specificity. Inactivation rates (k\sb{\rm obs}/I\sb{\rm o}), binding constants (K\sb{\rm I}), acylation rates (k\sb{\rm a}), and turnover numbers (TON) have been determined for the inhibition of HLE and -chymotrypsin by the lactone 12a, and the results are consistent with a mechanism-based inhibition process. Slow, partial reactivation of HLE was noted when the nucleophile hydrazine was added to a solution of the inactivated enzyme. A proposed mechanism for HLE inhibition involves the partitioning of the initially formed acyl enzyme intermediate into three species.In an unrelated study, the stability of the -substituted -phenylpropionyl chymotrypsin 48 derived from the protio enol lactone alternate substrate inhibitor 46 was investigated by preparing a series of -substituted -phenylpropionyl chymotrypsins possessing nonpolar, polar, and acylamino -substituents. The results indicate that the -substituent contributes to acyl enzyme stability by both steric and electronic interactions with the enzyme. An acyl enzyme structure that is twisted out of an orientation optimal for deacylation is proposed.Made available in DSpace on 2011-05-07T13:29:14Z (GMT). No. of bitstreams: 2
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Enolization of acetone in superheated water detected via radical formation
No full textPeer reviewedMuoniated free radicals have been detected in muon-irradiated aqueous solutions of acetone at high temperatures and pressures. At temperatures below 250 °C, the radical product is consistent with muonium addition to the keto form of acetone. However, at higher temperatures, a different radical was detected, which is attributed to muonium addition to the enol form. Muon hyperfine coupling constants have been determined for both radicals over a wide range of temperatures, significantly extending the range of conditions under which these radicals and the keto−enol equilibrium have been studied.Final article publishe
SPONTANEOUS HYDROGEN TRANSFER UPON IONIZATION: UV/VIS AND IR-SPECTROSCOPY OF ENOL RADICAL CATIONS FROM IONIZED O-CARBONYLTOLUENES IN ARGON MATRICES
No full text1. J. Gebicki, A. Marcinek, J. Michalak, J. Rogowski, T. Rally and W. Tang J. Mol. Struct, 275, 249 (1992); J. Chem. Soc. Perkin II 1992, 1353.Author Institution: Institute of Physical Chemistry, University of FribourgIt was recently shown that aromatic carbonyl compounds carrying an alkyl group in the ortho position undergo spontaneous hydrogen transfer upon ionization to form the more stable enol radical cations [1]. We have investigated the ``parent system'' of this class of molecules, o-methylbenzaldehyde, in some detail by matrix isolation UV/VIS and IR-speciroscopy. [FIGURE] The resulting enol radical cation is present in the form of several rotamers, some of which can be interconverted by selective photolyses. Three of the four possible rotamers were observed and identified by means of fitting quantum chemical force fields to the observed IR (difference) spectra. The resulting assignment is in agreement with theoretical predictions of the shifts in the UV/VIS spectra
Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases
No full textTwo classes of valero enol lactones were synthesized and examined as potential inhibitors of trypsin-like serine proteases. The first class of protio and iodo enol lactones had either a 4-guanidino phenyl substituent (3-(4-guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (1) and 3-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (2)) or a 4-guanidinomethyl phenyl substituent (3-(4-guanidinomethylphenyl)-6-methylidene tetrahydro-2-pyranone (3) and 3-(4-guanidinomethylphenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (4)) at the -position. The -aryl substituted system included the 4-guanidino phenyl substituted protio and iodo enol lactones 4-(4-guanidinophenyl)-6-(methylidene) tetrahydro-2-pyranone (5) and 4-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (6), as well as the corresponding -benzamido substituted analogs (3R*,4R*) 3-benzamido-4-(guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (7) and (3R*,4R*) 3-benzamido-4-(4-guanidinophenyl)-6(E)-iodomethylidene tetrahydro-2-pyranone (8).The lactones were tested for inhibitory activity against some trypsin-like enzymes, namely tyypsin, urokinase, tissue plasminogen activator (t-PA), plasmin and thrombin, as well as -chymotyypsin and human neutrophil elastase (HNE). The -(guanidino phenyl) substituted iodo lactone 2 was a suicide substrate of urokinase, plasmin, t-PA, thrombin and -chymotrypsin, with an exceptionally high specificity for the former two enzymes. The guanidinomethyl phenyl substituted iodo lactone 4 was a suicide substrate of all the trypsin-like enzymes tested, exhibiting exceptionally high specificity in its inhibition of trypsin and urokinase. The corresponding protio lactone 3 was an alternate substrate inhibitor of urokinase and thrombin, its potency being attributed to moderately stable acyl enzyme intermediates. Among the -aryl substituted lactones, no new suicide substrates for trypsin-like enzymes were found. The lactones 5 and 6 were alternate substrate inhibitors, selective for the trypsin-like enzymes. The iodo lactone 8 was a potent transient inactivator of trypsin and urokinase; in addition, it was a very selective and effective suicide substrate of -chymotrypsin.In general, the guanidino-aryl substituted enol lactones showed selectivity and superior specificities for trypsin-like enzymes, over -chymotrypsin and HNE. In addition, there was some selectivity within the class of trypsin-like enzymes. The -aryl substituted iodo lactones were suicide substrates and the -aryl substituted systems were potent alternate substrate inhibitors of some of the trypsin-like enzymes.Made available in DSpace on 2011-05-07T13:36:05Z (GMT). No. of bitstreams: 2
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Previous issue date: 1992Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding ([email protected]) on 2011-05-07T14:56:48Z
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Fluorination of Ketones Using Iodotoluene Difluoride
No full textFluorination of ketones was achieved by the reaction of silyl enol ethers with iodotoluene difluoride in the presence of BF3·OEt2 and a Et3N·HF complex
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