Transmission of the electronic effects of substituents by the thiophene ring

The shifts in the frequencies of the stretching vibrations of the hydroxyl group of phenol and pentachlorophenol that arise during the formation of hydrogen bonds with a number of substituted acetophenones and 2-acetylthiophenes, 2-acetylfuran, and 2-acetylselenophene and the frequencies of the stretching vibrations of the carbonyl group of the latter were subjected to a correlation analysis (with the Hammett, Brown, Taft, Yukawa-Tsuno, and Swain-Lupton equations), and it was shown that the thiophene ring in the investigated molecules in both the static state and during the formation of H complexes transmits the conjugation effects better than the benzene ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 918–923, July 1974.     

Transmission of electronic effects of substituents in vinyl esters

To elucidate the transmission mechanism of electronic effects of substituents in vinyl esters on the optical parameters of the absorption bands in the IR spectra, a comparison was made of the frequencies of corresponding absorption bands in vinyl ethers, vinyl esters, alkyl esters of carboxylic acids, ketones, and acid anhydrides. Calculation of the - and -electron structure of the molecules by the Hückel and Del Re approximations was made. The results were compared with the spectral characteristics. The conclusion was reached that the ester oxygen atom in vinyl esters reduces interaction of the carbonyl and vinyl groups, although it is not removed completely. In vinyl esters of aromatic acids the effect of benzene ring substituents is displayed by a change of the -electron structure of the CH₂=CH-O-CO- fragment. In vinyl esters of aliphatic acids the electronic influence of radicals of the acid portion is transmitted by the ester oxygen, mainly inductively, which, in its turn, shows a change in the ability of this atom to conjugate with the vinyl group.The authors express their thanks to Yu. A. Kruglyak for allowing use of the programs for the computation and for helpful advice.     

13C NMR spectra of N-substituted carbazoles. Transmission of the electronic effects of substituents through the nitrogen atom to the carbazole ring

The effect of substituents attached to the nitrogen atom on the ¹³C NMR chemical shifts was determined for a series of 9-substituted carbazoles. Correlation relationships between the inductive and resonance constants of the substituents and the chemical shifts of the carbon atoms were obtained. It was shown that carbazole derivatives are similar to anilines with respect to the conductivity of electronic effects through the nitrogen atom to the carbazole ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1184–1188, September, 1986.The authors thank N. V. Moskalev for providing them with a sample of carbazole Im.     

Irreversible enzyme inhibitors. XC. candidate active-site-directed irreversible inhibitors of thymidylate synthetase. I. 2-amino-5-(benzenesulfonamidopropyl)-6-methyl-4-pyrimidinol with substituents on the benzene ring

2-Amino-5-[p- (bromoacetamidomethyl)benzenesulfonamidopropyl]-6-methyl-4-pyrimidinol (XV) was synthesized by acylation of 2-amino-5-aminopropyl-6-methyl-4-pyrimidinol (III) with p-cyanobenzenesulfonyl chloride followed by catalytic reduction and reaction of the resultant aminomethyl group with p-nitrophenyl bromoacetate. A second irreversible inhibitor of thymidylate synthetase, namely 2-amino-5-[p-(bromoacetyl)benzene-sulfonamidopropyl]-6-methyl-4-pyrimidinol (XVI), was synthesized by acylation of in with p-acetylbenzenesulfonyl chloride followed by bromination. Both XV and XVI were good reversible inhibitors of thymidylate synthetase and inactivated the enzyme when the candidate compound was incubated with the enzyme. Iodoacetamide, which does not form a complex with enzyme, could inactivate thymidylate synthetase almost as well as XV; therefore it appears that XV inactivated the enzyme by a random bimolecular mechanism rather than by the desired active-site-directed mechanism via an enzyme-inhibitor complex. Similar conclusions were reached with XVI since phenacyl bromide could inactivate the enzyme somewhat more rapidly than XVI.     

Photochromism of 3H-2,1,4-benzoxadiazine 4-oxides with heterocyclic substituents on the benzene ring

Russian Journal of Organic Chemistry - 2H-Benzimidazole 1,3-dioxides undergo thermal isomerization to 3H-2,1,4-benzoxadiazine 4-oxides which are converted to 2H-benzimidazole 1-oxides on further...     

DFT study of 1-, 4-, and 5-substituted 2-oxo-1,2,3,4-tetrahydropyrimidines: substituent steric and electronic effects,and ring flipping

Steric and the electronic effects caused by the substituents in the 1-, 4-, and 5-positions of substituted 2-oxo-1,2,3,4-tetrahydropyrimidines were investigated using density functional theory at the B3LYP/6-31++G(d,p) level. Results of this study show that the heterocyclic ring adopts a pseudo-boat conformation, in which the C₄ and N₁ atoms are deviated from ring planarity. The C₄-substituent occupies a pseudo-axial position and the space orientation of the substituent depends on the type and position of the additional substituent in this aryl group. The heights of the C₄ and N₁ atoms from the boat plane and the orientation of 5-CO moiety toward the heterocyclic ring depend on the electronic and steric effects of the substituents in the various positions. Ring flip calculations for 4-phenyl substituent explain the extreme steric effect caused by the substituent in the 1-position. These calculations indicate the more favored pseudo-axial orientation of the phenyl group over the equatorial orientation.     

Proton magnetic resonance spectra of some 6- and 7-substituted 2-amino-4-hydroxypteridines

The conformations in solution of 6-phenyltetrahydropterin, 6,7-diphenyltetrahydropterin and 6-7, dimethyltetrahydropterin have been determined from their proton magnetic resonance spectra. The 6-phenyltetrahydropterin has the reduced pyrazine ring in a half chair conformation with the phenyl ring in the equatorial position. Both the 6,7-diphenyl- and 6,7-dimethyltetrahydropterins are of the cis configuration and have one substituent in an axial position. The enzymatic activity of these cofactors may be related to these conformations.     

Effect of fluoromethyl substituents on the spectral properties of the benzene ring

The electronic spectra of benzyl fluoride, benzal fluoride, and benzotrifluoride have been studied in polarized light at 4 K. An attempt is made to interpret the special features observed in the spectra by associating them with the effect of the different fluoromethyl substituents.     

Synthesis of new 1-substituted 4-(2-phenylquinazolin-4-yl)-and 4-(2-phenylquinazolin-4-ylidene) thiosemicarbazides

Two new 1-substituted 4-(2-phenylquinazolin-4-yl)-and 4-(2-phenylquinazolin-4-ylidene) thio-semicarbazides were formed by a multistep domino reaction of imidoyl isothiocyanate derivative with 1,1-di-R-hydrazine in acetone solution. Application of hydrazine hydrate under the same reaction conditions afforded 4-(2-phenylquinazolin-4(3H)-ylidene)-2-(propen-2-yl)-1-(propan-2-ylidene) thio-semicarbazide via a six-step triple-component domino reaction. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1688–1693, November, 2008.     

4-Methoxy- and 4-cyano-substituted lithium aryloxides: electronic effects of substituents on aggregation

The para-substituted lithium aryloxides [{4-NC-C6H4OLi.(Pyr)2}2.Pyr] 1a, [{4-NC-C6H4OLi.(THF)2}2] 1b, [{4-MeO-C6H4OLi.Pyr}4] 2a, [4-MeO-C6H4OLi.(THF)n] 2b, [{4-NC-2,6-(t-Bu)2-C6H2OLi.(Pyr)2}infinity] 3a, [{4-NC-2,6-(t-Bu)2-C6H2OLi.(THF)2}infinity] 3b, [{4-MeO-2,6-(t-Bu)2-C6H2OLi.Pyr}2.(Pyr)2] 4a, and [4-MeO-2,6-(t-Bu)2-C6H2OLi.(THF)n] 4b were prepared by the direct deprotonation of the corresponding phenol with an alkyllithium base (BuLi or MeLi) in the appropriate solvent, either pyridine or THF. All compounds were characterized by 1H and 13C NMR spectroscopy, and the crystal structures of 1a, 1b, 2a, 3a, 3b and 4a were elucidated. The cyano derivatives 1a and 1b adopt discrete tetrasolvated Li2O2 ring dimers whereas the methoxy analogue 2a crystallizes as a tetrasolvated molecular tetramer with a pseudo cubic Li4O4 core. The sterically encumbered cyano derivatives 3a and 3b form isostructural 1D polymeric chains of monomers via bridging of the phenolate ligands through Li...NC and Li-O contacts. In comparison, the crystal structure of the methoxy counterpart 4a is a disolvated molecular Li2O2 ring dimer. Solution NMR spectroscopic studies of 1-4 in d5-pyridine and d8-THF indicate that the methoxy complexes are more highly aggregated than the cyano derivatives, consistent with the solid-state studies. Ab initio molecular orbital calculations at the HF/6-31G* level of theory indicate that the origin of the aggregation state variations between the cyano and methoxy complexes is due to electronic effects.     

Evidence of substituent-induced electronic interplay. Effect of the remote aromatic ring substituent of phenyl benzoates on the sensitivity of the carbonyl unit to electronic effects of phenyl or benzoyl ring substituents

Carbonyl carbon (13)C NMR chemical shifts delta(C)(C[double bond]O) measured in this work for a wide set of substituted phenyl benzoates p-Y-C(6)H(4)CO(2)C(6)H(4)-p-X (X = NO(2), CN, Cl, Br, H, Me, or MeO; Y = NO(2), Cl, H, Me, MeO, or NMe(2) ) have been used as a tool to study substituent effects on the carbonyl unit. The goal of the work was to study the cross-interaction between X and Y in that respect. Both the phenyl substituents X and the benzoyl substituents Y have a reverse effect on delta(C)(C[double bond]O). Electron-withdrawing substituents cause shielding while electron-donating ones have an opposite influence, with both inductive and resonance effects being significant. The presence of cross-interaction between X and Y could be clearly verified. Electronic effects of the remote aromatic ring substituents systematically modify the sensitivity of the C[double bond]O group to the electronic effects of the phenyl or benzoyl ring substituents. Electron-withdrawing substituents in one ring decrease the sensitivity of delta(C)(C[double bond]O) to the substitution of another ring, while electron-donating substituents inversely affect the sensitivity. It is suggested that the results can be explained by substituent-sensitive balance of the contributions of different resonance structures (electron delocalization, Scheme 1).     

Synthesis of 4- and 6-substituted nitroindoles

Enolizable ketones react with m-nitroaniline in the presence of strong base such as t-BuOK to give 4- and 6-substituted nitroindoles. The reaction proceeds via oxidative nucleophilic substitution of hydrogen in m-nitroaniline with enolate anions in positions ortho to the amino group giving anionic σ^H adducts that are additionally stabilized by intramolecular interaction between the amino and the carbonyl group. Spontaneous oxidation of the σ^H adducts followed by the Bayer type condensation of the produced ortho-aminonitrobenzyl ketones gives 4- and 6-substituted nitroindoles. The scope of this reaction and its basic mechanistic features are discussed.     

Synthesis and reaction of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one derivatives

Reaction of aryl and styryl methyl ketones 1a-m with dimethyl bis(methylthio)methylenemalonate ( 2 ) in the presence of potassium hydroxide in dimethyl sulfoxide gave the corresponding methyl 6-aryl- and 6-styryl-4-methylthio-2-oxo-2H-pyran-3-carboxylates 3a-m . 6-Aryl derivatives 3a-d,g were treated with sodium methoxide in methanol to give the corresponding 6-aryl-4-methoxy-2H-pyran-2-ones 8a-d and 9. Phenylcoumalin ( 7a ) and paracotoin ( 7b ) were synthesized by the desulfurization of 6-aryl-4-methylthio-2H-pyran-2-ones 4a,b. Similarly, anibine ( 8e ) was also synthesized from 3g . Treatment of 3 with hydrogen peroxide or 3-chloroperoxybenzoic acid gave the corresponding 4-methylsulfiny-2H-pyran-2-ones 10a-f in good yields. Displacement reactions of 10a-f with nucleophilic reagents are also described.     

Synthesis and easy aromatisation of 5-substituted 6-(alkylthio)-2-methoxy-2,3-dihydropyridines. A new approach to the pyridine ring

Reaction of lithiated methoxyallene, 1-ethoxyethoxyallene, 1-(methylthio)propyne and 2-butyne with methoxymethyl isothiocyanate, MeOCH₂N=C=S followed by methylation affords the imidothioates H₂C=C=C(R)C(SMe)=NCH₂OMe [R=Me, OMe, OCH(Me)OEt, SMe]. Rearrangement to the fully conjugated systems H₂C=CH---C(R)=C(SMe)---N=CHOMe and subsequent electrocyclisation of these compounds leads to the 5-substituted 6-(methylthio)-2-methoxy-2,3-dihydropyridines with good to excellent yields. In the presence of acidic catalysts or by heating at elevated temperatures these dihydropyridines eliminate methanol to afford 3-substituted 2-(methylthio)pyridines. The aroma compound 2-(methylthio)-3-pyridinol was obtained by acid-catalysed treatment of 3-(1-ethoxyethoxy)-2-(methylthio)pyridine.     

Synthesis of 6-substituted pyrimidines by the wittig reaction. II . Via 2-acetamido-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde

Wittig condensations of both stabilized and unstabilized ylides were successfully achieved with 2-acetamido-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde (XI); functionalized Wittig reagents derived from dichloroacetone, ethyl 4-iodobutyrate, 4-bromobutyronitrile, phenylpropyl bromide, 3-bromopropylphthalimide, p - nitrobenzyl bromide, and p-nitrocinnamyl bromide were used. The resultant 6-substituted pyrimidines could be further transformed by reduction of the 6-side-chain double bond. Successful Wittig reactions were achieved with XI where the corresponding 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde (X) with its less electrophilic aldehyde group failed to give isolable yields of condensation products.     

Synthesis of 6-substituted pyrimidines by the wittig reaction. I. Via 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde

Condensation of isopropyl 6-phenylhexanoate with ethyl diethoxyacetate followed by guanidine afforded 2 - amino-6-diethoxymethyl-5-phenylbutyl-4-pyrimidinol (VII). Acid hydrolysis of VII gave an excellent yield of 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde (IV); the latter could be condensed with stabilized Wittig reagents such as carbethoxymethylene triphenyl phosphorane and cinnamylidene triphenyl phosphorane, but not unstabilized Wittig reagents such as carbethoxypropylene or cyano-propylene triphenyl phosphorane. Reduction of the Wittig products afforded pyrimidines with functionalized side-chains in the 6-position such as the 6-phenylbutyl (XVIII) and 6-carboxyethyl (XV) derivatives of 2-amino-5-phenylbutyl-4-pyrimidinol.     

Transformations of some 6- and 7-substituted 1,2,3-benzothiadiazoles

The preparation of some 6- and/or 7-substituted derivatives of 1,2,3-benzothiadiazole is described. The reactivity of some compounds was investigated in view of the possibility that 1,2,3-benzothiadiazoles may behave as masked diazo compounds. 7-Diazo or diazonium compounds were prepared but no interaction with the thiadiazole part could be observed.     

Substituent effects in the benzene dimer are due to direct interactions of the substituents with the unsubstituted benzene

The prevailing views of substituent effects in the sandwich configuration of the benzene dimer are flawed. For example, in the polar/pi model of Cozzi and co-workers (J. Am. Chem. Soc. 1992, 114, 5729), electron-withdrawing substituents enhance binding in the benzene dimer by withdrawing electron density from the pi-cloud of the substituted ring, reducing the repulsive electrostatic interaction with the nonsubstituted benzene. Conversely, electron-donating substituents donate excess electrons into the pi-system and diminish the pi-stacking interaction. We present computed interaction energies for the sandwich configuration of the benzene dimer and 24 substituted dimers, as well as sandwich complexes of substituted benzenes with perfluorobenzene. While the computed interaction energies correlate well with sigmam values for the substituents, interaction energies for related model systems demonstrate that this trend is independent of the substituted ring. Instead, the observed trends are consistent with direct electrostatic and dispersive interactions of the substituents with the unsubstituted ring.     

Synthesis and Use of 6-, 7-and 8-Membered P-Heterocycles

The synthesis of new families of P-heterocycles by reductive modifications, ring enlargement and Diels-Alder cycloaddition is described.