Mechanism Of Substitution Reactions Research Articles

Analysis of undergraduate chemistry students’ responses to substitution reaction mechanisms: a road to mastery

Abstract This study analyzed third-year undergraduate Chemistry major students’ drawings and written explanations of substitution reactions. Seventy (70) students were purposively selected for this study. The main data collection instrument was a diagnostic test and students’ responses were analyzed using deductive coding. The study aimed to unearth students’ conceptual understanding and difficulties on substitution reactions to provide significant insights into improving teaching strategies and learning outcomes. The findings revealed that: 1. Students were more familiar with SN2 reaction mechanisms and could answer questions on SN2 reaction mechanisms better than SN1 reaction mechanisms; 2. Students’ use of ‘chemical vocabulary’ did not translate into an understanding of electron movement and causal mechanistic explanation; 3. About 97 % of the students who gave a correct/partially correct description provided a description of what was happening in the reaction without any further explanation of why the reaction occurred; 4. Students had a slightly better understanding of drawing the correct mechanisms than providing accurate explanations. This study recommends that, in teaching organic reaction mechanisms, instructors should emphasize on electron-pushing formalisms and explain how and why reactions occur to encourage mechanistic thinking in students. Also, students should be given ample practice in organic reaction mechanisms to improve mastery.

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.

Nucleophilic Substitution at Phosphorus Centres - Old and Recent Studies and a Final Solution of Mechanistic and Related Stereochemical Problems.

Among many problems of a fundamental value in the heteroatom chemistry the mechanism and stereochemistry of the nucleophilic substitution reaction at the phosphorus and other heteroatom centres have attracted great attention of phosphorus chemists already in the middle of the last century. This review, which does not have a comprehensive character, summarizes the selected original contributions aimed at solution of the mechanism of SN2-P reaction and its relationship with stereochemistry. The breakthrough in these studies was the Westheimer's concept and his rules which is presented at the beginning of this article. Next, a series of papers is presented where the stereochemistry of the substitution at phosphorus was investigated in cyclic five-, four- and six-membered ring phosphorus compound. The majority of these reactions have been found to occur with retention of the P-configuration. In the third part of this account, the selected examples of substitution reactions at phosphorus in acyclic compounds are discussed. As the results of all the investigations discussed did not allow to undoubtedly ascribe the mechanism (SN2 or A-E) to the investigated reactions, in the last part the SN-P reactions are presented, the mechanism of which has been established by combination of the stereochemical and DFT-studies.

Experimental and theoretical studies of the substitution reactions of some bifunctional Au(III) complexes with biologically relevant thiols and thioethers

The kinetics of the substitution reactions between bifunctional Au(III) complexes, [AuCl2(bipy)]+, [AuCl2(dach)]+ and [AuCl2(en)]+ (bipy = 2,2″-bipyridine, dach = (1 R,2R)-1,2-diaminocyclohexane, en = ethylenediamine), with biologically relevant ligands such as glutathione (GSH), L-methionine (L-Met) and L-cysteine (L-Cys) is determined. All kinetic studies are performed in 25 mM Hepes buffer (pH = 7.2) in the presence of NaCl (25 mM) to prevent hydrolysis of the complexes. The reactions were followed under pseudo-first-order conditions using stopped-flow UV–Vis spectrophotometry at determined working wavelengths at three different temperatures (288.2, 298.1, and 309.8 K). DFT theoretical approach was applied to calculate thermodynamic and kinetic parameters that determined an operative mechanism of substitution reactions for all complexes and L-Cys as a selected model substituent. The obtained kinetic data showed that all complexes have similar reactivity; [AuCl2(bipy)]+ is the most reactive while [AuCl2(en)]+ is the least reactive. The second step of the substitution reaction is much faster than the first. The reactivity of the studied nucleophiles decreases in order L-Met > L-Cys > GSH. According to the values of the activation parameters determined experimentally and theoretically, all substitutions follow an associative model.

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.

Ionic Liquid-Aided Synthesis of Anatase TiO2 Nanoparticles: Photocatalytic Water Splitting and Electrochemical Applications

Titanium dioxide nanoparticles play a crucial role in the production of hydrogen gas evolution. Among the four polymorphic phases of TiO2 (anatase, rutile, brookite, and TiO2 (B)), the anatase phase shows good photo activity in catalytic applications. We prepared a single anatasephase of TiO2 nanoparticles usinga facile one-step ionothermal method with the existence of 1-(3,6-dioxa heptane) 3-methyl imidazolium methane sulfonate IL[DOMIMS]. The ionic liquid-based substitution reaction mechanism was utilized for the ionothermal synthesis of TiO2. The anatase phase structure and nanoparticle-like morphology of synthesized TiO2 nanomaterial were confirmed by XRD analysis and TEM studies. The vibrational frequency of the Ti–O–Ti bond at 544 cm−1 was measured usingthe FTIR spectrum, and the UV absorbance of the sample was studied usingthe UV/visible spectra. The prepared TiO2 nanoparticles showed the best results of H2 generation via awater-splitting reaction, liberating 2084 μmol·g−1·h−1 of H2 gas. TiO2 nanoparticles act as a good material for electrochemical applications such as supercapacitors and sensing of dopamine, as well as a better photocatalyst for the degradation of methylene blue.

A real space picture of the role of steric effects in SN 2 reactions.

Within substitution reactions, the Bimolecular Nucleophilic Substitution (SN2) reaction mechanism is one of the most frequently found and studied ones. Among other factors, the easiness of the SN2 pathway is classically considered to be determined by steric hindrance. However, the diffuse nature of the latter inevitably darkens these and other arguments holding the pillars of chemical intuition. In this work, we employ the steric energy (E ST ) descriptor, formulated within the Interacting Quantum Atoms approach, to offer insights regarding this problem. The steric demands of the substrate, nucleophile and leaving group were studied using the gas‐phase SN2 reaction with different organic skeletons (CH3—, CH3CH2—, (CH3)2CH—, (CH3)3C—, (CH3)3CCH2—) and halogens (F, Cl, and Br) as test‐bed systems. Our results show that, according to E ST , the SH experienced along these simple reactions fits, in the general case, the trends predicted by a meticulous and rigorous application of chemical intuition. However, steric clash alone should not be considered as the only argument used to explain the easiness of the SN2 reaction over different electrophiles.

Repurposing Halicin as a potent covalent inhibitor for the SARS-CoV-2 main protease.

The rapid spread of COVID-19 has caused a worldwide public health crisis. For prompt and effective development of antivirals for SARS-CoV-2, the pathogen of COVID-19, drug repurposing has been broadly conducted by targeting the main protease (MPro), a key enzyme responsible for the replication of virus inside the host. In this study, we evaluate the inhibition potency of a nitrothiazole-containing drug, halicin, and reveal its reaction and interaction mechanism with MPro. The in vitro potency test shows that halicin inhibits the activity of MPro an IC50 of 181.7 ​nM. Native mass spectrometry and X-ray crystallography studies clearly indicate that the nitrothiazole fragment of halicin covalently binds to the catalytic cysteine C145 of MPro. Interaction and conformational changes inside the active site of MPro suggest a favorable nucleophilic aromatic substitution reaction mechanism between MPro C145 and halicin, explaining the high inhibition potency of halicin towards MPro.

Photobromination (S<SUB>R</SUB>) and Corresp. S<SUB>N</SUB>1 Reactions – Key Reactions for the Development and the Application of the Concept of Hyperconjugation

This article first describes photochemical bromination reactions of two different reactants proceeding via electron septet intermediates according to the radical substitution reaction mechanism (SR). The case comparison is intended to enable learners – high school or university first-year organic chemistry students – to work out the concept of hyperconjugation, which is very significant for organic chemistry, by intertwining experimental results and theoretical interpretation (of free radical intermediates) closely. Since students often do not succeed in transferring concepts they have already learned from one mechanism to another, the second step will be to transfer and apply the concept of hyperconjugation to carbenium ions as reactive intermediates by means of an analogous experimental case comparison of first-order nucleophilic substitution reactions (SN1).

Development of chiral bisphosphoric acid/boronic acid co-catalyst system for enantioselective SN2’ reaction

An enantioselective intramolecular SN2’ reaction of geometrically defined allylic substrates was developed by introducing a co-catalyst system composed of chiral bisphosphoric acid and phenylboronic acid. In the enantioselective nucleophilic substitution reaction using chiral phosphoric acids and derivatives (CPAs) as the catalyst, the formation of the corresponding CPA ester, which is afforded through the SN2 reaction of the substrate with the nucleophilic phosphate anion generated during the activation of a leaving group, has been a serious problem because of the catalyst deactivation. The developed co-catalyst system surmounted this fundamental problem by efficiently suppressing the catalyst deactivation process to afford enantioenriched vinyl epoxides in good yields with moderate to high enantioselectivities. Mechanistic elucidation of the present enantioselective intramolecular SN2’ reaction using the co-catalyst system revealed that the leaving group is involved in the enantio-determining transition states, and the anti-SN2’ pathway is considered to be the rational mechanism of the present allylic substitution reaction. In addition, the stereospecific Meinwald rearrangement of the thus-formed enantioenriched vinyl epoxide was aided by an equimolar amount of a Lewis acid, affording the corresponding all-carbon quaternary α-vinyl cyclohexanone without marked loss of enantiomeric purity.

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.

A red-to-near-infrared fluorescent probe for the detection of thiophenol based on a novel hydroxylflavone-quinoline-amino molecular system with large Stokes shift

In this work, we synthesized a novel long-wavelength-emitting fluorophore FQ-OH based on a novel designed hydroxylflavone-quinoline-amino molecular system with both intramolecular charge transfer (ICT) and excited-state intramolecular proton transfer (ESIPT) process, enabling FQ-OH with strong fluorescence in a wide range of 550–800 nm, covering red-to-near-infrared emission region and large stokes shift as much as 162 nm. Due to the promising spectra property, FQ-OH was then fabricated into a red-to-near-infrared fluorescent probe FQ-DNP for the selective detection of thiophenol via aromatic nucleophilic substitution (SNAr) reaction mechanism. Spectra assays in the solution demonstrated that FQ-DNP displayed prominent turn-on fluorescence response to thiophenol in 550–800 nm with emission peak at 627 nm, excellent selectivity, and exceptional sensitivity (detection limit as low as 7.2 nM). In addition, thiophenol in vapor form could be detected by FQ-DNP coated test papers enabling naked eye detection. Moreover, FQ-DNP was utilized for detecting thiophenol in environmental samples and showed great recovery results. Furthermore, biological application of FQ-DNP in living cells through cell imaging study demonstrated apparent intracellular fluorescence enhancement before/after thiophenol addition.

Research on Battery Technology of Borohydride New Hydrogen Energy Material

Vehicle-mounted hydrogen storage is a “bottleneck” link in promoting the large-scale commercial application of hydrogen fuel vehicles. The development of high-performance vehicle-mounted hydrogen storage material technology has become a hot spot in the current energy and materials field. In recent years, with the continuous expansion of the field of hydrogen storage materials, high-storage coordination metal hydrides represented by lithium borohydride ( LiBH 4 ) have gradually become a new research focus of hydrogen storage materials. This article summarizes the latest modification research and application of metal borohydride hydrogen storage materials from the perspectives of substitution, recombination, doping, nanostructure confinement and corresponding reaction mechanism, and puts forward the existing problems and corresponding countermeasures, and points out the future research direction.

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.

Esterification of Guar Gum using Dodecanoyl and Myristoyl Acid Chlorides in N, N – dimethylacetamide / lithium chloride Solvent System

Guar gum, the naturally occurring polysaccharide which contains about 80% of galactomannan sugar consisting of mannose and galactose (2:1). This study aims to transform hydroxyl groups in the sugar structure into ester groups by reacting them with organic acid chlorides and producing biodegradable plasticized materials to overcome environmental pollution. Guar was purified using a modified procedure. Solublization of purified guar gum is carried out in N, N- dimethyl Acetamide (DMAc)/Lithium Chloride (LiCl) system. Treatment of solubilized guar gum with Dodecanoyl and Myristoyl acid chlorides in the presence of pyridine converts the hydroxyl groups of galactomannan sugar into ester groups through neucliophilic substitution reaction mechanism, and The maximum degree of esterification which can take place is three hydroxyl groups for every galactose and mannose unit, hence for lauriated guar gum the yield was 0.5g and Recuperation Yield (RY (%)) was 38.09% and for myristylated guar gum the yield was 0.652g and RY (%) was 38.56% Degree of Substitution (DS) value assumed to be 3 in both products. Occurrence of the reaction was confirmed using Fourier transform infrared spectroscopy (FT-IR). The structural modification of guar gum attained, did not result in a significant change in the solubility properties of guar gum., Further research is needed to evaluate the gum esters synthesized during the work for developing better internally plasticized material and making biodegradable plastics and polymers.

Flow Synthesis of 2‐[Methyl(pyridin‐2‐yl)amino]ethanol: An Experimental and Computational Study

AbstractMicroreactor technology is increasingly applied in the chemical‐pharmaceutical industry for safer and more efficient drug production as compared to the traditional batch process. This technology is employed for the first time to study the production of 2‐[methyl(pyridin‐2‐yl)amino]ethanol, the first intermediate in rosiglitazone synthesis. Under the optimum operating conditions, a single microreactor chip at 160 °C allowed to produce the equivalent of more than five batch reactors at 120 °C. The kinetic study indicated that the reaction is second order. Thermodynamic parameters were determined by the Eyring equation and density functional theory (DFT) calculations with good agreement. DFT results suggested a concerted nucleophilic aromatic substitution reaction mechanism.

The Degradation and Repolymerization Analysis on Solvolysis Liquefaction of Corn Stalk.

One of the most effective and renewable utilization methods for lignocellulosic feedstocks is the transformation from solid materials to liquid products. In this work, corn stalk (CS) was liquified with polyethylene glycol 400 (PEG400) and glycerol as the liquefaction solvents, and sulfuric acid as the catalyst. The liquefaction conditions were optimized with the liquefaction yield of 95.39% at the reaction conditions of 150 °C and 120 min. The properties of CS and liquefaction residues (LRs) were characterized using ATR–FTIR, TG, elemental analysis and SEM. The chemical components of liquefied product (LP) were also characterized by GC–MS. The results indicated that the depolymerization and repolymerization reaction took place simultaneously in the liquefaction process. The depolymerization of CS mainly occurred at the temperature of <150 °C, and the repolymerization of biomass derivatives dominated at a higher temperature of 170 °C by the lignin derivatives repolymerization with cellulose derivatives, hemicellulose derivatives and PEG400 and self-condensation of lignin derivatives. The solvolysis liquefaction of CS could be classified into the mechanism of electrophilic substitution reaction attacked by the hydrogen cation.

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.

Selective regeneration of lithium from spent lithium-ion batteries using ionic substitution stimulated by mechanochemistry

Utilization of acid/base or corrosive reagents is currently the preferred way to recover valuable metals from spent lithium−ion batteries (LIBs), but it is still likely to cause serious environmental risks. Herein we report an acid−free process for selective recycling of Li from cathode materials of spent LIBs, via an ionic substitution stimulated by mechanochemistry. The key innovation is that selective regeneration of Li2CO3 is easily achieved with safe and low−cost NaCl and SiO2 as mechanochemical reaction reagents, and Na2CO3 as precipitation reagent, via a sustainable recycling process. The corresponding ionic substitution reaction mechanism between Li+ and Na+ was explored and verified. Based on the ionic substitution reaction induced by mechanical forces, Li+ in the α−NaFeO2 layered structure of LiCoO2 was first successfully replaced by Na+ from NaCl. The separation of the generated LiCl, the recovery of Li2CO3, and the regeneration of NaCl were then simultaneously achieved by a sustainable chemical precipitation process using only Na2CO3 as the precipitant. The engineering applications confirmed that the designed mechanochemical approach can successfully achieve the selective recovery of Li2CO3 from various cathode materials of spent LIBs in a green manner and could be therefore applied as a preceding process for spent LIBs recycling.

A DFT investigation on aromatic nucleophilic substitution (SNAr) reaction between 4-fluoro-1-naphthaldehyde/4-fluoro-2-naphthaldehyde/1-fluoro-2-naphthaldehyde/1-fluoronaphthalene and methylthiolate ion in gas phase and in protic/aprotic solvents

We have investigated the mechanism of aromatic nucleophilic substitution (SNAr) reaction between 4-fluoro-1-naphthaldehyde/4-fluoro-2-naphthaldehyde/1-fluoro-2-naphthaldehyde/1-fluoronaphthalene with methylthiolate by DFT calculations at B3LYP/6–31+G (d,p) level of theory in gas phase and also in polar protic/aprotic solvents. The results show that aromatic nucleophilic substitution reaction proceeds by concerted mechanism via formation of single transition state as it has lower activation energy barrier as compared with stepwise mechanism. The introduction of solvent increases the activation energy barrier indicating significant effect of solvents on transition state. The activation energy barrier was found to be a minimum in gas phase then in DMSO which is followed by protic polar solvents methanol and water. Thus, the polar aprotic solvent DMSO works best for aromatic nucleophilic substitution of fluorine. The presence of a formyl group was found to be essential for reaction to take place, and in the gas phase as well as in solution phase, the order of reactivity was found to be 4-fluoro-1-naphthaldehyde > 1-fluoro-2-naphthaldehyde > 4-fluoro-2-naphthaldehyde > 1-fluoronaphthalene.