Frontside Attack Research Articles

Exploring the reaction mechanistic pathway for the sensing of G-Series nerve agent with Kemp's triacid derivative: A computational study

Kemp's triacid derivative have been reported as a candidate for sensing of nerve agents employing the photoinduced electron transfer (PET) processes. The sensor probe molecules were prepared with primary alcohol in very close proximity to a tertiary amine to acylate the alcohol with rapid intramolecular N-alkylation to produce quaternary ammonium salt. The reaction pathways for the formation of quaternary ammonium salt and isomethyl propyl phosphonate remain unexplored. In this report, the mechanistic pathways of G-series nerve agents sarin and its simulant diethylcholorophosphate (DCP) with Kemp's triacid derivatives has been explored computationally. The calculations performed with B3LYP-D3/6-311+G(d,p) level of theory in DCM solvent revealed that the reaction proceeds via intermolecular and intramolecular SN2 pathways. The probe molecule is sterically hindered, therefore, the frontside and backside SN2 reaction pathways have been examined. The computed results suggest that the first intermolecular SN2 reaction of Kemp's triacid derivatives (I &II) with sarin for the backside attack is energetically favored compared to the frontside attack and the following intramolecular SN2 reaction is a barrierless process. The calculations performed with simulant diethylcholorophosphate (DCP) and Kemp's triacid derivatives (I &II) show that the reactions are energetically more facile compared to the nerve agent sarin molecule. The Distortion-Interaction model and ΔNBOSteric analysis showed that the back side is energetically favored over the front side attack in such SN2 reactions. The designed Kemp's triacid derivative (II) with phosphorus center for sensing sarin and (DCP) suggests that the size of the hetero centers are important to facilitate the reaction in the probe molecule.

Computational Studies of Nucleophilic Substitution at Nitrogen Center: Reactions of NH2Cl with HO-, CH3O- and C2H5O.

The atomic-level mechanisms of the nucleophilic substitution reactions at the nitrogen center (SN2@N) were investigated for the reactions of chloramine (NH2Cl) with the alkoxide ions (RO-, where R = H, CH3, and C2H5) using DFT and MP2 methods. The computed potential energy profiles for the SN2@N pathways involving the back-side attack of the nucleophiles show the typical double-well potential with submerged barriers similar to the SN2@N reactions at the carbon center (SN2@C). However, the pre-reaction and post-reaction complexes are, respectively, the N-H…O and N-H…Cl hydrogen-bonded intermediates, which are different from those generally seen in SN2@C reactions. The SN2@N pathways involving front-side attack of the nucleophiles have high-energy barriers. The potential energy surfaces (PESs) along the proton-transfer pathways were flat. In addition to the proton-transfer and SN2 pathways, we also observed a new path for the methoxide and ethoxide nucleophiles where a hydride transfer from the nucleophile to chloramine resulted in the products Cl- + R'CHO + NH3, (R' = H, CH3), and was the most exoergic. A comparison of the energetics obtained used different DFT and MP2 methods with that of the benchmark coupled-cluster methods reveals that CAM-B3LYP best describes the PESs.

Benchmark ab initio characterization of the multi-channel Cl + CH3X [X = F, Cl, Br, I] reactive potential energy surfaces.

We determine benchmark geometries and relative energies for the stationary points of the Cl + CH3X [X = F, Cl, Br, I] reactions. We consider four possible reaction pathways: hydrogen abstraction, hydrogen substitution, halogen abstraction, and halogen substitution, where the substitution processes can proceed via either Walden inversion or front-side attack. We perform geometry optimizations and obtain harmonic vibrational frequencies at the explicitly-correlated UCCSD(T)-F12b/aug-cc-pVTZ level of theory, followed by UCCSD(T)-F12b/aug-cc-pVQZ single-point computations to make finite-basis-set error negligible. To reach chemical (<1 kcal mol-1), or even subchemical (<0.5 kcal mol-1) accuracy, we include core-correlation, scalar relativistic, post-(T), spin-orbit-splitting and zero-point-energy contributions, as well, in the relative energies of all the stationary points. Our benchmark 0 K reaction enthalpies are compared to available experimental results and show good agreement. The stationary-point structures and energetics are interpreted in terms of Hammond's postulate and used to make predictions related to the dynamical behavior of these reactive systems.

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.

Imaging Frontside and Backside Attack in Radical Ion-Molecule Reactive Scattering.

We report on the reactive scattering of methyl iodide, CH3I, with atomic oxygen anions O-. This radical ion-molecule reaction can produce different ionic products depending on the angle of attack of the nucleophile O- on the target molecule. We present results on the backside and frontside attack of O- on CH3I, which can lead to I- and IO- products, respectively. We combine crossed-beam velocity map imaging with quantum chemical calculations to unravel the chemical reaction dynamics. Energy-dependent scattering experiments in the range of 0.3-2.0 eV relative collision energy revealed that three different reaction pathways can lead to I- products, making it the predominant observed product. Backside attack occurs via a hydrogen-bonded complex with observed indirect, forward, and sideways scattered iodide products. Halide abstraction via frontside attack produces IO-, which mainly shows isotropic and backward scattered products at low energies. IO- is observed to dissociate further to I- + O at a certain energy threshold and favors more direct dynamics at higher collision energies.

Spectroscopic Study of the Br- +CH3 I→I- +CH3 Br SN 2 Reaction.

Mass spectrometry and anion photoelectron spectroscopy have been used to study the gas-phase reaction involving and . The anion photoelectron spectra associated with the reaction intermediates of this reaction are presented. High-level CCSD(T) calculations have been utilised to investigate the reaction intermediates that may form as a result of the reaction along various different reaction pathways, including back-side attack and front-side attack. In addition, simulated vertical detachment energies of each reaction intermediate have been calculated to rationalise the photoelectron spectra.

Benchmark Ab Initio Characterization of the Abstraction and Substitution Pathways of the Cl + CH3CN Reaction.

We investigate the reaction pathways of the Cl + CH3CN system: hydrogen abstraction, methyl substitution, hydrogen substitution, and cyanide substitution, leading to HCl + CH2CN, ClCN/CNCl + CH3, ClCH2CN + H, and CH3Cl + CN, respectively. Hydrogen abstraction is exothermic and has a low barrier, whereas the other channels are endothermic with high barriers. The latter two can proceed via a Walden inversion or front-side attack mechanism, and the front-side attack barriers are always higher. The C-side methyl substitution has a lower barrier and also a lower endothermicity than the N-side reaction. The computations utilize an accurate composite ab initio approach and the explicitly correlated CCSD(T)-F12b method. The benchmark classical and vibrationally adiabatic energies of the stationary points are determined with the most accurate CCSD(T)-F12b/aug-cc-pVQZ energies adding further contributions of the post-(T) and core correlation, scalar relativistic effects, spin–orbit coupling, and zero-point energy corrections. These contributions are found to be non-negligible to reach subchemical accuracy.

SN2 Reactions with an Ambident Nucleophile: A Benchmark Ab Initio Study of the CN- + CH3Y [Y = F, Cl, Br, and I] Systems.

We characterize the Walden-inversion, front-side attack, and double-inversion SN2 pathways leading to Y– + CH3CN/CH3NC and the product channels of proton abstraction (HCN/HNC + CH2Y–), hydride-ion substitution (H– + YH2CCN/YH2CNC), halogen abstraction (YCN–/YNC– + CH3 and YCN/YNC + CH3–), and YHCN–/YHNC– complex formation (YHCN–/YHNC– + 1CH2) of the CN– + CH3Y [Y = F, Cl, Br, and I] reactions. Benchmark structures and frequencies are computed at the CCSD(T)-F12b/aug-cc-pVTZ level of theory, and a composite approach is employed to obtain relative energies with sub-chemical accuracy considering (a) basis-set effects up to aug-cc-pVQZ, (b) post-CCSD(T) correlation up to CCSDT(Q), (c) core correlation, (d) relativistic effects, and (e) zero-point energy corrections. C–C bond formation is both thermodynamically and kinetically more preferred than N–C bond formation, though the kinetic preference is less significant. Walden inversion proceeds via low or submerged barriers (12.1/17.9(F), 0.0/4.3(Cl), −3.9/0.1(Br), and −5.8/–1.8(I) kcal/mol for C–C/N–C bond formation), front-side attack and double inversion have high barriers (30–64 kcal/mol), the latter is the lower-energy retention pathway, and the non-SN2 electronic ground-state product channels are endothermic (ΔH0 = 31–92 kcal/mol).

Computational Studies of Coinage Metal Anion M- + CH3X (X = F, Cl, Br, I) Reactions in Gas Phase.

We characterized the stationary points along the nucleophilic substitution (SN2), oxidative insertion (OI), halogen abstraction (XA), and proton transfer (PT) product channels of M− + CH3X (M = Cu, Ag, Au; X = F, Cl, Br, I) reactions using the CCSD(T)/aug-cc-pVTZ level of theory. In general, the reaction energies follow the order of PT > XA > SN2 > OI. The OI channel that results in oxidative insertion complex [CH3–M–X]− is most exothermic, and can be formed through a front-side attack of M on the C-X bond via a high transition state OxTS or through a SN2-mediated halogen rearrangement path via a much lower transition state invTS. The order of OxTS > invTS is inverted when changing M− to Pd, a d10 metal, because the symmetry of their HOMO orbital is different. The back-side attack SN2 pathway proceeds via typical Walden-inversion transition state that connects to pre- and post-reaction complexes. For X = Cl/Br/I, the invSN2-TS’s are, in general, submerged. The shape of this M− + CH3X SN2 PES is flatter as compared to that of a main-group base like F− + CH3X, whose PES has a double-well shape. When X = Br/I, a linear halogen-bonded complex [CH3−X∙··M]− can be formed as an intermediate upon the front-side attachment of M on the halogen atom X, and it either dissociates to CH3 + MX− through halogen abstraction or bends the C-X-M angle to continue the back-side SN2 path. Natural bond orbital analysis shows a polar covalent M−X bond is formed within oxidative insertion complex [CH3–M–X]−, whereas a noncovalent M–X halogen-bond interaction exists for the [CH3–X∙··M]− complex. This work explores competing channels of the M− + CH3X reaction in the gas phase and the potential energy surface is useful in understanding the dynamic behavior of the title and analogous reactions.

High-Level Systematic Ab Initio Comparison of Carbon- and Silicon-Centered SN2 Reactions.

We characterize the stationary points along the Walden inversion, front-side attack, and double-inversion pathways of the X– + CH3Y and X– + SiH3Y [X, Y = F, Cl, Br, I] SN2 reactions using chemically accurate CCSD(T)-F12b/aug-cc-pVnZ [n = D, T, Q] levels of theory. At the carbon center, Walden inversion dominates and proceeds via prereaction (X–···H3CY) and postreaction (XCH3···Y–) ion-dipole wells separated by a usually submerged transition state (X–H3C–Y)−, front-side attack occurs over high barriers, double inversion is the lowest-energy retention pathway for X = F, and hydrogen- (F–···HCH2Y) and halogen-bonded (X–···YCH3) complexes exist in the entrance channel. At the silicon center, Walden inversion proceeds through a single minimum (X–SiH3–Y)−, the front-side attack is competitive via a usually submerged transition state separating pre- and postreaction minima having X–Si–Y angles close to 90°, double inversion occurs over positive, often high barriers, and hydrogen- and halogen-bonded complexes are not found. In addition to the SN2 channels (Y– + CH3X/SiH3X), we report reaction enthalpies for proton abstraction (HX + CH2Y–/SiH2Y–), hydride substitution (H– + CH2XY/SiH2XY), XH···Y– complex formation (XH···Y– + 1CH2/1SiH2), and halogen abstraction (XY + CH3–/SiH3– and XY– + CH3/SiH3).

Detailed quasiclassical dynamics of the F- + CH3Br reaction on an ab initio analytical potential energy surface.

Dynamics and mechanisms of the F- + CH3Br(v = 0) → Br- + CH3F (SN2 via Walden inversion, front-side attack, and double inversion), F- + inverted-CH3Br (induced inversion), HF + CH2Br- (proton abstraction), and FH⋯Br- + 1CH2 reactions are investigated using a high-level global ab initio potential energy surface, the quasiclassical trajectory method, as well as non-standard configuration- and mode-specific analysis techniques. A vector-projection method is used to identify inversion and retention trajectories; then, a transition-state-attack-angle-based approach unambiguously separates the front-side attack and the double-inversion retention pathways. The Walden-inversion SN2 channel becomes direct rebound dominated with increasing collision energy as indicated by backward scattering, initial back-side attack preference, and the redshifting of product internal energy peaks in accord with CF stretching populations. In the minor retention and induced-inversion pathways, almost the entire available energy transfers into product rotation-vibration, and retention mainly proceeds with indirect, slow double inversion following induced inversion with about 50% probability. Proton abstraction is dominated by direct stripping (evidenced by forward scattering) with CH3-side initial attack preference, providing mainly vibrationally ground state products with significant zero-pointenergy violation.

Investigating the role of halogen-bonded complexes in microsolvated Y-(H2O)n + CH3I SN2 reactions.

The dynamics of bimolecular nucleophilic substitution (SN2) reactions in the gas phase are of great interest and several new mechanisms have been observed recently by theoretical studies. Here we investigate a recent-discovered SN2 reaction mechanism, called front-side complex (FSC) or halogen-bonded complex (XC) mechanism that couples the traditional front-side attack (FSA) and back-side attack (BSA) Walden-inversion mechanism. This XC-pathway begins with a front-side attack on the leaving group, then goes through a bending transition state (XTS) that is followed by Walden-inversion, and results in a configuration inverted product. We characterized the potential energy surface of the microsolvated Y-(H2O)n=0,1,2 + CH3I SN2 reaction using the B97-1/ECP/d method, where Y = HO, F, Cl, Br, and I, and n is the number of water molecules. It is found that the XCs have a deeper well depth than the back-side attack (BSA) pre-reaction complexes for HO-/F- nucleophiles, indicating that the system can easily become trapped in the halogen-bonded complex well. The barriers of both FSA- and BSA-paths increase with incremental solvation, whereas the change of XTS depends on the type of nucleophile. When Y = HO/F, the order of the barriers is BSA < XC < FSA for n = 0-2, and the order inverts to XC < BSA < FSA for n = 1 (Y = Br/I) and n = 2 (Y = Cl/Br/I), where the latter suggests an increasing participation of the halogen-bonded complex in the SN2 reactions. Comprehensive analyses on the structure, charge distribution, and energetics of XC and XTS are provided. This work indicates that the halogen-bonded complex mechanism may be common for alkyl iodides and the information on the potential energy surface is useful in understanding the dynamics behavior of the title and analogous reactions.

Reactions of sulfenic acids with amines, thiols, and thiolates studied by quantum chemical calculations

Biological sensor molecules for oxidative stress often rely on the oxidation of thiols to sulfenic acid intermediates. How this transformation induces a physiological response often relies on the fate of sulfenic acid. Sulfenic acids will react with other biologically relevant nucleophiles such as amines, thiols, and thiolates. In the presence of excess oxidants, the sulfenic acid can be further oxidized. The free energy of reaction (ΔG) and free energies of activation (ΔG‡) were determined for the reactions of sulfenic acid with amines, thiols, and thiolates. The methods employed included B3LYP, B3P86, HF, M06-2X, and MP2, and the effect of water solvation on the reactions was estimated using the integral equation formulation of the polarizable continuum model (IEF-PCM). A front-side approach of the sulfenic acid for amines, thiols, and thiolates was observed. In addition to front-side attack, a back-side transition state was converged for the more nucleophilic thiolates in several cases.

Numerical separation of the front-side attack and double-inversion retention pathways of SN2 reactions

We describe a vector-projection method to identify inversion and retention mechanisms in SN2 reactions and a transition state (TS) attack-angle-based approach allowing the separation of the front-side attack and double-inversion retention trajectories by following the leaving group backwards to the TS regions characterized by attack angles of 40–100° and 120–180°, respectively. The methods are tested for the F−+CH3Cl/CH3I SN2 reactions, revealing that double inversion is the dominant retention mechanism at low collision energies and the time-based separation of the front-side attack (fast, direct) and double-inversion (slow, indirect) pathways is only unambiguous for F−+CH3Cl.

The importance of the composite mechanisms with two transition states in the F- + NH2I SN2 reaction.

The dynamics of the bimolecular nucleophilic substitution (SN2) reactions at nitrogen are less understood than those of their corresponding reactions at carbon. In this paper, we report an ab initio molecular dynamics approach to investigate the reaction mechanisms of the F- + NH2I SN2 reaction at nitrogen. We found not only the one-transition-state mechanisms, but also the composite mechanisms with two and three transition states. For the two-transition-state mechanisms, the double inversion mechanism and the proton-abstraction roundabout followed by the backside-attack reaction mechanism have been reported before; but we discovered that there is also a new, front-side attack followed by the backside-attack Walden-inversion mechanism. Furthermore, a composite mechanism with three transition states also shows up in the reactive trajectories. Our results show that, as the collision energy increases, the SN2 reactivity decreases, and the proton-abstraction reactivity increases. The two-transition-state mechanisms, especially the double-inversion mechanism, make the largest contribution to the SN2 reactivity, followed then by the one-transition-state mechanisms, with the three-transition-state mechanism contributing the least. The potential energy profiles of the reaction mechanisms are characterized at the CCSD(T)/aug-cc-pVTZ(PP) level of theory. The analysis on stationary points shows that the proton-abstraction inversion transition state is ∼12.4 kcal mol-1 lower than the Walden-inversion transition state in contrast to the corresponding reaction at carbon F- + CH3I, in which the former is ∼26.1 kcal mol-1 higher than the latter. This might explain why the composite mechanism of the double inversion mechanism contributes the most to the SN2 reactivity in the F- + NH2I reaction.

Activation Strain Analyses of Counterion and Solvent Effects on the Ion-Pair SN 2 Reaction of and CH3 Cl.

We have computationally studied the bimolecular nucleophilic substitution (SN 2) reactions of Mn NH2 (n-1) + CH3 Cl (M+ = Li+ , Na+ , K+ , and MgCl+ ; n = 0, 1) in the gas phase and in tetrahydrofuran solution at OLYP/6-31++G(d,p) using polarizable continuum model implicit solvation. We wish to explore and understand the effect of the metal counterion M+ and of solvation on the reaction profile and the stereochemical preference, that is, backside (SN 2-b) versus frontside attack (SN 2-f). The results were compared to the corresponding ion-pair SN 2 reactions involving F- and OH- nucleophiles. Our analyses with an extended activation strain model of chemical reactivity uncover and explain various trends in SN 2 reactivity along the nucleophiles F- , OH- , and , including solvent and counterion effects. © 2019 Wiley Periodicals, Inc.

Probing Assessment Framework and Evaluation of Antiprobing Solutions

Probing attacks against integrated circuits has become a serious concern, especially for security-critical applications. With the help of modern circuit editing tools, an attacker could remove layers of materials and expose wires carrying sensitive on-chip assets, such as cryptographic keys and proprietary firmware, for probing. Most of the existing protection methods use an active shield that provides tamper-evident covers at the top-most metal layers to the circuitry below. However, they lack formal proofs of their effectiveness as some active shields have already been circumvented by hackers. In this paper, we investigate the problem of protection against front-side probing attacks and propose a framework to assess a design’s vulnerabilities against probing attacks. Metrics are developed to evaluate the resilience of designs to bypass an attack and reroute the attack, the two common techniques used to compromise an antiprobing mechanism. Exemplary assets from a system-on-chip layout are used to evaluate the proposed flow. The results show that long net and high layer wires are vulnerable to a probing attack equipped with high aspect ratio focused ion beam. Meanwhile, nets that occupy small area on the chip are probably compromised through rerouting shield wires. On the other hand, the multilayer internal orthogonal shield performs the best among common shield structures.

Uncovering the role of the stationary points in the dynamics of the F- + CH3I reaction.

We describe an analysis method which assigns geometries to stationary points along (quasi)classical trajectories. The method is applied to the F- + CH3I reaction, thereby uncovering the role of the minima and transition states in the dynamics of the SN2 inversion, SN2 retention via front-side attack and double inversion, induced inversion, and proton-transfer channels. Stationary-point probability distributions, stationary-point-specific trajectory orthogonal projections, root-mean-square distance distributions, transition probability matrices, and time evolutions of the stationary points reveal long-lived front-side (F-ICH3) and hydrogen-bonded (F-HCH2I) complexes in the entrance channel and significant post-reaction ion-dipole complex (FCH3I-) formation in the SN2 exit channel. Most of the proton-transfer stationary points (FHCH2I-) participate in all the reaction channels with larger distance deviations than the double-inversion transition state. Significant forward-backward transitions are observed between the minima and transition states indicating complex, indirect dynamics. The utility of distance and energy constraints is also investigated, thereby restricting the assignment into uniform configuration or energy ranges around the stationary points.

Photoelectron spectroscopic study of I-·ICF3: a frontside attack SN2 pre-reaction complex.

Photodetachment and 2D photoelectron spectra of the mass-selected I-·CF3I complex are presented together with electronic structure calculations. Calculations show that the I- is located at the iodine side of CF3I. Vertical and adiabatic detachment energies were measured at 4.03 and approximately 3.8 eV, respectively. The photoelectron spectra and molecular orbitals show a significant covalent bonding character in the cluster. The presence of electronic excited states is observed. Below threshold, iodide is generated which can be assigned to the photoexcitation of degenerate charge-transfer bands from the off-axis p-orbitals localised on iodide. Near the onset of two spin-orbit thresholds, bright excited states are seen in the experiment and calculations. Excitation of these leads to the formation of slow electrons. The spectroscopy of I-·CF3I is compared to the well-studied I-·CH3I cluster, a pre-reaction complex in the text-book I- + CH3I SN2 reaction. Despite the reversed stereodynamics (i.e. inversion of the CX3 between X = H and F) of the SN2 reaction, striking similarities are seen. Both complexes possess charge transfer excited states near their respective vertical detachment energies and exhibit vibrational structure in their photoelectron spectra. The strong binding is consistent with observations in crossed molecular beam studies and molecular dynamics simulations that suggest that iodine as a leaving group in an SN2 reaction affects the reaction dynamics.

High-Level-Optimized Stationary Points for the F-(H2O) + CH3I System: Proposing a New Water-Induced Double-Inversion Pathway.

We report 29 stationary points for the F-(H2O) + CH3I reaction obtained by using the high-level explicitly correlated CCSD(T)-F12b method with the aug-cc-pVDZ basis set for the determination of the benchmark structures and frequencies and the aug-cc-pVQZ basis for energy computations. The stationary points characterize the monohydrated F-- and OH--induced Walden-inversion pathways and, for the first time, the front-side attack and F--induced double-inversion mechanisms leading to CH3F with retention as well as the novel H2O-induced double-inversion retention pathway producing CH3OH. Hydration effectively increases the relative energies of the stationary points, but the monohydrated inversion pathways are still barrierless, whereas the front-side attack and double-inversion barrier heights are around 30 and 20 kcal/mol, respectively.