SN2 Reaction Research Articles

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.

A Computational Study of a Prebiotic Synthesis of D-Riboflavin (Vitamin B2)

Ab initio applied computing is used to determine the viability of a plausible mechanism for the formation of riboflavin from planetary and interstellar gases that contain the necessary essential elements. The immutable laws of chemical thermodynamics and kinetics enable the intermediates in the synthesis to be characterized and the activation energies to be established. The gases propyne, cyanogen, carbon monoxide, and hydrogen are invoked in a synthesis of the isoalloxazine precursor of the vitamin riboflavin (Vitamin B2), whilst the additional presence of hydrogen cyanide enables the surface-catalyzed, photochemically activated synthesis of a D-ribitylamine requiring the magnesium metalloporphyrin catalyst. These two molecules then bond in a Sn2 reaction to form the final vitamin structure. The reactions have been shown to be feasible from the overall enthalpy changes in the ZKE approximation at the HF and MP2 /6-31G* level and with acceptable activation energies.

Chemical Expansion of the Methyltransferase Reaction: Tools for DNA Labeling and Epigenome Analysis.

DNA is the genetic matter of life composed of four major nucleotides which can be further furnished with biologically important covalent modifications. Among the variety of enzymes involved in DNA metabolism, AdoMet-dependent methyltransferases (MTases) combine the recognition of specific sequences and covalent methylation of a target nucleotide. The naturally transferred methyl groups play important roles in biological signaling, but they are poor physical reporters and largely resistant to chemical derivatization. Therefore, an obvious strategy to unlock the practical utility of the methyltransferase reactions is to enable the transfer of "prederivatized" (extended) versions of the methyl group.However, previous enzymatic studies of extended AdoMet analogs indicated that the transalkylation reactions are drastically impaired as the size of the carbon chain increases. In collaborative efforts, we proposed that, akin to enhanced SN2 reactivity of allylic and propargylic systems, addition of a π orbital next to the transferable carbon atom might confer the needed activation of the reaction. Indeed, we found that MTase-catalyzed transalkylations of DNA with cofactors containing a double or a triple C-C bond in the β position occurred in a robust and sequence-specific manner. Altogether, this breakthrough approach named mTAG (methyltransferase-directed transfer of activated groups) has proven instrumental for targeted labeling of DNA and other types of biomolecules (using appropriate MTases) including RNA and proteins.Our further work focused on the propargylic cofactors and their reactions with DNA cytosine-5 MTases, a class of MTases common for both prokaryotes and eukaryotes. Here, we learned that the 4-X-but-2-yn-1-yl (X = polar group) cofactors suffered from a rapid loss of activity in aqueous buffers due to susceptibility of the triple bond to hydration. This problem was remedied by synthetically increasing the separation between X and the triple bond from one to three carbon units (6-X-hex-2-ynyl cofactors). To further optimize the transfer of the bulkier groups, we performed structure-guided engineering of the MTase cofactor pocket. Alanine replacements of two conserved residues conferred substantial improvements of the transalkylation activity with M.HhaI and three other engineered bacterial C5-MTases. Of particular interest were CpG-specific DNA MTases (M.SssI), which proved valuable tools for studies of mammalian methylomes and chemical probing of DNA function.Inspired by the successful repurposing of bacterial enzymes, we turned to more complex mammalian C5-MTases (Dnmt1, Dnmt3A, and Dnmt3B) and asked if they could ultimately lead to mTAG labeling inside mammalian cells. Our efforts to engineer mouse Dnmt1 produced a variant (Dnmt1*) that enabled efficient Dnmt1-directed deposition of 6-azide-hexynyl groups on DNA in vitro. CRISPR-Cas9 editing of the corresponding codons in the genomic Dnmt1 alleles established endogenous expression of Dnmt1* in mouse embryonic stem cells. To circumvent the poor cellular uptake of AdoMet and its analogs, we elaborated their efficient internalization by electroporation, which has finally enabled selective catalysis-dependent azide tagging of natural Dnmt1 targets in live mammalian cells. The deposited chemical groups were then exploited as "click" handles for reading adjoining sequences and precise genomic mapping of the methylation sites. These findings offer unprecedented inroads into studies of DNA methylation in a wide range of eukaryotic model systems.

An insight into the thermal decomposition mechanism of 1-Butyl-3-methyl-imidazolium-5-aminotetrazolate guided by Py-GC–MS and DFT

Ionic liquids containing azole-based heterocyclic rings are potentially energetic due to the high nitrogen content and positive heat of formation. The thermal decomposition mechanism of 1-Butyl-3-methyl-imidazolium-5-aminotetrazolate (BMIMAT) has been studied by use of Py-GC–MS and B3LYP/6–311 + G(d,p) level of density functional theory (DFT). The mechanism of decomposition observed is a bimolecular nucleophilic substitution (SN2) reaction. The kinetics of decomposition is studied using Kissinger and Ozawa-Flynn-Wall (FWO) methods and the activation energy (Ea) obtained is complemented with computational studies.

Taming secondary benzylic cations in catalytic asymmetric SN1 reactions.

Benzylic stereogenic centers are ubiquitous in natural products and pharmaceuticals. A potentially general, though challenging, approach toward their selective creation would be asymmetric unimolecular nucleophilic substitution (SN1) reactions that proceed through highly reactive benzylic cations. We now report a broadly applicable solution to this problem by identifying chiral counteranions that pair with secondary benzylic cations to engage in catalytic asymmetric C-C, C-O, and C-N bond-forming reactions with excellent enantioselectivity. The critical cationic intermediate can be accessed from different precursors via Lewis- or Brønsted acid catalysis. Key to our strategy is the use of only weakly basic, confined counteranions that are posited to prolong the lifetime of the carbocation, thereby avoiding nonproductive deprotonation pathways to the corresponding styrene.

Anion-Activated Bases and Nucleophiles Characterized by Photoelectron Spectroscopy.

Negative ion photoelectron spectra at 20 K along with ab initio [CCSD(T)] and M06-2X density functional theory calculations are reported for a series of six basic and nucleophilic pyridine derivatives with an anionic substituent [i.e., 3- and 4-PyrBX3-, where X = F, 4-t-BuC6H4, 4-MeOC6H4, and 3,5-(MeO)2C6H3]. Vertical detachment energies (VDEs) of these charge-activated reagents span from 4.50-5.85 eV and are well reproduced by M06-2X/aug-cc-pVTZ and CCSD(T)/maug-cc-pVTZ computations. Surprisingly, the VDEs are found to correlate with the SN2 reactivity of the PPh4+ salts of the substituted pyridine anions with 1-iodooctane in dichloromethane. This provides an experimental measure of the nucleophilicity of these charge-activated anions, which represent a new class of chemical reagent.

Reformulating Reactivity Design for Data-Efficient Machine Learning.

Machine learning (ML) can deliver rapid and accurate reaction barrier predictions for use in rational reactivity design. However, model training requires large data sets of typically thousands or tens of thousands of barriers that are very expensive to obtain computationally or experimentally. Furthermore, bespoke data sets are required for each region of interest in reaction space as models typically struggle to generalize. We have therefore reformulated the ML barrier prediction problem toward a much more data-efficient process: finding a reaction from a prespecified set with a desired target value. Our reformulation enables the rapid selection of reactions with purpose-specific activation barriers, for example, in the design of reactivity and selectivity in synthesis, catalyst design, toxicology, and covalent drug discovery, requiring just tens of accurately measured barriers. Importantly, our reformulation does not require generalization beyond the domain of the data set at hand, and we show excellent results for the highly toxicologically and synthetically relevant data sets of aza-Michael addition and transition-metal-catalyzed dihydrogen activation, typically requiring less than 20 accurately measured density functional theory (DFT) barriers. Even for incomplete data sets of E2 and SN2 reactions, with high numbers of missing barriers (74% and 56% respectively), our chosen ML search method still requires significantly fewer data points than the hundreds or thousands needed for more conventional uses of ML to predict activation barriers. Finally, we include a case study in which we use our process to guide the optimization of the dihydrogen activation catalyst. Our approach was able to identify a reaction within 1 kcal mol-1 of the target barrier by only having to run 12 DFT reaction barrier calculations, which illustrates the usage and real-world applicability of this reformulation for systems of high synthetic importance.

Visible-Light-Promoted Aryl Cation Formation: Aromatic SN1 Reactions of Areneazo-2-(2-nitro)propanes.

The visible light excitation of areneazo-2-(2-nitro)propane·HCl salts generated the singlet aryl cation that readily underwent aromatic SN1 reactions with a variety of nucleophiles. The in situ generated singlet aryl cation was stabilized by a counter nitronate anion that prevented other intersystem crossing and single electron transfer processes. With the improved safety features of neutral areneazo-2-(2-nitro)propane derivatives, the current visible-light-promoted aromatic SN1 reactions provide an alternative aryl Csp2-X bond forming strategy.

The isocyanide SN2 reaction

The SN2 nucleophilic substitution reaction is a vital organic transformation used for drug and natural product synthesis. Nucleophiles like cyanide, oxygen, nitrogen, sulfur, or phosphorous replace halogens or sulfonyl esters, forming new bonds. Isocyanides exhibit unique C-centered lone pair σ and π* orbitals, enabling diverse radical and multicomponent reactions. Despite this, their nucleophilic potential in SN2 reactions remains unexplored. We have uncovered that isocyanides act as versatile nucleophiles in SN2 reactions with alkyl halides. This yields highly substituted secondary amides through in situ nitrilium ion hydrolysis introducing an alternative bond break compared to classical amide synthesis. This novel 3-component process accommodates various isocyanide and electrophile structures, functional groups, scalability, late-stage drug modifications, and complex compound synthesis. This reaction greatly expands chemical diversity, nearly doubling the classical amid coupling’s chemical space. Notably, the isocyanide nucleophile presents an unconventional Umpolung amide carbanion synthon (R-NHC(-) = O), an alternative to classical amide couplings.

Molecular basis for bacterial N-glycosylation by a soluble HMW1C-like N-glycosyltransferase

Soluble HMW1C-like N-glycosyltransferases (NGTs) catalyze the glycosylation of Asn residues in proteins, a process fundamental for bacterial autoaggregation, adhesion and pathogenicity. However, our understanding of their molecular mechanisms is hindered by the lack of structures of enzymatic complexes. Here, we report structures of binary and ternary NGT complexes of Aggregatibacter aphrophilus NGT (AaNGT), revealing an essential dyad of basic/acidic residues located in the N-terminal all α-domain (AAD) that intimately recognizes the Thr residue within the conserved motif Asn0-X+1-Ser/Thr+2. Poor substrates and inhibitors such as UDP-galactose and UDP-glucose mimetics adopt non-productive conformations, decreasing or impeding catalysis. QM/MM simulations rationalize these results, showing that AaNGT follows a SN2 reaction mechanism in which the acceptor asparagine uses its imidic form for catalysis and the UDP-glucose phosphate group acts as a general base. These findings provide key insights into the mechanism of NGTs and will facilitate the design of structure-based inhibitors to treat diseases caused by non-typeable H. influenzae or other Gram-negative bacteria.

Alternating Stereospecificity upon Central-Atom Change: Dynamics of the F- +PH2 Cl SN 2 Reaction Compared to its C- and N-Centered Analogues.

Central-atom effects on bimolecular nucleophilic substitution (SN 2) reactions are well-known in chemistry, however, the atomic-level SN 2 dynamics at phosphorous (P) centers has never been studied. We investigate the dynamics of the F- +PH2 Cl reaction with the quasi-classical trajectory method on a novel full-dimensional analytical potential energy surface fitted on high-level ab initio data. Our computations reveal intermediate dynamics compared to the F- +CH3 Cl and the F- +NH2 Cl SN 2 reactions: phosphorus as central atom leads to a more indirect SN 2 reaction with extensive complex-formation with respect to the carbon-centered one, however, the title reaction is more direct than its N-centered pair. Stereospecificity, characteristic at C-center, does not appear here either, due to the submerged front-side-attack retention path and the repeated entrance-channel inversional motion, whereas the multi-inversion mechanism discovered at nitrogen center is also undermined by the deep Walden-well. At low collision energies, 6 % of the PH2 F products form with retained configuration, mostly through complex-mediated mechanisms, while this ratio reaches 24 % at the highest energy due to the increasing dominance of the direct front-side mechanism and the smaller chance for hitting the deep Walden-inversion minimum. Our results suggest pronounced central-atom effects in SN 2 reactions, which can fundamentally change their (stereo)dynamics.

Regular reaction dynamics in analytical form in the vicinity of symmetrical transition states. Central barrier crossings in SN2 reactions.

When an activated complex, as defined in transition state theory (TST), has a polyhedral shape, its kinetic energy is found to be diagonal in a system of spherical polar coordinates. If, in addition, the polyhedron is characterized by a high symmetry, then its dynamics considerably simplifies. An application of this approach to the most symmetrical TS known to date, i.e., that which controls the Cl- + CH3Cl → ClCH3 + Cl- SN2 nucleophilic substitution, is presented and an analytical expression of its potential energy surface is provided. In a substantial range around the saddle point, approximate equations of motion for the two components of the reaction coordinate, i.e., the antisymmetrical stretching motion of the ClCCl core and the wagging motion of the hydrogen triad, can be derived in an analytical form. During an extensive period of time, the main component of the reaction coordinate is governed by an unexpectedly simple equation of motion that depends on a single initial condition, irrespective of the other ones and of the internal energy. Reactive trajectories are observed to form a perfectly collimated bundle characterized by undetectable dispersion, thereby giving a spectacular example of regular dynamics in an anharmonic potential. Regularity and collimation are brought about by local symmetry, which is a widespread feature of potential energy surfaces. Anharmonicity is observed to influence the dynamics only at a late stage. As energy increases, trajectories tend to fan out and to deviate from the analytical equation. For the wagging motion, chaos sets in at much lower energies.

Competition between Elimination and Substitution for Ambident Nucleophiles CN- and Iodoethane Reactions in Gaseous and Aqueous Medium.

Nucleophilic substitution (SN2) and elimination (E2) reactions between ambident nucleophiles have long been considered as typical reactions in organic chemistry, and exploring the competition between the two reactions is of great importance in chemical synthesis. As a nucleophile, CN- can use its C and N atoms as the reactive centers to undergo E2 and SN2 reactions, but related research is currently limited. This study uses the CCSD(T)/pp/t//MP2/ECP/d electronic structure method to perform detailed investigations on the potential energy profiles for SN2 and E2 reactions between CN- and CH3CH2I in gaseous and aqueous media. The potential energy profiles reveal that the energy barriers for SN2 and E2 reactions with the C atom as the reactive center are consistently lower than those with the N atom, indicating that the C atom has a stronger nucleophilic ability and stronger basicity. Furthermore, the potential energy profiles in both gas and aqueous environments show that the barriers of SN2 reactions are lower than those for E2 reactions with both C and N as the attacking atom. By using the frontier molecular orbital and activation strain models to explain the interesting phenomenon, the transition from the gas phase to solution was investigated, specifically in the gas-microsolvation-water transition. The results show that water molecules reduce the nucleophilicity and basicity of CN-, while strain energy (ΔEstrain) causes a greater increase in the energy barrier for E2 reactions. This study provides new insights and perspectives on the understanding of CN- as a nucleophile in SN2 reactions and serves as theoretical guidance for organic synthesis.

Effects of Methyl Substitution and Leaving Group on E2/SN2 Competition for Reactions of F- with RY (R = CH3, C2H5, iC3H7, tC4H9; Y = Cl, I).

The competition between base-induced elimination (E2) and bimolecular nucleophilic substitution (SN2) is of significant importance in organic chemistry and is influenced by many factors. The electronic structure calculations for the gas-phase reactions of F- + RY (R = CH3, C2H5, iC3H7, tC4H9, and Y = Cl, I) are executed at the MP2 level with aug-cc-pVDZ or ECP/d basis set to investigate the α-methyl substitution effect. The variation in barrier height, reaction enthalpy, and competition of SN2/E2 as a function of methyl-substitution and leaving group ability has been emphasized. And the nature of these rules has been explored. As the degree of methyl substitution on α-carbon increases, the E2 channel becomes more competitive and dominant with R varying from C2H5, iC3H7, to tC4H9. Energy decomposition analysis offers new insights into the competition between E2 and SN2 processes, which suggests that the drop in interaction energy with an increasing degree of substitution cannot compensate for the rapid growth of preparation energy, leading to a rapid increase in the SN2 energy barrier. By altering the leaving group from Cl to I, the barriers of both SN2 and E2 monotonically decrease, and, with the increased number of substituents, they reduce more dramatically, which is attributed to the looser transition state structures with the stronger leaving group ability. Interestingly, ∆E0‡ exhibits a positive linear correlation with reaction enthalpy (∆H) and halogen electronegativity. With the added number of substituents, the differences in ∆E0‡ and ∆H between Y = Cl and I likewise exhibit good linearity.

Synergistic interaction and alkali resistance of N-spirocyclic cations with piperidine cations for poly(biphenyl piperidine) membranes

The conformation of N-spirocyclic cations has a high alkaline stability and the construction of microphase-separated structures with poly(biphenyl piperidine) (PBP) is one way to improve the performance of AEM. Here, a variety of N-spirocyclic cations were prepared and formed into polycationic side chains with the PBP main chain via the -(CH2)4- spacer group. The ion transport efficiency was greatly enhanced by the synergistic effect of the main chain piperidine cations, and the hydroxide conductivity and peak power density of the MDSU-MPBP membrane reached 132.7 mS cm-1 and 295.2 mW cm-2 at 80 °C, respectively. The BM-DSU cation was degraded to a single cation mainly by the SN2 reaction after 96 h in a 5 M NaOH/D2O solution at 80 °C. The N-spirocyclic mono-cation has extremely high alkali resistance, especially the MDSU cation without significant degradation at 80 °C for 1008 h. The B-MDSU double cation tends to undergo the SN2 reaction at the C2 and C4 positions. The asymmetrically grafted main-chain piperidine cations exhibit poor chemical stability due to the electron-absorbing effect of the phenyl group. the degradation of the MDSU cations increases the hydrophobicity of the side chains, and the MDSU-MPBP membrane has the best alkali resistance, with a conductivity residual of more than 92.8% after immersion in a 5 M NaOH solution at 80 °C for 480 h.

Influence of Lewis acids on the symmetric SN2 reaction

This paper presents a theoretical analysis the effect of non-covalent interactions (NCI) in three different SN2 reactions (X–:CH3X → XCH3:X–, X = Cl, Br and I) has been theoretically analysed in the pre-reactive complexes, TS and products. A total of eighteen Lewis acids (LAs: FH, ClH, FCl, I2, SeHF, SeF2, PH2F, PF3, SiH3F, SiF4, BH3, BF3, BeH2, BeF2, LiH, LiF, Au2 and AgCl) interact with the halogen atom of the CH3X molecule. To analyse the strength of the non-covalent interactions, both the independent gradient model tool and electron density maps have been employed. The results reveal that in all cases, the interaction between the anion and the Lewis acid leads to an increase in the transition barriers compared to the parental reaction.

Nickel-Catalyzed Amination of Alkyl Electrophiles.

Bimolecular nucleophilic substitution SN2 is the earliest and most important means of amination of alkyl electrophiles; its practical utilization is largely limited to primary or activated substrates. Furthermore, a persistent challenge lies in establishing C(sp3)-N bonds from alkyl substrates in cross-coupling chemistry using palladium and nickel catalysts. Therefore, the methods of constructing C(sp3)-N bonds remain rare from alkyl electrophiles. The existing routes are limited to copper catalysis and photoredox catalysis. Here, we demonstrate an alternative amination strategy for rapid construction of C(sp3)-N bonds from accessible alkyl electrophiles, which were used as radical precursors under nickel catalysis by Ni (III) species reductive eliminations in high efficiency.

Electrostatically Enhanced 3- and 4-Pyridyl Borate Salt Nucleophiles and Bases.

A variety of electrostatically enhanced 3- and 4-pyridylborate salt catalysts are reported and show significant improvement over an activated noncharged neutral control compound. Their nucleophilicity in a stoichiometric SN2 reaction and catalytic performance in a urethane synthesis are evaluated along with three methods for rapidly evaluating the basicity of these species. That is, qualitative titrations in CH2Cl2 and CHCl3 were carried out, two separate solution-state IR studies in CCl4 and CDCl3 are reported, and the proton affinities of the anionic components of the salts were computed. Charge differences between the anion and its protonated zwitterionic conjugate acid are evaluated along with the highest occupied molecular orbitals of the anions in relationship to some of the surprising reactivity findings that were observed in the two kinetic studies.

Spontaneous Generation of Aryl Carbocations from Phenols in Aqueous Microdroplets: Aromatic SN1 Reactions at the Air-Water Interface.

Although phenol is stable in bulk water, we report an exceptional phenomenon in which phenol is spontaneously transformed into a phenyl carbocation (Ph+) in water microdroplets. The high electric field at the air-water interface is proposed to break the phenolic Csp2-OH bond, forming Ph+, which remains in equilibrium with phenol as deciphered by mass spectrometry. We detected up to 70% conversion of phenol to Ph+ in aqueous microdroplets, although catalyst-free activation of the phenolic Csp2-OH bond is challenging. This transformation is well tolerated by a wide range of electron-donating and -withdrawing substituents in phenolic compounds. The Ph+ in water microdroplets could be reacted with various nucleophiles (amine, pyridine, azide, thiol, carboxylic acid, alcohol, and 18O-water), yielding the ipso-substitution products of phenol through an aromatic SN1 mechanism. Despite the fleeting life of Ph+ in the bulk, this study demonstrates its unusual stability at the aqueous microdroplet surface, enabling its detection and transformation.