SN2-type Reaction Research Articles

Enantioselective SN1-type reaction via electrochemically generated chiral α-Imino carbocation intermediate

Electrochemical reactions via carbocation intermediates remain fundamental transformations that build up molecular functionality and complexity in a sustainable manner. Enantioselective control of such processes is a great challenge in a highly ionic electrolyte solution. Here, we report an anodic generation of chiral α-imino carbocation intermediates by enamine catalysis. The chiral carbocation intermediates can be intercepted by a variety of nucleophiles such as alcohols, water and thiols with high stereoselectivity. The key SN1 step proceeds via a tertiary amine-mediated proton shuttle that facilitates facial selection in reacting with carbocation.

Elucidating the Binding Mode of Sulfur- and Selenium-Based Cationic Chalcogen-Bond Donors.

For a comparison of the interaction modes of various chalcogen-bond donors, 2-chalcogeno-imidazolium salts have been designed, synthesized, and studied by single crystal X-ray diffraction, solution NMR and DFT as well as for their ability to act as activators in an SN1-type substitution reaction. Their interaction modes in solution were elucidated based on NMR diffusion and chemical shift perturbation experiments, which were supported by DFT-calculations. Our finding is that going from lighter to the heavier chalcogens, hydrogen bonding plays a less, while chalcogen bonding an increasingly important role for the coordination of anions. Anion-π interactions also show importance, especially for the sulfur and selenium derivatives.

Synthesis of a tetralone derivative of ampicillin to control ampicillin-resistant Staphylococcusaureus

Due to the rapid emergence of antibiotic resistant new bacterial strains and new infections, there is an urgent need for novel or newly modified and efficient alternatives of treatment. However, conventional antibiotics are still used in therapeutic settings but their efficacy is uncertain due to the rapid evolution of drug resistance. In the present study, we have synthesized a new derivative of conventional antibiotic ampicillin using SN2-type substitution reaction. NMR and mass analysis of the newly synthesized derivative of ampicillin confirmed it as ampicillin-bromo-methoxy-tetralone (ABMT). Importantly, ABMT is revealed to have efficient activity against Staphylococcus aureus (S. aureus) with a MIC value of 32 μg ml−1 while ampicillin was not effective, even at 64 μg ml−1 of concentration. Electron microscopy results confirmed the membrane-specific killing of S. aureus at 1 h of treatment. Additionally, molecular docking analysis revealed a strong binding affinity of ABMT with β-lactamase via the formation of a closed compact bridge. Our findings, avail a new derivative of ampicillin that could be a potential alternative to fight ampicillin-resistant bacteria possibly by neutralizing the β-lactamase action.

Synthesis of oxime ethers via a formal reductive O-H bond insertion of oximes to α-keto esters.

This study describes an efficient approach to access oxime ethers via P(III)-mediated O-H bond insertion reaction of oximes with α-keto esters. The strategy involves the protonation of in situ generated Kukhtin-Ramirez adducts, followed by SN2-type reaction. Important features include a good functional group tolerance, operational simplicity, and application to gram scale synthesis and the synthesis of an acaricide.

Preparation of Fluorous Aza-crown Ether with Two Bisfluorous Chain Type Propionyl Groups: An Investigation of its Partition Ratios in Fluorous Biphasic Systems and Recyclability During SN2-type Acetoxylation Reactions

Abstract: In this study, a new fluorous aza-crown ether derivative (1) conjugated with two Bfp (bisfluorous chain type propionyl) groups was prepared; then, the partition ratios of 1 in biphasic systems using FC 72 and several organic solvents were investigated. Next, the activities of 1 in an FC 72/acetonitrile biphasic system were assessed via the SN2-type acetoxylation reaction using 2- (bromomethyl)naphthalene and potassium acetate. Finally, the recyclability of 1 in a two-layer system based on its immobilization in an FC 72 solvent was examined during acetoxylation reactions.

Heterogeneous phosphonium–carbon based PTC catalyst: From mechanochemical synthesis to SN2 type reaction in water

The use of phosphonium-carbon-based PTC as a catalyst in water solution is here described and its performances are discussed. The synthesis is realized via a mechanochemical process in solvent-free conditions respecting most of the green metrics for a sustainable procedure. The heterogeneous phase-transfer catalyst is fully characterized and used for SN2-type reaction of NaSCN with variously substituted benzyl bromides. The reaction proceeds with high efficiency in the presence of 5mol% of catalyst in water up to >99% of conversion. The catalyst can be easily recycled without losing productivity providing a green procedure.

Kinetic and Spectroscopic Studies of Methyl Ester Promoted Methanol Dehydration to Dimethyl Ether on ZSM-5 Zeolite

Methyl carboxylate esters have been shown to be potent promoters of low-temperature methanol dehydration to dimethyl ether (DME) using various zeolite catalysts. In the present work, catalytic kinetic studies, in-situ Fourier-transform infrared spectroscopy (FT-IR) and solid-state nuclear magnetic resonance spectroscopy (NMR) techniques were used to elucidate the promotional mechanism of methyl carboxylate esters on methanol dehydration to DME, using the medium pore zeolite H-ZSM-5 (MFI) as the catalyst. Kinetic studies were performed using the very potent methyl n-hexanoate promoter. The DME yield was dependent on both the methanol and methyl n-hexanoate partial pressures across the temperature ranges used in this study (110 to 130 °C). This is consistent with the promoted reaction being a bimolecular reaction between methanol and ester species adsorbed at the catalyst active sites, via an SN2 type reaction, as previously postulated. The in-situ FT-IR studies reveal that the Brønsted acid (BA) sites on H-ZSM-5 were very rapidly titrated by ester carbonyl group adsorption and bonded more strongly with esters than with methanol. Upon methanol addition, an even lower DME formation temperature (30 °C) was observed with methyl n-hexanoate pretreated H-ZSM-5 samples in the in-situ NMR studies, further confirming the strong promotion of this methyl ester on methanol dehydration to DME. The adsorption and reactivity of different methyl esters on H-ZSM-5 indicates that while methyl formate more easily dissociates into a surface methoxy species, [Si(OMe)Al], and carboxylic acid, it is a less potent promoter than alkyl-chain-containing methyl esters in methanol dehydration to DME, which in turn did not show this dissociative behavior in the low-temperature NMR studies. This indicates that methyl alkyl carboxylates do not need to be dissociated to a surface methoxy species to promote the methanol dehydration reaction and that a bimolecular associative mechanism plays an important role in promoting DME formation.

Carbon black intercalation compound as catalyst for unprecedent phase-transfer-catalyzed nucleophilic substitution (SN2) in water

Carbon black intercalation compound was used for the first time as a heterogeneous phase-transfer-catalyst for SN2 type reaction of NaSCN with 4-nitrobenzyl bromide. The reaction proceeds in the presence of 5 mol% of catalyst with high efficiency in a liquid-liquid biphasic system (CHCl3/H2O), providing 98% conversion after only 4 h. Furthermore, an unprecedent efficient nucleophilic substitution was reported in water solution in the presence of the new catalyst, providing 95% yield in 8 h. The reaction is green, and the heterogeneous catalyst can be recovered and recycled without losing efficiency.

Mechanism of Methanol Dehydration Catalyzed by Al8O12 Nodes Assisted by Linker Amine Groups of the Metal–Organic Framework CAU-1

Elucidation of catalytic sites and mechanisms of reactions on metal oxides is hindered by the complexity and heterogeneity of the surfaces. In contrast, the metal oxide cluster nodes of metal–organic frameworks (MOFs) have well-defined, essentially molecular structures that provide excellent platforms for understanding catalytic reactions in depth. We report an experimental and density functional theory (DFT) investigation of methanol dehydration on the Al8O12 nodes of the MOF CAU-1, presenting catalyst performance data obtained with vapor-phase methanol contacting MOF particles in a flow reactor at temperatures in the range of 180–250 °C. These data and infrared spectra of the MOF characterizing its reactivity with methanol and water show that the reactivities of node μ2-OH groups, influenced by the coordination environments of the node aluminum atoms, react with methanol to form catalytic sites incorporating methoxy ligands that bridge paired aluminum atoms, with the dehydration mechanism engaging nearby MOF linker amine groups that bond to methanol. DFT investigations of the mechanism suggest that the SN2-type methanol dehydration reaction is energetically favored to occur at MOF linker amine groups, which allow for a near-linear transition state (TS) geometry; in contrast, the central cavity of the Al8O12 node adsorbs methanol strongly but, because of geometric constraints, renders the TS for methanol dehydration energetically unfavorable.

Synthesis and Electrochemical Investigation of π Expanded Vitamin B12 Derivative, Pyrocobester

Vitamin B12 is a unique metal complex which has the cobalt ion and the corrin as a centered metal and a ligand, respectively. The Co(I) state of the vitamin B12 reacts alkyl halide to form alkylated complex by the SN2 type reaction and proceed the several catalytic reactions via alkyl radicals formed by homolysis of the cobalt-carbon bond.[1] Based on these properties of the vitamin B12, many B12-inspired reactions have been developed.[2] In general, many researchers have used the cobyrinate complex (1) as the B12 derivatives. Here, we report the synthesis and characterization of the Co(II) state of pyrocobseter (2) with π-expanded structure and the reactivities of the complex will be discussed.The pyrocobester was synthesized by the pyrolysis of the cobyrinate.[3] The absorption of the pyrocobester showed efficiently red-shift compared to the cobyrinate because of the conjugated corrin ligand. Furthermore, Co(II)/Co(I) redox potentials were +0.3 V shifted (Figure 1). In addition, the spectrum was dramatically changed after adding the CH3I as the substrate. It is suggested that Co(I) state of pyrocobester reacted with CH3I and alkylated complex (CH3-Co(III)) was formed. In this presentation, we will report experimental detail of pyrocobester chemistry.

Molecular Transformation Based on an Innovative Catalytic System.

Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,β-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,β-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an SN2-type reaction).

Computational Investigation into the Mechanistic Features of Bromide-Catalyzed Alcohol Oxidation by PhIO in Water.

Iodosobenzene (PhIO) is known to be a potent oxidant for alcohols in the presence of catalytic bromide in water. In order to understand this important and practical oxidation process, we have conducted density functional theory studies to shed light on the reaction mechanism. The key finding of this study is that PhIO is not the reactive oxidant itself. Instead, the active oxidant is hypobromite (BrO-), which is generated by the reaction of PhIO with bromide through an SN2-type reaction. Critically, water acts as a cocatalyst in the generation of BrO- through lowering the activation energy of this process. This investigation also demonstrates why BrO- is a more powerful oxidant than PhIO in the oxidation of alcohols. Other halide additives have been reported experimentally to be less effective catalysts than bromide-our calculations provide a clear rationale for these observations. We also examined the effect of replacing water with methanol on the ease of the SN2 reaction, finding that the replacement resulted in a higher activation barrier for the generation of BrO-. Overall, this work demonstrates that the hypervalent iodine(III) reagent PhIO can act as a convenient and controlled precursor of the oxidant hypobromite if the right conditions are present.

Computational evidence of glycosyl cations.

Glycosyl cations are key intermediates in the glycosylation reactions taking place through a SN1-type mechanism. To obtain a reliable description of the glycosylation reaction mechanism a combination of computational studies and experimental data such as kinetic isotopic effects is needed. Computational studies have elucidated SN2-type glycosylation reaction mechanisms, but elucidation of mechanisms in which ion pairs can be formed presents some difficulties because of the recombination of the ions. Recent topological and dynamic studies open the door to the ultimate confirmation of the presence of glycosyl cations in the form of intimate ion pairs during certain glycosylation reactions. This review covers the state-of-the-art tools and applications of computational chemistry mainly developed during the last ten years to understand glycosylation reactions in which an oxocarbenium ion could be involved.

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles.

The sulfur(VI) fluoride exchange (SuFEx) reaction is an emerging scheme for connecting molecular building blocks. Due to its broad functional group tolerance and rather stable resulting linkage, it is seeing rapid adoption in various fields of chemistry. Still, to date the reaction mechanism is poorly understood, which hampers further development. Here, we show that the mechanism of the SuFEx reaction for the prototypical example of methanesulfonyl fluoride reacting with methylamine can be understood as an SN2-type reaction. By analyzing the reaction path with the help of density functional theory in vacuo and under consideration of solvent and co-reactant influence, we identify the often used complementary base as a crucial ingredient to lower the reaction barrier significantly by increasing the nucleophilicity of the primary amine. With the help of energy decomposition analysis at the transition state structures, we quantify the underlying stereoelectronic effects and propose new avenues for experimental exploration of the potential of SuFEx chemistry.

NBO/NRT Two-State Theory of Bond-Shift Spectral Excitation.

We show that natural bond orbital (NBO) and natural resonance theory (NRT) analysis methods provide both optimized Lewis-structural bonding descriptors for ground-state electronic properties as well as suitable building blocks for idealized “diabatic” two-state models of the associated spectroscopic excitations. Specifically, in the framework of single-determinant Hartree-Fock or density functional methods for a resonance-stabilized molecule or supramolecular complex, we employ NBO/NRT descriptors of the ground-state determinant to develop a qualitative picture of the associated charge-transfer excitation that dominates the valence region of the electronic spectrum. We illustrate the procedure for the elementary bond shifts of SN2-type halide exchange reaction as well as the more complex bond shifts in a series of conjugated cyanine dyes. In each case, we show how NBO-based descriptors of resonance-type 3-center, 4-electron (3c/4e) interactions provide simple estimates of spectroscopic excitation energy, bond orders, and other vibronic details of the excited-state PES that anticipate important features of the full multi-configuration description. The deep 3c/4e connections to measurable spectral properties also provide evidence for NBO-based estimates of ground-state donor-acceptor stabilization energies (sometimes criticized as “too large” compared to alternative analysis methods) that are also found to be of proper magnitude to provide useful estimates of excitation energies and structure-dependent spectral shifts.

Methane Generation and Reductive Debromination of Benzylic Position by Reconstituted Myoglobin Containing Nickel Tetradehydrocorrin as a Model of Methyl-coenzyme M Reductase.

Methyl-coenzyme M reductase (MCR), which contains the nickel hydrocorphinoid cofactor F430, is responsible for biological methane generation under anaerobic conditions via a reaction mechanism which has not been completely elucidated. In this work, myoglobin reconstituted with an artificial cofactor, nickel(I) tetradehydrocorrin (NiI(TDHC)), is used as a protein-based functional model for MCR. The reconstituted protein, rMb(NiI(TDHC)), is found to react with methyl donors such as methyl p-toluenesulfonate and trimethylsulfonium iodide with methane evolution observed in aqueous media containing dithionite. Moreover, rMb(NiI(TDHC)) is found to convert benzyl bromide derivatives to reductively debrominated products without homocoupling products. The reactivity increases in the order of primary > secondary > tertiary benzylic carbons, indicating steric effects on the reaction of the nickel center with the benzylic carbon in the initial step. In addition, Hammett plots using a series of para-substituted benzyl bromides exhibit enhancement of the reactivity with introduction of electron-withdrawing substituents, as shown by the positive slope against polar substituent constants. These results suggest a nucleophilic SN2-type reaction of the Ni(I) species with the benzylic carbon to provide an organonickel species as an intermediate. The reaction in D2O buffer at pD 7.0 causes a complete isotope shift of the product by +1 mass unit, supporting our proposal that protonation of the organonickel intermediate occurs during product formation. Although the turnover numbers are limited due to inactivation of the cofactor by side reactions, the present findings will contribute to elucidating the reaction mechanism of MCR-catalyzed methane generation from activated methyl sources and dehalogenation.

Gram-Scale Synthesis of Flavoring Ketones in One Pot via Alkylation-Decarboxylation on Benzylic Carbon Using a Commercial Solid Acid Catalyst.

The gram-scale synthesis of important flavoring ketones via alkylation of acetoacetic ester on substituted benzylic carbon followed by decarboxylation using a heterogeneous, commercial, solid acid catalyst is reported. The flavoring ketones were synthesized by the alkylation of acetoacetic ester, which proceeds through an SN1-type reaction to generate an alkylated (β-ketoester) intermediate at the benzylic carbon, which is decarboxylated under the acidic condition. Among the solid acid catalysts used, Amberlyst-15 was found to be the best catalyst under the solvent-free condition. This protocol was successfully employed for the synthesis of various flavoring ketones such as raspberry ketone and ginger ketone with almost complete conversion and 82% isolated yield. The para-donating groups on the benzylic alcohol showed a high rate of reaction. The catalyst was easily recovered and reused 6 times without losing its activity and selectivity. Moreover, this reaction was demonstrated at a 10 g scale, which implicated the potential applicability of the protocol in the industry.

A facile end-functionalization of polystyrene by ATRP and click chemistry: Chain end effect on the glass transition temperature

The present work describes the detailed macromolecular design, synthesis, and characterization of a series of mono- and bi-terminal functionalized polystyrenes (PSs) by the combination of atom transfer radical polymerization (ATRP) and copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. We further study the effect of the incorporated end groups on the glass transition behavior of the resulting polymers. The mono and bi functionalized polystyrenes were synthesized by using 1-phenylethyl bromide and 1,4-bis(bromomethyl)benzene as the initiators to form bromo mono-end functionalized PS (PS-Br) and bromo bi-terminal functionalized PS (Br-PS-Br), respectively. PS-Br and Br-PS-Br were then transformed to azido mono- and bi-terminal functionalized PSs (PS-N3 and N3-PS-N3) by SN2-type reaction with sodium azide. PS-N3 and N3-PS-N3 were then subjected to CuAAC reactions with various alkynes like 1-decyne, 1-hexyne, trimethylsilylacetylene, phenylacetylene, and 4-ethynyl-1,1′-biphenyl respectively to give a series of alkyl or aromatic mono- and bi-terminal functionalized PSs (PS-Rs and R-PS-Rs), such as PS-Rs of PS-C8H17, PS-C4H9, PS-SiMe3, PS-Ph, PS-biPh, and R-PS-Rs of C8H17-PS-C8H17, C4H9-PS-C4H9, SiMe3-PS-SiMe3, Ph-PS-Ph, and biPh-PS-biPh. PS-SiMe3 and SiMe3-PS-SiMe3 were then transformed to the corresponding PS-H and H-PS-H through the detrimetylsilylation reaction with tetra-n-butylammonium fluoride (TBAF). Among the five end groups, -C8H17 and -C4H9 were with great flexibility; -H was viewed as a standard; and -Ph and -biPh groups represented the typical rigid moieties. The effect of these end groups on glass transition behavior was thoroughly investigated based on the above macromolecular design.

Mutational Analysis of N-Ethyl-N-Nitrosourea (ENU) in the Fission Yeast Schizosaccharomyces pombe.

Forward genetics in model organisms has boosted our knowledge of the genetic bases of development, aging, and human diseases. In this experimental pipeline, it is crucial to start by inducing a large number of random mutations in the genome of the model organism to search for phenotypes of interest. Many chemical mutagens are used to this end because most of them display particular reactivity properties and act differently over DNA. Here we report the use of N-ethyl-N-nitrosourea (ENU) as a mutagen in the fission yeast Schizosaccharomyces pombe. As opposed to many other alkylating agents, ENU only induces an SN1-type reaction with a low s constant (s = 0.26), attacking preferentially O and O in thymine and O deoxyguanosine, leading to base substitutions rather than indels, which are extremely rare in its resulting mutagenic repertoire. Using ENU, we gathered a collection of 13 temperature-sensitive mutants and 80 auxotrophic mutants including two deleterious alleles of the human ortholog ATIC. Defective alleles of this gene cause AICA-ribosiduria, a severe genetic disease. In this screen, we also identified 13 aminoglycoside-resistance inactivating mutations in APH genes. Mutations reported here may be of interest for metabolism related diseases and antibiotic resistance research fields.

Stereocontrolled Preparation of Diversely Trifunctionalized Cyclobutanes.

The expedient and stereoselective syntheses of small libraries of trifunctionalized cyclobutane scaffolds bearing an acid, an amine, and a third functional group are described. Starting from a single precursor, the readily available protected derivative of all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid, cis-trans stereoisomers are obtained following an SN2-type reaction, while all-trans stereoisomers are obtained using the same strategy preceded by a C1 epimerization reaction.