Nucleophile-electrophile Interactions Research Articles

Backside versus Frontside SN2 Reactions of Alkyl Triflates and Alcohols.

Nucleophilic substitution reactions are elementary reactions in organic chemistry that are used in many synthetic routes. By quantum chemical methods, we have investigated the intrinsic competition between the backside SN2 (SN2-b) and frontside SN2 (SN2-f) pathways using a set of simple alkyl triflates as the electrophile in combination with a systematic series of phenols and partially fluorinated ethanol nucleophiles. It is revealed how and why the well-established mechanistic preference for the SN2-b pathway slowly erodes and can even be overruled by the unusual SN2-f substitution mechanism going from strong to weak alcohol nucleophiles. Activation strain analyses disclose that the SN2-b pathway is favored for strong alcohol nucleophiles because of the well-known intrinsically more efficient approach to the electrophile resulting in a more stabilizing nucleophile-electrophile interaction. In contrast, the preference of weaker alcohol nucleophiles shifts to the SN2-f pathway, benefiting from a stabilizing hydrogen bond interaction between the incoming alcohol and the leaving group. This hydrogen bond interaction is strengthened by the increased acidity of the weaker alcohol nucleophiles, thereby steering the mechanistic preference toward the frontside SN2 pathway.

Local nucleophile-electrophile interactions in [3+2] cycloaddition reactions between benzonitrile N-oxide and selected conjugated nitroalkenes in the light of MEDT computational study

Local nucleophile-electrophile interactions in [3+2] cycloaddition reactions between benzonitrile N-oxide and selected conjugated nitroalkenes in the light of MEDT computational study

Synergistic effects of combinatorial chitosan and polyphenol biomolecules on enhanced antibacterial activity of biofunctionalized silver nanoparticles

The present study reports the synergistic antibacterial activity of biosynthesized silver nanoparticles (AgNPs) with the aid of a combination of chitosan and seaweed-derived polyphenols as a green synthetic route. Under optimum synthesis conditions, the rapid color change from yellowish to dark brown and UV–visible absorption peak at 425 confirmed the initial formation of AgNPs. DLS, TEM, XRD, and EDX analyses revealed the spherical shape of pure biogenic AgNPs with a mean diameter size of 12 nm ± 1.5 nm, and a face-centered cubic crystal structure, respectively. FTIR and TGA results indicated the significant contribution of chitosan and polyphenol components into silver ions bioreduction and thermal stability of freshly formed AgNPs. Long-term colloidal stability of AgNPs was obtained after 6-month storage at room temperature. The bio-prepared AgNPs possessed a negative surface charge with a zeta potential value of − 27 mV. In contrast to naked chemical silver nanoparticles, the green Ag nanosamples demonstrated the distinct synergistic antibacterial in vitro toward all selected human pathogens presumably due to the presence of high content of biomolecules on their surface. The results show that synergy between chitosan and polyphenol results in the enhancement of bactericidal properties of biogenic AgNPs. We also highlighted the underlying mechanism involved in AgNPs formation based on nucleophile–electrophile interaction.

A novel High-Gravity AOP process for enhanced NOx attenuation using alkaline H2O2 as a strong oxidizing reagent: Reaction mechanisms and kinetics

A novel High-Gravity Advanced Oxidation Process (HiGee-AOP) using basic H2O2 solution as a liquid oxidizing reagent was examined for enhanced NOx removal efficiency in this study. At ambient temperature and optimal conditions, the process achieved a 99% removal of the inlet 1000 ppm NO. Spectroscopic experiments and radical-quenching tests indicated that the nucleophilic hydroperoxyl anion (−OOH) dissociated from H2O2 was the strongest reactive oxygen species (ROS) responsible for NO oxidation in alkaline H2O2, producing peroxynitrite (ONOO−) as detected by Fluorescence Spectroscopy. A mass transfer model coupling the reaction kinetics and gas diffusion under high liquid-film renewal conditions was established to simulate the HiGee-AOP process for NO absorption, and it achieved a model-prediction accuracy of within 10% of experimental data. It is speculated that the improved NO removal efficiency by the HiGee-AOP/alkaline H2O2 process stems from the enhanced mass transfer of NO in the heterogeneous reaction system provided by HiGee and the strong affinity of −OOH to NO. Oxidation of NO by −OOH may proceed first to form the [NO⋯OOH]− intermediate due to a strong nucleophile–electrophile interaction, which is followed by an electron transfer within the intermediate producing ONOO− and ultimately as nitrate.

Synthesis, structural characterization and comparison of experimental and theoretical results by DFT level of molecular structures of 1,2,3-triazoles derived from 5-chloroisatin

This work deals about the synthesis, NMR characterization and the density functional method (B3LYP) with the 6-31G basis set of 1, 3-dipolar cycloaddition reactions between the two azides as dipoles and propargylchloroisatin as dipolarophile. Furthermore, DFT calculations were used to study the nucleophile–electrophile interactions of the azides and dipolarophile and also the stability between the regioisomers comparing their energy. Our calculations are in a good agreement with the experimental findings.

Nucleophile-electrophile interactions in the reaction of oxiranes with carboxylic acids in the presence of tertiary amines

The nucleophile-electrophile interactions in the reaction system “N,N-dimethylaniline – acetic acid – epichlorohydrin” have been investigated using kinetic methods and computer modeling. The observed orders of reactions have been determined for the overall reaction as well as for individual stages. The kinetic equations have been proposed; the activation parameters of the reactions have been evaluated. The behavior of the initial (amine) and intermediate (carboxylate) nucleophiles has been detailed in reaction pathway. Amine reacts with oxirane activated by acidic reagent while carboxylate-anion—with both activated and nonactivated epichlorohydrin. The mechanism of oxirane ring opening by acid reagent in the presence of tertiary amine has been proposed, which comprise parallel-consecutive compensation stages of reaction product formation. It has been demonstrated that the observed reaction order with respect to acid reactant depends upon the nature of electrophilic reagent (activated/nonactivated oxirane) and the ratio of the rates of compensation stages.

Experimental and Theoretical DFT Study on Synthesis of Sterically Crowded 2,3,3,(4)5‐Tetrasubstituted‐4‐nitroisoxazolidines via 1,3‐Dipolar Cycloaddition Reactions Between Ketonitrones and Conjugated Nitroalkenes

1,3‐Dipolar cycloaddition reactions between ketonitrones (1a, 1b, 1c, 1d, 1e) and β‐substituted nitroalkenes (2a, 2b, 2c, 2d) proceed under mild conditions, with complete regioselectivity, and lead with high yields to sterically crowded 2,3,3,5‐tetrasubstituted‐4‐nitroisoxazolidines (3a, 3b, 3c, 3d, 3e, 3f). Reaction course may be interpreted on the basis of nature of local, nucleophile–electrophile interactions. Moreover, density functional theory (DFT) simulations of reaction paths suggest that these reactions should be considered as polar, “one‐step two‐stage” cycloadditions. Subsequently, it has been found that similar reactions between ketonitrones and α‐substituted nitroalkenes do not allow to obtain the expected 2,3,3,4‐tetrasubstituted‐4‐nitroisoxazolidines.

Specific nucleophile–electrophile interactions in nucleophilic aromatic substitutions

We herein report results obtained from an integrated experimental and theoretical study on aromatic nucleophilic substitution (S(N)Ar) reactions of a series of amines towards 1-fluoro-2,4-dinitrobenzene in water. Specific nucleophile-electrophile interactions in the title reactions have been kinetically evaluated. The whole series undergoes S(N)Ar reactions where the formation of the Meisenheimer complex is rate determining. Theoretical studies concerning specific interactions are discussed in detail. It is found that H-bonding effects along the intrinsic reaction coordinate profile promote the activation of both the electrophile and the nucleophile. Using these results, it is possible to establish a hierarchy of reactivity that is in agreement with the experimental data. Second order energy perturbation energy analysis highlights the strong interaction between the ortho-nitro group and the acidic hydrogen atom of the amine. The present study strongly suggests that any theoretical analysis must be performed at the activated transition state structure, because the static model developed around the reactant states hides most of the relevant specific interactions that characterize the aromatic substitution process.

First‐Principles Prediction of Nucleophilicity Parameters for π Nucleophiles: Implications for Mechanistic Origin of Mayr’s Equation

Quantitative nucleophilicity scales are fundamental to organic chemistry and are usually constructed on the basis of Mayr's equation [log k=s(N+E)] by using benzhydrylium ions as reference electrophiles. Here an ab initio protocol was developed for the first time to predict the nucleophilicity parameters N of various pi nucleophiles in CH(2)Cl(2) through transition-state calculations. The optimized theoretical model (BH&HLYP/6-311++G(3df,2p)//B3LYP/6-311+G(d,p)/PCM/UAHF) could predict the N values of structurally unrelated pi nucleophiles within a precision of ca. 1.14 units and therefore may find applications for the prediction of nucleophilicity of compounds that are not readily amenable to experimental characterization. The success in predicting N parameters from first principles also allowed us to analyze in depth the electrostatic, steric, and solvation energies involved in electrophile-nucleophile reactions. We found that solvation does not play an important role in the validity of Mayr's equation. On the other hand, the correlations of the E, N, and log k values with the energies of the frontier molecular orbitals indicated that electrostatic/charge-transfer interactions play vital roles in Mayr's equation. Surprising correlations observed between the electrophile-nucleophile C-C distances in the transition state, the activation energy barriers, and the E and N parameters indicate the importance of steric interactions in Mayr's equation. A method is then proposed to separate the attraction and repulsion energies in the nucleophile-electrophile interaction. It was found that the attraction energy correlated with N+E, whereas the repulsion energy correlated to the s parameter.

Regio- and stereoselectivity of [2+3]cycloaddition of nitroethene to (Z)-N-aryl-C-phenylnitrones

The cycloaddition reactions of nitroethene to (Z)-N-aryl-C-phenylnitrones lead to mixtures of stereoisomeric cis- and trans-2-aryl-4-nitro-3-phenylisoxazolidines. Regioselectivity of these reactions is determined by the character of nucleophile–electrophile interactions, while stereoselectivity is determined by the steric factors and the character of secondary orbital interactions.

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)

Supramolecular Chemistry of Halogens: Complementary Features of Inorganic (M−X) and Organic (C−X‘) Halogens Applied to M−X···X‘−C Halogen Bond Formation

Electronic differences between inorganic (M-X) and organic (C-X) halogens in conjunction with the anisotropic charge distribution associated with terminal halogens have been exploited in supramolecular synthesis based upon intermolecular M-X...X'-C halogen bonds. The synthesis and crystal structures of a family of compounds trans-[MCl(2)(NC(5)H(4)X-3)(2)] (M = Pd(II), Pt(II); X = F, Cl, Br, I; NC(5)H(4)X-3 = 3-halopyridine) are reported. With the exception of the fluoropyridine compounds, network structures propagated by M-Cl...X-C halogen bonds are adopted and involve all M-Cl and all C-X groups. M-Cl...X-C interactions show Cl...X separations shorter than van der Waals values, shorter distances being observed for heavier halogens (X). Geometries with near linear Cl...X-C angles (155-172 degrees ) and markedly bent M-Cl...X angles (92-137 degrees ) are consistently observed. DFT calculations on the model dimers {trans-[MCl(2)(NH(3))(NC(5)H(4)X-3)]}(2) show association through M-Cl...X-C (X not equal F) interactions with geometries similar to experimental values. DFT calculations of the electrostatic potential distributions for the compounds trans-[PdCl(2)(NC(5)H(4)X-3)(2)] (X = F, Cl, Br, I) demonstrate the effectiveness of the strategy to activate C-X groups toward halogen bond formation by enhancing their electrophilicity, and explain the absence of M-Cl...F-C interactions. The M-Cl...X-C halogen bonds described here can be viewed unambiguously as nucleophile-electrophile interactions that involve an attractive electrostatic contribution. This contrasts with some types of halogen-halogen interactions previously described and suggests that M-Cl...X-C halogen bonds could provide a valuable new synthon for supramolecular chemists.

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.

The role of nucleophile--electrophile interactions in the unimolecular and bimolecular gas-phase ion chemistry of peptides and related systems.

This account describes the experimental tools (multi-stage mass spectrometric experiments, isotopic and structural labelling, kinetics and theoretical modelling) and physical organic concepts (influence of charge, the intermediacy of ion-molecule complexes, etc.) that can be used to unravel the mechanisms of gas-phase unimolecular and bimolecular ionic reactions of peptides. The role that nucleophile-electrophile interactions play in charge-directed reactions is highlighted for both unimolecular fragmentations (examples are illustrated for protonated sulfur-containing amino acids and peptides) and bimolecular ion-molecule reactions which cleave peptide bonds.

Five-membered ring formation in unimolecular reactions of peptides: a key structural element controlling low-energy collision-induced dissociation of peptides.

Unimolecular fragmentation reactions of peptides in low-energy collision-induced dissociation are reviewed in the mechanistic context of five-membered ring formation. This structure of intermediates or of fragment ions is recognized as a key element that governs unimolecular peptide fragmentation within the structural framework determined by the peptide backbone and its side-chains. A collection of collision-induced dissociation reactions is presented covering (i) b-ion formation, (ii) the fragmentation of N-terminally acylated peptides, (iii) neutral loss of the C-terminal amino acid in alkali or silver cationized peptides, (iv) the fragmentation of isoAsp-containing peptides and (v) the fragmentation of negatively charged Asp- or Glu-containing peptides. It appears that for all possible nucleophile-electrophile interactions leading to a five-membered ring structure an associated unimolecular peptide fragmentation reaction can be observed.

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.

Nucleophile–Electrophile Interactions in 1,8-Disubstituted Naphthalenes: Structures of Three 1-Naphthaldehydes and a 1-Naphthyl Methyl Ketone

4,8-Dimethoxy-5-(tosyloxy)-1-naphthaldehyde (1) and 8-methoxy-5-(tosyloxy)-1-naphthaldehyde (2) crystallize such that the formyl groups approach coplanarity with the naphthalene rings. 4′,8′-Dimethoxy-5′-(tosyloxy)-1′-acetonaphthone (4), however, crystallizes such that the acetyl group approaches orthogonality to the naphthalene ring. In all three compounds the methoxy group and carbonyl groups exhibit a leaning effect typical of nucleophile–electrophile interactions in 1,8-disubstituted naphthalenes. 8-(Benzoyloxy)-4-methoxy-1-naphthaldehyde (3) crystallizes with the formyl group nearly coplanar to the naphthalene ring and does not exhibit the leaning effect. It is suggested that these structural differences are largely due to differences in the steric requirements of formyl and acetyl groups.

Mechanistic study of the acid catalyzed formation and hydrolysis of MTBE in nonpolar media

The acid catalyzed hydrolysis of MTBE using p-toluenesulfonic acid was studied in nonpolar medium to ascertain the effect of nucleophile upon reaction. NMR measurements showed protonation of both MTBE and methanol by p-toluenesulfonic acid in nonpolar medium but no nucleophile-electrophile interaction of MTBE with p-toluenesulfonic acid methyl ester as potential nucleophile. Addition or in situ generation of a nucleophile did not accelerate the reaction. At low conversions and low catalyst concentration the reaction exhibited pseudo zero order with respect to reactant concentration and second order with respect to catalyst concentration. The results suggest protonation of MTBE in a fast preequilibrium step in which the acid catalyst exhibits cooperative effect. No nucleophilic assistance in the transition state of MTBE hydrolysis in nonpolar medium occurs.

ChemInform Abstract: Electron Transfer and Charge Transfer: Twin Themes in Unifying the Mechanisms of Organic and Organometallic Reactions

The broad varieties of organic and organometallic reactions merge into a common unifying mechanism by considering all nucleophiles and electrophiles as electron donors (D) and electron acceptors (A), respectively. Comparison of outer-sphere and inner-sphere electron transfers with the aid of Marcus theory provides the thermochemical basis for the generalized free energy relationship for electron transfer (FERET) in Equation (37) and its corollaries in Equations (43) and (44) that have wide predictive applicability to electrophilic aromatic substitutions, olefin additions, organometallic cleavages, etc. The FERET is based on the conversion of the weak nucleophile–electrophile interactions extant in the ubiquitous electron donor—acceptor (EDA) precursor complex [D, A] to the radical ion pair [D⊕, A⊖], for which the free energy change can be evaluated from the charge-transfer absorption spectra according to Mulliken theory. FERET analysis thus indicates that the charge-transfer ion pairs [D⊕, A⊖] are energetically equivalent to the transition states for nucleophile/electrophile transformations. The behavior of such ion pairs can be directly observed immediately following the irradiation of the charge-transfer bands of various EDA complexes with a 25-ps laser pulse. Such studies confirm the radical ion pair [Arene⊕, NO2] as a viable intermediate in electrophilic aromatic nitration, as presented in the electron-transfer mechanism between arenes and the nitryl cation (NO) electrophile.