Theoretical Analysis of the Detailed Mechanism of Native Chemical Ligation Reactions

The method of native chemical ligation between an unprotected peptide α‐thioester and an N‐terminal cysteine–peptide to give a native peptide in aqueous solution is one of the most effective peptide ligation methods. In this work, a systematic theoretical study was carried out to fully understand the detailed mechanism of ligation. It was found that for the conventional native chemical ligation reaction between a peptide thioalkyl ester and a cysteine in combination with an added aryl thiol as catalyst, both the thiol‐thioester exchange step and the transthioesterification step proceed by an anionic concerted S_N2 displacement mechanism, whereas the intramolecular rearrangement proceeds by an addition–elimination mechanism, and the rate‐limiting step is the thiol‐thioester exchange step. The theoretical method was then extended to study the detailed mechanism of the auxiliary‐mediated peptide ligation between a peptide thiophenyl ester and an N‐2‐mercaptobenzyl peptide in which both the thiol‐thioester exchange step and intramolecular acyl‐transfer step proceed by a concerted S_N2‐type displacement mechanism. The energy barrier of the thiol‐thioester exchange step depends on the side‐chain steric hindrance of the C‐terminal amino acid, whereas that of the acyl‐transfer step depends on the side‐chain steric hindrance of the N‐terminal amino acid.     

Computational SN2‐Type Mechanism for the Difluoromethylation of Lithium Enolate with Fluoroform through Bimetallic C−F Bond Dual Activation

The reaction mechanism for difluoromethylation of lithium enolates with fluoroform was analyzed computationally (DFT calculations with the artificial force induced reaction (AFIR) method and solvation model based on density (SMD) solvation model (THF)), showing an S_N2‐type carbon–carbon bond formation; the “bimetallic” lithium enolate and lithium trifluoromethyl carbenoid exert the C?F bond “dual” activation, in contrast to the monometallic butterfly‐shaped carbenoid in the Simmons–Smith reaction. Lithium enolates, generated by the reaction of 2 equiv. of lithium hexamethyldisilazide (rather than 1 or 3 equiv.) with the cheap difluoromethylating species fluoroform, are the most useful alkali metal intermediates for the synthesis of pharmaceutically important α‐difluoromethylated carbonyl products.     

Rapid and Slow Generation of 1‐Trifluoromethylvinyllithium: Syntheses and Applications of CF3‐Containing Allylic Alcohols,Allylic Amines,and Vinyl Ketones

1‐(Trifluoromethyl)vinylation is accomplished in two protocols by the in situ generation of thermally unstable 3,3,3‐trifluoroprop‐1‐en‐2‐yllithium ( 1 ): 1) a rapid lithium–halogen‐exchange reaction of 2‐bromo‐3,3,3‐trifluoroprop‐1‐ene ( 2 ) takes effect with sec‐BuLi at ?105 °C to generate vinyllithium 1 , which reacts with more reactive electrophiles, such as aldehydes and N‐tosylimines before its decomposition, to afford 2‐(trifluoromethyl)allyl alcohols and N‐[2‐(trifluoromethyl)allyl] sulfoamides in good yield; 2) treatment of 2 with nBuLi at ?100 °C causes a slow lithium–halogen exchange of 2 , which gives rise to a mixture of 1 and nBuLi. Vinyllithium 1 is preferentially trapped with less reactive electrophiles, such as N,N‐dimethylamides in the presence of BF₃?OEt₂, to afford 1‐(trifluoromethyl)vinyl ketones in good yield. Versatility of the products toward syntheses of CF₃‐containing ring‐fused cyclopentenones is also demonstrated by the Pauson–Khand reaction and the Nazarov cyclization.     

Isotope Effects in the Solvolysis of Sterically Hindered Arenesulfonyl Chlorides

Solvent isotope effects in the ethanolysis of sterically hindered arenesulfonyl chlorides ruled out a proton transfer in the rate‐determining step and agreed with a S_N2 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 S_N2 mechanism involving the participation of solvent molecules in the TS, possibly forming a cyclic TS through a chain of solvent molecules.     

Mechanism of the Deaquation of Aquopentaaminocobalt（Ⅲ）Bromide

There are two theories,SN1 and SN2, for the mechanism of the deaquation of aquopentaamincobalt(Ⅲ） bromide(AAC-B). Both of the theories are supported by some experimental and calculated data. But there are not any experiments to determine directly the structure of the intermediates at dififferent reaction time.In this paper the structures of the intermediates at different reaction time in deaquation-anation of AACB were determined by extended X-ray absorption fine structure (EXAFS) and the reaction process was studied by the combination of X-ray powder diffraction and EXAFS.It was demonstrated that the deaquation-anation of AACB obeys the SN2 theory.     

Theoretical investigation of von Braun and von Braun-like reactions

The von Braun reaction, discovered at the dawn of the past century, consists of the reaction between a tertiary amine and cyanogen bromide. It leads to the cleavage of a C─N bond with the formation of an N-dialkylcyanamide and an alkyl bromide and has been extensively used in organic synthesis. A detailed in silico study (PCM/density functional theory [DFT]/B3LYP/6-31++G(d,p) calculations) of this venerable reaction has shown that in the first stage a zwitterionic adduct with a multibonded bromine atom is formed. The widely accepted mechanism involving an S_N2 reaction occurs in the second step, thus accounting for its selectivity. Quantum chemical calculations were performed for the von Braun-like reactions in systems formed by cyclic tertiary amines (N-alkyl azetidines). In these cases, the first stage is almost the same as in the classical von Braun processes, and selective S_N2 mechanisms can occur in the second step.     

Selectivity under microwave irradiation. Benzylation of 2-pyridone: an experimental and theoretical study

The reaction of 2-pyridone with benzyl bromide in the absence of base and under solvent-free conditions has been studied experimentally and by computational methods. This reaction was one of the first reported examples in which modification of selectivity under microwave irradiation was observed. C- and/or N-alkylations were obtained depending on the benzyl halide and the heating system. N-Alkylation through mechanism A (S_N2 mechanism) is kinetically favoured while C-alkylation through an S_N1-type mechanism is thermodynamically favoured and is observed under microwave irradiation. Two S_N1-type mechanisms (mechanisms B and C) have been calculated, mechanism C being a kind of S_Ni. The influence of the pyridone/benzyl bromide ratio was studied. A second molecule of pyridone stabilizes the transition state and assists the leaving of the bromide ion. The occurrence of C-alkylation under microwave irradiation is explained by the predominance of the thermodynamic control in these conditions. Under microwave irradiation N-alkylation through an S_N1-type mechanism (mechanism C) can also occur. The dependence of the outcome of N-alkylation on the benzyl bromide ratio has been explained by a shift in the mechanism from S_N2 to S_N1 under microwave irradiation. Computational calculations have shown to be a useful tool for determination of the origin of the selectivity under microwave irradiation.     

Theoretical study on the reaction mechanisms and stereoselectivities of DABCO‐catalyzed Rauhut–Currier/cyclization reaction of methyl acrylate with 2‐benzoyl‐3‐phenyl‐acrylonitrile

With the aid of density functional theory (DFT) calculations, we have investigated the mechanisms and stereoselectivities of the tandem cross Rauhut–Currier/cyclization reaction of methyl acrylate R₁ with (E)‐2‐benzoyl‐3‐phenyl‐acrylonitrile R₂ catalyzed by a tertiary amine DABCO. The results of the DFT calculations indicate that the favorable mechanism (mechanism A) includes three steps: the first step is the nucleophilic attack of DABCO on R₁ to form intermediates Int1 and Int1‐1, the second step is the reaction of Int1 and Int1‐1 with R₂ to generate intermediate Int2(SS,RR,SR&RS), and the last step is an intramolecular S_N2 process to give the final product P(SS,RR,SR&RS) and release catalyst DABCO. The S_N2 substitution is computed to be the rate‐determining step, whereas the second step is the stereoselectivity‐determining step. The present study may be helpful for understanding the reaction mechanism of similar tandem reactions.     

Theoretical investigation of ion pair SN2 reactions of alkali isothiocyanates with alkyl halides. Part 1. Reaction of lithium isothiocyanate and methyl fluoride with inversion mechanism

The gas‐phase ionic S_N2 reactions NCS^‐ + CH₃F and ion pair S_N2 reaction LiNCS + CH₃F with inversion mechanism were investigated at the level of MP2(full)/6‐311+G**//HF/6‐311+G**. Both of them involve the reactants complex, inversion transition state, and products complex. There are two possible reaction pathways in the ionic S_N2 reaction but four reaction pathways in the ion pair S_N2 reaction. Our results indicate that the introduction of lithium significantly lower the reaction barrier and make the ion pair displacement reaction more facile. For both ionic and ion pair reaction, methyl thiocyanate is predicted to be the major product, but the latter is more selective. More‐stable methyl isothiocyanate can be prepared by thermal rearrangement of methyl thiocyanate. The theoretical predictions are consistent with the known experimental results. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Exchange of halogen bonded on aromatic core. Heterogeneous catalysis—I : Reaction mechanism of iodine exchange in o-iodobenzoic acid

Reaction mechanism of halogen exchange between arylhalogenide and halogenide anion is studied in a case when the aromatic core is inactivated with respect to the S_NAr substitution by other substituents. The exchange of iodine between o-iodobenzoic acid and ¹³¹I labelled NaI serves as a modelling reaction. The reaction was found to proceed heterogeneously on a glass surface. In the case of a rapid course of the surface reaction the reaction mechanism is more complicated and the equation derived by McKay cannot be applied for expressing the time dependence of the degree of isotopic exchange. Reaction mechanism was proposed for this reaction and compared with experimental data.     

SN1‐SN2 and SN2‐SN3 mechanistic changes revealed by transition states of the hydrolyses of benzyl chlorides and benzenesulfonyl chlorides

Hydrolysis reactions of benzyl chlorides and benzenesulfonyl chlorides were theoretically investigated with the density functional theory method, where the water molecules are explicitly considered. For the hydrolysis of benzyl chlorides (para‐Z? C₆H₄? CH₂? Cl), the number of water molecules (n) slightly influences the transition‐state (TS) structure. However, the para‐substituent (Z) of the phenyl group significantly changes the reaction process from the stepwise (S_N1) to the concerted (S_N2) pathway when it changes from the typical electron‐donating group (EDG) to the typical electron‐withdrawing one (EWG). The EDG stabilizes the carbocation (MeO? C₆H₄? CH₂⁺), which in turn makes the S_N1 mechanism more favorable and vice versa. For the hydrolysis of benzenesulfonyl chlorides (para‐Z? C₆H₄? SO₂? Cl), both the Z group and n influence the TS structure. For the combination of the large n value (n > 9) and EDG, the S_N2 mechanism was preferred. Conversely, for the combination of the small n value and EWG, the S_N3 one was more favorable. © 2014 Wiley Periodicals, Inc.     

Copper(II) Complexes of a Hexadentate Mixed‐Donor N3S3 Macrobicyclic Cage: Facile Rearrangements and Interconversions

The potentially hexadentate mixed‐donor cage ligand 1‐methyl‐8‐amino‐3,13,16‐trithia‐6,10,19‐triazabicyclo[6.6.6]eicosane (AMME‐N₃S₃sar; sar=sarcophagine) displays variable coordination modes in a complex with copper(II). In the absence of coordinating anions, the ligand adopts a conventional hexadentate N₃S₃ binding mode in the complex [Cu(AMME‐N₃S₃sar)](ClO₄)₂ that is typical of cage ligands. This structure was determined by X‐ray crystallography and solution spectroscopy (EPR and NIR UV/Vis). However, in the presence of bromide ions in DMSO, clean conversion to a five‐coordinate bromido complex [Cu(AMME‐N₃S₃sar)Br]⁺ is observed that features a novel tetradentate (N₂S₂)‐coordinated form of the cage ligand. This copper(II) complex has also been characterized by X‐ray crystallography and solution spectroscopy. The mechanism of the reversible interconversion between the six‐ and five‐coordinated copper(II) complexes has been studied and the reaction has been resolved into two steps; the rate of the first is linearly dependent on bromide ion concentration and the second is bromide independent. Electrochemistry of both [Cu(AMME‐N₃S₃sar)]²⁺ and [Cu(AMME‐N₃S₃sar)Br]⁺ in DMSO shows that upon reduction to the monovalent state, they share a common five‐coordinated form in which the ligand is bound to copper in a tetradentate form exclusively, regardless of whether a six‐ or five‐coordinated copper(II) complex is the precursor.     

Kinetic Evidence for a Non‐Langmuir‐Hinshelwood Surface Reaction: H/D Exchange over Pd Nanoparticles and Pd(111)

The mechanism of hydrogen recombination on a Pd(111) single crystal and well‐defined Pd nanoparticles is studied using pulsed multi‐molecular beam techniques and the H₂/D₂ isotope exchange reaction. The focus of this study is to obtain a microscopic understanding of the role of subsurface hydrogen in enhancing the associative desorption of molecular hydrogen. HD production from H₂ and D₂ over Pd is investigated using pulsed molecular beams, and the temperature dependence and reaction orders are obtained for the rate of HD production under various reaction conditions designed to modulate the amount of subsurface hydrogen present. The experimental data are compared to the results of kinetic modeling based on different mechanisms for hydrogen recombination. We found that under conditions where virtually no subsurface hydrogen species are present, the HD formation rate can be described exceptionally well by a classic Langmuir–Hinshelwood model. However, this model completely fails to reproduce the experimentally observed high HD formation rates and the reaction orders under reaction conditions where subsurface hydrogen is present. To analyze this phenomenon, we develop two kinetic models that account for the role of subsurface hydrogen. First, we investigate the possibility of a change in the reaction mechanism, where recombination of one subsurface and one surface hydrogen species (known as a breakthrough mechanism) becomes dominant when subsurface hydrogen is present. Second, we investigate the possibility of the modified Langmuir–Hinshelwood mechanism with subsurface hydrogen lowering the activation energy for recombination of two hydrogen species adsorbed on the surface. We show that the experimental reaction kinetics can be well described by both kinetic models based on non‐Langmuir–Hinshelwood‐type mechanisms.     

Frontside versus Backside SN2 Substitution at Group 14 Atoms: Origin of Reaction Barriers and Reasons for Their Absence

We have theoretically studied the gas‐phase nucleophilic substitution at group‐14 atoms (S_N2@A) in the model reactions of Cl^?+AH₃Cl (A=C, Si, Ge, Sn, and Pb) using relativistic density functional theory (DFT) at ZORA‐OLYP/TZ2P. Firstly, we wish to explore and understand how the reaction coordinate ζ, and potential energy surfaces (PES) along ζ, vary as the center of nucleophilic attack changes from carbon to the heavier group‐14 atoms. Secondly, a comparison between the more common backside reaction (S_N2‐b) and the frontside pathway (S_N2‐f) is performed. The S_N2‐b reaction is found to have a central barrier for A=C, but none for the other group‐14 atoms, A=Si–Pb. Relativistic effects destabilize reactant complexes and transition species by up to 10 kcal mol^?1 (for S_N2‐f@Pb), but they do not change relative heights of barriers. We also address the nature of the transformation in the frontside S_N2‐f reactions in terms of turnstile rotation versus Berry‐pseudorotation mechanism.     

Computational study of SN2 reactions promoted by crown ether: Contact ion pair versus solvent‐separated ion pair mechanism

We examined by quantum chemical methods the mechanism of S_N2 reaction using metal bromide MBr (M = Na, K, Cs) and KX (X= F, Cl) in CH₃CN promoted by crown ether (18‐crown‐6). We focus on whether the metal salts react as a contact ion pair (CIP; M⁺ and X^– in close contact) or as a solvent‐separated ion pair (SSIP; M⁺ and X^– at large distance). In SSIP mechanism, X^– is removed far enough from M⁺ for the metal salt to be considered as “separated” by the effects of the crown ether and the solvent. In the CIP picture, conversely, the coordination of 18‐crown‐6 to M⁺ is not sufficient to overcome the powerful Coulombic interactions between M⁺ and X^–. We find that the CIP route is favored for S_N2 bromination processes using MBr (M = Na, K, Cs). For S_N2 reaction using KF, the feasibility of the two pathways is essentially equal, whereas for S_N2 chlorination by KCl the SSIP route is predicted to be favored.     

Oxidative Coupling of Aryl Boron Reagents with sp3‐Carbon Nucleophiles: The Enolate Chan–Evans–Lam Reaction

Reported is a versatile new oxidative method for the arylation of activated methylene species. Under mild reaction conditions (RT to 40 °C), Cu(OTf)₂ mediates the selective coupling of functionalized aryl boron species with a variety of stabilized sp³‐nucleophiles. Tertiary malonates and amido esters can be employed as substrates to generate quaternary centers. Complementing either traditional cross‐coupling or S_NAr protocols, the transformation is chemoselective in the presence of halogen electrophiles, including aryl bromides and iodides. Substrates bearing amide, sulfonyl, and phosphonyl groups, which are not amenable to coupling under mild Hurtley‐type conditions, are suitable reaction partners.     

Nucleophilic Substitution Reactions of Meta‐ and Para‐Substituted Benzylamines with Benzyl Bromide in Methanol Medium

The rates of reactions of para‐ and meta‐substituted benzylamines with benzyl bromide were measured using conductivity technique in methanol medium. The reaction followed a total second‐order path. The end product of the reaction is identified as dibenzylamine (X‐C₆H₄CH₂NHCH₂C₆H₅) (where X = 4‐OCH₃, 4‐CH₃, H, 4‐Cl, 4‐CF₃, 3‐CF₃, 4‐NO₂). Electron‐withdrawing groups such as chloro, trifluoromethyl, and nitro in the benzylamine moiety decrease the rate of the reaction, whereas the electron‐donating groups, such as methoxy and methyl, increase the rate compared to the unsubstituted compound. A mechanism involving formation of an S_N2‐type transition state between the amine nucleophiles and the benzyl bromide and its subsequent decomposition is proposed. Hammett's reaction constant ρ of the reaction decreases with an increase in temperature. Activation parameters were calculated and discussed.     

Synthesis of α-Functionalized Allenes

It is known, since the work of Landor et al, that α-allenic alcohols can be specifically obtained by treating the monotetrahydropyranyl ether of a butyn-1,4-diol with lithium aluminium hydride (1). In this reaction, which can be also realized with another leaving group (halogen, ammonium) (2), the allenic linkage is formed by an S_N ^2′ process where the nucleophilic hydride is transferred from the initially formed alcoholate (scheme 1).     

Nucleophilic catalysis of halide displacement from brominated poly(isobutylene-co-isoprene)

The dynamics of halide displacement from brominated poly(isobutylene-co-isoprene)(BIIR) by carboxylate nucleophiles are detailed and discussed in terms of a general reaction mechanism. The exomethylene allylic bromide isomer within BIIR is shown to undergo simultaneous S_N2 alkylation of Bu₄Nacetate and S_N2′ rearrangement with Bu₄NBr. The latter generates a Z-BrMe isomer that is more reactive toward esterification. Hence, overall polymer modification rates are auto-accelerating, as Bu₄NBr liberated by esterification catalyzes allylic bromide rearrangement to a more reactive electrophile. This knowledge of reaction mechanisms is used to develop nucleophilic catalysis techniques involving iodide intermediates.     

A QM/MM Investigation of the Catalytic Mechanism of Metal‐Ion‐Independent Core 2 β1,6‐N‐Acetylglucosaminyltransferase

β1,6‐GlcNAc‐transferase (C2GnT) is an important controlling factor of biological functions for many glycoproteins and its activity has been found to be altered in breast, colon, and lung cancer cells, in leukemia cells, in the lymhomonocytes of multiple sclerosis patients, leukocytes from diabetes patients, and in conditions causing an immune deficiency. The result of the action of C2GnT is the core 2 structure that is essential for the further elongation of the carbohydrate chains of O‐glycans. The catalytic mechanism of this metal‐ion‐independent glycosyltransferase is of paramount importance and is investigated here by using quantum mechanical (QM) (density functional theory (DFT))/molecular modeling (MM) methods with different levels of theory. The structural model of the reaction site used in this report is based on the crystal structures of C2GnT. The entire enzyme–substrate system was subdivided into two different subsystems: the QM subsystem containing 206 atoms and the MM region containing 5914 atoms. Three predefined reaction coordinates were employed to investigate the catalytic mechanism. The calculated potential energy surfaces discovered the existence of a concerted S_N2‐like mechanism. In this mechanism, a nucleophilic attack by O6 facilitated by proton transfer to the catalytic base and the separation of the leaving group all occur almost simultaneously. The transition state for the proposed reaction mechanism at the M06‐2X/6‐31G** (with diffuse functions on the O1′, O5′, O_Glu, and O6 atoms) level was located at C1? O6=1.74 Å and C1? O1=2.86 Å. The activation energy for this mechanism was estimated to be between 20 and 29 kcal mol^?1, depending on the method used. These calculations also identified a low‐barrier hydrogen bond between the nucleophile O6H and the catalytic base Glu320, and a hydrogen bond between the N‐acetamino group and the glycosidic oxygen of the donor in the TS. It is proposed that these interactions contribute to a stabilization of TS and participate in the catalytic mechanism.