Gas-phase SN2 Reactions Research Articles

Electronic Distribution of SN2 IRC and TS Structures: Infrared Intensities of Imaginary Frequencies.

A novel IRC-TS-CCTDP method to investigate transition states (TS) is proposed in which changes in the molecular geometry follow atomic displacements corresponding to the imaginary frequency normal coordinate. Electronic charge structure changes can be analyzed using the charge-charge-transfer-dipolar polarization (CCTDP) model. An application is presented for the gas-phase SN2 reaction transition state structures for nine NuCX3LG- systems, with Nu and LG = H, F, Cl and X = H, F. Using quantum theory of atoms in molecules (QTAIM) at the QCISD/aug-cc-pVTZ level, atomic charges and atomic dipoles were obtained and applied to calculate the CCTDP contributions to their imaginary normal mode intensities. The results show that the imaginary bands are exceptionally strong, ranging from 1217 to 16 086 km·mol-1, much higher than the stretching intensities found in the methyl halides (that are all less than 100 km·mol-1). For all systems, the CT contributions are responsible for 63% of the total dipole moment derivatives. The charge contributions are slightly higher for transition states where X = F. Dipolar polarization contributions are always small and only reflect the molecular orientation change when the nucleophile displaces the leaving group and, therefore, can be neglected. The same occurs for contributions from the X atoms. Only atoms aligned with the reaction axis Nu--C-LG contribute to the total intensity. Almost all of the infrared intensities are determined by electron transfers from the nucleophile to carbon and subsequently from carbon to the leaving group. The mechanism of charge transfer revealed by the CCTDP model is consistent with the well-accepted reaction mechanism. Open-access codes for performing the IRC-TS-CCTDP analysis are described and provided for potential users in the Supporting Information.

Fifty years of nucleophilic substitution in the gas phase.

Bimolecular nucleophilic substitution (SN2) reactions have become a model system for the investigation of structure–reactivity relationships, stereochemistry, solvent influences, and detailed atomistic dynamics. In this review, the progress during five decades of experimental and theoretical research on gas phase SN2 reactions is discussed. Many advancements of the employed methods have led to a tremendous increase in our understanding of the properties and the dynamics of these reactions. For reactions involving six atoms a quantitative agreement of the differential reactive scattering cross sections has already been achieved, in the future it is expected that even larger polyatomic reactions systems become tractable. Furthermore, studies with higher precision, improved reactant control, and a more accurate theoretical treatment of quantum effects are envisioned.

On the Role of Hydrogen Bonding in Gas-Phase SN2 Reactions at Silicon.

The shape of the potential energy surface (PES) of gas-phase SN2 reactions at silicon is determined by the type of nucleophile, the leaving group, and substituents which remain bonded to silicon. In this study, we present PES scans along the reaction coordinate of six symmetrical SN2 reactions: X- + SiR3X → XSiR3 + X-, where X = Cl or F and R = H, Me, or OMe. While the fluorine systems and the ClSiH3Cl system only give single-well PESs, ClSiMe3Cl and ClSi(OMe)3Cl give triple- and double-well PESs with stable pre- and post-reaction complexes. A complementary bonding analysis (energy decomposition analysis, quantum theory of atoms in molecules, and natural bond orbitals) reveals that the leaving group (X-) is stabilized by hydrogen bonding in the XSiMe3X and XSi(OMe)3X systems. It is shown that this so far neglected stabilizing contribution, along with σ-hole bonding, is responsible for the shapes of the PESs of ClSiMe3Cl and ClSi(OMe)3Cl in the gas phase.

Ground State Destabilization in Uracil DNA Glycosylase: Let's Not Forget "Tautomeric Strain" in Substrates.

Enzymes like uracil DNA glycosylase (UDG) can achieve ground state destabilization, by polarizing substrates to mimic rare tautomers. On the basis of computed nucleus independent chemical shifts, NICS(1)zz, and harmonic oscillator model of electron delocalization (HOMED) analyses, of quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM) models of the UDG active site, uracil is strongly polarized when bound to UDG and resembles a tautomer >12 kcal/mol higher in energy. Natural resonance theory (NRT) analyses identified a dominant O2 imidate resonance form for residue bound 1-methyl-uracil. This "tautomeric strain" raises the energy of uracil, making uracilate a better than expected leaving group. Computed gas-phase SN2 reactions of free and hydrogen bonded 1-methyl-uracil demonstrate the relationship between the degree of polarization in uracil and the leaving group ability of uracilate.

Microsolvation effects on the reactivity of oxy-nucleophiles: the case of gas-phase SN2 reactions of YO-(CH3OH) n=1,2 towards CH3Cl.

The modified G4(MP2) method was applied to explore microsolvation effects on the reactivity of four solvated normal oxy-nucleophiles YO-(CH3OH) n=1,2 (Y=CH3, C2H5, FC2H4, ClC2H4), and five α-oxy-nucleophiles YO-(CH3OH) n=1,2 (Y=HO, CH3O, F, Cl, Br), in gas-phase SN2 reactions towards the substrate CH3Cl. Based on a Brønsted-type plot, our calculations reveal that the overall activation barriers of five microsolvated α-oxy-nucleophiles are obviously smaller than the prediction from the correlation line constructed by four normal microsolvated ones to different degrees, and clearly demonstrate the existence of an α-effect in the presence of one or two methanol molecule(s). Moreover, it was found that the α-effect of the mono-methanol microsolvated α-nucleophile is stronger than that of the monohydrated α-nucleophile. However, the α-effect of YO-(CH3OH)2 becomes weaker for Y=HO and CH3O, whereas it becomes stronger for Y=F, Cl, Br than that of YO-(H2O)2, which can be explained by analyses of the activation strain model in the two cases. It was also found that the rationale about the low ionization energy of α-nucleophile inducing the α-effect was not widely significant. Graphical abstract Variation of alpha-effect in the gas-phase SN2 reaction with the microsolvation.

Orbital Energy-Based Reaction Analysis of SN2 Reactions

An orbital energy-based reaction analysis theory is presented as an extension of the orbital-based conceptual density functional theory. In the orbital energy-based theory, the orbitals contributing to reactions are interpreted to be valence orbitals giving the largest orbital energy variation from reactants to products. Reactions are taken to be electron transfer-driven when they provide small variations for the gaps between the contributing occupied and unoccupied orbital energies on the intrinsic reaction coordinates in the initial processes. The orbital energy-based theory is then applied to the calculations of several S N2 reactions. Using a reaction path search method, the Cl− + CH3I → ClCH3 + I− reaction, for which another reaction path called “roundabout path” is proposed, is found to have a precursor process similar to the roundabout path just before this SN2 reaction process. The orbital energy-based theory indicates that this precursor process is obviously driven by structural change, while the successor SN2 reaction proceeds through electron transfer between the contributing orbitals. Comparing the calculated results of the SN2 reactions in gas phase and in aqueous solution shows that the contributing orbitals significantly depend on solvent effects and these orbitals can be correctly determined by this theory.

Why Do Enolate Anions Favor O-Alkylation over C-Alkylation in the Gas Phase? The Roles of Resonance and Inductive Effects in the Gas-Phase SN2 Reaction between the Acetaldehyde Enolate Anion and Methyl Fluoride.

Contributions by resonance and inductive effects toward the net activation barrier were determined computationally for the gas-phase SN2 reaction between the acetaldehyde enolate anion and methyl fluoride, for both O-methylation and C-methylation, in order to understand why this reaction favors O-methylation. With the use of the vinylogue extrapolation methodology, resonance effects were determined to contribute toward increasing the size of the barrier by about 9.5 kcal/mol for O-methylation and by about 21.2 kcal/mol for C-methylation. Inductive effects were determined to contribute toward increasing the size of the barrier by about 1.7 kcal/mol for O-methylation and 4.2 kcal/mol for C-methylation. Employing our block-localized wave function methodology, we determined the contributions by resonance to be 12.8 kcal/mol for O-methylation and 22.3 kcal/mol for C-methylation. Thus, whereas inductive effects have significant contributions, resonance is the dominant factor that leads to O-methylation being favored. More specifically, resonance serves to increase the size the barrier for C-methylation significantly more than it does for O-methylation.

Beyond textbook SN2 chemistry

Organic Chemistry In one of best-studied organic reactions, a negatively charged ion such as chlorine replaces another atom or group of atoms in an organic molecule. According to the traditional understanding of this SN2 reaction, pre- and post-reaction complexes form, and the configuration at the carbon that binds the ion is inverted during the reaction. In a Perspective, Xie and Hase highlight recent studies that have revealed a host of other mechanisms in the gas-phase SN2 reaction. In some of these mechanisms, the configuration of the resulting molecule is not inverted. The dominant mechanism depends on the nature of the reactants and on the reaction conditions. For one SN2 reaction, 28 different mechanisms have been found. Science , this issue p. [32][1] [1]: /lookup/doi/10.1126/science.aaf5172

Dissociation Enthalpies of Chloride Adducts of Nitrate and Nitrite Explosives Determined by Ion Mobility Spectrometry.

The kinetics for thermal dissociations of the chloride adducts of the nitrate explosives 1,3-dinitroglycerin (1,3-NG), 1,2-dinitroglycerin (1,2-NG), the nitrite explosive 3,4-dinitrotoluene (3,4-DNT), and the explosive taggant 2,3-dimethyl-2,3-dinitrobutane (DMNB) have been studied by atmospheric pressure ion mobility spectrometry. Both 1,3-NG·Cl(-) and1,2-NG·Cl(-) decompose in a gas-phase SN2 reaction in which Cl(-) displaces NO3(-) while 3,4-DNT·Cl(-) and DMNB·Cl(-) decompose by loss of Cl(-). The determined activation energy (kJ mol(-1)) and pre-exponential factor (s(-1)) values for the dissociations respectively are 1,3-NG·Cl(-), 86 ± 2 and 2.2 × 10(12); 1,2-NG·Cl(-), 97 ± 2 and 3.5 × 10(12); 3,4-DNT·Cl(-), 81 ± 2 and 4.8 × 10(13); and DMNB·Cl(-), 68 ± 2 and 9.7 × 10(11). Calculations by density functional theory show the structures of the nitrate ester adducts involve three hydrogen bonds: one from the hydroxyl group and the other two from the two nitrated carbons. The relative Cl(-) dissociation energies of the nitrates together with the previously reported smaller value for glycerol trinitrate and the calculated highest value for glycerol 1-mononitrate are explicable in terms of the number of hydroxyl hydrogen bond participants. The theoretical enthalpy changes for the nitrate ester displacement reactions are in agreement with those derived from the experimental activation energies but considerably higher for the nitro compounds.

Influence of the leaving group on the dynamics of a gas-phase SN2 reaction.

In addition to the nucleophile and solvent, the leaving group has a significant influence on SN2 nucleophilic substitution reactions. Its role is frequently discussed with respect to reactivity, but its influence on the reaction dynamics remains unclear. Here, we uncover the influence of the leaving group on the gas-phase dynamics of SN2 reactions in a combined approach of crossed-beam imaging and dynamics simulations. We have studied the reaction F(-) + CH3Cl and compared it to F(-) + CH3I. For the two leaving groups, Cl and I, we find very similar structures and energetics, but the dynamics show qualitatively different features. Simple scaling of the leaving group mass does not explain these differences. Instead, the relevant impact parameters for the reaction mechanisms are found to be crucial and the differences are attributed to the relative orientation of the approaching reactants. This effect occurs on short timescales and may also prevail in solution-phase conditions.

Influence of a β-OH substituent on SN2 reactions of fluoroethane: Intramolecular hydrogen bonding catalysis or inhibition? A theoretical study

Computational investigations on the gas phase SN2 reactions of X ions (X-=OH-,F-,Cl-,Br-, and I-) with fluoroethane and 2-fluoroethanol (β-hydroxyl ethyl fluoride) were performed by using MPW1K, M06 and CCSD(T) methods with a range of basis sets including 66-311++G∗∗, TZVP, aug-cc-pVDZ and SDD. To better understand the nature of the corresponding intermolecular interactions, we performed natural bond orbital (NBO) analysis and Bader’s quantum theory of atoms in molecules (QTAIM). In our calculations, we took into account two possible pathways for these reactions, i.e. SN2 reactions of 2-fluoroethanol. In path(i), β-hydroxyl group participates in hydrogen bonding (H-bonding) with fluoride ion as leaving group in transition state. However, in path(ii), transition state includes H-bonding between hydroxyl group and nucleophile X−. Results indicate that in comparison with the absence of β-OH substituent i.e. reactions of fluoroethane, the activation barrier decreases in path(i), but increases in path(ii). The progress of each pathway depends on H-bonding character of nucleophile and leaving group. In addition, for X-=Cl- we compared β-OH group effect in the gas phase with its effect in dimethyl sulfoxide (DMSO).

Charge Distributions of Gas-phase SN2 Reactions: ABEEM-σπ Method Compared with Potential Acting on an Electron in a Molecule

Abstract The SN2 reactions at C and Si have been investigated by ABEEM-σπ method compared with the potential acting on an electron in a molecule (PAEM). The ABEEM-σπ model demonstrates the charge distributions of the atom region, bond region, and lone-pair electron region during the course of the reaction. The differences between title reactions have been demonstrated. Studies indicate that there are good linear correlations among the charges obtained by ABEEM-σπ method, the force constants, the relative energies, the ionization potentials, etc. This study enhances our understanding of the electron transfer from the nucleophile to the leaving group.

An ion mobility and theoretical study of the thermal decomposition of the adduct formed between ethylene glycol dinitrate and chloride

An ion mobility spectrometer has been used to isolate and study the decomposition of the adduct formed between the chloride ion and ethylene glycol dinitrate (EGDN). Two shutter operation allows isolation of the adduct and observation of its decomposition to 2-chloroethyl nitrate (ClEN)+NO3− as it travels along the spectrometer drift region. The reaction is the expulsion of one of the NO3 groups of EGDN by Cl. The rate constants for the decomposition reaction measured over the temperature range 79–97°C give the Arrhenius parameters Ea=59.2±1.1kJmol−1 and ln A(s−1)=24.0±0.5. Ab initio calculations show that the reaction is a gas-phase SN2 reaction with a penta-coordinated carbon in the transition state between two stable intermediate ion-molecule complexes EGDN·Cl− and ClEN·NO3−. Calculation shows that NO2− reacts with EGDN in an analogous manner to Cl−, replacing one of the nitrate groups to form ethylene nitrate nitrite (ENN)+NO3−. The implication of these results for the ion chemistry of nitrate esters in the presence and absence of dopants over a range of temperatures is discussed.

Investigating the α-Effect in Gas-Phase SN2 Reactions of Microsolvated Anions

The α-effect-enhanced reactivity of nucleophiles with a lone-pair adjacent to the attacking center-was recently demonstrated for gas-phase S(N)2 reactions of HOO(-), supporting an intrinsic component of the α-effect. In the present work we explore the gas-phase reactivity of microsolvated nucleophiles in order to investigate in detail how the α-effect is influenced by solvent. We compare the gas-phase reactivity of the microsolvated α-nucleophile HOO(-)(H2O) to that of microsolvated normal alkoxy nucleophiles, RO(-)(H2O), in reaction with CH3Cl using a flowing afterglow-selected ion flow tube instrument. The results reveal enhanced reactivity of HOO(-)(H2O) and clearly demonstrate the presence of an α-effect for the microsolvated α-nucleophile. The association of the nucleophile with a single water molecule results in a larger Brønsted βnuc value than is the case for the unsolvated nucleophiles. Accordingly, the reactions of the microsolvated nucleophiles proceed through later transition states in which bond formation has progressed further. Calculations show a significant difference in solvent interaction for HOO(-) relative to the normal nucleophiles at the transition states, indicating that differential solvation may well contribute to the α-effect. The reactions of the microsolvated anions with CH3Cl can lead to formation of either the bare Cl(-) anion or the Cl(-)(H2O) cluster. The product distributions show preferential formation of the Cl(-) anion even though the formation of Cl(-)(H2O) would be favored thermodynamically. Although the structure of the HOO(-)(H2O) cluster resembles HO(-)(HOOH), we demonstrate that HOO(-) is the active nucleophile when the cluster reacts.

Theoretical analysis on the kinetic isotope effects of bimolecular nucleophilic substitution (S(N)2) reactions and their temperature dependence.

Factors affecting the kinetic isotope effects (KIEs) of the gas-phase SN2 reactions and their temperature dependence have been analyzed using the ion-molecule collision theory and the transition state theory (TST). The quantum-mechanical tunneling effects were also considered using the canonical variational theory with small curvature tunneling (CVT/SCT). We have benchmarked a few ab initio and density functional theory (DFT) methods for their performance in predicting the deuterium KIEs against eleven experimental values. The results showed that the MP2/aug-cc-pVDZ method gave the most accurate prediction overall. The slight inverse deuterium KIEs usually observed for the gas-phase SN2 reactions at room temperature were due to the balance of the normal rotational contribution and the significant inverse vibrational contribution. Since the vibrational contribution is a sensitive function of temperature while the rotation contribution is temperature independent, the KIEs are thus also temperature dependent. For SN2 reactions with appreciable barrier heights, the tunneling effects were predicted to contribute significantly both to the rate constants and to the carbon-13, and carbon-14 KIEs, which suggested important carbon atom tunneling at and below room temperature.

Theoretical Study on the Gas‐Phase SN2 Reaction of Microhydrated Fluoride with Methyl Fluoride

AbstractThe rate constants for the gas‐phase SN2 reaction of F−(H2O) with CH3F have been calculated using the dual‐level variational transition state theory including multidimensional tunneling from 50 to 500 K. Tunneling was found to dominate the reaction below 200 K. The deuterium, 13C, and 14C kinetic isotope effects (KIEs) and solvent (D2O) isotope effects (SKIEs) were also calculated in the same temperature range. The results indicated that the deuterium and heavy water substitutions resulted in inverse KIEs (0.6∼0.8 ) while the 13C and 14C substitutions resulted in normal KIEs (1.0∼1.2) at room temperature. The calculated carbon KIEs increased significantly below 80 K due to the differences in the magnitude of the tunneling effects for different isotopic substitutions.

Neutral Metal Atoms Acting as a Leaving Group in Gas-Phase SN2 Reactions: M(CH3)+ + NH3 → CH3NH3+ + M (M = Zn, Cd, Hg)

Under ambient conditions, mass-selected “bare” M(CH3)+ ions (M = Zn, Cd, Hg) react with ammonia with cleavage of the metal–carbon bond and concomitant C–N coupling, yielding N-protonated methylamine, CH3NH3+; the neutral atomic metals M serve as a novel type of leaving group. In contrast, all three cationic metal amides, M(NH2)+, do not afford C–N bond formation in quasi-thermal ion/molecule reactions with methane. With regard to the mechanism, computational studies reveal that CH3NH3+ is generated in a clean gas-phase SN2 reaction with inversion of configuration at the carbon center; nucleophilic substitution with configurational retention is prohibited by a kinetic barrier. Further, N–H bond activation in the couples M(CH3)+/NH3 and C–H bond activation in M(NH2)+/CH4 are kinetically inhibited by transition structures which are higher in energy in comparison to the entrance channels.

Resolving the α-effect in gas phase SN2 reactions: A Marcus theory approach

Recently we reported experimental validation of the α-effect in the gas phase. However, an earlier study by our group showed a lack of enhanced reactivity in a series of SN2 reactions of α-nucleophiles with methyl chloride conflicting with computational predictions. In an attempt to resolve these discrepancies, we investigate the SN2 reactions for methyl chloride of low exothermicity where the smaller thermodynamic component of the activation barrier may expose α-nucleophilicity. The efficiencies for the reactions of several normal nucleophiles [C6H5O−, HC(O)O−, CH3C(O)O−] and alpha-nucleophiles [HC(O)OO−, CH3C(O)OO−] with CH3Cl are added to our previous Brønsted plot of normal and α-nucleophile reactions with methyl chloride. While the presence of an α-effect is suggested in some of the reactions with methyl chloride at lower basicities, the homologous properties of the “normal” ions in this region deviate from straight-chain alkoxides making the definition of “normal” reactivity more difficult. Application of Marcus theory provides insight into the intrinsic nature of the α-effect and how easily intrinsic differences can be masked. Computational barriers were utilized to estimate an “average” Marcus intrinsic barrier for several reactions at two different levels of theory. The “average” intrinsic barrier for the identity reaction of HOO− lies roughly 15kJmol−1 below those of the “normal” nucleophiles, but this intrinsic difference is a maximum that can be significantly masked by leaving group barrier contributions to the overall Marcus activation barrier and thermodynamic driving forces. Variations in the intrinsic Marcus barriers of the anion(s) defining “normal” reactivity will play a key role in the magnitude of the α-effect. Significantly lower electron affinities (∼0.6eV) are associated with the formation of the α-oxyanions compared to the normal oxyanions (X+e−→X−) suggesting that the ease of charge transfer between the nucleophile and transition state is responsible for the lower barriers of the α-nucleophiles.

Differential reaction cross sections from rotationally resolved quantum scattering calculations: application to gas-phase SN2 reactions

Differential reaction cross sections have been computed based on previous rotationally resolved time-independent quantum-mechanical scattering calculations for the complex-forming S(N)2 reaction Cl(-) + CH(3)Br → ClCH(3) + Br(-). The results show almost isotropic cross sections for reactant molecules with high rotational quantum numbers. Backward scattering is disfavoured for reaction out of states with small rotational excitation, in particular the rovibrational ground state. This is a quantum-mechanical effect (interference of partial waves) that can partly be rationalized by simple classical arguments. In particular for higher vibrational excitations, an umbrella effect can be observed that favours the backward direction. It can be explained by the strong enhancement of the reactivity by opening a direct mechanism. The ion-dipole interaction exerts a torque onto the molecule which carries out a rotation by about 90° and then completes the reaction.

Ethyl Anomaly in the Nucleophilic Substitution at a Series of β-Methylated Alkyl RCH2Z and Carbonyl RCOZ Carbon Centers for R = Me, Et, i-Pr, t-Bu, and Z = LG.

We have carried out DFT studies to explore the cause of anomalously fast reaction rates of ethyl group (R = Et) in the gas-phase S(N)2 reactions of RCH(2)Cl+Cl(-) and RCH(CN)Cl+Cl(-), and also for those in the cationic forms of RCH(2)(+) and RCH(CN)(+) with R = Me, Et, i-Pr, and t-Bu. The TS stabilization by hyperconjugative donor-acceptor vicinal charge transfers (CTs) from R to the major NBOs at the reaction center carbon in the S(N)2 TSs were estimated using natural bond orbital (NBO) analyses. In all cases the hyperconjugative CT stabilization increases in the order R = t-Bu < i-Pr < Me < Et in agreement with the experimental as well as theoretical rate orders, exhibiting an ethyl anomaly. We have also determined the reorganization energies and hyperconjugative CTs from R to the two major NBOs, C-O(-) and C-N(+), in the tetrahedral intermediate formed with five water molecules, T(5w), by transformation of sp(2) to sp(3) centers in the reactions of RC(═O)OC(6)H(5) with NH(3). The reorganization energy is the lowest and CT stabilization is the strongest with R = Et in line with the fastest experimental rate. We conclude that C-H is a better donor than C-C bond orbital and hyperconjugative vicinal σ chain extension leads to a stronger CT stabilization in the TS. The stronger CT stabilization for R = Et rather than Me is achieved by enhanced hyperconjugative CT to the reaction center in the TS as a result of narrower energy gap and greater overlap brought about by long-range orbital mixing as the C-H σ-chain is extended from n = 2 for Me to n = 3 for Et. We find that CT properties of the all-trans vicinal hyprconjugative C-H σ-chains are closely analogous to the corresponding conjugative polyene π-chains although skeletal patterns of bridge bonds are different and the stabilization energy gained by extension of the σ-chain is much weaker than that gained by the π-chain.