SN2 Reaction Research Articles

Theoretical Studies on OH−+NH2Cl Reaction: Nucleophilic Substitution at Neutral Nitrogen

The SN2 and proton transfer (PT) pathways for [Formula: see text]Cl reaction are represented by employing various electronic structure computations. Both back-side SN2 and PT channels are exothermic and stationary points of PESs are below the reactant asymptote. Overall, the PES is similar to the C-centered SN2 reactions. Conversely, ion-dipole complex was not found for [Formula: see text]Cl system. The N–HOH/NH–Cl hydrogen bond characterizes on either side of the reaction barrier of nitrogen complexes. Moreover, a halogen-bonded complex (HO−–ClNH2) and two types of H-bond complexes (HONH2–Cl− and Cl−–HONH2) were described, predicting an important role in dynamics. The PT pathway may be the major channel in the title system, which is contradictory to [Formula: see text]Cl and [Formula: see text]Cl reactions. Here, MP2, B3LYP and CAM-B3LYP methods show overall excellent consistency with CCSD(T)/CBS energies and are recommended to carry out dynamics simulations.

Thermoresponsive Ionic Liquid with Different Cation-Anion Pairs as Draw Solutes in Forward Osmosis.

We synthesized various phosphonium- and ammonium-based ionic liquids (ILs), using benzenesulfonate (BS) and 4-methylbenzenesulfonate (MBS) to establish the criteria for designing an ideal draw solute in a forward osmosis (FO) system. Additionally, the effects of monocationic, dicationic, and anionic species on FO performance were studied. Monocationic compounds ([P4444][BS], [P4444][MBS], [N4444][BS], and [N4444][MBS]) were obtained in one step via anion exchange. Dicationic compounds ([(P4444)2][BS], [(P4444)2][MBS], [(N4444)2][BS], and [(N4444)2][MBS]) were prepared in two steps via a Menshutkin SN2 reaction and anion exchange. We also investigated the suitability of ILs as draw solutes for FO systems. The aqueous [P4444][BS], [N4444][BS], [N4444][MBS], and [(N4444)2][BS] solutions did not exhibit thermoresponsive behavior. However, 20 wt% [P4444][MBS], [(P4444)2][BS], [(P4444)2][MBS], and [(N4444)2][MBS] had critical temperatures of approximately 43, 33, 22, and 60 °C, respectively, enabling their recovery using temperature. An increase in IL hydrophobicity and bulkiness reduces its miscibility with water, demonstrating that it can be used to tune its thermoresponsive properties. Moreover, the FO performance of 20 wt% aqueous [(P4444)2][MBS] solution was tested for water flux and found to be approximately 10.58 LMH with the active layer facing the draw solution mode and 9.40 LMH with the active layer facing the feed solution.

Rhodium‐Catalyzed Dynamic Kinetic Asymmetric Hydrosilylation to Access Silicon‐Stereogenic Center

AbstractStrategies on the construction of enantiomerically pure silicon‐stereogenic silanes generally relies on desymmetrization of prochiral and symmetric substrates. However, dynamic kinetic asymmetric transformations of organosilicon compounds have remained underdeveloped and unforeseen owing to a lack of an effective method for deracemization of the static silicon stereocenters. Here we report the first Rh‐catalyzed dynamic kinetic asymmetric intramolecular hydrosilylation (DyKAH) with “silicon‐centered” racemic hydrosilanes that enables the facile preparation of silicon‐stereogenic benzosiloles in good yields and excellent enantioselectivities. The special rhodium catalyst controlled by non‐diastereopure‐type mixed phosphine‐phosphoramidite ligand with axial chirality and multiple stereocenters can induce enantioselectivity efficiently in this novel DyKAH reaction. Density functional theory (DFT) calculations suggest that the amide moiety in chiral ligand plays important role in facilitating the SN2 substitution of chloride ion to realize the chiral inversion of silicon center.

Critical Assessment of Data-Driven versus Heuristic Reaction Coordinates in Solution Chemistry.

Reaction coordinates are an essential ingredient of theoretical studies of rare events in chemistry and physics because they carry information about reaction mechanism and allow the computation of free-energy landscapes and kinetic rates. We present a critical assessment of the merits and disadvantages of heuristic reaction coordinates, largely employed today, with respect to coordinates optimized on the basis of reliable transition-path sampling data. We take as a test bed multinanosecond ab initio molecular dynamics simulations of chloride SN2 substitution on methyl chloride in explicit water. The computational protocol we devise allows the unsupervised optimization of agnostic coordinates able to account for solute and solvent contributions, yielding a free-energy reconstruction of quality comparable to the best heuristic coordinates without requiring chemical intuition.

The Essential Role of Water Molecules in the Reaction Mechanism of Protein O‐ Fucosyltransferase 2

Protein O-fucosyltransferase 2 (PoFUT2) is an inverting glycosyltransferase (GT) that fucosylates thrombospondin repeats (TSRs) from group 1 and 2. PoFUT2 recognizes a large and diverse number of TSRs through a dynamic network of water-mediated interactions. By X-ray structural studies of C. elegans PoFUT2 complexed to a TSR of group 2, we demonstrate that this GT recognizes similarly the 3D structure of TSRs from both groups 1 and 2. Its active site is highly exposed to the solvent, suggesting that water molecules might also play an essential role in the fucosylation mechanism. We applied QM/MM methods using human PoFUT2 as a model, and found that HsPoFUT2 follows a classical SN2 reaction mechanism in which water molecules contribute to a great extent in facilitating the release of the leaving pyrophosphate unit, causing the H transfer from the acceptor nucleophile (Thr/Ser) to the catalytic base, which is the last event in the reaction. This demonstrates the importance of water molecules not only in recognition of the ligands but also in catalysis.

Reaction of CHCl[rad]− with HCHO and H2O: A theoretical study

To compare the ion–molecule reaction mechanism of CHCl− with HCHO and H2O, the DFT-BHandHLYP level of theory with the aug-cc-pVDZ basis set was used. Our theoretical findings show that the H-abstraction reaction pattern identified pathway 5 as the preferred pathway for the reactions of CHCl− + H2O. When the direct H- and O-abstraction data are examined, the intramolecular SN2 reaction pattern appears to be the preferred pathway for the CHCl− + HCHO reaction. The reaction between CHCl− and H2O should be less competitive based on the principal reactive pathways of CHCl− + HCHO. As a result, in the atmospheric process the reaction of HCHO with CHCl− may not be appreciably accelerated by the breakdown of HCHO with and without the H2O molecule.

Me2(CH2Cl)SiCF3 Facilitated Tandem Synthesis of Oxasilacycles Featuring a Trifluoromethyl Group.

An unprecedented tandem trifluoromethylsilylation/intramolecular SN2 substitution sequence was realized by using bifunctional reagent Me2(CH2Cl)SiCF3, allowing efficient construction of valuable trifluoromethylated oxasilacyclohexanes that are difficult to access by known methods. Initial attempts into developing asymmetric variant reveal that using cinchonine-derived dimeric PTC catalyst could afford chiral oxasilacyclohexanes in up to 92% enantiomeric excess.

Predicting Solvent Effects on SN2 Reaction Rates: Comparison of QM/MM, Implicit, and MM Explicit Solvent Models.

Solvents are one of the key variables in the optimization of a synthesis yield or properties of a synthesis product. In this paper, contemporary solvent models are applied to predict the rates of SN2 reactions in a range of aqueous and non-aqueous solvents. High-level CCSD(T)/CBS//M06-2X/6-31+G(d) gas phase energies were combined with solvation free energies from SMD, SM12, and ADF-COSMO-RS continuum solvent models, as well as molecular mechanics (MM) explicit solvent models with different atomic charge schemes to predict the rate constants of three SN2 reactions in eight protic and aprotic solvents. It is revealed that the prediction of rate constants in organic solvents is not necessarily less challenging than in water and popular solvent models struggle to predict their rate constants to within 3 log units of experimental values. Among the continuum solvent models, the ADF-COSMO-RS model performed the best in predicting absolute rate contants while the SM12 model was best at predicting relative rate constants with an average accuracy of about 1.5 and 0.8 log units, respectively. The use of computationally more demanding MM explicit solvent models did not translate to improvements in absolute rate constants but was quite effective at predicting relative rate constants due to systematic error cancellation. Free energy barriers obtained from umbrella sampling with explicit solvent QM/MM simulations led to excellent agreement with experimental values, provided that a validated level of theory is used to treat the QM region.

Predicting DNA-Reactivity of N-Nitrosamines: A Quantum Chemical Approach.

N-Nitrosamines (NAs) are a class of reactive organic chemicals that humans may be exposed to from environmental sources, food but also impurities in pharmaceutical preparations. Some NAs were identified as DNA-reactive mutagens and many of those have been classified as probable human carcinogens. Beyond high-potency mutagenic carcinogens that need to be strictly controlled, NAs of low potency need to be considered for risk assessment as well. NA impurities and nitrosylated products of active pharmaceutical ingredients (APIs) often arise from production processes or degradation. Most NAs require metabolic activation to ultimately become carcinogens, and their activation can be appropriately described by first-principles computational chemistry approaches. To this end, we treat NA-induced DNA alkylation as a series of subsequent association and dissociation reaction steps that can be calculated stringently by density functional theory (DFT), including α-hydroxylation, proton transfer, hydroxyl elimination, direct SN2/SNAr DNA alkylation, competing hydrolysis and SN1 reactions. Both toxification and detoxification reactions are considered. The activation reactions are modeled by DFT at a high level of theory with an appropriate solvent model to compute Gibbs free energies of the reactions (thermodynamical effects) and activation barriers (kinetic effects). We study congeneric series of aliphatic and cyclic NAs to identify trends. Overall, this work reveals detailed insight into mechanisms of activation for NAs, suggesting that individual steric and electronic factors have directing and rate-determining influence on the formation of carbenium ions as the ultimate pro-mutagens and thus carcinogens. Therefore, an individual risk assessment of NAs is suggested, as exemplified for the complex API-like 4-(N-nitroso-N-methyl)aminoantipyrine which is considered as low-potency NA by in silico prediction.

New dinuclear chromium complexes supported by thioether-triphenolate ligands as active catalysts for the cycloaddition of CO2 to epoxides

A new family of dinuclear chromium complexes bearing thioether-triphenolate ligands has been developed for the cycloaddition of CO2 with epoxides. The catalytic systems resulting from the combination of complexes 1–3 with tetrabutylammonium chloride (TBAC) show high activity and selectivity for the synthesis of cyclic carbonates with a broad range of substrates including terminal and internal epoxides. Notably, in the case of epichlorohydrin, a TOF up to 4650 h-1 (120 °C, 2 MPa) was recorded, showing one of the highest activity for chromium complexes. In the case of internal epoxides, the reaction proceeds with the retention of the substrate configuration highlighting that the mechanism proceeds through two consecutive SN2 reactions.

Environmental degradation of human metabolites of cyclophosphamide leads to toxic and non-biodegradable transformation products

The present study assessed the ready biodegradability of the prodrug cyclophosphamide (CPA) and its stable human metabolites in the closed bottle test (CBT). The results of the CBT showed that only the main human metabolite, carboxyphosphamide (CXP), was biodegradable to a certain extent (23 ± 2.4 % ThODNH3). All other metabolites showed neither biodegradation under these conditions nor were any toxic effects on the inoculum observed. Yet, HRMSn results revealed partial primary elimination of all human metabolites and formation of 25 new transformation products. Abiotic degradation via SNi and SN2 reactions was proposed as the main degradation pathway during the CBT. The main degradation products were assigned as 3-(2-chloroethyl)oxazolidin-2-one (COAZ), cytotoxic N-2-chloroethylaziridine (CEZ) and nor‑nitrogen mustard (NNM), an analogue of the chemical warfare agent HN2. While the acute ecotoxicity of the detected products is widely unknown, many have already been reported in medical literature to be either mutagenic, genotoxic, cytotoxic or carcinogenic and may therefore cause a greater risk than their precursors. QSAR models predicted that 16 of them are mutagenic and genotoxic, thus classifying the majority of the chemicals as potential environmental hazards. The central intermediates during the degradation process were proposed as CEZ and its corresponding aziridinium ion. However, other degradation products may occur depending on the type and strength of nucleophiles present in the matrices. Overall, the results demonstrated the importance to include human metabolites in the evaluation of the environmental fate of pharmaceuticals and their risk assessment especially when investigating prodrugs. The results underline the importance of identifying possible degradation products of metabolites, as they can be more toxic than related parent compounds and metabolites and can cause a greater risk to the environment and humans.

C–F Bonds as “Frozen” Nucleophiles: Unconsummated SN2 Reactions

In this note, we present a series of rigid molecules that show close enforced interactions between Ar-F moieties and -CH2X groups in a "tetrel bond" configuration similar to a nascent SN2 attack. We explore the spectroscopic, crystallographic, and chemical reactivity consequences of these unusual interactions, including significant through-space spin-spin couplings, short C-F···CH2X distances, and differential SN1 and SN2 reaction pathways. We also reveal experimental evidence of carbon-based tetrel bonds influencing chemical reactivity in solution. Finally, density functional theory (DFT) calculations are employed throughout this study to confirm and illuminate our experimental data.

Quantitative dynamics of paradigmatic SN2 reaction OH- + CH3F on accurate full-dimensional potential energy surface.

The bimolecular reaction between OH- and CH3F is not just a prototypical SN2 process, but it has three other product channels. Here, we develop an accurate full-dimensional potential energy surface (PES) based on 191 193 points calculated at the level CCSD(T)-F12a/aug-cc-pVTZ. A detailed dynamics and mechanism analysis was carried out on this potential energy surface using the quasi-classical trajectory approach. It is verified that the trajectories do not follow the minimum energy path (MEP), but directly dissociate to F- and CH3OH. In addition, a new transition state for proton exchange and a new product complex CH2F-⋯H2O for proton abstraction were discovered. The trajectories avoid the transition state or this complex, instead dissociate to H2O and CH2F- directly through the ridge regions of the minimum energy path before the transition state. These non-MEP dynamics become more pronounced at high collision energies. Detailed dynamic simulations provide new insights into the atomic-level mechanisms of the title reaction, thanks to the new chemically accurate PES, with the aid of machine learning.

Controlling tosylation versus chlorination during end group modification of PCL

Synthetic biodegradable materials are commonly used to create constructs for medical devices and tissue engineered constructs. However, many of the homopolymers used in FDA approved devices such as poly(ε-caprolactone) (PCL), poly(lactic acid), or poly(carbonates) lack biogically relevant functional groups to steer biological responses in a controlled fashion. Commonly, an interconversion of the end groups is required to insert addressable moieties for the attachment of biologically active groups. In this study, the activation of the hydroxyl groups of a low molecular weight PCL-diol to the corresponding p-toluene sulfonate ester using p-toluenesulfonyl chloride was performed in both dichloromethane (DCM) and dimethylformamide (DMF). To our initial surprise, we only yielded the chlorinated product in DMF, while in DCM the tosylate ester was obtained. In a small series of reactions, we studied the solvent dependent switchability between tosylation and chlorination on PCL. We concluded that in polar aprotic solvents (DMF and dimethylsulfoxide), we rapidly and efficiently converted the hydroxyl into the chloride group, whereas in inert solvents (DCM and chloroform) we yielded the tosylated product. The data suggested that solvation effects of the polar aprotic solvents led to a Sn2 reaction of the tosyl group by the chloride. Furthermore, we utilized a polyethylene glycol (PEG) polymer to show translatability of the chlorination reaction to other (biomedical) polymers. This work highlights a new reaction pathway during the tosylation of a polymer end group, and presents a new useful strategy to insert clickable groups on synthetic polymers that are only soluble in polar aprotic solvents.

The reciprocal SN2 and SE2 reactions of ammonia borane

The reactions here explored are microscopic analogs of Newton cradle: left thing attack, right thing leaves and central thing remains unaffected. We have studied symmetric SX2 reactions, X = N or E, where the attacking and leaving molecules are the same: H3N, H3B, H3C(–) and the central molecules are H3B (SN2@B), H3N (SE2) or H3C (SN2@C). Non-symmetric reactions with different initial and final complexes were also studied and examples where the elements of the lateral molecules differ, P vs N.

Kinetic model, recycling, regeneration, and reusing of tri-phase catalytic nucleophilic substitution esterification

This research aims to develop a liquid–solid–liquid phase-transfer catalyst (PTC) catalytic kinetic model of carboxylate esterification unpublished previously. The bimolecular nucleophilic substitution reaction of sodium benzoate with benzyl bromide has been experimented with the immobilized solid PTC to propose the kinetic model and calculate the apparent reaction rate constant and activation energy. We proposed the proper kinetic model of the esterification successfully. In addition, the experimental results comprehensively matched the pseudo-first-order reaction formula. Under the multiple steps of recovery, reuse, and regeneration, the structure of tri-phase PTC support remains well, nor will it destroy the activated site immobilized on the support. Comparing the reactivity of the fresh PTC with PTCs recovered four times, the reactivity does not decrease with the continued recovery, indicating excellent catalytic reactivity. Besides, the esterification, etherification, and benzylation reactions catalyzed by regenerated PTCs and their yields are not much different from those of the original fresh PTCs. It shows that the catalytic activity of regenerated PTC is quite excellent. In our opinion, exploring the regeneration and reduction of PTC can reduce cost, save resources, possesses the potential to apply to other reaction systems, and improve conventional production.

A SN1 mechanistic approach to the Williamson ether reaction via photoredox catalysis applied to benzylic C(sp3)–H bonds

Dedication: This article is dedicated to Professor Stephen F. Martin, whose lab I got my start in when I was an undergraduate student. It was here I realized my love for organic chemistry, which I attribute to the caring environment Steve worked hard to establish amongst his group. This work: The Williamson ether reaction typically requires harsh conditions including strong base, elevated temperatures and long reaction times. The importance of ethers in valuable small molecules has thus motivated a search for mild alternatives. We report on a photochemical SN1 reaction that employs C–H precursors in place of C–Br/Cl/OTs electrophiles. The key design in achieving the SN1 approach relies on the direct generation of a carbocation from a given C–H bond via a photoredox-catalyzed formal hydride abstraction process. A wide substrate scope consisting of 1°, 2° and 3° alcohols was achieved, including examples of base-sensitive functionalities that are not compatible with Williamson ether conditions. Late-stage etherification of drug scaffolds is also demonstrated.

Total Synthesis of 2-Isocyanoallopupukeanane: Construction of Caged Skeleton by Intramolecular Alkylation of Bromonitriles.

A new method for constructing the bicyclo[3.2.1]octane skeleton was developed by the intramolecular alkylation of a nitrile-side-chain-containing cyclohexanone derivative. The cyclization precursors were prepared via the stereoselective bromination of the triisopropylsilyl enol ethers of 4-substituted cyclohexanones. Upon treatment with LiNEt2, the bromonitriles underwent a stereoselective intramolecular SN2 reaction to afford bicyclo[3.2.1]octane derivatives with a cyano group on the convex face. The total synthesis of 2-isocyanoallopupukeanane (6.5% yield) from methyl vinyl ketone was accomplished via a 17-step transformation.

A theoretical study of the reactivity of pyrazaboles with nitrogen nucleophiles (amines and pyrazoles): the ring-opening mechanism

A theoretical study of the reactivity of pyrazaboles with amines and pyrazoles has been carried out at DFT level in gas phase, toluene and water media. The reaction with amines yields two molecules of pyrazolylboranes, while the reaction with pyrazoles allows to understand the interchange of such molecules in the pyrazaboles. The reaction of three pyrazaboles with two amines [NH3and NMe3] and pyrazole itself has been considered. The SN2 and SN1 mechanisms have been analyzed. The SN2 reaction is more favorable than the SN1 in the absence or presence of amines.

A local pair-natural orbital-based complete-active space perturbation theory using orthogonal localized virtual molecular orbitals.

The multireference second-order perturbation theory (CASPT2) is known to deliver a quantitative description of various complex electronic states. Despite its near-size-consistent nature, the applicability of the CASPT2 method to large, real-life systems is mostly hindered by large computational and storage costs for the two-external tensors, such as two-electron integrals, amplitudes, and residuum. To this end, Menezes and co-workers developed a reduced-scaling CASPT2 scheme by incorporating the local pair-natural orbital (PNO) representation of the many-body wave functions using non-orthonormal projected atomic orbitals (PAOs) into the CASPT theory [F. Menezes et al., J. Chem. Phys. 145, 124115 (2016)]. Alternatively, in this paper, we develop a new PNO-based CASPT2 scheme using the orthonormal localized virtual molecular orbitals (LVMOs) and assess its performance and accuracy in comparison with the conventional PAO-based counterpart. Albeit the compactness, the LVMOs were considered to perform somewhat poorly compared to PAOs in the local correlation framework because they caused enormously large orbital domains. In this work, we show that the size of LVMO domains can be rendered comparable to or even smaller than that of PAOs by the use of the differential overlap integrals for domain construction. Optimality of the MOs from the CASSCF treatment is a key to reducing the LVMO domain size for the multireference case. Due to the augmented Hessian-based localization algorithm, an additional computational cost for obtaining the LVMOs is relatively minor. We demonstrate that the LVMO-based PNO-CASPT2 method is routinely applicable to large, real-life molecules such as Menshutkin SN2 reaction in a single-walled carbon nanotube reaction field.