Origin of the SN2 benzylic effect

The S N2 identity exchange reactions of the fluoride ion with benzyl fluoride and 10 para-substituted derivatives (RC6H 4CH 2F, R = CH3, OH, OCH 3, NH2, F, Cl, CCH, CN, COF, and NO2) have been investigated by both rigorous ab initio methods and carefully calibrated density functional theory. Groundbreaking focal-point computations were executed for the C6H5CH 2F + F (-) and C 6H 5CH2Cl + Cl (-) SN2 reactions at the highest possible levels of electronic structure theory, employing complete basis set (CBS) extrapolations of aug-cc-pV XZ (X = 2-5) Hartree-Fock and MP2 energies, and including higher-order electron correlation via CCSD/aug-cc-pVQZ and CCSD(T)/aug-cc-pVTZ coupled cluster wave functions. Strong linear dependences are found between the computed electrostatic potential at the reaction-center carbon atom and the effective SN2 activation energies within the series of para-substituted benzyl fluorides. An activation strain energy decomposition indicates that the SN2 reactivity of these benzylic compounds is governed by the intrinsic electrostatic interaction between the reacting fragments. The delocalization of nucleophilic charge into the aromatic ring in the SN2 transition states is quite limited and should not be considered the origin of benzylic acceleration of SN2 reactions. Our rigorous focal-point computations validate the benzylic effect by establishing SN2 barriers for (F (-), Cl (-)) identity exchange in (C6H5CH2F, C6H 5CH2Cl) that are lower than those of (CH3F, CH3Cl) by (3.8, 1.6) kcal mol (-1), in order.     

Nucleophilic substitution at silicon (SN2@Si) via a central reaction barrier

It is textbook knowledge that nucleophilic substitution at carbon (SN2@C) proceeds via a central reaction barrier which disappears in the corresponding nucleophilic substitution reaction at silicon (SN2@Si). Here, we address the question why the central barrier disappears from SN2@C to SN2@Si despite the fact that these processes are isostructural and isoelectronic. To this end, we have explored and analyzed the potential energy surfaces (PES) of various Cl-+CR3Cl (R=H, CH3) and Cl-+SiR3Cl model reactions (R=H, CH3, C2H5, and OCH3). Our results show that the nature of the SN2 reaction barrier is in essence steric, but that it can be modulated by electronic factors. Thus, simply by increasing the steric demand of the substituents R around the silicon atom, the SN2@Si mechanism changes from its regular single-well PES (with a stable intermediate transition complex, TC), via a triple-well PES (with a pre- and a post-TS before and after the central TC), to a double-well PES (with a TS; R=OCH3), which is normally encountered for SN2@C reactions.     

Theoretical study on the identity ion pair SN2 reactions of LiX with CH3SX (X=Cl, Br, and I): structure, mechanism, and potential energy surface

Three archetypal ion pair nucleophilic substitution reactions at the methylsulfenyl sulfur atom LiX+CH3SX-->XSCH3+LiX (X=Cl, Br, and I) are investigated by the modified Gaussian-2 theory. Including lithium cation in the anionic models makes the ion pair reactions proceed along an SN2 mechanism, contrary to the addition-elimination pathway occurring in the corresponding anionic nucleophilic substitution reactions X-+CH3SX-->XSCH3+X-. Two reaction pathways for the ion pair SN2 reactions at sulfur, inversion and retention, are proposed. Results indicate the inversion pathway is favorable for all the halogens. Comparison of the transition structures and energetics for the ion pair SN2 at sulfur with the potential competition ion pair SN2 reactions at carbon LiX+CH3SX-->XCH3+LiXS shows that the SN2 reactions at carbon are not favorable from the viewpoints of kinetics and thermodynamics.     

Quantum dynamics of gas-phase SN2 reactions.

Understanding the state-resolved dynamics of elementary chemical reactions involving polyatomic molecules, such as the well-known reaction mechanism of nucleophilic bimolecular substitution (SN2), is one of the principal goals in chemistry. In this Review, the progress in the quantum mechanical treatment of SN2 reactions in the gas phase is reviewed. The potential energy profile of this class of reactions is characterized by two relatively deep wells, which correspond to pre- and post-reaction chargedipole complexes. As a consequence, the complex-forming reaction is dominated by Feshbach resonances. Calculations in the energetic continuum constitute a major challenge because the high density of resonance states imposes considerable requirements on the convergence and the energetic resolution of the scattering data. However, the effort is rewarding because new insights into the details of multimode quantum dynamics of elementary chemical reactions can be obtained.     

Studies on highly stereoselective addition-elimination reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX. An efficient synthesis of 3-(methoxycarbonyl)-2-halo-1,3(Z)-dienes

3-(Methoxycarbonyl)-2-halo-1,3(Z)-dienes were prepared highly stereoselectively via SN2'-type addition-elimination reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX. These products may easily undergo Negishi or Sonogashira coupling reactions to yield a series of stereodefined polysubstituted (E)-1,3-dienes.     

Ab initio study of the SN1Ar and SN2Ar reactions of benzenediazonium ion with water. On the conception of "unimolecular dediazoniation" in solvolysis reactions

The nucleophilic substitution of N2 in benzenediazonium ion 1 by one H2O molecule to form protonated phenol 2 has been studied with ab initio (RHF, MP2, QCISD(T)//MP2) and hybrid density functional (B3LYP) methods. Three mechanisms were considered: (a) the unimolecular process SN1Ar with steps 1 --> Ph+ + N2 and Ph+ + H2O --> 2, (b) the bimolecular process SN2Ar with precoordination 1 + H2O --> 1 x H2O, SN reaction 1 x H2O --> [TS]++ --> 2 x N2 and dissociation of the postcoordination complex 2 x N2 --> 2 + N2, and (c) the direct bimolecular process SN2Ar that bypasses precoordination and involves just the SN reaction 1 + H2O --> [TS]++ --> 2 + N2. The SN2Ar reactions proceed by way of a Cs symmetric SN2Ar transition state structure that is rather loose, contains essentially a phenyl cation weakly bound to N2 and OH2, and is analogous to the transition state structures of front-side nucleophilic replacement at saturated centers. In solvolysis reactions, all of these processes follow first-order kinetics, and the electronic relaxation is essentially the same. It is argued that "unimolecular dediazoniations" have to proceed by way of SN2Ar transition state structures because strict SN1Ar reactions cannot be realized in solvolyses, despite the fact that the Gibbs free energy profile favors the strict SN1Ar process over the SN2Ar reaction by 6.7 kcal/mol. It is further argued that the direct SN2Ar process is the best model for the solvolysis reaction for dynamic reasons, and its Gibbs free energy of activation is 19.3 kcal/mol and remains higher than the SN1Ar value. Even though the SN1Ar and SN2Ar models provide activation enthalpies and SKIE values that closely match the experimental data, the analysis leads us to the unavoidable conclusion that this agreement is fortuitous. While the experiments do show that the solvent effect on the activation energy is about the same for all solvents, they do not show the absence of a solvent effect. The ab initio results presented here suggest that the solvent effect on the direct SN2Ar dediazoniation is approximately 12 kcal/mol, and computation of solvent effects with the isodensity polarized continuum model (IPCM) support this conclusion.     

Asymmetric total synthesis of (+)-K01-0509 B: determination of absolute configuration

K01-0509 B is a novel natural product which contains a carbamoylated cyclic guanidine. Our asymmetric total synthesis features a Sharpless asymmetric epoxidation and a stereocontrolled construction of the cyclic guanidine via an asymmetric nitroaldol reaction, followed by intramolecular SN2 cyclization. These reactions allowed the cyclic guanidine and the adjacent hydroxy group to be assembled, facilitating the asymmetric total synthesis and determination of the absolute stereochemistry of K01-0509 B. [reaction: see text].     

Sources of artefacts in the electrospray ionization mass spectra of saturated diacylglycerophosphocholines: From condensed phase hydrolysis reactions through to gas phase intercluster reactions

The mass spectra of diacylglycerophosphocholine phospholipids comprised of saturated fatty acids (1,2-dipentanoyl-sn-glycero-3-phosphocholine (D5PC); 1,2-dihexanoyl-sn-glycero-3-phosphocholine (D6PC), and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (D14PC)) are sensitive to the electrospray ionization (ESI) conditions. When fresh solutions of phospholipid in 10 mM ammonium acetate are subjected to ESI, protonated oligomeric clusters, [DxPCn + H]+ (x = 5, 6, and 14) are observed in the following different types of mass spectrometers: 3D-quadrupole ion trap; linear ion trap, and triple quadrupole. The formation of the protonated cluster ions is not unique to the ion trap instruments, although they tend to be more abundant in these instruments. As the ESI solutions age, new ions are observed, which correspond to acid-catalyzed solution phase deacylation reactions. The collision induced dissociation fragmentation reactions of the oligomer cluster ions exhibit a distinct dependence on the cluster size, with the larger clusters (n > 2) simply fragmenting via the loss of lipid monomers. In contrast, the fragmentation of the dimeric cluster ion is unique, resulting in a number of additional reactions including covalent bond formation via intermolecular cluster SN2 reactions and SN2 transfer of a methyl group. The nature of the charge has a significant role in the formation of products via these intermolecular cluster reactions. Changing the head group to phosphoethanolamine "switches off" the SN2 reactions, while changing the cation from a proton to either a sodium or a potassium ion, diminishes the intermolecular reactions relative to monomer loss. Semi empirical PM3 calculations on [D6PC2 + H]+ suggest that the SN2 reactions are thermodynamically favored over simple monomer loss. These results have important implications in the field of lipidomics.     

Kinetics and mechanism of the aminolysis of aryl phenyl chlorothiophosphates with anilines

Kinetic studies of the reactions of aryl phenyl chlorothiophosphates (1) and aryl 4-chlorophenyl chlorothiophosphates (2) with substituted anilines in acetonitrile at 55.0 degrees C are reported. The negative values of the cross-interaction constant rhoXY (rhoXY = -0.22 and -0.50 for 1 and 2, respectively) between substituents in the nucleophile (X) and substrate (Y) indicate that the reactions proceed by concerted SN2 mechanism. The primary kinetic isotope effects (kH/kD = 1.11-1.13 and 1.10-1.46 for 1 and 2, respectively) involving deuterated aniline nucleophiles are obtained. Front- and back-side nucleophilic attack on the substrates is proposed mainly on the basis of the primary kinetic isotope effects. A hydrogen-bonded, four-center-type transition state is suggested for a front-side attack, while the trigonal bipyramidal pentacoordinate transition state is suggested for a back-side attack. The MO theoretical calculations of the model reactions of dimethyl chlorothiophosphate (1') and dimethyl chlorophosphate (3') with ammonia are carried out. Considering the specific solvation effect, the front-side nucleophilic attack can occur competitively with the back-side attack in the reaction of 1'.     

碳纳米管内P—Ylide反应的理论研究

碳纳米管空腔不仅可以改变填充到其内部分子的性质,而且对其内部的SN2取代反应有促进或抑制作用,因而被视为一种新型的“固体溶剂”．本文通过密度泛函理论研究了CH2O和PH3CH2在气相、苯溶液和碳纳米管空腔内的[2＋2]加成反应．结果表明,与气相相比,碳纳米管空腔对于[2＋2]环加成反应影响不大,这是因为所研究的[2＋2]环加成反应中,反应物并不是轴对称的,不同于SN2取代反应的一维线性排列,所以具有较大轴向极化率的碳纳米管对[2＋2]环加成反应影响较小．     

Gas-phase SN2 reactivity of dicoordinated borinium cations using pentaquadrupole mass spectrometry

We report gas phase ion/molecule reactions between dialkoxyborinium cations (RO-B+-OR) and small organic amides, such as N,N-dimethylformamide and N,N-diethylpropionamide. Besides direct addition at boron, the results show efficient SN2 methyl transfer from the borinium ion to the amide. Isotopic labeling and collision-induced dissociation (CID) of the methyl transfer products demonstrate O-methylation of the amide. Methyl substitution at the alpha-carbon of the amide affects the degree of alkylation and adduct formation. Direct proton abstraction via beta-elimination is a major competitive reaction for substituents other than methyl. Ab initio calculations at the B3LYP/6-31G(d) level indicate that SN2 transmethylation is highly exothermic with O-methylation favored over N-methylation by 14.8 kcal/mol.     

羟基负离子与一氟甲烷双分子亲核取代反应的量子化学研究

本文用LCAO-MO-SCF ab initio方法, 对OH^-+CH3F→CH3OH+F^-反应进行了过渡态理论及前线轨道理论的量子化学研究, 以4-31G为基组, 计算了反应进程的势能曲线,得到了过渡态的几何构型, 并用MP2方法进行了电子库仑相关效应的校正, 反应活化能的计算值与实验数据较为一致。用前线轨道理论对反应中分子重新组合过程进行了轨道分析, 较全面地解释了该反应的机理。     

应用分子形貌理论研究类SN2反应

应用分子形貌理论, 研究了类SN2反应过程中的沿着IRC路径上固定点的分子形貌的特征, 计算给出了形状和电子密度特征参数以及各键的Dpb值. 应用Matlab程序绘制了分子特征边界轮廓上的电子密度分布的三维图像, 即分子形貌像, 给出了这类反应的动态变化过程.     

Synthetic and Structural Studies of Cyclophosphathiazenes and their Adducts with Lewis Acids

Abstract

The reactions of (Me₃SiNR)PPh₂ (NSiMe₃) (R=H, SiMe₃) with (NSCl)₃ or S_xCl₂ (x=1, 2) provide improved preparative routes to mixed phosphazene-thia-zene ring systems, e.g. (Ph₂PN) (SN)₂, 1,3- and 1,5-(Ph₂PN)₂(SN)₂. The interaction of these heterocycles with protonic and Lewis acids, e.g. HBF₄, BCl₃, MeSO₃CF₃, has been investigated in order to determine the site of attack and the effect of adduct formation on the molecular and electronic structures of these ring systems. These reactions have been monitored by UV-visible and ³¹P NMR spectroscopies and the structures of crystalline adducts have been determined by X-ray crystallography. For example, the interaction of 1,3-(Ph₂PN)₂(SN)₂ with MeSO₃CF₃ gives a product in which the methyl group is attached to a nitrogen atom between phosphorus and sulfur. The resulting structural distortion in this and related adducts will be analyzed in the context of the electronic structures of mixed phosphazene-thiazene systems and their adducts with Lewis acids.     

Kinetic studies of the N-alkylation of secondary amines with 1,2-dichloroethane

The reactions of 1,2-dichloroethane with 2-(ethylamino)ethanol or diethylamine have been investigated in several solvents from 51 to 80°C. A reaction mechanism has been proposed where 1,2-dichloroethane reacts with the secondary amines in both bimolecular substitution (SN 2) and elimination (E2) reactions; the substitution product is rapidly converted in an aziridinium ion and undergoes a consecutive reaction with the starting amine to give a tetrasubstituted ethylenediamine. The rate constants as well as the activation energies of these reactions have been determined. © 1994 John Wiley & Sons, Inc.     

Studies of the formation of all-carbon quaternary centres, en route to lyngbyatoxin A. A comparison of phenyl and 7-substituted indole systems

Copper mediated allylic substitutions and conjugate additions to geranyl, cinnamyl and allylic indole compounds have been investigated with the aim of finding a method for the creation of the all-carbon quaternary centre present in the natural product lyngbyatoxin A. Reaction conditions have been found giving a 68% SN2' selectivity in the copper mediated addition of PhMgBr to geranyl chloride, as well as 99% and 95% SN2' selectivity in the copper catalysed addition of EtMgBr to cinnamyl chloride and acetate, respectively. When the optimised reaction conditions were applied to the corresponding allylic compounds containing a 7-substituted indole moiety, the regioselectivity was reversed giving only the SN2 product. The allylic indole-containing substrates were also found to be unproductive in Pd- or Mo-catalysed SN2'-type substitution reactions. In related studies, copper catalysed conjugate addition of EtMgBr to the tricyclic lactam 6-methyl-pyrrolo[3,2,1-ij]quinolin-4-one gave a maximum of 20% of the 1,4-addition product.     

Theoretical study of the effect of coordinating solvent on ion pair SN2 reactions: the role of unsymmetrical transition structures

Computations are reported at the HF/6-31+g* level for ion pair SN2 reactions of methyl, ethyl, n-propyl, isopropyl, and allyl halides with LiX.E, LiX.2E, and LiX.3E (X = F, Cl, Br; E = dimethyl ether as a model for THF). Some calculations were also done at the MP2, B3LYP, and mPW1PW91 levels. In addition to normal SN2-type (type I) transition structures (TSs), novel unsymmetrical TSs were found in which the Li is coordinated to a single halide. With LiX.2E, such structures are already competitive with the type I structures, and with LiX.3E, only the type II structures were found. With incorporation of dielectric solvation, the type II structures are relatively even more stable. The results suggest that such structures are better models for ion pair displacement reactions in ethereal solvents.     

Dramatic effects of halogen substitution and solvent on the rates and mechanisms of nucleophilic substitution reactions of aziridines

In a previous study we reported that fluorine substitution at the carbon positions of aziridine results in profound enhancements of the rate of reaction with ammonia, a typical nucleophile, in the gas phase. In this study the investigation is extended to include chloro- and bromoaziridines. Because syntheses are largely performed in the condensed phase, the present computational investigation [(MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level] was conducted with three typical solvents that cover a wide range of polarity: THF, CH3CN, and H2O. Nucleophiles can react with haloaziridines 1 by displacing a substituted amide ion by means of an SN2 mechanism (pathway a), producing 1,2-diaminohaloethanes (from the initially formed dipolar species 2). Alternatively, a rearrangement mechanism involving rate-determining departure of a halide ion (pathway b) to form an imidoyl halide, 3, is possible. Transition-state theory was used to compute relative reaction rates of these mechanistic possibilities and to assess the role of the halogen substituents and the reaction solvent. Gas-phase results provided the basis of mechanistic insights that were more apparent in the absence of intermolecular interactions. Fluoroaziridines were found to react at accelerated rates relative to aziridine exclusively by means of the a Menshutkin-type mechanism (SN2) in each solvent tested, while the reactions of the chloro- and bromoaziridines could be directed toward 2 in the highly nonpolar solvent, cyclohexane, or toward 3 in the more polar solvents. An assessment is made of the feasibility of using this chemistry of the haloazirdines in the synthetic laboratory.     

Competing elimination and substitution reactions of simple acyclic disulfides

MP2/aug-cc-pVDZ and B3LYP/cc-pVDZ calculations of the reactions of CH3SSR (R = H or CH3) with fluoride, hydroxide or allyl anion in the gas-phase were performed to determine the mechanism for both elimination and substitution reactions. The elimination reactions were shown to follow the E2 mechanism. The substitution reactions with hydroxide and fluoride proceed by the addition-elimination mechanism, but those with allyl anion proceed by the SN2 mechanism. The elimination reactions with F- and HO- are preferred to the substitution reactions, while allyl anion prefers the substitution route.     

CH_3SH+CN微观反应机理的理论研究

采用BMC-CCSD//B3LYP/6-311G(d,p)方法对CH3SH+CN反应机理进行了详细的理论研究.反应中涉及的各稳定点的构型、振动频率和零点能在B3LYP/6-311G(d,p)水平下计算得到,计算结果表明,该反应存在两种反应机理,5条可能的反应通道.SN2机理由于能垒太高,与直接氢抽提机理相比可以忽略.该反应的最可行通道为CN中的C原子进攻SH中的H原子经由一个前期和一个后期分子络合物生成产物CH3S和HCN.计算得到的反应焓变与已有实验值非常吻合.