SN2 Reaction Research Articles

Expedient deaminative phosphorylation and sulfonylation of benzylic tertiary amines enabled by difluorocarbene

A deaminative functionalization of aliphatic tertiary amines via the cleavage of C(sp3)–N bonds under transition metal-free conditions was disclosed, which goes through SN2 reaction with various phosphorus and sulfur nucleophiles.

Alcohol synthesis based on the SN2 reactions of alkyl halides with the squarate dianion.

A convenient method has been developed for transforming alkyl halides into the corresponding alcohols via an SN2 reaction. Treatment of an alkyl halide with the squarate dianion at high temperature produces mono-alkyl squarate, and a one-pot basic hydrolysis of the intermediate affords the alcohol in good yield.

Reactivities of tertiary phosphines towards allenic, acetylenic, and vinylic Michael acceptors.

The addition of phosphines (PR3) to Michael acceptors is a key step in many Lewis-base catalysed reactions. The kinetics of the reactions of ten phosphines with ethyl acrylate, ethyl allenoate, ethyl propiolate, ethenesulfonyl fluoride, and ethyl 2-butynoate in dichloromethane at 20 °C was followed by photometric and NMR spectroscopic methods. The experimentally determined second-order rate constants k 2 show that electronic effects in sterically unencumbered phosphines affect their nucleophilicity towards different classes of Michael acceptors in the same ordering. Michael acceptors with sp-hybridised electrophilic centres, however, are less susceptible to changes in the PR3 nucleophilicity than those with sp2-hybridised reactive sites. Linear correlations of lg k 2 from this work with published rate constants for SN2 and SN1 reactions as well as with Brønsted basicities and fugalities for PR3 demonstrate the generality of the detected reactivity trends. Computed reaction barriers (ΔG ‡ calc) as well as reaction energies (ΔG add) for Michael adduct formations show excellent correlations with experimentally obtained reaction barriers (ΔG ‡ exp) corroborating the interpretation of the kinetic data and revealing the philicity/fugality features of the reactants in phospha-Michael additions.

Benchmark ab initio characterization of the complex potential energy surfaces of the HOO- + CH3Y [Y = F, Cl, Br, I] reactions.

The α-effect is a well-known phenomenon in organic chemistry, and is related to the enhanced reactivity of nucleophiles involving one or more lone-pair electrons adjacent to the nucleophilic center. The gas-phase bimolecular nucleophilic substitution (SN2) reactions of α-nucleophile HOO- with methyl halides have been thoroughly investigated experimentally and theoretically; however, these investigations have mainly focused on identifying and characterizing the α-effect of HOO-. Here, we perform the first comprehensive high-level ab initio mapping for the HOO- + CH3Y [Y = F, Cl, Br and I] reactions utilizing the modern explicitly-correlated CCSD(T)-F12b method with the aug-cc-pVnZ [n = 2-4] basis sets. The present ab initio characterization considers five distinct product channels of SN2: (CH3OOH + Y-), proton abstraction (CH2Y- + H2O2), peroxide ion substitution (CH3OO- + HY), SN2-induced elimination (CH2O + HY + HO-) and SN2-induced rearrangement (CH2(OH)O- + HY). Moreover, besides the traditional back-side attack Walden inversion, the pathways of front-side attack, double inversion and halogen-bond complex formation have also been explored for SN2. With regard to the Walden inversion of HOO- + CH3Cl, the previously unaddressed discrepancies concerning the geometry of the corresponding transition state are clarified. For the HOO- + CH3F reaction, the recently identified SN2-induced elimination is found to be more exothermic than the SN2 channel, submerged by ∼36 kcal mol-1. The accuracy of our high-level ab initio calculations performed in the present study is validated by the fact that our new benchmark 0 K reaction enthalpies show excellent agreement with the experimental data in nearly all cases.

Selective hydrogenolysis of the Csp2-O bond in the furan ring using hydride-proton pairs derived from hydrogen spillover.

Selective hydrogenolysis of biomass-derived furanic compounds is a promising approach for synthesizing aliphatic polyols by opening the furan ring. However, there remains a significant need for highly efficient catalysts that selectively target the Csp2-O bond in the furan ring, as well as for a deeper understanding of the fundamental atomistic mechanisms behind these reactions. In this study, we present the use of Pt-Fe bimetallic catalysts supported on layered double hydroxides [PtFe x /LDH] for the hydrogenolysis of furanic compounds into aliphatic alcohols, achieving over 90% selectivity toward diols and triols. Our findings reveal that the synergy between Pt nanoparticles, atomically dispersed Pt sites and the support facilitates the formation of hydride-proton pair at the Pt δ+⋯O2- Lewis acid-base unit of PtFe x /LDH through hydrogen spillover. The hydride specifically targets the Csp2-O bond in the furan ring, initiating an SN2 reaction and ring cleavage. Moreover, the presence of Fe improves the yield of desired alcohols by inhibiting the adsorption of vinyl groups, thereby suppressing the hydrogenation of the furan ring.

Massive acceleration of SN2 reaction using the oriented external electric field.

Nucleophilic substitution is one of the most fundamental chemical reactions, and the pursuit of high reaction rates of the reaction is one of the ultimate goals in catalytic and organic chemistry. The reaction barrier of the nucleophilic substitution originates from the highly polar nature of the transition state that can be stabilized under the electric field created by the solvent environment. However, the intensity of the induced solvent-electric field is relatively small due to the random orientation of solvent molecules, which hinders the catalytic effects and restricts the reaction rates. This work shows that oriented external electric fields applied within a confined nanogap between two nanoscopic tips could accelerate the Menshutkin reaction by more than four orders of magnitude (over 39 000 times). The theoretical calculations reveal that the electric field inside the nanogap reduces the energy barrier to increase the reaction rate. Our work suggests the great potential of electrostatic catalysis for green synthesis in the future.

Solvent-induced dual nucleophiles and the α-effect in the SN2 versus E2 competition.

We have quantum chemically investigated how microsolvation affects the various E2 and SN2 pathways, their mutual competition, and the α-effect of the model reaction system HOO-(H2O)n + CH3CH2Cl, at the CCSD(T) level. Interestingly, we identify the dual nature of the α-nucleophile HOO- which, upon solvation, is in equilibrium with HO-. This solvent-induced dual appearance gives rise to a rich network of competing reaction channels. Among both nucleophiles, SN2 is always favored over E2, and this preference increases upon increasing microsolvation. Furthermore, we found a pronounced α-effect, not only for SN2 substitution but also for E2 elimination, i.e., HOO- is more reactive than HO- in both cases. Our activation strain and quantitative molecular orbital analyses reveal the physical mechanisms behind the various computed trends. In particular, we demonstrate that two recently proposed criteria, required for solvent-free nucleophiles to display the α-effect, must also be satisfied by microsolvated HOO-(H2O)n nucleophiles.

A thermodynamic approach to analyzing relative permittivity and solvent mole fraction models, and application to SN1 reactions.

The standard methods for analyzing solvent effects on chemical reactions largely include linear free energy relations that relate kinetic and spectroscopic terms to solvent interactive parameters. The number of these parameters has grown over the years in order to make linear free energy techniques more accurate and cover a wider range of reaction systems. However, even with the myriad of parameters, the details of specific reaction systems make the application of these techniques sometimes unreliable. On the other hand, a thermodynamic approach provides a more precise analysis, and has proven particularly useful for reactions in multi-component solvent systems. In this article we present the mathematical formalism for relating the activation free energy to the bulk thermodynamic properties for a binary (cosolvent) system. We then use this thermodynamic approach, coupled with selected solvent models, to analyze the hydrolysis rates of tert-butyl chloride in the acetonitrile/water solvent system under iso-mole fraction, isodielectric, and isothermal conditions. These analyses allow us to differentiate and quantify bulk electrostatic effects and the effects of close-range solute-solvent interactions.

Trinity Strategy: Enabling Perovskite as Hydrophilic and Efficient Fluorescent Nanozyme for Constructing Biomarker Reporting Platform.

Water instability and sensing homogeneity are the Achilles' heel of CsPbX3 NPs in biological fluids application. This work reports the preparation of Mn2+:CsPbCl3@SiO2 yolk-shell nanoparticles (YSNPs) in aqueous solutions created through the integration of ligand, surface, and crystal engineering strategies. The SN2 reaction between 4-chlorobutyric acid (CBA) and oleylamine (OAm) yields a zwitterionic ligand that facilitates the dispersion of YSNPs in water, while the robust SiO2 shell enhances their overall stability. Besides, Mn2+ doping in YSNPs not only introduces a second emission center but also enables potential postsynthetic designability, leading to the switching from YSNPs to MnO2@YSNPs with excellent oxidase (OXD)-like activity. Theoretical calculations reveal that electron transfer from CsPbCl3 to in situ MnO2 and the adsorption-desorption process of 3,3',5,5'-tetramethylbenzidine (TMB) synergistically amplify the OXD-like activity. In the presence of ascorbic acid (AA), Mn4+ in MnO2@YSNPs (fluorescent nanozyme) is reduced to Mn2+ and dissociated, thereby inhibiting the OXD-like activity and triggering fluorescence "turn-on/off", i.e., dual-mode recognition. Finally, a biomarker reporting platform based on MnO2@YSNPs fluorescent nanozyme is constructed with AA as the reporter molecule, and the accurate detection of human serum alkaline phosphatase (ALP) is realized, demonstrating the vast potential of perovskites in biosensing.

The intramolecular SN2 reaction tautomeric ent-Kauranoids isolated from the aerial parts of Isodon amethystoides

As our ongoing searching for the bioactive natural terpenoids, nine ent-kauranoids (1–9), including three previously undescribed ones (1, 2, and 9), were isolated from the aerial parts of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic data analysis, including NMR, MS, and ECD. Compounds 1 and 2 were a pair of tautomeric compounds, which was confirmed by the HPLC analysis and low temperature NMR testing. The underlying mechanism of the tautomer was proposed as an intramolecular SN2 reaction, which was explained by quantum chemical calculation. The HOMO-LUMO gap and the free energy revealed the spontaneous of the tautomeric of the 1 and 2. Additionally, the similar phenomena were also found in the two groups of known compounds 3 and 4 and 6 and 7, respectively. Apart from the tautomer, compounds 3 and 4 can be hydrolyzed into 5 through ester hydrolysis in CDCl3, while compounds 6, 7 can be hydrolyzed into 8 through ester hydrolysis. These phenomena were also confirmed through HPLC analysis and low temperature nuclear magnetic resonance tests and the mechanism was studied using quantum chemical calculation.

Rational Design and Synthesis of an Artificial Enzyme for SN2 Reactions through Micellar Imprinting.

The rational design of catalysts with enzyme-like properties is an elusive goal of chemists despite tremendous interest. Molecular imprinting inside surfactant micelles, followed by postmodification, creates a tailored active site in a water-soluble polymeric "artificial enzyme" for the benzylation of 4-nitrophenol. The reaction happens under neutral conditions with excellent substrate selectivity. Similar to many enzymes, electrostatics play vital roles in catalysis and can be tuned through different bases introduced into the active site.

Simultaneous Preparation of Sulfides/Selenides and Sulfones via Synergistic Nickel-Catalyzed Reductive Coupling and SN2 Reaction.

Sulfone compounds and thioether compounds are two highly valuable classes of compounds, but it is challenging to prepare sulfone and thioether compounds simultaneously and efficiently. Here we report that sulfides/selenides and sulfones can be obtained simultaneously using allyl bromide/benzyl bromide-activated alkyl bromides and thiosulfonates/selenosulfonates using a nickel-catalyzed reductive coupling and SN2 synergistic strategy, which is characterized by excellent atom and step economy, mild reaction conditions, broad functional group compatibility, and excellent yields.

Cationic indium catalysis as a powerful tool for generating α-alkyl propargyl cations for SN1 reactions

Dehydration is an abundant and promising process in chemical, biochemical, and industrial fields. Dehydration methods can contribute to building a modern and sustainable society with minimal environmental impact. Breakthrough advances in the dehydrative SN1 reaction can be achieved through the discovery of new cationic indium catalysts. Here we show that the breakthrough advances in the dehydrative SN1 reaction can be achieved using the cationic indium catalysts. The dehydrative carbon–carbon bond formation of α-alkyl propargyl alcohols afforded a wide variety of α-aryl- and heteroaryl-propargyl compounds. Mechanistic investigations into this process revealed that the InCl3/AgClO4/Bu4NPF6/1,1’-binaphthol catalytic system generated a powerful cationic indium catalyst that could promote the dehydration of alcohols. Labile α-alkyl propargyl cations were found to self-condense, and the catalyst system efficiently regenerated propargyl cations for reaction with nucleophiles. This propargylation reaction directly proceeded from the corresponding alcohols under mild and open-air conditions and tolerated a broad scope of functional groups. Furthermore, a wide variety of nucleophiles, including aromatic and heteroaromatic compounds, phenols, alcohols, and sulfonamides, reacted with the corresponding cations to afford the propargyl compounds in good to high yields. Finally, the synthetic utility of this reaction was demonstrated by the synthesis of colchicine and allocolchicine analogues. The dehydration process could help create new compounds that were previously impossible to synthesize and is more eco-friendly and efficient than conventional methods.

Controlling the reactivity of La@C82 by reduction: reaction of the La@C82 anion with alkyl halide with high regioselectivity.

Endohedral metallofullerenes have excellent redox properties, which can be used to vary their reactivity to certain classes of molecules, such as alkyl halides. In this study, the thermal reaction of the La@C2v-C82 anion with benzyl bromide derivatives 1 at 110 °C afforded single-bonded adducts 2-5 with high regioselectivity. The products were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and visible-near infrared spectroscopy. The reaction of La@C2v-C82 with alkyl halides using the same conditions showed no consumption of La@C2v-C82, indicating that the reactivity of La@C2v-C82 toward alkyl halides was effectively increased by one-electron reduction. Single-crystal X-ray diffraction analysis of the single-bonded adduct 3a revealed the addition site of the p-methoxybenzyl group on La@C2v-C82. Theoretical calculations indicated that the addition site carbons in neutral La@C2v-C82 have high spin density, whereas those in the La@C2v-C82 anion do not have high charge densities. Thus, the reaction is believed to occur via electron transfer, followed by the radical coupling of La@C2v-C82 and benzyl radicals, rather than by bimolecular nucleophilic substitution reaction of La@C2v-C82 anion with 1.

The new Schiff‐base complex of copper(II) grafted on mesoporous KIT‐6 as an effective nanostructure catalyst for the homoselective synthesis of various tetrazoles

In this work, KIT‐6 mesoporous silica material was used to create heterogeneous catalyst due to its excellent surface area, substantial pore volume, and highly functionalized surface. A copper(II) Schiff‐base complex was fabricated on the surface of KIT‐6. For this purpose, (3‐iodopropyl)trimethoxysilane (IPTMS) was synthesized as a linker from (3‐choloropropyl)trimethoxysilane through a simple SN2 reaction using NaI. On the other hand, ligand (a) was synthesized from condensation of diethylenetriamine (DETA) and salicylaldehyde (SA), which was identified by IR and 1H‐NMR techniques. In order to, prepare Sal(PMeOSi)DETA (b), ligand (a) was reacted with IPTMS. One of the challenges of this synthesis was to prove the linkage between the ligand (a) and the IPTMS, which was proved by 1H‐NMR technique. In the next step, the Schiff base complex of copper(Cu(II)[Sal(PMeOSi)DETA]) (c) was synthesized using a complexation reaction of Cu(NO3)2.3 H2O and b. Finally, the obtained copper complex was fixed on KIT‐6, {Cu(II)[Sal(PMeOSi)DETA]} as the new reusable and practical catalyst. This catalyst has been identified using IR, BET, EDS, XRD, SEM, and TGA methods and employed in the synthesis of different tetrazoles for the first time. All tetrazoles were prepared with high yields, and good TOF and TON values, indicating excellent catalytic performance. This catalyst shows excellent homoselectivity in the synthesis of five‐substituted 1H‐tetrazoles. Also, it can be recovered and reused several times without a significant decrease in its catalytic activity or copper leaching.

Computational Insights into SN 2 and Proton Transfer Reactions of CH3 O- with NH2 Y and CH3 Y.

Bimolecular nucleophilic substitution (SN 2) reactions have been extensively studied in both theory and experiment. While research on C-centered SN 2 reactions (SN 2@C) has been ongoing, SN 2 reactions at neutral nitrogen (SN 2@N) have received increased attention in recent years. To recommend methods for dynamics simulations, the comparison for the properties of the geometries, vibrational frequencies, and energies is done between MP2 and six DFT functional calculations and experimental data as well as the high-level CCSD(T) method for CH3 O- +NH2 Cl/CH3 Cl reactions. The relative energy diagrams at the M06 method for CH3 O- with CH3 Y/NH2 Y reactions (Y=F, Cl, Br, I) in the gas and solution phase are explored to investigate the effects of the leaving groups, different reaction centers, and solvents. We mainly focus on the computational of inv-SN 2 and proton transfer (PT) pathways. The PT channel in the gas phase is more competitive than the SN 2 channel for N-center reactions, while the opposite is observed for C-centered reactions. Solvation completely inhibits the PT channel, making SN 2 the dominant pathway. Our study provides new insight into the SN 2 reaction mechanisms and rich the novel reaction model in gas-phase organic chemistry.

Total Syntheses of Rhodomollins A and B.

The first and asymmetric total syntheses of rhodomollins A and B, two rhodomollane type grayanoids featuring a d-homograyanane carbon skeleton and an oxa-bicyclo[3.2.1] core, were accomplished via a convergent strategy. A Stille coupling and a lithium-halogen exchange/intramolecular nucleophilic addition to the aldehyde sequence were employed to assemble two enantioenriched fragments. The oxa-bicyclo[3.2.1] core was achieved through an intramolecular SN2 substitution of cyclic sulfate of 1,2-diols (Williamson ether synthesis). The A ring oxidation states were adjusted by a Payne/Meinwald rearrangement sequence and subsequent redox transformations.

An efficient, concise synthetic approach to γ-aminobutyric acid (GABA) derivatives bearing bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane rings

An efficient, concise 5-step synthetic approach to γ-aminobutyric acid (GABA) derivatives bearing bridged bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane rings was developed, which consists of Diels-Alder cycloaddition to construct the bridged bicyclic rings with a nitrile functionality, hydrogenation, LDA-mediated SN2 alkylation to introduce acetate moiety at the α-position of nitrile, reduction of the nitrile functionality to amino group followed by intramolecular formation of lactam and finally acidic hydrolysis of lactam to give the desired GABA derivatives (1 and 19 as HBr salts). The reaction conditions of Diels-Alder cycloaddition and LDA-mediated SN2 alkylation were intensively optimized to improve the yields. The stereochemistry of the SN2 reaction involved in the bicyclo[2.2.1]heptane ring system was unambiguously elucidated by single-crystal X-ray diffraction. This synthetic approach possesses advantages of less reaction steps, high overall yields and avoidance of toxic reagents, and may find wide applications in the synthesis of other GABA derivatives with similar bicyclic or polycyclic rings.

Versatile Surface Chemistry of Carbon-Based Nanoplatforms by Covalent Bonding, Non-Covalent Linking, Crosslinking, and Self-Assembling

This mini-review discussed the best-known chemical and synthetic methodologies used in the last years to modify carbon allotropes, with an interest in nanotechnology. In this perspective, chemistry with optoelectronics applications and recent trends within bio-applications focusing mainly on graphene and its derivatives were considered. So, the mini-review intended to focus on methodologies to add functional groups with varied reactivities, polymer chemistry, and nanoscale control. These methodologies provide insight for further developments. In this manner, traditional methods using strong acid media to convert simple carbon bonds into carboxylic acid and aldehydes organic functional groups were shown and discussed. Hence, chemical modifications in a variety of solvents could be developed. Notably, many organic chemical reactions, such as bimolecular nucleophilic substitution (SN2), click chemistry, and photochemical reactions, showed essential insights in designing the carbon-based material modifications and the bottom-up method. Moreover, incorporating atomic entities within graphene material defects led to interesting spectroscopic and quantum properties. The atomic change added blemishes to this homogeneous structure, which was tuned to modify optical properties. In addition, the review was also oriented towards the discussion on incorporating polymeric films, such as boron- and silicon-based monomers, to form polymeric-modified carbon-based slides. In this way, organoboranes and organosilanes permitted chemical functionalization because their chemical modification was more accessible on nanosurfaces. Moreover, emphasis was placed on exploiting non-covalent bonding with ions and polarized molecules with the highly electronic densities of graphene and its derivatives. In this manner, the manuscript intends to summarize the main types of reactions and synthetic pathways reported until today. Therefore, particular focus was given to chemical composition, 2D and 3D chemical structures, and their properties related to non-covalent interactions. Thus, based on the properties and reactivity of carbon allotropes, the review was intended to open the analysis and discussion, considering the design of new carbon-based materials, hybrid nanocomposites, and metamaterials.

A Trade-off between Solvation and Collision Activation in Steering Competing E2 and SN2 Dynamics.

The prototypical E2 elimination and SN2 substitution reactions between microsolvated fluoride and ethyl bromide show unexpected dynamic behaviors in mechanistic evolution driven by solvation and collision activation. Considering the steric effects, the gas-phase selectivity favors an E2 pathway barely dependent on collision energies. Remarkably, base solvation steers the reaction in an effective way toward substitution at a near-thermal energy, whereas the governing high-energy events retain elimination. Chemical dynamics simulations reproduce experimental findings and uncover a crucial solute-solvent coupling in determining such competing processes. Interestingly, collision activation can tune the underlying atomistic dynamics essentially in the reactant entrance channel and cause a mechanism shift. These features for the ubiquitous competing E2/SN2 dynamics remain quite unknown, providing unique insight into reaction selectivity for complex chemical networks.