Para-substituted Phenols Research Articles

Characterization of the arene-oxidizing intermediate in ToMOH as a diiron(III) species.

We report the generation and characterization of a diiron(III) intermediate formed during reaction with dioxygen of the reduced hydroxylase component of toluene/o-xylene monooxygenase from Pseudomonas sp. OX1. The decay rate of this species is accelerated upon mixing with phenol, a substrate for this system. Under steady-state conditions, hydrogen peroxide was generated in the absence of substrate. The oxidized hydroxylase also decomposed hydrogen peroxide to liberate dioxygen in the absence of reducing equivalents. This activity suggests that dioxygen activation may be reversible. The linear free energy relationship determined from hydroxylation of para-substituted phenols under steady-state turnover has a negative slope. A value of rho < 0 is consistent with electrophilic attack by the oxidizing intermediate on the aromatic substrates. The results from these steady and pre-steady-state experiments provide compelling evidence that the diiron(III) intermediate is the active oxidant in the toluene/o-xylene monooxygenase system and is a peroxodiiron(III) transient, despite differences between its optical and Mössbauer spectroscopic parameters and those of other peroxodiiron(III) centers.

Polarization Effects for Hydrogen-Bonded Complexes of Substituted Phenols with Water and Chloride Ion

Variations in hydrogen-bond strengths are investigated for complexes of nine para-substituted phenols (XPhOH) with a water molecule and chloride ion. Results from ab initio HF/6-311+G(d, p) and MP2/6-311+G(d, p)//HF/6-311+G(d, p) calculations are compared with those from the OPLS-AA and OPLS/CM1A force fields. In the OPLS-AA model, the partial charges on the hydroxyl group of phenol are not affected by the choice of para substituent, while the use of CM1A charges in the OPLS/CM1A approach does provide charge redistribution. The ab initio calculations reveal a 2.0-kcal/mol range in hydrogen-bond strengths for the XPhOH⋯OH(2) complexes in the order X = NO(2) > CN > CF(3) > Cl > F > H >OH >CH(3) > NH(2). The pattern is not well-reproduced with OPLS-AA, which also compresses the variation to 0.7 kcal/mol. However, the OPLS/CM1A results are in good accord with the ab initio findings for both the ordering and range, 2.3 kcal/mol. The hydrogen bonding is, of course, weaker with XPhOH as acceptor, the order for X is largely inverted, and the range is reduced to ca. 1.0 kcal/mol. The substituent effects are found to be much greater for the chloride ion complexes with a range of 11 kcal/mol. For quantitative treatment of such strong ion-molecule interactions the need for fully polarizable force fields is demonstrated.

Host plant-dependent metabolism of 4-hydroxybenzylglucosinolate in Pieris rapae: Substrate specificity and effects of genetic modification and plant nitrile hydratase

After ingestion of transgenic Arabidopsis thaliana CYP79A1 containing sinalbin (4-hydroxybenzylglucosinolate) due to genetic modification, only one major sinalbin-derived sulphate ester (the sulphate ester of 4-hydroxyphenylacetonitrile) was excreted by Pieris rapae caterpillars (corresponding to 69 mol% of ingested sinalbin). An additional sulphate ester (the sulphate ester of 4-hydroxyphenylacetamide) was excreted when the caterpillars were reared on two plant species ( Sinapis alba and Sinapis arvensis) that contained sinalbin naturally. Artificial addition of sinalbin to S. arvensis leaves resulted in increased levels of the sulphated amide, and an enzymatic activity (nitrile hydratase) explaining the formation of the sulphated amide from sinalbin was detected in both Sinapis species, but not in A. thaliana. In agreement with the suggested minor metabolic pathway, the caterpillars were able to sulphate 4-hydroxyphenylacetamide offered as part of an artificial diet. In fact, phenol and seven para-substituted phenol derivatives with substituents of moderate size were sulphated and excreted, but all tested phenols devoid of a nitrile functional group were less efficiently sulphated than the primary sinalbin detoxification product, 4-hydroxyphenylacetonitrile. This suggests that the specificity of the sulphation step involved in sinalbin metabolism may be adapted to nitriles formed as metabolites of phenolic glucosinolates. On the contrary, there was no specificity for products (4-hydroxybenzylascorbigen and 4-hydroxybenzylalcohol) derived from the semistable isothiocyanate produced from sinalbin in the absence of nitrile specifier protein.

Calculation of the relative acidities and oxidation potentials of para-substituted phenols. A model for α-tocopherol in solution

Relative acidities (Delta pK(a)) of phenols and oxidation potentials (Delta E(ox)) of the phenoxide anions have been calculated for nine para-substituted phenols using density functional theory. Solvent effects were incorporated using the conductor-like polarisable continuum method. Using the calculated Delta pK(a) and Delta E(ox) values in a thermodynamic cycle, the DeltaBDE (bond dissociation enthalpy) of the phenols were also determined with all values calculated to within 1.5 kcal mol(-1) of experiment. The Delta pK(a) and Delta E(ox) values were calculated for 6-hydroxy-2,2,5,7,8-pentamethylchroman (HPMC), a model for alpha-tocopherol for which there are no known experimental values. The acidity of this compound is raised by 2.4 pK(a) units and lowered by -0.79 V relative to phenol with a calculated Delta BDE of -14.9 kcal mol(-1). There is a negative correlation (r(2) = 0.86) between the Delta pK(a) and the Delta BDE values. A stronger and positive correlation is found between the Delta E(ox) (r(2) = 0.98) and the Delta BDE values. Using these correlations it is uncovered that hydrogen abstraction of phenols, as measured by the Delta BDE, is driven by electron transfer rather than by proton transfer.

Enantioselective constructions of quaternary carbons and their application to the asymmetric total syntheses of fredericamycin A and discorhabdin A

Abstract An efficient enantioselective construction of quaternary carbons including spiro carbons is an area of intense interest due to the importance of these units as components of biologically active natural products. Prominent methods are presented for the synthesis of chiral, nonracemic quaternary carbon centers by (i) stereospecific rearrangement of optically active epoxides, (ii) enzyme-catalyzed resolution, and (iii) hypervalent iodine reagent-induced ipso-substitution of para-substituted phenol derivatives. These methods were applied to the total syntheses of fredericamycin A and discorhabdin A.

Novel Metabolic Pathways of p-n-Nonylphenol Catalyzed by Cytochrome P450 and Estrogen Receptor Binding Activity of New Metabolites

Nonylphenol, which is used industrially as a surfactant, is an endocrine-disrupting chemical (EDC) which has estrogenic activity. The novel biotransformation of nonylphenol was investigated, based on our previously reported ipso-metabolism of para-substituted phenols by cytochrome P450 (P450). Three novel metabolites of nonylphenol, i.e., nonylquinol, 4'-hydroxynonanophenone (CO-NP) as benzyl-oxidized nonylphenol, and hydroquinone, were detected in a rat liver microsome reaction mixture. On the other hand, production of 1-(4'-hydroxyphenyl)nonan-1-ol (OH-NP), namely benzyl-hydroxylated nonylphenol, was detected in a human liver microsome reaction mixture. The formation of all these metabolites was suppressed by the addition of P450 inhibitor. This showed that all nonylphenol metabolism was catalyzed by P450. To identify which P450 isoenzyme is involved in each reaction, fourteen human P450 (CYP) isozymes, CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and CYP4A11, were examined. CYP1A1, 1A2, and CYP2B6 effectively catalyzed the production of nonylquinol. CYP2B6 also catalyzed the benzyl-hydroxylation to give OH-NP. Hydroquinone was formed mainly from OH-NP, not via CO-NP. We examined the estrogenic activity of these new metabolites by estrogen receptor (ER)-binding reporter gene assay. Nonylquinol, OH-NP and hydroquinone have no ER-binding activity. However, CO-NP showed the same level of estrogen receptor binding activity as nonylphenol. Moreover, the amount of CO-NP formed was small. Therefore, the novel metabolic pathways led overall to metabolic inactivation, as concerns the estrogenic activity of nonylphenol through the ER.

DFT/B3LYP study of the substituent effect on the reaction enthalpies of the individual steps of sequential proton loss electron transfer mechanism of phenols antioxidant action: Correlation with phenolic C [sbnd]O bond length

The reaction enthalpies related to the individual steps of sequential proton loss electron transfer (SPLET) mechanism, for phenol and 30 meta- and para-substituted phenols (ArOH) were calculated using DFT/B3LYP method. This newly discovered mechanism represents an alternative way to the extensively studied hydrogen atom transfer (HAT) mechanism. Except the comparison of calculated reaction enthalpies with available experimental and theoretical values, obtained enthalpies were correlated with Hammett constants. We have found that electron-donating substituents induce the rise in the proton affinities of phenoxide anions ArO − (reaction enthalpy of the first step). Electron-withdrawing groups induce the increase in the reaction enthalpy of the second step of SPLET where electron from ArO − is abstracted. Found results indicate that dependences of reaction enthalpies on Hammett constants of the substituents are linear. Moreover, we found, that proton affinities and electron transfer enthalpies from ArO − can be successfully correlated with the length of phenolic C O bonds of the studied substituted phenol molecules.

Dramatic Solvent and Hydration Effects on the Transition State of Soybean Peroxidase

Enzymes are shown to function in nonaqueous media; however, relatively little information is available on the influence of the organic solvent as well as its associated water content on the properties of the enzymatic transition states. A better understanding of these effects will be useful in developing kinetic models that can then be used to predict optimal solvent and substrate choices for enzymatic reactions in organic media. The influence of the reaction media on soybean peroxidase-catalyzed oxidation of para-substituted phenols was studied using Hammett analysis for several organic solvent systems. The catalytic activity and substrate specificity of the enzyme are influenced by the nature of the solvent and its associated hydration. These findings may allow one to draw conclusions about the reaction mechanism and the roles of solvent and solvent hydration on enzyme function.

DFT/B3LYP Study of the Substituent Effect on the Reaction Enthalpies of the Individual Steps of Single Electron Transfer−Proton Transfer and Sequential Proton Loss Electron Transfer Mechanisms of Phenols Antioxidant Action

The reaction enthalpies related to the individual steps of two phenolic antioxidants action mechanisms, single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET), for 30 meta and para-substituted phenols (ArOH) were calculated using DFT/B3LYP method. These mechanisms represent the alternative ways to the extensively studied hydrogen atom transfer (HAT) mechanism. Except the comparison of calculated reaction enthalpies with available experimental and/or theoretical values, obtained enthalpies were correlated with Hammett constants. We have found that electron-donating substituents induce the rise in the enthalpy of proton dissociation (PDE) from ArOH+* radical cation (second step in SET-PT) and in the proton affinities of phenoxide ions ArO- (reaction enthalpy of the first step in SPLET). Electron-withdrawing groups cause the increase in the reaction enthalpies of the processes where electron is abstracted, i.e., in the ionization potentials of ArOH (first step in SET-PT) and in the enthalpy of electron transfer from ArO- (second step in SPLET). Found results indicate that all dependences of reaction enthalpies on Hammett constants of the substituents are linear. The calculations of liquid-phase reaction enthalpies for several para-substituted phenols indicate that found trends hold also in water, although substituent effects are weaker. From the thermodynamic point of view, entering SPLET mechanism represents the most probable process in water.

Study of gas-phase O–H bond dissociation enthalpies and ionization potentials of substituted phenols – Applicability of ab initio and DFT/B3LYP methods

In this paper, the study of phenol and 37 compounds representing various ortho-, para-, and meta-substituted phenols is presented. Molecules and their radical structures were studied using ab initio methods with inclusion of correlation energy and DFT in order to calculate the O–H bond dissociation enthalpies (BDEs) and vertical ionization potentials (IPs). Calculated BDEs and IPs were compared with available experimental values to ascertain the suitability of used methods, especially for the description of the substituent induced changes in BDE and IP. MP2, MP3, and MP4 methods do not give reliable results, since they significantly underestimate substituent induced changes in BDE and do not reflect distinct effect of substituents related to para and meta position correctly. DFT/B3LYP method reflects the effect of substituents on BDE satisfactorily, though ΔBDEs are in narrower range than experimental values. BDE of phenol was calculated also using CCSD(T) method in various basis sets. Both, DFT and HF methods describe the effect of substituents on IP identically. However, DFT considerably underestimates individual values. HF method gives IPs in very good agreement with experimental data. Obtained results show that dependences of BDEs and IPs on Hammett constants of the substituents are linear. Linearity of DFT BDE vs. IP dependence is even better than the dependences on Hammett constants and obtained equations allow estimating of O–H BDEs of meta- and para-substituted phenols from calculated IPs.

Acid-Catalyzed Synthesis of Methylene-Bridged (S)-Tyrosine−Phenol Dimers

The efficient synthesis of 2,2'-arylmethylene dimers from 3-hydroxymethyl or 3-methoxymethyl-5-halo-(S)-tyrosines and para-substituted phenols under acid-catalyzed reaction conditions using either conventional or microwave-assisted protocols is described.

Proton Exchanges between Phenols and Ammonia or Amines: A Computational Study

Density functional theory calculations at the B3LYP/6-31+G(d,p) level of theory have been performed to explore proton exchanges between phenols and ammonia or amines, which can be used to account for previous NMR experiments. For the parent phenol-NH(3) system, a transition state with a symmetric phenolate-NH(4)(+)-like structure, which lies about 35 kcal mol(-1) in energy above the hydrogen-bonded complex, has been successfully located. An intrinsic reaction coordinate (IRC) analysis indicates that the proton exchange is a concerted process, which can be roughly divided into four continuous subprocesses. A series of para-substituted phenol-NH(3) systems have been considered to investigate the substituent effect. Whereas introduction of an electron-withdrawing group on the phenol appreciably reduces the barrier, an opposite effect is observed for an electron-donating group. Moreover, it has been disclosed that there exists a good linear correlation between the activation barriers and the interaction energies between the phenols and NH(3), indicating the important role of proton transfer (or hydrogen bonding) in determining the proton exchange. Also considered are the proton exchanges between phenol and amines and those for some sterically hindered systems. The results show that the phenol tends to exchange hydrogen with the amines, preferably the secondary amines, and that the steric effect is favorable for the proton exchange, which imply that, as the IRC analysis suggested, besides the proton transfer, the flip of the ammonium-like moiety may play a significant role in the course of proton exchange. For all of these systems, we investigated the solvent effects and found that the barrier heights of proton exchange decrease remarkably as compared to those in a vacuum due to the ion pair feature of the transition state. Finally, we explored the phenol radical cation-NH(3) system; the barrierless proton transfer and remarkably low barrier (5.2 kcal mol(-1)) of proton exchange provide further evidence for the importance of proton transfer in the proton exchange.

Photochemical Cleavage and Release of Para-Substituted Phenols from α-Keto Amides

In aqueous media alpha-keto amides 4-YC6H4OCH2COCON(R)CH(R')CH3 (5a, R = Et, R' = H; 5b, R = iPr, R' = Me) with para-substituted phenolic substituents (Y = CN, CF3, H) undergo photocleavage and release of 4-YC6H4OH with formation of 5-methyleneoxazolidin-4-ones 7a,b. For both 5a,b quantum yields range from 0.2 to 0.3. The proposed mechanism involves transfer of hydrogen from an N-alkyl group to the keto oxygen to produce zwitterionic intermediates 8a-c that eliminate the para-substituted phenolate leaving groups. The resultant imminium ions H2C=C(OH)CON+(R)=C(R')CH3 9a,b cyclize intramolecularly to give 7a,b. The quantum yields for photoelimination decrease in CH3CN, CH2Cl2, or C6H6 due to competing cyclization of 8a,b to give oxazolidin-4-one products which retain the leaving group 4-YC6H4O- (Y = H, CN). A greater tendency to undergo cyclization in nonaqueous media is observed for the N,N-diethyl amides 5a than the N,N-diisopropyl amides 5b. With para electron releasing groups Y = CH3 and OCH3 quantum yields for photoelimination significantly decrease and 1,3-photorearrangment of the phenolic group is observed. The 1,3-rearrangement involves excited state ArO-C bond homolysis to give para-substituted phenoxyl radicals, which can be observed directly in laser flash photolysis experiments.

Esterase activity of glycosylasparaginase

Glycosylasparaginase (GA) catalyzes the hydrolysis of the N-glycosylic bond in β-N-acetylglucosaminyl-L-asparagine to give N-acetylglucosamine, aspartic acid and ammonium ion in the catabolism of N-linked glycoproteins. A deficiency or absence of activity of GA gives rise to the most common inherited disorder of glycoprotein metabolism, aspartylglycosaminuria. The mechanism for GA has been proposed to be analogous to that of serine proteases, involving an acylation reaction to an acyl-enzyme intermediate, followed by a deacylation reaction. Studies of the mechanism thus far show that some properties of GA are similar to properties of serine proteases, although differences exist in some of the properties. Serine proteases have esterase activity where the rate-limiting step in the hydrolysis of substituted phenyl esters is the deacylation step. The esterase activity of GA was investigated using O4-(parasubstituted phenyl)-L-aspartate esters synthesized for the first time. The release of the parasubstituted phenolate was measured upon incubation with GA from human amniotic fluid. The rates of hydrolysis of the esters were dependent on the electronic properties of the parasubstitution. The rate-determining step in the hydrolysis of the esters by GA is the acylation step, opposite to that of serine proteases. The analogy of the mechanisms for serine proteases and GA is not absolute. The research was supported in part by funds provided by The University of North Carolina at Charlotte.

Triadic analysis of substituent effects—gas-phase acidity of para-substituted phenols

A large variety of para-substituted phenols was examined and their acidities in the gas-phase were rationalized by a triadic formula, which is capable of delineating the initial, intermediate and final state effects in the deprotonation process. It is shown that triadic analysis is equivalent to the homodesmotic reactions approach, while being much more informative at the same time. The applied MP2(fc)/6-311+G(d,p)//B3LYP/6-31G(d) theoretical method gives acidities in very good agreement with available measured values, meaning that calculations can safely replace the missing experimental data for compounds not easily amenable to laboratory examinations. It is found that the underlying principle leading to enhanced acidity of para-substituted phenols containing strong π-electron acceptor groups is the final state effect. It reflects a more pronounced ability to accommodate the excess negative charge. Particular attention has been focused on superacidifying NO 2, SO 2CF 3 and S(O)( NSO 2CF 3)CF 3 and C(CN) C(CN) 2 moieties. It is shown that their influence on acidity is strong and that the deprotonation ability increases along the sequence of substituents NO 2<SO 2CF 3<S(O)( NSO 2CF 3)CF 3<C(CN) C(CN) 2. On the contrary, the electron releasing substituents NH 2, OCH 3, OH and CH 3 decrease acidity of phenol albeit to a small extent. Finally, it is demonstrated that pentacyano derivative of phenol is a powerful OH superacid as evidenced by Δ H acid value of 287.5 kcal mol −1.

Synthetic Approaches for the Nanoencapsulation of Fullerenes

Encapsulation of [60]fullerene by cyclic molecules like cyclodextrins and calixarenes has many different applications. One of the earliest among them was to enhance the solubility of [60]fullerene in both polar as well as non-polar solvents and this has had immense application potential in materials research and medicine. Molecular modeling studies are efficient tools to study the supramolecular structures and have the advantage of predicting the structures even before carrying out an experiment. Unlike the naturally occurring cyclodextrins that cannot be easily obtained by a totally synthetic procedure, calixarenes are the product of the condensation reactions between para-substituted phenols and formaldehyde. These bowl-shaped molecules have cavities that can hold metals as well as molecules and have been used to sequester metal ions. This review highlights the research done in the nanoencapsulation of fullerenes by cyclodextrins and calixarenes during the last decade and looks at the emerging trends in this area. Keywords: Calixarenes, cyclodextrins, fullerene, macrocycle, nanoencapsulation, supramolecular

Convergent synthesis of two14C-labeled β3-adrenergic receptor agonists

The synthesis of β3-adrenergic receptor agonists A and B with radiolabeled amide fragment, required for drug disposition studies, was accomplished based on initial formation of 2-(4-(2-amino-2-methylpropyl)phenoxy)-5-[14C]-cyanopyridine by the reaction of 2-bromo-5-iodopyridine with para-substituted phenol, and following cyanation of aromatic iodide with potassium cyanide-[14C]. After the coupling of the resulted amine with glycidyl derivatives of 4-hydroxyindole and 4-hydroxycarbazole, the corresponding nitriles were hydrolyzed with basic hydrogen peroxide to obtain target amides A and B. Copyright © 2006 John Wiley & Sons, Ltd.

Kinetics of fast reactions of triplet states and radicals under photolysis of 4,4′-dimethylbenzophenone in the presence of 4-halophenols in micellar solutions of sodium dodecyl sulfate in magnetic field

Quenching kinetics of the 4,4′-dimethylbenzophenone triplet state with para-substituted phenol derivatives RC6H4OH (R = H, F, Cl, Br, I) was studied by nanosecond laser photolysis in aqueous micellar solutions of sodium dodecyl sulfate. The kinetic data were processed in the framework of a model with the Poisson distribution of phenols between micelles. The partition constants of RC6H4OH between the aqueous and micellar phases and the rate constants of their escape from a micelle and quenching of the 4,4′-dimethylbenzophenone triplet state with phenols in micelles were obtained. The quenching proceeds with high rate constants through hydrogen atom transfer to form the ketyl and phenoxyl radicals (no radicals are formed in the case of 4-iodophenol), which then recombine in a micelle or escape into the outer aqueous volume. The application of an external magnetic field retards radical pair recombination in a micelle and increases the fraction of radicals escaped into the aqueous phase. The quantum yield of radical pairs decreases 2.5-fold, and the rate of their recombination in micelles increases 2.5-fold on going from 4-chloro- to 4-bromophenol. This is caused by the acceleration of triplet radical pair recombination in the solvent cage.

Kinetics of radical formation and decay in photooxidation of 4-halophenols sensitized by 4-carboxybenzophenone in aqueous solutions

Kinetics of formation and recombination of radicals formed by quenching of the triplet state of 4-carboxybenzophenone (CB) with para-substituted phenol derivatives RC6H4OH (R = OMe, H, Cl, Br, I) in aqueous solutions was studied by nanosecond laser photolysis. At pH ≥ 5.4, quenching proceeds with high rate constants ((1–3)⋅109 L mol−1 s−1) through electron transfer to form the radical anion CB⋅− and radical cation RC6H4OH⋅+. The latter is transformed into the phenoxyl radical within ≤10 ns. At pH ≤ 8, the CB⋅− radical anion is protonated in a phosphate buffer with the rate constant increasing from 4⋅106 to 15⋅106 s−1 with a decrease in the pH from 8 to 5.4. The yield of radicals decreases from 100 to 13% as the atomic weight of halogen in the RC6H4OH molecule increases due to an increase in the probability of recombination of the primary triplet radical pair in the solvent cage and partial intersystem crossing in an encounter complex (3CB, RC6H4OH). The effect of heavy atom is also observed in the kinetics of volume recombination of the radicals, the magnitude of effect corresponds to the acceleration of the primary recombination of the triplet radical pair.

A modification of the Hammett equation for predicting ionisation constants of p-vinyl phenols

Currently there are several compounds used as drugs or studied as new chemical entities, which have an electron withdrawing group connected to a vinylic double bond in a phenolic or catecholic core structure. These compounds share a common feature – current computational methods utilizing the Hammett type equation for the prediction of ionisation constants fail to give accurate prediction of p K a's for compounds containing the vinylic moiety. The hypothesis was that the effect of electron-withdrawing substituents on the p K a of p-vinyl phenols is due to the delocalized electronic structure of these compounds. Thus, this effect should be additive for multiple substituents attached to the vinylic double bond and quantifiable by LFER-based methods. The aim of this study was to produce an improved equation with a reduced tendency to underestimate the effect of the double bond on the ionisation of the phenolic hydroxyl. To this end a set of 19 para-substituted vinyl phenols was used. The ionisation constants were measured potentiometrically, and a training set of 10 compounds was selected to build a regression model ( r 2 = 0.987 and S.E. = 0.09). The average error with an external test set of six compounds was 0.19 for our model and 1.27 for the ACD-labs 7.0. Thus, we have been able to significantly improve the existing model for prediction of the ionisation constants of substituted p-vinyl phenols.