SN2 Mechanism Research Articles

Mechanistic Analysis of 4‐Methylthiobenzoyl Chloride in Solvolysis

The solvolysis mechanism of 4‐methylthiobenzoyl chloride (1) was studied by kinetic methods, and these results were compared with 4‐methoxy (2) and 3,4,5‐trimethoxybenzoyl chlorides (3) reported previously. The analysis of kinetic data was carried out using both the simple and extended Grunwald–Winstein (G–W) equations, thermodynamic parameters, and kinetic solvent isotope effects (KSIE). In fact, 4‐methylthiobenzoyl chloride (1) has a sulfur atom which is bigger in size and has more electrons than oxygen in the para‐position. The results were obtained and showed typical dispersed plots from the simple (R = 0.939) and extended G–W equations (l/m = 0.33, R = 0.952) for all data, and when the data from some of the most dispersed points were removed, the correlation coefficients were improved remarkably. Thermodynamic parameters revealed that the change of enthalpies were 16.2 ~ 17.6 kJ/mol and the change of entropies were −16.5 ~ −8.6 J/K‐mol. The KSIE of MeOH/MeOD was 1.42. The above results for 4‐methylthiobenzoyl chloride supported a unimolecular pathway, or more precisely, a dissociated SN2 mechanism classified by l/m ratio.

Introducing Aliphatic Substitution with a Discovery Experiment Using Competing Electrophiles

A facile, discovery-based experiment is described that introduces aliphatic substitution in an introductory undergraduate organic chemistry curriculum. Unlike other discovery-based experiments that examine substitution using two competing nucleophiles with a single electrophile, this experiment compares two isomeric, competing electrophiles (primary and secondary halides) with a single nucleophile (phenoxide ion). The question posed to students at the start of the experiment is what mechanism explains formation of the observed ether product from reaction of the phenoxide with an alkyl halide. If the reaction proceeds via an SN1 mechanism, then the major product will come from reaction of the secondary halide. If the reaction proceeds via an SN2 mechanism, the major product will come from reaction of the primary halide. In this experiment, students are able to discover that the primary halide reacts faster than the secondary halide by a roughly 4:1 margin. This discovery allows students to conclude that the reaction proceeds via an SN2 mechanism.

Mechanisms and energetics for N-glycosidic bond cleavage of protonated 2'-deoxyguanosine and guanosine.

Experimental and theoretical investigations suggest that hydrolysis of N-glycosidic bonds generally involves a concerted SN2 or a stepwise SN1 mechanism. While theoretical investigations have provided estimates for the intrinsic activation energies associated with N-glycosidic bond cleavage reactions, experimental measurements to validate the theoretical studies remain elusive. Here we report experimental investigations for N-glycosidic bond cleavage of the protonated guanine nucleosides, [dGuo+H](+) and [Guo+H](+), using threshold collision-induced dissociation (TCID) techniques. Two major dissociation pathways involving N-glycosidic bond cleavage, resulting in production of protonated guanine or the elimination of neutral guanine are observed in competition for both [dGuo+H](+) and [Guo+H](+). The detailed mechanistic pathways for the N-glycosidic bond cleavage reactions observed are mapped via electronic structure calculations. Excellent agreement between the measured and B3LYP calculated activation energies and reaction enthalpies for N-glycosidic bond cleavage of [dGuo+H](+) and [Guo+H](+) in the gas phase is found indicating that these dissociation pathways involve stepwise E1 mechanisms in analogy to the SN1 mechanisms that occur in the condensed phase. In contrast, MP2 is found to significantly overestimate the activation energies and slightly overestimate the reaction enthalpies. The 2'-hydroxyl substituent is found to stabilize the N-glycosidic bond such that [Guo+H](+) requires ∼25 kJ mol(-1) more than [dGuo+H](+) to activate the glycosidic bond.

Platinum(0)-mediated C–O bond activation of ethers via an SN2 mechanism

A computational study of the C(methyl)-O bond activation of fluorinated aryl methyl ethers by a platinum(0) complex Pt(PCyp3)2 (Cyp = cyclopentyl) (N. A. Jasim, R. N. Perutz, B. Procacci and A. C. Whitwood, Chem. Commun., 2014, 50, 3914) demonstrates that the reaction proceeds via an SN2 mechanism. Nucleophilic attack of Pt(0) generates an ion pair consisting of a T-shaped platinum cation with an agostic interaction with a cyclopentyl group and a fluoroaryloxy anion. This ion-pair is converted to a 4-coordinate Pt(ii) product trans-[PtMe(OArF)(PCyp3)2]. Structure-reactivity correlations are fully consistent with this mechanism. The Gibbs energy of activation is calculated to be substantially higher for aryl methyl ethers without fluorine substituents and higher still for alkyl methyl ethers. These conclusions are in accord with the experimental results. Further support was obtained in an experimental study of the reaction of Pt(PCy3)2 with 2,3,5,6-tetrafluoro-4-allyloxypyridine yielding the salt of the Pt(η3-allyl) cation and the tetrafluoropyridinolate anion [Pt(PCy3)2(η3-allyl)][OC5NF4]. The calculated activation energy for this reaction is significantly lower than that for fluorinated aryl methyl ethers.

Cycloplatinated(II) complex bearing 2-vinylpyridine and monodentate phosphine ligands: Optical properties and kinetic study

The 2-vinylpyridinate complex [PtMe(Vpy)(DMSO)], C, is successfully prepared from dimeric platinum(II) complex cis,cis-[Me2Pt(μ-SMe2)2PtMe2], B, in the presence of DMSO and 2-vinylpyridine ligand. The DMSO molecule in complex C can be readily substituted by methyldiphenylphosphine (PPh2Me), allowing synthesis of [PtMe(Vpy)(PPh2Me)], 1, which has been fully characterized spectroscopically. Complex 1 is emissive in solid state and solution at room temperature and at 77 K. This complex displays an intense phosphorescence emission (with a significantly long lifetime) which is originated from mixed 3ILCT/3MLCT excited state. Additionally, complex 1 undergoes oxidative addition with alkyl halide (MeI) bearing [PtMe2I(Vpy)(PPh2Me)], 2, after 2 h. Kinetic studies suggest that the latter reaction (oxidative addition) proceed by a classical SN2 mechanism. The rate of oxidative addition reaction at different temperatures is measured and high negative ΔS# value is obtained for the reaction which supported the proposed mechanism. On the basis of NMR spectroscopy, when complex 1 reacts with MeI under extended time (5 days), complex 2 gradually converts to a mixture of platinum complexes trans-[PtMeI(PPh2Me)2], 3, [{PtMe2(Vpy)2(μ-I)2], 4, and a free ligand Z/E-[C8H9N], 5, based on the carbon–carbon bond coupling.

Molecular Electronic Effects on the Thermal Grafting of Aryl Iodides to TiO2 Surfaces

Recent studies have shown that aromatic iodides can readily graft to hydroxylated surfaces of TiO2 and other metal oxides, forming a convenient route to molecular functionalization of metal oxides. While these reactions appear similar to the Williamson ether synthesis of organic chemistry, the SN2 mechanism typically invoked in solution phase reactions is less accessible on surfaces, and the mechanism of the surface reactions is poorly understood. We have undertaken a combined experimental and computational study in an effort to understand how the molecular electronic structure impacts the surface reactivity. Computational studies of reaction enthalpies were compared were used to generate Hammett plots that were then compared to experimental measurements of surface grafting rate for molecules with different substituent groups. Our results show that there is poor correlation between Hammett parameters and surface reactivity. Additional experiments were conducted to evaluate the impact of molecular hydropho...

Mechanistic study of bismuth-catalyzed direct benzylation of 2,4-pentanediones: the case of BiCl3 and generalization

At present, we investigate the mechanisms for bismuth-catalyzed direct benzylation of 2,4-pentanediones using various density functional theories and post-Hartree–Fock ab initio methods. First, we deeply consider the role of BiCl3, where six scenarios are proposed. All of them start with the formation of a weakly bound complex between the BiCl3 catalyst and the alcohol or the dione. The most favorable one corresponds to the direct access to the products via a unique transition state (SN2-type mechanism). We also examined the effects of various nonpolar and polar solvents, which are viewed to slightly affect the energy profiles for SN2 and internal nucleophilic substitution (SNi) types of mechanism, whereas strong perturbations are observed for SN1 mechanism. For instance, the later one becomes the most thermodynamically favorable in DMSO solvent. In addition, several classes of benzyl alcohols and catalysts (BiX3, where X = Cl, Br, I, NO3, and OTf) were considered within the framework of SN2 and SNi mechanisms. The reactivity of these alcohols increases going from primary to secondary to tertiary. These findings are in line with the present available experimental results. Finally, our computations suggest that Bi(NO3)3 could be an excellent catalyst for the title reaction.

Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals.

Although transfer of electrophilic alkoxyl (“RO+”) from organic peroxides to organometallics offers a complement to traditional methods for etherification, application has been limited by constraints associated with peroxide reactivity and stability. We now demonstrate that readily prepared tetrahydropyranyl monoperoxyacetals react with sp3 and sp2 organolithium and organomagnesium reagents to furnish moderate to high yields of ethers. The method is successfully applied to the synthesis of alkyl, alkenyl, aryl, heteroaryl, and cyclopropyl ethers, mixed O,O-acetals, and S,S,O-orthoesters. In contrast to reactions of dialkyl and alkyl/silyl peroxides, the displacements of monoperoxyacetals provide no evidence for alkoxy radical intermediates. At the same time, the high yields observed for transfer of primary, secondary, or tertiary alkoxides, the latter involving attack on neopentyl oxygen, are inconsistent with an SN2 mechanism. Theoretical studies suggest a mechanism involving Lewis acid promoted insertion of organometallics into the O–O bond.

Dicarbonyl chelates from 1-cymantrenylalkylamides with the dendrite structure: formation, photochromism, and kinetics of dark reaction with carbon monoxide

Photolysis of carboxamides of the dendrite structure with aminomethyland 1-aminoethylcymantrenes leads to the formation of six-membered dicarbonyl chelates with the Mn—O bond which are stable in solutions. The chelates in the reversed dark reaction with carbon monoxide give the starting tricarbonyl complexes. The formation of the chelates and their dark reaction are accompanied by the reversible change of color by the compounds. The rate determining step of the thermal reaction of chelates with CO is a chelate ring opening with the ligand substitution by the SN1 mechanism. A possibility of solvent-free photoinduced ligand-exchange reaction in a number of cymantrene derivatives was demonstrated.

SN2 Mechanism of Cationic Micelles on the Hydrolysis of Bis-p-Methoxyphenyl Phosphate Ester

Hydrolysis of bis-p-methoxyphenyl phosphate ester (bis-p-MPPE) was studied in micellar solutions of cityltrimethylammoniumbromide n-C16H33N+(CH3)3Br- (CTABr) at pH-9.0. The hydrolysis followed first order kinetics with respect to bis-p-MPPE concentration. At the concentration of critical micelle concentration (CMC) the rate of hydrolysis increased with increasing CTABr concentration. Surfactant with cationic or polar head group form micelles in water with hydrocarbon like interior or polar groups at the surface and bind cationic solute. The binding constant of micelle for bis-p-MPPE and the rate constant in micellar pseudo phase were determined from kinetic data using the pseudophase model.

Computational Study of Ethanol Conversion on Al8O12 as a Model for γ-Al2O3

Correlated molecular orbital theory at the coupled cluster CCSD(T) level with density functional theory geometries is used to study ethanol dehydration, dehydrogenation, and condensation reactions on an the Al8O12 cluster which is a model for γ-Al2O3. The Al in the active site on the cluster is a strong Lewis acid. The reactions begin with formation of a very stable Lewis acid–base ethanol–cluster adduct. Dehydration proceeds by β-H transfer to a bicoordinate oxygen leading to the direct formation of ethylene and two OH groups following an E2 mechanism. Dehydrogenation proceeds directly by α-H transfer to the active metal center and a proton transfer to a bicoordinate bridge O to form acetaldehyde plus a metal hydride and a hydroxyl, again an E2 mechanism. After addition of a second ethanol, diethyl ether is generated by an α-C transfer from the first to the second ethanol, an acid-driven SN2 mechanism. Condensation and dehydration with two alcohols have comparable energy barriers. The addition of a secon...

Isotope Effects in the Solvolysis of Sterically Hindered Arenesulfonyl Chlorides

ABSTRACTSolvent isotope effects in the ethanolysis of sterically hindered arenesulfonyl chlorides ruled out a proton transfer in the rate‐determining step and agreed with a SN2 mechanism involving at least a second solvent molecule in the transition state (TS). The lack of a secondary kinetic isotope effect in the o‐alkyl groups allows us to disregard the possible contribution of σ–π hyperconjugation. The measured activation parameters are consistent with a SN2 mechanism involving the participation of solvent molecules in the TS, possibly forming a cyclic TS through a chain of solvent molecules.

Correlation of Rates of Solvolysis of Diphenylacetyl Chloride Using Extended Grunwald–Winstein Equation

Rate constants for solvolysis involving the displacement of chloride from the carbonyl carbon of diphenylacetyl chloride ((C6H5)2CHCOCl, 1) in ethanol, methanol, aqueous binary mixtures incorporating ethanol, methanol, acetone, 2,2,2‐trifluoroethanol (TFE), and 1,1,1,3,3,3‐hexafluoro‐2‐propanol, and binary mixtures of TFE with ethanol are reported. The kinetic data obtained from the reactions in 34 different solvents and solvent mixtures gave an extended Grunwald–Winstein correlation with the l value of 0.76 ± 0.06, the m value of 0.34 ± 0.04, and the correlation coefficient (R2) of 0.932. The appreciable values for both l and m suggest that the bond formation is ahead of the bond breaking with an SN2 mechanism, and the l/m ratio of 2.2 is also in the range of values found for SN2 reaction. This interpretation is further supported by the activation parameters, i.e., relatively small positive ΔH≠ (7.7–16.3 kcal/mol) values and large negative ΔS≠ (−24.6 to −53.4 cal/mol/K) values, and the solvent kinetic isotope effect (1.62).

Search for a Symmetrical C-F-C Fluoronium Ion in Solution: Kinetic Isotope Effects, Synthetic Labeling, and Computational, Solvent, and Rate Studies.

Recently, we reported evidence for the generation of a symmetrical fluoronium ion (a [C-F-C](+) interaction) in solution from a cage-like precursor, relying heavily on a single isotopic-labeling experiment. Paraphrasing the axiom that a strong claim must be met by as much evidence as possible, we seek to expand upon our initial findings with comprehensive labeling studies, rate measurements, kinetic isotope effect (KIE) experiments, synthetic studies, and computations. We also chronicle the development of the system, our thought process, and how it evolved from a tantalizing indication of fluoronium ion assistance in a dibromination reaction to the final, optimized system. Our experiments show secondary KIE experiments that are fully consistent with a transition state involving fluorine participation; this is also confirmed by a significant remote isotope effect. Paired with DFT calculations, the KIE experiments are indicative of the trapping of a symmetrical intermediate. Additionally, starting with an epimeric in-triflate precursor that hydrolyzes through a putative frontside SNi mechanism involving fluorine participation, KIE studies indicate that an identical intermediate is trapped (the fluoronium ion). Studies also show that the rate-determining step of the fluoronium forming SN1 reaction can be changed on the basis of solvent and additives. We also report the synthesis of a nonfluorinated control substrate to measure a relative anchimeric role of the fluorine atom in hydrolysis versus μ-hydrido bridging. After extensive testing, we can make the remarkable conclusion that our system reacts solely through a "tunable" SN1 mechanism involving a fluoronium ion intermediate. Alternative scenarios, such as SN2 reactivity, do not occur even under forced conditions where they should be highly favored.

Reductive functionalization of 3d metal–methyl complexes: The greater importance of ligand than metal

Selective oxidation of methane, which is the primary component of natural gas, to methanol, as a more easily transportable liquid, using organometallic catalysis, has become more important recently due to the abundance of domestic natural gas. In this regard, reductive functionalization (RF) of methyl ligands in [M(diimine)2(CH3)(Cl)] complexes, where M is a 3d metal with oxidation state of 2+ has been studied computationally using density functional techniques. The metal ions chosen for study were VII (d3) through CuII (d9) in the 3d row of the periodic table to assess changes in RF energetics as a function of d orbital occupation. A SN2 mechanism for the nucleophilic attack of hydroxide on the metal–methyl bond, resulting in the formation of methanol, was studied. Similar highly exergonic pathways with very low energy SN2 barriers were observed for the proposed RF mechanism for all the studied complexes. Changes in spin state occurred through the RF pathway for most of the metals studied. To modulate RF pathways closer to thermoneutral for catalytic purposes, a future challenge, paradoxically, requires finding a way to strengthen the metal–carbon bond. Furthermore, the DFT calculations suggest that for 3d metals, ligand properties will be of greater importance than metal identity in identifying suitable catalysts for alkane hydroxylation in which reductive functionalization is used to form the C–O bond.

Unsymmetrical Diarylmethanes by Ferroceniumboronic Acid Catalyzed Direct Friedel-Crafts Reactions with Deactivated Benzylic Alcohols: Enhanced Reactivity due to Ion-Pairing Effects.

The development of general and more atom-economical catalytic processes for Friedel-Crafts alkylations of unactivated arenes is an important objective of interest for the production of pharmaceuticals and commodity chemicals. Ferroceniumboronic acid hexafluoroantimonate salt (1) was identified as a superior air- and moisture-tolerant catalyst for direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes with stable and readily available primary and secondary benzylic alcohols. Compared to the use of classical metal-catalyzed alkylations with toxic benzylic halides, this methodology employs exceptionally mild conditions to provide a wide variety of unsymmetrical diarylmethanes and other 1,1-diarylalkane products in high yield with good to high regioselectivity. The optimal method, using the bench-stable ferroceniumboronic acid salt 1 in hexafluoroisopropanol as cosolvent, displays a broader scope compared to previously reported catalysts for similar Friedel-Crafts reactions of benzylic alcohols, including other boronic acids such as 2,3,4,5-tetrafluorophenylboronic acid. The efficacy of the new boronic acid catalyst was confirmed by its ability to activate primary benzylic alcohols functionalized with destabilizing electron-withdrawing groups like halides, carboxyesters, and nitro substituents. Arene benzylation was demonstrated on a gram scale at up to 1 M concentration with catalyst recovery. Mechanistic studies point toward the importance of the ionic nature of the catalyst and suggest that factors other than the Lewis acidity (pKa) of the boronic acid are at play. A SN1 mechanism is proposed where ion exchange within the initial boronate anion affords a more reactive carbocation paired with the non-nucleophilic hexafluoroantimonate counteranion.

Theoretical studies of methyl iodide oxidative addition to adjacent metal centers in diplatinum(II) complexes

The density functional theory calculations were used to study the electronic and steric effects between two adjacent platinum centers on the oxidative addition of methyl iodide to dimeric complex [Me2Pt(μ-bipym)PtMe2], in which bipym=2,2′-bipyrimidine. A double MeI oxidative addition was considered and the classical SN2 mechanism was suggested for both steps, and the involved transition states and intermediates were proposed. Consistent with the suggested mechanism, large negative ΔS‡ values were found in each step. The calculated energy barrier was larger in the second step as compared to the first step because of the electronic effects transmitted through the 2,2′-bipyrimidine ligand and the steric effects. In a comparative study, the monomeric complex [PtMe2(bipym)] was used in the MeI oxidative reaction as a “calibration reaction” to evaluate the effect of bipym ligand on the rate of the reaction of MeI with dimeric complex, [Me2Pt(μ-bipym)PtMe2].

Oxidation of Half-Lantern Pt2(II,II) Compounds by Halocarbons. Evidence of Dioxygen Insertion into a Pt(III)-CH3 Bond.

The half-lantern compound [{Pt(bzq)(μ-N^S)}2] (1) [bzq = benzo[h]quinoline, HN^S = 2-mercaptopyrimidine (C4H3N2HS)] reacts with CH3I and haloforms CHX3 (X = Cl, Br, I) to give the corresponding oxidized diplatinum(III) derivatives [{Pt(bzq)(μ-N^S)X}2] (X = Cl 2a, Br 2b, I 2c). These compounds exhibit half-lantern structures with short intermetallic distances (∼2.6 Å) due to Pt-Pt bond formation. The halogen abstraction mechanisms from the halocarbon molecules by the Pt2(II,II) compound 1 were investigated. NMR spectroscopic evidence using labeled reagents support that in the case of (13)CH3I the reaction initiates with an oxidative addition through an SN2 mechanism giving rise to the intermediate species [I(bzq)Pt(μ-N^S)2Pt(bzq)((13)CH3)}]. However, with haloforms the reactions proceed through a radical-like mechanism, thermally (CHBr3, CHI3) or photochemically (CHCl3) activated, giving rise to mixtures of species [X(bzq)Pt(μ-N^S)2Pt(bzq)R] (3a-c) and [X(bzq)Pt(μ-N^S)2Pt(bzq)X] (2a-c). In these cases the presence of O2 favors the formation of species 2 over 3. Transformation of 3 into 2 was possible upon irradiation with UV light. In the case of [I(bzq)Pt(μ-N^S)2Pt(bzq)((13)CH3)}] (3d), in the presence of O2 the formation of the unusual methylperoxo derivative [I(bzq)Pt(μ-N^S)2Pt(bzq)(O-O(13)CH3)}] (4d) was detected, which in the presence of (13)CH3I rendered the final product [{Pt(bzq)(μ-N^S)I}2] (2c) and (13)CH3OH.

Secondary kinetic deuterium isotope effect in oxidative addition reaction of cycloplatinated(II) complexes with MeI

Oxidative addition reaction of CH3I or CD3I with the cycloplatinated(II) complexes [PtMe(CˆN)L], 1a–1e, in which CˆN = 2-phenylpyridinate (ppy) or benzo[h]quinolinate (bhq), and L = PPh3, PMePh2 or P(OPh)3, in CH2Cl2 solvent gave the organoplatinum(IV) products [PtMe2I(CˆN)L]. NMR spectroscopy (1H and 31P), and X-ray crystallography (supported by DFT calculations) clearly indicated that in each case the thermodynamic isomer products 2a–2e, with I ligand trans to C of CˆN rather than the related kinetic isomer in which I ligand is trans to Me, is obtained. Kinetics of the reactions were studied by using UV–vis spectroscopy and the reactions are suggested to occur by a common SN2 mechanism, on the basis of their clean second-order kinetics, failure of radical traps to inhibit the reactions, and the observation of large negative values of ΔS‡. Rates of the reactions are significantly dependent on nature of the phosphine ligand L with the trend being PMePh2 > PPh3 > P(OPh)3. The kinetic isotope effect (KIE) values, kH/kD, were obtained in the present study and are found to be close to the normal value of 1 in the corresponding reactions, showing that nature of the ancillary ligands containing phosphorous donor atoms and the cycloplatinated ligands, CˆN, are not effective on the values of kH/kD. For example, KIE values, in reactions involving the ppy complexes [PtMe(ppy)L], 1a–1c, at 20 °C are 1.06 (L = PPh3, 1a), 0.97 (L = P(OPh)3, 1c) and 0.92 (L = PMePh2, 1b). Note that nature of the CˆN ligands are found to be almost non-effective on both rates of the reactions and the related KIE values.

Theoretical investigation of the role of chelating biphosphine ligands in oxidative addition reactions of platinum complexes

DFT investigation of MeI oxidative addition reaction of the phosphine chelating platinum(II) complexes, [PtMe2(Me2P(CH2)nPMe2)] (n = 1–4) to afford the organoplatinum(IV) complexes, [PtMe3I(Me2P(CH2)nPMe2)], is reported. The first step of the oxidative addition reaction that proceeds via the usual SN2 mechanism is the nucleophilic attack of Pt center of platinum(II) complex to carbon atom of MeI. The reaction proceeds by formation of a transition state, which includes the Pt…C…I fragment, followed by formation of the intermediate [PtMe3(Me2P(CH2)nPMe2)]+I− with the incoming Me group in the apical position of five-coordinate intermediate and with the iodide ion out of coordination sphere of Pt(IV) intermediate. The effect of the P–Pt–P bite angle of phosphine chelate on the energy barrier of the reaction has been investigated in terms of the length of the diphosphine ligand backbone. The DFT studies are in agreement with the experimental findings.