Mechanism Of Nucleophilic Substitution Reactions Research Articles

Mechanisms and energetics of calcium aluminosilicate glass dissolution through ab initio molecular dynamics-metadynamics simulations

The dissolution of silicate glasses has implications in diverse fields ranging from the immobilization of radioactive waste to the development of sustainable alternatives to Portland cement. Here, we used ab initio molecular dynamics simulations biased with well-tempered metadynamics to study Si-O-T bridge dissociation in calcium aluminosilicate glasses, crucial for understanding their dissolution. In a departure from the conventional Michalske-Freiman model, our findings reveal a nucleophilic substitution reaction mechanism characterized by a short-lived, 5-fold coordinated Si intermediate or transition state, depending on the Si bridge coordination, with a near-trigonal bipyramidal geometry. We find that the reorganization required for reaching this state causes the activation energy barriers to be dependent on the Si bridge coordination, with Si Q3 species serving as the rate-limiting step in the dissolution reaction. Our findings not only challenge long-standing theoretical models but also pave the way for more accurate and comprehensive frameworks for understanding the dissolution of silicate glasses in various applications.

Sequential hydrothermal extraction chemistry for recovering bioactives from potato peels

Sequential Hydrothermal Extraction (SeqHTE) provides a versatile platform to produce phytochemicals from potato peels. However, there is a lack of understanding of the SeqHTE reaction mechanisms and pathways. In this study, the chemistry of SeqHTE for the recovery of valuable bioactives from peels was investigated. The slightly more polar conditions of the first stage of SeqHTE favored the retrieval of free form polyphenols and extraction of polysaccharides and glycoalkaloids. In contrast, the second stage displayed preferential recovery of bound-type polyphenols and extraction of solanidine. The acid-catalyzed acyl bimolecular and the unimolecular nucleophilic substitution reaction mechanisms were identified. Additionally, the kinetics indicated that the ideal conditions to enhance bioactive recovery while reducing degradation were a temperature range from 140 ℃ to 160 ℃ and 170–190 ℃ for the first and second stage, respectively. The results demonstrated that SeqHTE offers a suitable environment to break down the peels for the recovery of structurally diverse bioactives.

Online discovery of the molecular mechanism for directionally detoxification of Fuzi using real-time extractive electrospray ionization mass spectrometry

Ethnopharmacological relevanceAconitum carmichaelii Debeaux, a famous traditional medicinal herb for collapse, rheumatic fever, and painful joints, always raises global concerns about its fatal toxicity from toxic alkaloids when improperly processed. Therefore, it is urgent to clarify the internal molecular mechanism of processing detoxification on Aconitum and develop simple and reliable approaches for clinical application, which is also of great significance to the rational medicinal use of Aconitum. Aim of the studyThe study aimed at developing a complete molecular mechanism exploration strategy in complex medicinal herb decocting system, clarifying the internal molecular mechanism of processing detoxification on Aconitum, and exploring valid approaches for detoxification. Materials and methodsAconiti Lateralis Radix Praeparata (Fuzi) was selected as the model for exploring the complex Aconitum detoxification mechanism using an advanced online real-time platform based on extractive electrospray ionization mass spectrometry. The methods realized the sensitive capture of dynamic trace intermediates, accurate qualitative and quantitative analysis, and real-time and long-term monitoring of multi-components with satisfactory accuracy and resistance to complex matrices. ResultsComponents in the complex Aconitum decocting system were real-timely characterized and fat meat was discovered and verified to directionally detoxify Aconitum while reserving the therapy effect. More importantly, the dynamic detoxification mechanism in the chemically complex Aconitum decoction was molecularly profiled. A novel reaction pathway based on nucleophilic substitution reaction mechanism was proposed. As confirmed by the theoretic calculations at DFT B3LYP/6-31G (d) levels, fatty acids (e.g., palmitic acid) acted as a green, cheap, and high-performance catalyst and promote the decomposition of toxic diester alkaloids to non-toxic and active benzoyl-monoester alkaloids through the discovered mechanism. ConclusionThe study exposed a novel detoxification molecular mechanism of Aconitum and provided an effective method for the safe use of Aconitum, which could effectively guide the development of traditional processing technology and compatibility regulation of the toxic herb and had great value to the modernization and standardization development of traditional medicine.

Influence of temperature for the azide displacement in benzodiazepine derivatives: Experimental and DFT study of competing SN1, SN2 and double SN2 reaction pathways

Molecules carrying the azido functionality are widely used as intermediates in medicinal chemistry. Pyrrolobenzodiazepines are molecules with a broad range of interesting pharmacological properties. Due to the wide importance of azido-PBD as a key intermediate in many synthetic pathways, in this work we have investigated the effect of a variety of experimental parameters on the mechanism of nucleophilic substitution reaction for introducing an azide group into the PBD scaffold. This study was carried out by combined experimental and DFT approaches, showing that SN2 and double SN2 pathways are possible and highly dependent on the reaction temperature.

Nucleophilic substitution reaction mechanisms: An atomic-molecular perspective on chemical speciation and transport properties in silicate melts

There has been no systematic attempt to determine if nucleophilic substitution (SN) reactions proceed in silicate melts, even though they commonly occur in gaseous and liquid phases containing C, Si, P, and Ge centered tetrahedra. The oversight is here rectified by providing such an analysis. Conditions required for nucleophilic substitution reactions to occur are: (1) the presence of nucleophiles (Lewis bases) which in silicate melts are bridging oxygen (BO), non-bridging oxygen (NBO−) and free oxygen (O2−); (2) the presence of tetrahedra (Q species) with strongly electrophilic centers (i.e., Si atoms); (3) the presence of Si transition species containing pentahedrally coordinated Si (i.e., VSi species); (4) rapid reaction rates among tetrahedral species. All conditions are met for silicate melts. For example, the strong nucleophile, NBO− exists at high temperatures in binary alkali and alkaline earths silicate melts due primarily to thermal agitation whereby some Si-NBO-M bonds are ruptured to produce the nucleophilic Si-NBO− moiety. This nucleophile attacks the Si center of an adjacent tetrahedron to form a SiO bond thereby producing a VSi transition species. The transition species decomposes by rupture of another SiO bond located on the polar opposite side of the transition species. Three types of SN reaction are recognized and all involve VSi transition species. They are NBO-BO exchange reactions (e.g., Q3 + Q4 → Q4 + Q3), disproportionation reactions (e.g., 2Q3 → Q4 + Q2) and polymerization reactions (e.g., Q3 → Q4 + 1/2O2−). H2O and OH− are also nucleophiles and their reaction with Q species proceeds via SN reaction mechanisms, and may cause depolymerization of melts. Hydrogen bonding of H2O to BO and NBO may also occur, as in ice and water, thereby enhancing H2O solubilities in melts. These latter reactions should neither depolymerize melts nor affect NBO/T values.The diffusivity of Si and O in melts, anionic conductivity and chemical speciation (e.g. Q species abundances) proceed via one or other SN reaction, with the transition species assuming a critical role in diffusivity, conductivity and viscosity. The SN reaction mechanism, coupled with transition state theory, provides explanations for: (1) the formation of pentahedrally coordinated Si (VSi) and its apparent restriction to highly siliceous glasses; (2) the remarkably similar diffusivities of Si and O in silicate melts; (3) the ‘jump distance’ (α) of the Eyring equation, which by the SN mechanism is ~3.5 Å (i.e., diameter of the VSi transition species); (4) the minimum number of monomeric units (i.e., Q species) involved in the ‘cooperative region’ of the Adam-Gibbs equation; and (5) the quantitative distribution of Q species in Na silicate glasses up to ~50 mol% Na2O.

Crystal structure of adenylate kinase from an extremophilic archaeon Aeropyrum pernix with ATP and AMP.

The crystal structure of an adenylate kinase from an extremophilic archaeon Aeropyrum pernix was determined in complex with full ligands, ATP-Mg2+ and AMP, at a resolution of 2.0 Å. The protein forms a trimer as found for other adenylate kinases from archaea. Interestingly, the reacting three atoms, two phosphorus and one oxygen atoms, were located almost in line, supporting the SN2 nucleophilic substitution reaction mechanism. Based on the crystal structure obtained, the reaction coordinate was estimated by the quantum mechanics calculations combined with molecular dynamics. It was found that the reaction undergoes two energy barriers; the steps for breaking the bond between the oxygen and γ-phosphorus atoms of ATP to produce a phosphoryl fragment and creating the bond between the phosphoryl fragment and the oxygen atom of the β-phosphate group of ADP. The reaction coordinate analysis also suggested the role of amino-acid residues for the catalysis of adenylate kinase.

The Syntheses, Characterization and Crystal Structures of a Series of Heterocyclic β-Diketones and Their Isoxazole Compounds.

In the field of coordination chemistry, the introduction of heterocyclic substituents into the structure of β-diketone enables ligand to produce multiple coordination sites. The adoption of small steric oxime group into the structure of heterocyclic β-diketone by Schiff-base condensation will further increase coordination sites and facilitate the generation of polynuclear structures. A series of β-diketones (2a-2c) containing different heterocycles such as pyridine, thiophene and furan and their corresponding isoxazole compounds (3a-3c) were synthesized. The Claisen condensations were investigated in a solvent-free rheological phase system at room temperature to obtain heterocyclic β-diketones 2a-2c, which further reacted with hydroxylamine hydrochloride to obtain heterocyclic isoxazoles 3a-3c. All these compounds were well characterized by EA, IR, 1H NMR and X-ray crystal diffraction to confirm the structures. Synthetic mechanisms of compounds and the effects of different heterocycles on reactivity were discussed deeply. 1H NMR indicated that these β-diketones do not exist as a total diketonic form but an equilibration between diketone and enol forms in CDCl3 solvent, in which the enol form accounts for 98.0% in 2a, 94.3% in 2b, 95.5% in 2c. While the crystal structures of 2a-2c showed that the reaction allows to isolate diketones in solid state. Crystal structures of 3a-3c showed that the neutral β-ketone oximes resonate and cyclize to form the target heterocyclic isoxazoles. SN1 nucleophilic substitution mechanism of Claisen ketoester condensation was proposed for the syntheses of 2a-2c, and SN1 single molecule nucleophilic substitution reaction mechanism was put forward for 3a-3c.

ASSESSMENT OF CANCER TARGETING POTENTIAL OF DOXORUBICIN CONJUGATED WITH SURFACE FUNCTIONALIZED MULTI-WALLED CARBON NANOTUBES

Our main aim in the present investigation was to assess the cancer targeting potential of doxorubicin conjugated with folic acid (FA), ethylene di-amine (EDA) and surface F- MWCNTs (FA-EDA-MWCNTs- DOX) conjugate employing on MCF-7 (breast cancer cell line) for efficient tumor targeting. We developed a highly effective novel targeted drug delivery based on DOX-conjugated with the surface of F-MWCNTs by using nucleophilic substitution reaction mechanism and evaluated in facile strategy for cancer treatment. The in vitro drug release study shows that the percentage of drug release under an acidic condition pH-5.4 is higher than that under normal physiological conditions. The FA-EDAMWCNTs- DOX nano-conjugate affords higher efficacy in tumor growth suppression due to its stealth nature and most preferentially taken up by cultured MCF-7 cells through receptor-mediated endocytosis mechanism. Fourier Transform Infrared Spectroscopy (FTIR), UV-Visible Spectroscopy, Nuclear Magnetic Resonance Spectroscopy (NMR) and Scanning Electron Microscopy (SEM) measurements clearly confirmed the functionalization & conjugation steps. The results concluded that developed watersoluble nano-conjugate might emerge as “safe and effective” nano-medicine in cancer treatment by minimizing the side effects with generally regarded as a safe prominence.

Mechanism of nucleophilic substitution reactions of 4-(4ˊ-nitro)phenylnitrobenzofurazan ether with aniline in acetonitrile.

Abstract Rate constants and activation parameters obtained for the nucleophilic aromatic substitution reactions (SNAr) of 4-substitutedphenoxy-7-nitrobenzoxadiazole (1) with aniline in acetonitrile at varying temperature using Nuclear Magnetic Resonance (NMR) techniques were reported. These results were compared with the theoretical study which identifies transformations and intermediates using Density Functional Theory (DFT).

Oxatriquinane Derivatives: A Theoretical Investigation of SN1-SN2 Reactions Borderline

This study investigated the nucleophilic substitution reaction mechanisms of 5 oxatriquinane derivatives, namely: oxatriquinane (OTQ), 1,4,7-trimethyloxatriquinane (TMO), 1,4,7-triethyloxatriquinane (TEO), 1,4,7-tri-iso-propyloxatriquinane (TIO) and 1,4,7-tri-tert-butyloxatriquinane (TTO). In addition to the G3 conformation (one with the substituent groups at 1,4 and 7 positions pointing into the plane of the paper) originally proposed by the previous workers, Mascal et al. in 2008 and Gunbas et al. in 2013, one more geometrical isomer was considered again for each of the derivatives, the 2G1 isomer (one in which only 2 of the 3 substituent groups at 1,4 and 7 positions are into the paper plane). Geometry optimization and determination of transition state properties of the conformers corresponding to each molecule (in the presence of azide ion, N3-) provided theoretical evidences on the possible reaction mechanisms. The 2G1 conformer for TTO was found to be unstable. The reactions of OTQ, TMO and TEO with azide ion (N3-) followed SN2 pathway, with SN1mechanism completely lacking. This finding is in agreement with the first set of reports published on this subject in 2008 and 2010 by Mascal’s group. For TIO (in the presence of azide ion), only the presence of SN1 mechanism could be proved without any observation of transition state (TS), even though, it possesses a 2G1 conformer. TTO surprisingly, showed marked evidence of SN1 mechanism also without any evidence of TS. The results obtained showed that OTQ derivatives up to TEO undergo nucleophilic substitution predominantly via SN2, and above which (i.e. for TIO and TTO) the mechanisms predominantly become SN1.

Recognition of nucleophilic substitution reaction mechanisms of carboxylic esters based on support vector machine

The nucleophilic substitution reactions of carboxylic esters (R1COOR2) follow 2 possible mechanisms, namely, stepwise mechanism and concerted mechanism. The reaction mechanism is affected by the structures of the nonleaving group (NLG, ie, R1), the leaving group (LG, ie, OR2) of carboxylic esters, and the nucleophiles (Nu). The traditional approach for the determination of reaction mechanism by dynamic experiments is not only laborious and time consuming but also only applicable for the situation with single structural factor variation. Benefiting from the ample existing kinetic data, this article aimed to construct a molecular structure-based classification model by support vector machine (SVM). The polarizability effect index of the NLG (PEI(NLG)), the pKa of the conjugate acid of the LG (pKa(LG)), and the pKa of the conjugate acid of the Nu (pKa(Nu)) were used to characterize the structural information of the 3 influencing factors, respectively. On the basis of these structural descriptors, the SVM classification model was established for the reaction mechanisms of 225 nucleophilic substitution reactions in the training set. The total prediction accuracy of 99.11% was achieved by 5-fold cross validation. Then the reaction mechanisms of 56 reactions in test set A were predicted by this SVM model, and the prediction accuracy was up to 98.21%. Furthermore, test set B consisting of 24 reactions were used as another external data set for prediction, where the reaction mechanisms were controversially reported by different studies. The prediction results of test set B by the SVM model built in this article were amazingly consistent with the conclusions drawn by Um et al.

A novel and highly efficient polymerization of sulfomethylated alkaline lignins via alkyl chain cross-linking method

AbstractA new family of water-soluble lignosulfonate polymers with ultrahigh molecular weight (Mw) was developed based on alkali lignin (AL) as starting material in a one-pot reaction in two steps: sulfomethylation of AL as raw material led to AL-S and this material was subsequently cross-linked via alkylation with 1,6-dibromohexane (alkAL-S). Gel permeation chromatography showed a significant increase of Mw from 5200 Da of AL-S to 201 000 Da of alkAL-S with high degree of alkylation. Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance spectroscopy and functional group analysis confirmed the efficient polymerization by a nucleophilic substitution reaction mechanism. Additionally, alkAL-S with high Mw showed unexpected viscosity-reducing effect, stability and good rheological properties on a low-rank coal-water slurry (CWS), which are even better than those obtained by naphthalene sulfonate formaldehyde (NSF) as additive. The adsorption properties of the new products were also characterized via a quartz crystal microbalance combined with dissipation monitoring (QCM-D method). Cross-linked structure, large steric hindrance from high Mw and suitable amphiphilic properties of alkAL-S polymers contribute together to the highly improved dispersion performances for CWS.

Alkyl Chain Cross-Linked Sulfobutylated Lignosulfonate: A Highly Efficient Dispersant for Carbendazim Suspension Concentrate

A new family of highly water-soluble alkyl chain cross-linked sulfobutylated lignosulfonates (AASLSs) with a three-dimensional network structure and naked alkyl sulfonic acid groups were readily prepared by using 1,4-butane sultone (BS) and C6H12Br2 by a one step reaction in water, which simultaneously improved the sulfonation degree and molecular weight. GPC, 1H NMR, FTIR and functional group content tests confirmed their cross-linked chemical structure and efficient nucleophilic substitution reaction mechanism. Furthermore, the dispersion properties of AASLSs in a carbendazim suspension concentrate (SC) system were investigated. AASLS4 with high molecular weights (Mw) and moderate sulfonation degrees showed suspensibility of 99% in 45% carbendazim SC after hot storage at 50 °C for 14 days. Meanwhile, AASLS4 also showed smaller SC particle size and better rheological performance than commercial lignosulfonate. The adsorption isotherms and ζ-potential of AASLSs on carbendazim SC particles were studied to ...

Attachment of Docetaxel to Multiwalled Carbon Nanotubes for Drug Delivery Applications

In this manuscript we report the development of multiwalled carbon nanotubes-docetaxel conjugate by covalent interaction, involving nucleophilic substitution reaction mechanism. The surface functionalization of nanotubes was carried out by enrichment of carboxylic groups with optimized oxidation treatment. The carboxyl groups were converted to acyl groups followed by covalent attachment of docetaxel to multiwalled carbon nanotubes with a cleavable ester linkage. The drug carbon nanotube conjugate was characterized by Fourier Transform Infra red, UV-Visible, Raman spectroscopy, Scanning and Transmission electron microscopy. The drug release from the conjugate was studied in vitro in phosphate buffers having pH 5, 6.8 and 7.4. It was demonstrated that conjugate showed drug release faster in acidic pH, which resembles the pH of cancerous cells, as compared to buffer of normal cell pH. This property would reduce the drug dosage thereby substantially benefit the antitumor effect and would boost significantly the applications of carbon nanotubes in the biomedicine field.

Perfluoro Allyl Fluorosulfate (FAFS): A Versatile Building Block for New Fluoroallylic Compounds

In this study we will present and discuss both the synthesis of CF2=CFCF2OSO2F (perfluoroallyl fluorosulfate, FAFS), focusing in particular on the important role of C3F6/SO3 ratio, reaction temperature and boron catalyst/SO3 ratio on FAFS’ yield and selectivity, as well as a wide variety of ionic and radical reactions possible with FAFS. We focused our attention on reactions of FAFS with aliphatic and aromatic alcohols, acyl halides, halides, H2O2, ketones and radicals whose synthesis and reaction mechanisms will be presented and discussed. Particular attention will be devoted to the novel diallyl-fluoroalkyl peroxide obtained. Factors such as pKa and Lowry and Pearson’s Hard/Soft Acid-Base Theory which determine the selectivity between Addition/Elimination vs. Nucleophilic Substitution reaction mechanisms on FAFS will also be presented and discussed.

Kinetics and Mechanism of Nucleophilic Substitution Reaction of 4-Substituted-2,6-dinitrochlorobenzene with Benzylamines in MeOH-MeCN Mixtures

The reaction rates of 4-X-2,6-dinitrochlorobenzenes (X = <TEX>$NO_2$</TEX>, CN, <TEX>$CF_3$</TEX>) with Y-substituted benzylamines (Y = p-<TEX>$OCH_3$</TEX>, p-<TEX>$CH_3$</TEX>, H, p-Cl) in MeOH-MeCN mixtures were measured by conductometry at <TEX>$25^{\circ}C$</TEX>. It was observed that the rate constant increased in the order of X = <TEX>$NO_2$</TEX> > CN > <TEX>$CF_3$</TEX> and in the order of Y = p-<TEX>$OCH_3$</TEX> > p-<TEX>$CH_3$</TEX> > H > p-Cl. When the solvent composition was varied, the rate constant increased in the order of 100% MeOH < 50% (v/v) MeOH-MeCN < 100% MeCN. These results may be ascribed to the formation of hydrogen bonds between the alcoholic hydrogen and nitrogen of benzylamines in groud state (GS). We conclude that the reaction takes place via <TEX>$S_NAr$</TEX> base on the transition state parameters <TEX>${\rho}x$</TEX>, <TEX>${\rho}Y$</TEX>, <TEX>$\beta_{nuc}$</TEX>, and solvent effects.

ChemInform Abstract: The Mechanisms of Nucleophilic Substitution Reactions of Aromatic Ethers with Amines in Benzene.

The variation of the second-order rate constants with nucleophile concentration has been determined for the following reactions of some aromatic ethers with primary and secondary amines in benzene: 6-methyl-2,4-dinitrophenyl- and 2,6-dinitrophenyl phenyl ethers with piperidine, n-butylamine, morpholine and benzylamine; 2-phenoxy-3,5-dinitropyridine with these four nucleophiles and aniline; and 2,4,6-trinitrophenyl 4-nitrophenyl ether with N-methylaniline. An attempt has been made to rationalise the kinetic forms of these and similar reactions of other aromatic ethers in benzene.

Absence of SN1 Involvement in the Solvolysis of Secondary Alkyl Compounds

There are significant contradictions in undergraduate organic chemistry textbooks as to the mechanism of nucleophilic substitution reactions at saturated secondary carbons. Some texts say that only the SN2 mechanism operates, others say that solvolysis reactions go entirely by the SN1 mechanism, while most texts say that both mechanisms can be involved. This inconsistency greatly complicates the understanding of these reactions by students, and it leads to biases in testing. The root of this dilemma is traced to the initial studies by Hughes, Ingold, and co-workers in the 1930s. Despite discussing the difference between the kinetic order of a reaction and its molecularity, they often deferred to kinetic order in assigning a mechanism to these reactions. In 1969 Ingold considered it plausible that a first-order solvolysis reaction yielding a 100% inverted product was nonetheless going by an SN1 mechanism and suggested that the solvolysis of secondary compounds went primarily by SN1. The solvolysis of optically active 2-bromooctane should have resolved this issue, but major experimental difficulties confounded the results and lead to the continuing confusion. Based the results of Hughes, Ingold, and co-workers and significant additional evidence, it is concluded that all substitution reactions at saturated secondary carbons go exclusively via the SN2 mechanism under usual conditions.

ChemInform Abstract: Dramatic Effects of Halogen Substitution and Solvent on the Rates and Mechanisms of Nucleophilic Substitution Reactions of Aziridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.

Mechanism of the Nucleophilic Substitution of Acyl Electrophiles using Lithium Organocuprates

AbstractThe mechanism of nucleophilic substitution reaction at an sp2 carbon center of a thioester or an acid chloride with a lithium organocuprate reagent has been investigated. Density functional calculations indicated that the thioester undergoes oxidative addition of the CS bond to the copper(I) atom through a three‐centered transition state to afford an organocopper(III) intermediate, which gives the product through reductive elimination of the alkyl and the acyl groups. On the other hand, the acid chloride loses a chloride anion very easily when it interacts with the cuprate, because the chloride anion is captured by a lithium(I) cation rather than a copper(I) atom. 13C kinetic isotope effect (KIE) experiments showed excellent agreement with computational predictions for the thioester reaction, but suggested that the nucleophilic displacement transition state of the acid chloride occurs much more advanced than the calculations predict.