Electrophilic Interaction Research Articles

Electrophilic Coordination Catalysis: A Summary of Previous Thought and a New Angle of Analysis

One of the most common, and yet least well understood, enzymatic transformations is proton abstraction from activated carbon acids such as carbonyls. Understanding the mechanism for these proton abstractions is basic to a good understanding of enzyme function. Significant controversy has arisen over the means by which a given enzyme might facilitate these deprotonations. Creating small molecule mimics of enzymes and physical organic studies that model enzymes are good approaches to probing mechanistic enzymology. This Account details a number of molecular recognition and physical organic studies, both from our laboratory and others, dealing with the elucidation of this quandary. Our analysis launches from an examination of the active sites and proposed mechanism of several enzyme-catalyzed deprotonations of carbon acids. This analysis highlights the geometries of the hydrogen bonds found at the enzyme active sites. We find evidence to support pi-oriented hydrogen bonding, rather than lone pair oriented hydrogen bonding. Our observations prompted us to study the stereochemistry of hydrogen bonding that activates carbonyl alpha-carbons to deprotonation. The results from our own thermodynamic, kinetics, and computational studies, all of which are reviewed herein, suggest that an unanticipated level of intermediate stabilization occurs via an electrophilic interaction through the pi-molecular orbital as opposed to traditional lone pair directed coordination. We do not postulate that hydrogen bonding to pi-systems is intrinsically stronger than to lone pairs, but rather that there is a greater change in bond strength during deprotonation when the hydrogen bonds are oriented at the pi-system. Through these studies, we conclude that many enzymes preferentially activate their carbon acid substrates through an electrophilic coordination directed towards the pi-bond of the carbonyl rather than the conventional lone pair directed model.

Asymmetric Induction by a Remote Chiral Substituent – Computationally Determined Stereodifferentiation in Michael Additions of α‐Lithiated Allyl Sulfones

AbstractThe mechanism of stereoselectivity has been elucidated for the formation of two stereogenic centers in the products of Michael addition to ethyl crotonate by lithiated α‐anions of allylic sulfones bearing a remote chiral N‐substituent. In order to single out reactive carbanion structures, their conformational analysis was performed by ab initio calculations, finally at the B3LYP/6‐31+G(d) level. Low‐energy reactant structures were aligned taking intermolecular steric contacts into account. It appeared that only two cyclic conformers of the sulfone nucleophile in which the Li cation is chelated by the anionic carbon, as well as the S=O and NH moieties, are sterically accessible to the crotonate approach. Chiral discrimination of one of these conformers is due to an additional Li–π interaction provided by the remote Ph group of the N‐substituent. The enantioselectivity for the formation of the second stereocenter is due to a different asymmetry of the molecular electrostatic potential (calculated ab initio) in nucleophile–electrophile interactions. Thus, the observed diastereoselectivity is the result of a Ph–Li+ interaction, as well as a combination of steric and electrostatic factors. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Electrophilic Interaction of 2,3‐Allenoates with PhSeCl. An Unexpected Highly Stereoselective Synthesis of 3‐Phenylseleno‐4‐oxo‐2(E)‐alkenoates.

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Electrophilic Interaction of 2,3-Allenoates with PhSeCl. An Unexpected Highly Stereoselective Synthesis of 3-Phenylseleno-4-oxo-2(E)-alkenoates

We have previously reported an efficient synthesis of beta-phenylselenium-substituted butenolides via electrophilic cyclization of 2,3-allenoates with PhSeCl in aqueous MeCN. However, when 2,3-allenoates were treated with PhSeCl in MeCN, 3-phenylseleno-4-oxo-2(E)-alkenoates were formed unexpectedly. The addition of Li2CO3 improved the yield and the selectivity of the reaction. A possible mechanism involving a decomposition of selenate esters was proposed.

Helicase: mystery of progression

Helicases mode of unwinding the nucleic acids and translocation along single stranded nucleic acids is still a subject of great curiosity. Based on the energy transduction and electrophilic interactions, we present a model to explain the mode of action of active helicases. This model considers that both strand separation as well as translocation is active processes fueled by NTP hydrolysis. The model proposes that the translocation appears to involve creeping of helicase over the ssNA lattice rather than inchworm movement.

CoIII Complexes with Square‐Planar N2S2‐ and N2(SO2)2‐Type Ligands as An Active Site Structural Model for Nitrile Hydratase – Biological Implications of an Amidate Coordination

AbstractIn an attempt to understand the unique active site structure of nitrile hydratase, four CoIII complexes with square‐planar N2S2‐ or N2(SO2)2‐type donor sets, Na[CoIII(L:N2S2)] (1‐Na), PPh4[CoIII(L:N2S2)] (1‐PPh4), PPh4[CoIII(L:N2S2)(tBuNC)2] (2), and PPh4[CoIII{L:N2(SO2)2}(tBuNC)2] (3) were synthesized and characterized on the basis of electronic absorption spectroscopy, IR spectroscopy, cyclic voltammetry, and X‐ray structural analysis. Both of the crystal structures of complexes 1‐Na and 1‐PPh4 revealed a square planar structure with N2S2 donating atoms, and 2 exhibited an octahedral structure coordinated with two tert‐butylisocyanide (tBuNC) molecules at the axial sites of complex 1‐PPh4. Complex 3, which showed an octahedral structure with sulfinate sulfur atoms equatorially coordinated to the center, was synthesized by the treatment of 2 with a suitable oxidant. The reduction potential values from CoIII to CoII for complex 3 in solution demonstrated a larger positive shift when compared with those of complexes 1‐PPh4 and 2, which indicates that the oxygenation of the sulfur atoms increased the Lewis acidity of the CoIII center. Interestingly, the coordination equilibrium, the C=O stretching frequency, and the redox potential for 1‐PPh4 were all closely related to the acceptor number (AN) of the solvents. Furthermore, the coordination of monodentate tBuNC to the axial position of 1‐PPh4 was dependent on the solvents used. These findings indicate that an electrophilic interaction between the carbonyl oxygen atoms and the solvent molecules control the Lewis acidity of the metal ion. On the other hand, such a solvent dependence was not detected in the S=O stretching frequency of sulfinates 3. We have concluded that the increase in the redox potential/Lewis acidity of the metal center is a result of the oxygenation of sulfur, and that this increase is controlled by the interaction of the amidate carbonyl oxygen with the secondary coordination sphere. As demonstrated in previous mutation studies, this study suggests that the interaction of the nitrile hydratase active site with the functional groups from the peptide backbone is essential for the catalytic activity of the complex. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Adsorption of benzothiophene on Y zeolites investigated by infrared spectroscopy and flow calorimetry

Diffuse reflectance infrared spectra of benzothiophene adsorbed on different Y zeolites reveal that the cations and protons in the zeolites are the sites responsible for the adsorption of benzothiophene. On NaY, benzothiophene was molecularly adsorbed on the cations through the electrophilic interaction between the cations and the thiophenic rings. On the transition metal ion exchanged NiY and CuY zeolites, because of the presence of the d-electrons in the cations, the thiophenic rings interact with the cations to form the π-complexes through the σ–π electron donations. In the presence of hydroxyl species in the zeolites, the adsorbed sulfur compounds attach to the protons molecularly via the electrophilic interaction and undergo the opening of the thiophenic rings depending on the acidity of the zeolites and the adsorption amount. The apparent heat of adsorption of benzothiophene in normal octane on the Y zeolites determined by flow calorimetry shows that the adsorption strength based on the measured heat for each mole sulfur adsorbed on the Y zeolite is in the order of CuY > NiY > NaY ∼ USY. For USY, due to the endothermic breakage of the thiophenic ring of benzothiophene induced by the acid sites of the zeolite, the apparent heat of adsorption is similar to that obtained from the adsorption on NaY. This work demonstrates that the transition metal ion exchanged zeolites exhibit excellent properties for sulfur adsorption because of the formation of the π-complexes and that the acidity of the zeolites is not advantageous for sulfur removal due to the strong adsorption and decomposition of the adsorbed species.

Efficient Two‐Step Synthesis of 3‐Halo‐3‐enals or 2‐Halo‐2‐alkenyl Ketones from Propargylic Bromides via a Unique Cationic 1,2‐Aryl or Proton Shift in Electrophilic Addition Reaction of 2,3‐Allenols with X+.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Broadly distributed nucleophilic reactivity of proteins coordinated with specific ligand binding activity

Covalent nucleophile-electrophile interactions have been established to be important for recognition of substrates by several enzymes. Here, we employed an electrophilic amidino phosphonate ester (EP1) to study the nucleophilic reactivity of the following proteins: albumin, soluble epidermal growth factor receptor (sEGFR), soluble CD4 (sCD4), calmodulin, casein, alpha-lactalbumin, ovalbumin, soybean trypsin inhibitor and HIV-1 gp120. Except for soybean trypsin inhibitor and alpha-lactalbumin, these proteins formed adducts with EP1 that were not dissociated by denaturing treatments. Despite their negligible proteolytic activity, gp120, sEGFR and albumin reacted irreversibly with EP1 at rates comparable to the serine protease trypsin. The neutral counterpart of EP1 reacted marginally with the proteins, indicating the requirement for a positive charge close to the electrophilic group. Prior heating resulted in altered rates of formation of the EP1-protein adducts accompanied by discrete changes in the fluorescence emission spectra of the proteins, suggesting that the three-dimensional protein structure governs the nucleophilic reactivity. sCD4 and vasoactive intestinal peptide (VIP) containing phosphonate groups (EP3 and EP4, respectively) reacted with their cognate high-affinity binding proteins gp120 and calmodulin, respectively, at rates exceeding the corresponding reactions with EP1. Reduced formation of EP3-gp120 adducts and EP4-calmodulin adducts in the presence of sCD4 and VIP devoid of the phosphonate groups was evident, suggesting that the nucleophilic reactivity is expressed in coordination with non-covalent recognition of peptide determinants. These observations suggest the potential of EPs for specific and covalent targeting of proteins, and raise the possibility of nucleophile-electrophile pairing as a novel mechanism stabilizing protein-protein complexes.

Efficient two-step synthesis of 3-halo-3-enals or 2-halo-2-alkenyl ketones from propargylic bromides via a unique cationic 1,2-aryl or proton shift in electrophilic addition reaction of 2,3-allenols with X+

The reaction of readily available 1-substituted 2,3-allenols with Br2, NBS, or I2 afforded the not-easily-available but synthetically useful 3-halo-3-alkenals or 2-halo-2-alkenyl ketones in good yields via a sequential electrophilic interaction of X+ with the allene moiety , a 1,2-aryl or proton shift, and a H+-elimination process; the structures of the products were established by X-ray diffraction study.

Contact allergy caused by air oxidation of common materials – diagnosis and prevention

When considering the allergenic activity of a compound not only the possibility of bioactivation by skin metabolism but also air activation by autoxidation must be taken into account.Natural compounds (terpenes) easily oxidize at air exposure. They are found in products that are common causes of allergic contact dermatitis (ACD) i.e. colophony and fragrances.The introduction of oxygen enables the molecules to form antigens with skin proteins via a nucleophilic‐ electrophilic interaction or via a radical reaction. The latter mechanism seems to be important since the primary oxidation products, the hydroperoxides, are the most potent sensitizers formed. Oxidative decomposition at air exposure resulting in allergenic oxidation products is observed also for other common compounds e.g. ethoxylated fatty alcohols used as surfactants.It is important to test the patient with the offending compounds for diagnosis of ACD. A negative diagnosis can be due to failure in testing with the correct substances. In the case of air activated compounds, testing should not be performed with the pure substances but rather with the oxidation mixture or the most sensitizing oxidation products (the hydroperoxides). We have in multicenter‐studies shown that the common fragrance terpenes, limonene and linalool, are frequent sensitizers when oxidized. This is a challenge in clinical practice since such patch test materials are not easily standardized.Compounds, easily activated at air exposure, should be prevented from oxidative decomposition by addition of antioxidants and proper handling and storage. More research is needed in this area.

Plant uptake and transport models for neutral and ionic chemicals.

Models for predicting uptake and transport of chemicals in plants are applied in pesticide design, risk assessment, and environmental biotechnology. This review considers the theoretical basics of the most popular models, and discusses what they have in common. The line is drawn between models for neutral compounds, and models for weak and strong electrolytes. Neutral Compounds. Neutral compounds undergo only very few processes inside plants (lipophilic interactions, metabolism), in contrast to weak electrolytes. The models developed for neutral compounds are widely applied in the risk assessment of environmental contaminants, but are not of much use for weak electrolytes, such as pesticides. Weak electrolytes. A very important process for weak electrolytes is the 'ion trap', which traps chemicals that dissociate inside plant cells. This is considered in the popular models of Kleier, Satchivi and Briggs. Other relevant processes for electrolytes are electrophilic interactions, speciation and complex formation. None of the currently used models considers these processes. The accuracy of models for neutral compounds is satisfactory, but the prediction of electrolyte behavior inside plants is still quite difficult due to gaps in knowledge.

Role of initial complexes in 1,2-addition reactions of disilene derivatives

Mechanisms of four 1,2-addition reactions, H2Si=SiHMe + H2O, H2Si=SiHF + H2O, H2Si=SiH(C≡CH) + H2O, H2Si=SiH(NH2) + HF, were investigated in detail by the ab initio MO method using a recent approach combined with frontier MO theory. Twelve reaction pathways were found. The initial step of each reaction is the formation of a weakly bonded complex. According to the structure and the charge distribution of the complexes, the reactions are categorized into two types. Reactions starting from electrophilic interaction between the LUMO of water (or hydrogen fluoride) and the HOMO of disilene always result in syn-adducts. On the other hand, nucleophilic interaction between the HOMO of the water and the LUMO of disilene leads both syn and anti adducts. Depending on the acidity of the reagent and the charge on the silicon to be attacked, the reactions proceed in simple one-step mechanisms or in two-step ones via a Lewis-type complex. The paired interacting orbitals of the initial complexes were examined in order to predict the reaction pathways.

Structure–activity relationships and response–surface analysis of nitroaromatics toxicity to the yeast ( Saccharomyces cerevisiae)

Inhibition of growth of the yeast Saccharomyces cerevisiae ( C miz, the minimum concentration that produced a clear inhibition zone within 12 h) for 24 nitroaromatic compounds was investigated and a quantitative structure–activity relationship (QSAR) developed based on hydrophobicity expressed as the 1-octanol/water partition coefficient in logarithm form, log K ow, electrophilicity based on the energy of the lowest unoccupied orbital ( E lumo). All nitrobenzene derivatives exhibited enhanced reactive toxicity than baseline. The toxicities of mono-nitrobenzenes and di-nitrobenzenes were elicited by different mechanisms of toxic action. For mono-nitro-derivatives, both significant log K ow based and strong E lumo-dependent relationships were observed indicating that their toxicities were affected both by the penetration process and the interaction with target sites of interaction. The toxicities of di-nitrobenzenes were greater than mono-nitrobenzenes and no log K ow-dependent but highly significant E lumo-based relationship was obtained. This suggests that toxicity of di-nitrobenzenes was highly electrophilic and involved mainly their in vivo electrophilic interaction with biomacromolecules. In an effort to model the elevated toxicity of all nitrobenzenes, a response–surface analysis was performed and this resulted in a highly predictive two-variable QSAR without reference to their exact mechanisms ( C miz=0.41 log K ow−0.89 E lumo−0.46, r 2=0.87, Q 2=0.86, n=24).

Synthesis of ethylene carbonate from supercritical carbon dioxide/ethylene oxide mixture in the presence of bifunctional catalyst

Ethylene carbonate was rapidly synthesized from supercritical carbon dioxide/ethylene oxide mixture by using as catalyst the system of tetradentate schiff-base aluminum complexes (designated as SalenAlX) coupling with a quaternary ammonium or phosphonium salt. The high rate of reaction was attributed to rapid diffusion and high miscibility of ethylene oxide in supercritical carbon dioxide under employed conditions. Various reaction periods present different formation rate of ethylene carbonate, mainly due to the existence of phase change during the reaction. The synergistic effect of the binary catalyst for ring-opening of ethylene oxide results from nucleophilicity of highly reactive anions of quaternary salts and the electrophilic interaction of SalenAlX with ethylene oxide. The activation of CO 2 was generally initiated by nucleophilic attack of the alcoholate(OCH 2CH 2BrNBu 4) at the carbon atom of CO 2, and weak interaction between the central metal ion of SalenAlX and the lone pairs of one oxygen atom of CO 2. It resulted in the insertion of CO 2 to AlO bond of Salen(X)AlOCH 2CH 2BrN( n-Bu) 4 or SalenAlOCH 2CH 2X to form linear carbonate which was transformed into ethylene carbonate by intramolecular substitution of halides. The experimental results demonstrate that supercritical carbon dioxide could be used as not only an environmentally benign solvent but also a carbon precursor in synthesis.

Structure-Toxicity Analyses of Tetrahymena Pyriformis Exposed to Pyridines - An Examination Into Extension of Surface-Response Domains

A selection of mechanistically diverse substituted pyridines were tested in the Tetrahymena pyriformis population growth impairment assay. The response-surface approach was used to derive multiple-regression type structure-toxicity relationships between T. pyriformis population growth impairment toxicity data (log(IGC−1 50)) and the 1-octanol/water partition coefficient (log K ow) and one of two different descriptors of molecular orbital interaction: energy of the lowest unoccupied molecular orbital (E LUMO) and maximum acceptor superdelocalizability (S MAX). A statistically robust model (log(IGC−1 50) = −3.91 + 0.50(log K ow) + 10.70(S MAX); n = 83, r 2 = 0.756, s = 0.38, F = 124, Pr > F = 0.0001) was developed with S MAX as the indicator of reactivity. This model was not statistically different in fit from the model (log(IGC−1 50) = −1.19 + 0.56(log K ow) −0.61(E LUMO); n = 86, r 2 = 0.749, s = 0.38, F = 124, Pr > F = 0.0001) derived using the alternative descriptor of electrophilic interaction. Compounds with high residual values were removed. An examination of these outliers from both response-surfaces, revealed that pyridines substituted in the 2-position with electron-releasing groups and halogenated nitro-substituted pyridines did not fit the above models well. A third group of outliers, the mono-halogenated pyridines, was unique to the S MAX response-surface, which are neutral narcotics with potentially high volatility. A comparison of observed and predicted toxicities for a validation set of pyridines for the S MAX surface (log (observed IGC−1 50) = 0.10 + 0.75(log(predicted IGC−1 50)); n = 10, r 2 = 0.662, s = 0.49, F = 15.7, Pr > F = 0.004) and the E LUMO surface (log(observed IGC−1 50) = 0.17 + 0.80(log(predicted IGC−1 50)); n = 10, r 2 = 0.707, s = 0.45, F = 19.3, Pr > F = 0.002) validated the above models, with the fit in the same range as the parent model. The model derived with S MAX was compared to the response-surface derived for substituted benzenes (log(IGC−1 50) = −3.47 + 0.50(log K ow) + 9.85(S MAX); n = 197, r 2 = 0.816, s = 0.34, F = 429, Pr > F = 0.0001) revealing the similarities in slope and intercept between the two response-surfaces. The model fit was poorer for the pyridine surface, which may be a factor of increased reactivity due to the presence of nitrogen and the associated pair of unshared electrons in the ring not present in benzene. However, the similarity of the pyridine and benzene response-surfaces suggests that the domain defined for benzenes may be extended to encompass nitrogen heterocyclic pyridines.

N-Méthyl succinimide

The molecular structure of 1-methylpyrrolidine-2,5-dione, C5H7NO2, corresponds to the dicarbonyl tautomer with an envelope ring conformation. The packing is stabilized by weak intermolecular hydrogen bonds and presents push–pull nucleophile–electrophile interactions of the carbonyl groups.

N-Méthyl succinimide

The molecular structure of 1-methylpyrrolidine-2,5-dione, C5H7NO2, corresponds to the dicarbonyl tautomer with an envelope ring conformation. The packing is stabilized by weak intermolecular hydrogen bonds and presents push–pull nucleophile–electrophile interactions of the carbonyl groups.

Synthesis of acetic acid from methanol alone by homogeneous metal complex catalyst. Part 4 . In-situ formation of catalyst species and halogen effect in the RuCl 3·3H 2O–SnX 2 (X=F, Cl, Br, I) composite system

Highly selective formation of methyl acetate has been found possible from methanol alone using the catalyst generated in situ from RuCl 3·3H 2O and SnCl 2 as well as SnX 2 (X=F, Br, I). The reaction did not occur in the absence of SnCl 2 added and the optimum [Sn]/[Ru] ratio appeared at about 16. The halogen effect showed the order of SnF 2>SnCl 2>SnBr 2>SnI 2, which indicates the importance of cationic character of Ru(II) center to facilitate its electrophilic interaction with β-hydrogen of Ru–OCH 3 intermediate in the rate-limiting dehydrogenation step.

Raman study of solvent-solute interactions in solutions of mercury(II)-thiocyanate complexes

Raman spectra of the Hg(SCN)2, [Hg(SCN)3]- and [Hg(SCN)4]2- complex species in solution were investigated for 10 donor solvents in the ν(CN) and ν(CS) wavenumber regions. Attempts were made to relate the solvent donor strength to overall vibrational properties of the complexes. A good correlation of ν(CN) with ν(HgS) and consequently with solvent donor properties was found in solutions of Hg(SCN)2 and [Hg (SCN)3]-. Wavenumber differences Δν˜(CN), calculated as the difference between wavenumbers of coordinated and free SCN- ligands, correlate well with the solvent donor strength scale, DS. The Δν˜(CN) values for Hg(SCN)2 and [Hg(SCN)3]- can be used as an indicator of solvent donor capacity. Data derived from the Δν(CN) shifts show a better correlation with solvent donor ability than those obtained from the ν(CS) wavenumber. The spectral properties of [Hg(SCN)4]2- complex depend only on the electrophilic properties of the solvent and not on its donor strength, because solvent molecules cannot penetrate into the first coordination sphere and donate an electron pair to Hg(II). Solvent electrophilic interaction with coordinated thiocyanate is proportional to its acceptor number. ©1998 John Wiley & Sons, Ltd.