Electrophilic Substituents Research Articles

Non-bonded intra-molecular interactions in 1,8-disubstituted naphthalenes with a cyano group as the electrophilic substituent

Ab initio, self-consistent field, molecular-orbital, calculations were carried out for two 1,8-disubstituted naphthalene compounds to probe non-bonded, intra-molecular, interactions between electrophilic and nucleophilic substituents located at the 1 and 8 positions of the naphthalene rings. The cyano (–CN) group is the electrophilic substituent; the cyano carbon atom is the electrophilic center. The nucleophilic substituents were each, a nitro (–NO2) group in compound I, and a methoxy (–OCH3) group in compound II. The X-ray structure showed that the nitro-nitrile compound existed as two distinct structures, each with different bond distances and bond-angles of the peri substituents. We probed the nature of intra-molecular interactions in these compounds by calculating the electronic charges and molecular electrostatic potentials adjacent to the substituents. Similar studies for carbonyl group as the electrophilic substituent indicated the presence of electronic interactions for naphthalene compounds with the carbonyl group as the electrophilic substituent.

Intramolecular, Oxidatively Induced Substitution on a Coordinated Terpyridyl Ligand

In recent experiments, the authors demonstrated that in the Os-hydrazido complexes, trans-[Os{sup VI}(L{sub 3})(Cl){sub 2}(NN(CH{sub 2}){sub 4}O)]{sup 2+} (L{sub 3} = 2,2{prime}:6{prime},2{double{underscore}prime}-terpyridine or tris(1-pyrazolyl)-methane and N(CH{sub 2}){sub 4}O{sup {minus}} = morpholide), there are four interconvertible oxidation states with Os(VI), Os(V), Os(IV), and Os(III) accessible within the solvent limit in CH{sub 3}CN. Examples of Os(VI), Os(V), and Os(IV) have been characterized by X-ray crystallography. The authors report here a remarkable reaction between trans-[Os{sup VI}(tpy)(Cl){sub 2}(NN(CH{sub 2}){sub 4}O)]{sup 2+} (2), has been characterized crystallographically. An extraordinary electrophilic substituent effect of Os(VI) on the tpy ligand and the ability of Os(VI) to undergo reversible intramolecular Os(VI {yields} IV) electron transfer appear to play essential roles in these reactions.

Effect of substituents on the 13C chemical shifts of the azomethine carbon atom of N-(phenyl substituted) pyridine-4-aldimines

13C chemical shifts of the azomethine carbon atom for N-(substituted phenyl)pyridine-4-aldimines, 4-Py–CHN–C6H4–X, X having a wide range of substituent effects, have been determined in CDCl3 solution. Exceptionally good Hammett correlations of 13C NMR chemical shifts of azomethine carbons with electrophilic substituent constants σ+ points out to a strong resonance interaction of substituents on the aniline ring with the azomethine carbon atom of the investigated imines. The increased demand for electrons in the investigated system is being compared with that of the N-benzylidenaniline. The mode of transmission of substituent effects, both inductive and resonance, in both systems, is discussed.

Effect of the solvent nature and the number of electrophilic substituents in the molecule on hydration of nitro derivatives of phenanthrene-9,10-quinone

Solvates (1⩺2) of 10,10-dihydroxy-2,4,7-trinitro-9,10-dihydrophenanthren-9-one with DMSO and of 10,10-dihydroxy-2,7-dinitro-9,10-dihydrophenanthren-9-one with HMPA were prepared. The crystal structure of 2,5-dinitrophenanthrene-9,10-quinone was established. The results of X-ray diffraction analysis and IR spectroscopy of a series of mono-, di-, and trinitro derivatives of phenanthrene-9,10-quinone demonstrated that the ability of carbonyl groups to participate in nucleophilic addition of water increases as the number of nitro groups in substituted phenanthrene-9,10-quinone increases. The nature of the solvent (HMPA, DMF, or DMSO) affects hydration of phenanthrenequinones primarily due to the difference in the strength of intermolecular hydrogen bonds stabilizing di- and tetrahydroxy-dihydrophenanetherenes.

A Quantum Chemical and Electrostatic Study of Alkyl and Substituted Benzenonium Cations and Related Molecules: The Effect of Atomic Charge Distribution on Carbocation Energy and Geometry

Geometries, NMR chemical shifts, atomic charges, and bond orders were calculated at the MP2/6-31G* level of theory for the isopropyl, sec-butyl, tert-butyl, benzenonium, and six methyl- and trifluoromethyl-substituted benzenonium ions. The NPA charges correlate better than the CHELPG, MK, and AIM charges with the experimental and calculated carbon chemical shifts. The electrostatic energies of isomeric ions, calculated by treatment of the NPA charges as point charges, are comparable to their MP2 energy differences. The electrostatic calculations, although classical approximations, provide a qualitative understanding of the coulombic basis of the methyl and trifluoromethyl substituent effects. It is apparent that these species are stabilized by having adjacent, oppositely charged atoms (for example, having the negatively charged carbon of a methyl group bonded to a positive carbon). It is proposed that a methyl group be termed a nucleophilic (rather than electron-donating) substituent and that a trifluoromethyl group be termed an electrophilic substituent. In the benzenonium ions and in toluene, fluoromethylbenzene, difluoromethylbenzene, and benzotrifluoride, the endocyclic angle at the substituent increases with increasing electrophilicity of the substituent. An electrostatic calculation again provides some insight into the coulombic basis of these changes.

Use of electrostatic potentials to study non-bonded intramolecular interactions in 1,8-disubstituted naphthalenes with carbonyl groups as electrophilic substituents

Ab initio Self-Consistent Field molecular orbital calculations were carried out on seven 1,8-disubstituted naphthalene compounds to probe the non-bonded intramolecular interactions between electrophilic and nucleophilic substituents located at the 1 and 8 positions. The electrophilic substituents were characterized by the CO group with the carbonyl carbon as the electrophilic center. The nucleophilic substituents were amino [(CH 3) 2N–], methoxy (CH 3O–) and hydroxy (–OH) groups. The nature of the intramolecular interaction was probed by calculating the molecular electrostatic potential on the molecular surface adjacent to the substituents. Differences in net atomic charges and surface molecular electrostatic potentials with and without an adjacent substituent showed the presence of significant non-bonded interactions between the electrophilic and nucleophilic centers in these compounds.

On enantioselective separation of phenoxypropionates using permethylated β-cyclodextrin HPLC and GC columns

Investigations on chiral phenoxypropionates using permethylated β-cyclodextrin HPLC and GC columns showed a decrease in enantioselective separation efficiency from mecoprop-methyl and dichlorprop-methyl to the threefold chlorinated fenoprop-methyl. This corresponded to decreasing electron density in the aromatic system due to the increasing negative inductive effect of 3 chlorine substituents. Investigation on methyl-(RS)-2-(2,4-dichloro-3,6-dinitrophenoxy)-propionate confirmed the influence of electrophilic substituents while determination of ethyl-(RS)-2-methoxypropionate emphasized the necessity of an aromatic system for enantioselective separation on β-cyclodextrin stationary phases. For fenoprop-methyl as well as for the aryloxyphenoxypropionates diclofop-methyl and fluazifop-butyl, reversed phase HPLC showed higher separation performance than high resolution capillary GC.

Saturated heterocycles. 251. Determination of σ+ values of heteroaryl‐substituted phenyl groups via ring‐chain tautomerism

AbstractThe Hammett‐Brown electrophilic substituent constants σ+ for five heteroaryl‐substituted phenyl groups were estimated via the ring‐chain tautomeric equilibria of three sets of oxazolidines and 1,3‐oxazines in deuteriochloroform solution. For oxazolidines derived from norephedrine and norpseudoephedrine, the σ+ values were also determined via the gas‐phase ring‐chain equilibria, by means of mass spectrometry. The results show that the heteroaromatic substituents studied have a slight electron‐withdrawing character, with σ+ in the range ‐0.03 to 0.59. The gas‐phase σ+ values are significantly higher than the solution values.

Excited-state properties of asymmetric pentaazadentate expanded porphyrins

The research results of the excited-state properties of asymmetric pentaazadentate ex-panded-porphyrins are reported. The results show that the emission spectra appear in the 770-820 nm region in accord with the different substituents on the benzene ring. The quantum yield of fluorescence is less than 0.02, and the lifetime of the first singlet excited state (S1) is shorter than 1ns. There are excellent linear relationships between the energy of the S1 and the Hammett constants as well as the quantum yield of fluorescence and the electrophilic substituent constants σ+. The energies of the lowest excited triplet state (T1) of the complexes are in the range of 94 -130kJ/mol. The lifetime of T 1 is as long as tens of microseconds. The T1-Tn transient absorption spectra appear in 450-550 nm region. And the quantum yield of title compounds for generating singlet oxygen is as high as 0.9.

A New Poly(3-alkylthiophene) Synthesis via Pd-Catalyzed Coupling of Thienyl Mercuric Chlorides

A new coupling reaction based on the Pd-catalyzed reductive coupling of thienyl mercuric chlorides is described. A variety of substituted thiophenes react with HgCl2 to produce thienyl mercuric chlorides. The degree of substitution can be controlled by the choice of temperature, solvent, and reaction time, and the resulting chloromercuri thiophenes or bis(chloromercuri)thiophenes are stable to air and water. Heating the thienyl mercuric chlorides in pyridine solvent with Cu powder and PdCl2 catalyst gave good yields of the coupled thiophenes. Poly(alkyl)thiophenes, poly(alkyl thienylacetate esters), and copolymers of alkylthiophenes with unsubstituted thiophene were formed in good yields. Molecular weights, Mw, were in the range 5300−83000. This coupling reaction was demonstrated to be compatible with the presence of an electrophilic substituent that is attacked by more nucleophilic intermediates, e.g., thienyllithium or thienyl Grignard reagents. Thus, this synthesis should be compatible with substituents known to be unreactive toward arylmercuric chlorides or arylpalladium compounds and is therefore complementary to the organometallic coupling schemes currently in use.

Mutagenicity of benzoquinones for Ames Salmonella tester strains

The mutagenicity of 12 simple benzoquinone (BQ) derivatives was studied using five different Ames Salmonella mutagenicity tester strains in the presence and absence of S9 mix. Seven of the BQs used displayed mutagenicity with and/or without S9 mix, and most of them produced a marginal increase in revertants. p-Benzoquinone (p-BQ) showed the most potent mutagenic activity (17 induced revertants/nmol/plate for strain TA104 without S9 mix) among the BQs tested. TA104, which is sensitive to oxidative mutagens, was the most sensitive to the mutagenicity of the BQs of the five strains used, while the second most sensitive strain was TA2637, which detects bulky DNA adducts. Significant reductions in the mutagenicity of p-BQ, and 2,3-diCl-5,6-diCN-BQ without S9 mix were observed in the presence of catalase. These findings suggest that the mutagenicity of BQs for S. typhimurium is attributable to oxidative injury after BQ reduction and to DNA adducts that form with BQs that have electrophilic substituents.

Synthesis of novel thiol-containing citric acid analogues. Kinetic evaluation of these and other potential active-site-directed and mechanism-based inhibitors of ATP citrate lyase.

ATP citrate lyase is an enzyme involved in mammalian lipogenesis and cholesterogenesis. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agents. Citric acid analogues 5-16 bearing electrophilic and latent electrophilic substituents were synthesized and evaluated as irreversible inhibitors of the enzyme. The design of these agents was based on the classical enzymatic mechanism where an active-site nucleophile (thiol) was believed to be critically involved in catalysis. Reversible inhibition (Ki's ranging from ca. 20 to 500 microM) was observed for compounds 5, 10, and 12-16. Compounds 6-9 and 11 had no appreciable affinity for enzyme (Ki > 1 mM). Time-dependent inactivation of the enzyme by 5-16 was not detected following long incubation times (> 1 h, 37 degrees C) at 2 mM inhibitor concentrations.

ChemInform Abstract: Ring‐Chain Tautomerism and Crystal Structure of Some 1,3‐Oxazacyclanes, and the Electrophilic Substituent Constants for Some Heteroaryl Groups in Solution and in the Gas‐Phase.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Protonation of fused aromatic systems: Ab initio study of some model Wheland intermediates

AbstractStructure and properties of Wheland's intermediates are studied in some model systems. The effect of the annelated small ring is simulated by bending two vicinal CH bonds in benzene toward each other. The extent of bending describes the ring‐size effect of a small fused fragment molecule. The electrophilic substituent is represented by a proton. Calculations at the HF/6‐31G* and MP2/HF/6–31G* levels of sophistication confirm the Mills–Nixon (MN) hypothesis. It is conclusively shown that ß‐complexes are more stable than are α‐protonated species. The results are interpreted in terms of the ground‐state density distribution dictated by rehybridization and of the transition structure π‐electron redistribution triggered by protonation. Their effects are additive to a large extent as far as CC bond distances are concerned. Energetic properties are determined by the interplay of two characteristic π‐electron localization patterns, one caused by the initial angular strain and the accompanying rehybridization related to the ground state and the other one occurring during formation of the proton σ‐complex. This interplay destabilizes α‐intermediates relative to ß‐intermediates. © 1994 John Wiley & Sons, Inc.

Steroidal affinity labels of the estrogen receptor. 1. 17 alpha-(Bromoacetoxy)alkyl/alkynylestradiols.

To develop steroidal affinity labels for the estrogen receptor, we prepared five electrophilic estradiol derivatives bearing the 17 alpha-propyl, 17 alpha-(1'-butynyl), or 17 alpha-(1'octynyl) chain, with either a terminal epoxy function (for the 17 alpha-propyl substituent) or a terminal bromoacetoxy function (for all three 17 alpha-substituent types). These compounds displayed low affinity for the lamb uterine estrogen receptor; with apparent relative affinity constants ranging from 0.02% to 0.24% that of estradiol. They were also rapidly transformed in cytosol, probably to the corresponding vicinal diols (epoxy compounds) or primary alcohols (bromoacetoxy compounds). Nevertheless, bromoacetates induced irreversible inactivation of the hormone-binding site but only with ligand-free binding sites. The effect of bromoacetates was prevented by treatment of the cytosol with the thiol-specific reagent methyl methanethiosulfonate. Inactivation of the receptor at 0 degrees C was rapid (< 1 h) and strongly dependent on both compound concentration and pH, with significant effects obtained at either > 150 nM (at pH 9) or pH > 7.5 (at 5 microM). Regardless of the conditions used, the order of efficiency for bromoacetates was always: 17 alpha-propyl derivative < 17 alpha-butynyl derivative < 17 alpha-octynyl derivative, with maximal inactivation of approximately 30% and approximately 70% of the hormone-binding sites obtained for the less active and more active compounds, respectively. Characteristics of the receptor inactivation suggest that (i) prepared bromoacetates are highly reactive affinity labels for the estrogen receptor, (ii) they react with similar (or even a single) nucleophilic amino acid residues located within or near the hormone-binding site of the receptor; these residues are probably the -SH of cysteines, and (iii) position 17 alpha of steroidal ligands is suitable for introducing electrophilic substituents to develop efficient affinity labels for the receptor.

Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins

A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(omega-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) omega-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethyl-amino)ethyl]-3-nitrothiophene-5- carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.

Dexamethasone 21-(.beta.-isothiocyanatoethyl)thio ether: a new affinity label for glucocorticoid receptors

The C-21 methanesulfonate ester of the synthetic glucocorticoid dexamethasone (Dex) is an efficient electrophilic affinity label of glucocorticoid receptors and exhibits irreversible antiglucocorticoid activity. In an effort to obtain other affinity labeling steroids with differing biological activities, several new derivatives of Dex were prepared which contained a reactive electrophilic substituent at various distances from the C-21 position. All compounds displayed relatively low affinity for rat glucocorticoid receptors (less than or equal to 8% of that of Dex) in a cell-free competition assay. Nevertheless, one compound, dexamethasone 21-(beta-isothiocyanatoethyl) thioether (Dex-NCS), appeared to be an affinity label by virtue of its ability to block the cell-free exchange binding of [3H]Dex. [3H]Dex-NCS was thus synthesized and reacted with cell-free receptors to give, after analysis on denaturing SDS-polyacrylamide gels, only one specifically labeled species at 98 kDa, which is the molecular weight of authentic rat glucocorticoid receptor. These data directly establish Dex-NCS as a new affinity label for glucocorticoid receptors. Data on the reactivity of Dex-NCS and the stability of [3H]Dex-NCS-labeled receptors suggest that a cysteine SH group has been labeled.

Evaluation of nitric oxide chemical ionization mass spectra of substituted benzenes

AbstractNitric oxide chemical ionization mass spectra of substituted benzenes obtained with the Townsend discharge technique were studied. There were four kinds of base peaks in the mass spectra, i.e. [M + NO]+˙, M+˙, [M − H]+ and [M − OR]+ (R = H, CH3). The formation of the specific ion [M + NO]+˙ was highly dependent on the kind of substituent, and it was produced more abundantly in the case of substitutions involving electron‐accepting groups. The measure of [M + NO]+˙ production was evaluated from the value of the ratio [M + NO]+˙/M+˙. In mono‐substitutions, it was clarified that the ratios of [M + NO]+˙/M +˙ were correlated with the Hammett substituent constant s̀p or the electrophilic substituent constant s̀p+. Monosubstitutions (C6H5R) and toluene substitutions (CH3C6H4R) could be classified into six groups in terms of base peak species, [M + NO]+˙/M+˙ ratios and substituents. In disubstitutions, the mass spectral patterns were governed by the combination of substituents. Mass spectral distinctions among ortho, meta and para isomers could be made in many cases.

Perfluorobutylperoxyl radical as an oxidant in various solvents

Perfluorobutylperoxyl radicals were produced by pulse radiolysis of aerated solutions of perfluorobutyl iodide. The rate constants for reaction of this radical with several organic reductants, chlorpromazine, trolox, hydroquinone, and several other phenols, were determined in various solvents and were found to be in the range of 10{sup 5}-10{sup 9} M{sup {minus}1} s{sup {minus}1}. By comparison with other haloalkylperoxyl radicals, C{sub 4}F{sub 9}OO{sup {sm bullet}} was found to be a much more powerful oxidant, whose reactions took place more rapidly and were less sensitive to solvent and substituent effects. The rate constants (k) for oxidation of a series of para-substituted phenols by C{sub 4}F{sub 9}OO{sup {sm bullet}} gave a good linear correlation between log k and the electrophilic substituent constant {sigma}{sup +}, with a slope of {rho}{sup +} = {minus}2.3, indicating formation of a positively charged transition state. Parallel experiments with CCl{sub 3}OO{sup {sm bullet}} were limited to the most reactive phenols and gave a higher slope, {rho}{sup +} = {minus}3.3. The rates of reaction of C{sub 4}F{sub 9}OO{sup {sm bullet}} with trolox and chlorpromazine were found to depend on solvent viscosity, but much less on solvent polarity and acid-base properties, probably because they were closer to the diffusion-controlled limit. Themore » longer chain C{sub 10}F{sub 21}OO{sup {sm bullet}} was somewhat less reactive than C{sub 4}F{sub 9}OO{sup {sm bullet}} because of geometric factors.« less

Formation of acetylplatina(IV)cyclobutane: methodology for the synthesis of platina(IV)cyclobutane complexes bearing electrophilic substituents

A methodology for the syntheses of platina (IV) cyclobutanes bearing an electron-withdrawing keto group has been achieved. This method, which involves protection of cyclopropyl methyl ketone, platinum insertion, and subsequent deprotection, yields acetylplatinacyclobutane