SN2 Mechanism Research Articles

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether.

Eliglustat (Cerdelga®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the SNi and the SN1 mechanisms, leading to the retention of stereochemistry.

Role of trichloroacetic acid in the catalytic activity of oxovanadium(IV)-salen in the sulfoxidation of phenylmercaptoacetic acids

The catalytic role of trichloroacetic acid (TCA) in the kinetics of the sulfoxidation of twelve phenylmercaptoacetic acids (PMAA) by H2O2 catalyzed by three oxovanadium(IV)-salen complexes, having varied substituents on PMAA and salen with regard to the position, size and inductive effect, has been studied spectrophotometrically in 100 % acetonitrile medium. The observed order of reactivity among the oxovanadium(IV)-salen complexes in the presence of TCA is II > III > I. The rate of reaction increases with the increase in concentration of the axial ligand, TCA. From the observed kinetics data, a mononuclear [VO(salen)]+ species has been proposed as the sole active oxidizing species. Both electron donating and electron withdrawing substituents on PMAA accelerate the sulfoxidation rate significantly. The Hammett correlation between the rate constants and the substituent constants shows a non-linear concave upward curve, which is explained by the existence of two different mechanisms - direct oxygen atom transfer from the oxovanadium(IV)-salen complexes to PMAA for electron withdrawing substituents and an SN2 mechanism involving electrophilic attack by the oxygen atom of the complex on the electron rich sulfur centre of PMAA with the formation of a sulfonium cation intermediate for electron donating substituents.

Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A4 to Leukotriene B4 Catalysed by the Enzyme Leukotriene A4 Hydrolase.

LTA4H is a bifunctional zinc metalloenzyme that converts leukotriene A4 (LTA4) into leukotriene B4 (LTB4), one of the most potent chemotactic agents involved in acute and chronic inflammatory diseases. In this reaction, LTA4H acts as an epoxide hydrolase with a unique and fascinating mechanism, which includes the stereoselective attachment of one water molecule to the carbon backbone of LTA4 several methylene units away from the epoxide moiety. By combining Molecular Dynamics simulations and Quantum Mechanics/Molecular Mechanics calculations, we obtained a very detailed molecular picture of the different consecutive steps of that mechanism. By means of a rather unusual 1,7-nucleophilic substitution through a clear SN1 mechanism, the epoxide opens and the triene moiety of the substrate twists in such a way that the bond C6-C7 adopts its cis (Z) configuration, thus exposing the R face of C12 to the addition of a water molecule hydrogen-bonded to ASP375. Thus, the two stereochemical features that are required for the bioactivity of LTB4 appear to be closely related. The noncovalent π-π stacking interactions between the triene moiety and two tyrosines (TYR267 and, especially, TYR378) that wrap the triene system along the whole reaction explain the preference for the cis configuration inside LTA4H.

Photoredox Activation of Inert Alkyl Chlorides for the Reductive Cross-Coupling with Aromatic Alkenes.

The inertness of chloroalkanes has precluded them as coupling partners for cross-coupling reactions. Herein we disclose a general strategy for the activation of inert alkyl chlorides through photoredox catalysis and their use as coupling partners with alkenes. The catalytic system is formed by [Ni(OTf)(Py2 Ts tacn)](OTf) (1Ni ), which is responsible for the Csp3 -Cl bond activation, and [Ir(NMe2 bpy)(ppy)2 ]PF6, (PCIr NMe2 ), which is the photoredox catalyst. Combined experimental and theoretical studies show an in situ photogenerated NiI intermediate ([Ni(Py2 Ts tacn)]+ ) which is catalytically competent for the Csp3 -Cl bond cleavage via a SN 2 mechanism for primary alkyl chlorides, forming carbon-centered free radicals, which react with the olefin leading to the formation of the Csp3 -Csp3 bond. These results suggest inert alkyl chlorides can be electrophiles for developing new intermolecular strategies in which low-valent aminopyridine nickel complexes act as key catalytic species.

Photoredox Activation of Inert Alkyl Chlorides for the Reductive Cross‐Coupling with Aromatic Alkenes

AbstractThe inertness of chloroalkanes has precluded them as coupling partners for cross‐coupling reactions. Herein we disclose a general strategy for the activation of inert alkyl chlorides through photoredox catalysis and their use as coupling partners with alkenes. The catalytic system is formed by [Ni(OTf)(Py2Tstacn)](OTf) (1Ni), which is responsible for the Csp3−Cl bond activation, and [Ir(NMe2bpy)(ppy)2]PF6, (PCIrNMe2), which is the photoredox catalyst. Combined experimental and theoretical studies show an in situ photogenerated NiI intermediate ([Ni(Py2Tstacn)]+) which is catalytically competent for the Csp3−Cl bond cleavage via a SN2 mechanism for primary alkyl chlorides, forming carbon‐centered free radicals, which react with the olefin leading to the formation of the Csp3−Csp3 bond. These results suggest inert alkyl chlorides can be electrophiles for developing new intermolecular strategies in which low‐valent aminopyridine nickel complexes act as key catalytic species.

Thermal decomposition of amino acid ionic liquids: Mechanism insight

The thermal decomposition mechanism of amino acid ionic liquids (AAILs) is an important feature, which affects their industrial application, especially in the gas absorption process. In this study, thermal decomposition mechanisms including SN2, alkyl rearrangement, and Hoffman elimination mechanisms were investigated by density functional theory. AAILs consist of 1-ethyl-3-methylimidazolium ([C2mim]) as the cation and lycine (Lys−), arginine (Arg−), histidine (His−), methionine (Met−), and proline (Pro−) as the anions. The polarizable continuum model was used to examine the effect of environment polarity on the thermal decomposition mechanism of the AAILs. The SN2 and alkyl rearrangement mechanisms are the most probable routes from the kinetic and thermodynamic viewpoints. In the case of [Emim][Arg], the energy barrier of the reaction is lower than that of other AAILs that shows the rate of reaction increases by increase in the number of amine groups of the amino acid anions. Moreover, the environment polarity is a key factor that has negative effects on the thermodynamic and kinetic of different mechanisms. Also, the effect of environment polarity in the alkyl rearrangement route is more than other mechanisms.

Formation of two isomers in the replacement reactions of bay area dibromine atoms in perylene diimides

Three reaction mechanisms were reported in the replacement reaction of bay area dibromine atoms in perylene diimide derivatives in previous studies. However, the effect of the reaction solvents and intermediate compound (perylene diimide radical anion) on the reaction mechanisms and product structure had not been reported. Here, we report the role of the reaction solvents and the perylene diimide radical anion in replacement reactions of bay area dibromine atoms of perylene diimide. Two isomers in the replacement reactions of bay area dibromine atoms in perylene diimides were found when using proton solvents (such as ethanol), and presenting the about 41% 1-bromo-7- ethoxy substituted perylene diimide derivative changed into 1,6- diethoxy substutent perylene diimide derivative in double substituted reaction. In polar non-proton solvents, inorganic base (K2CO3) can induce dibromo perylene diimide to form its radical anion. Further, the substitution reactions is a SN1 mechanism in proton solvents, and the substitution reactions is belong to a SN2 and SRN1 mechanism in polar non-proton solvents.

Organic carboxylate salt-enabled alternative synthetic routes for bio-functional cyclic carbonates and aliphatic polycarbonates

A cyclic carbonate with an ammonium carboxylate residue was found to serve as a nucleophile for esterification with alkyl bromides via the SN2 mechanism.

اصطناع بوليميرات آزو ببلمرة مشتاقات إيتيرية لبروميد الآليل ودراسة فجوتها الطاقية وتعيين بعض خصائصها الفيزيائية

في هذا البحث، اُصطنع مشتقان ايتريين لاصبغة ازو فينولية عن طريق تفاعل ويليمسون وفقاً لآلية. الاستبدال النيكلوفيلي SN2. تمت بلمرة المركبات المحضرة بلمرةً جذرية باستخدام (AIBN) كبادئ وأُثبتت بنى المركبات المصطنعة بواسطة مطيافيات FT-IR و 1H-NMR. بالإضافة إلى دراسة الخصائص الحرارية للبوليميرات المُحضرة بواسطة (DSC). دُرست عرض الفجوة الطاقية وذلك لمعرفة امكانية استعمال البوليميرات كأنصاف نواقل ضوئية وكانت قيمتها 2.4ev, 2.8ev لكل من P(AO2) و P(AON1) على التوالي. كماعُينت كل من قرينة الانكسار واللزوجة الكيناميكية والكثافة ودرجة العكارة.

Catalytic coupling of CO2 and epoxides by lignin-based catalysts: A combined experimental and theoretical study

A new strategy for the construction of an amine-modified lignin has been developed through the Mannich reaction. The lignin-based catalyst, (PEI(70000)-SL/ZnBr2), acted as a green and reusable heterogeneous catalyst for the catalytic conversion of CO2 and epoxides into cyclic carbonates. This catalyst exhibited excellent conversion and selectivity in the CO2 cycloaddition reaction due to the synergistic effects of the hydroxyls (-OH) and metal (Zn2+) as Lewis acid sites, and organic amines (-NH2) and halogen anions (Br-) as nucleophiles. Some lignin model compounds were used to study the relationship between structure and activity in order to evaluate the synergistic effects during the cycloaddition reaction. Functional groups, such as Zn2+, -OH and -NH2, in adjacent positions of the lignin-based catalyst yielded the cyclic carbonates in high efficiencies and selectivities. Furthermore, DFT calculation and the experimental results revealed that Zn2+ enhanced the ring-opening process via SN1 mechanism, with the energy barrier of the ring-opening process of 18.9 kcal mol-1 due to the cooperation of the Zn2+ with phenolic hydroxyl groups. These findings do not only provide a novel design concept for biomass-based catalysts but also accomplished the transformation of CO2 into valuable products.

Photoredox-Catalyzed Ring-Opening Addition Reaction between Benzyl Bromides and Cyclic Ethers

AbstractA novel nucleophilic reaction between cyclic ethers and benzyl bromides is achieved under photoredox catalysis. The reaction proceeds through a single-electron-transfer (SET) pathway rather than a common SN2 mechanism. By two steps of reduction and oxidation, a benzyl bromide heterolyzes to give a carbocation and bromide ion under mild conditions, and then a cyclic ether captures both the carbo­cation and bromide ion to afford the addition product.

Mechanism of solvolysis of substituted benzyl chlorides in aqueous ethanol

The mechanism of solvolyses of activated ortho-, meta- and para-substituted benzyl chlorides in aqueous ethanol has been studied by using the Hammett-Brown and Yukawa-Tsuno treatments as well as by correlating logarithms of solvolysis rate constants with relative stabilities of corresponding benzyl carbocations in water calculated at the IEFPCM-M06–2X/6-311+G(3df,3pd) level of theory. Benzyl chlorides containing strong conjugative electron-donors in the para-position solvolyze by the SN1 mechanism, whereas other activated benzyl chlorides solvolyze by the SN2 mechanism via loose transition states.

Synthesis and Hydrolysis of Atmospherically Relevant Monoterpene-Derived Organic Nitrates.

The partition of gas-phase organic nitrates (ONs) to aerosols and subsequent hydrolysis are regarded as important loss mechanisms for ON species. However, the hydrolysis mechanisms and the major factors controlling the hydrolysis lifetime are not fully understood. In this work, we synthesized seven monoterpene-derived ONs and systematically investigated their hydrolysis in bulk solutions at different pH values. The hydrolysis lifetimes ranged from 12.9 min to 8.5 h for allylic primary ON and tertiary ONs, but secondary ONs were stable at neutral pH. The alkyl substitution numbers, functional groups, and carbon skeletons were three important factors controlling hydrolysis rates. Tertiary and secondary ONs were found to hydrolyze via the acid-catalyzed unimolecular (SN1) mechanism, while a competition of SN1 and bimolecular (SN2) mechanisms accounted for the hydrolysis of primary ONs. The consistency of experimental and theoretical hydrolysis rates calculated by density functional theory further supported the proposed mechanisms. Reversible reactions including hydrolysis and nitration were first reported to explain the hydrolysis of ONs, highlighting the possibility that particulate nitric acid can participate in nitration to generate new nitrogen-containing compounds. These findings demonstrate that ON hydrolysis is a complex reaction that proceeds via different mechanisms and is controlled by various parameters.

Electrostatic Potential Field Effects on Amine Macrocyclizations within Yoctoliter Spaces: Supramolecular Electron Withdrawing/Donating Groups.

The central role of Coulombic interactions in enzyme catalysis has inspired multiple approaches to sculpting electrostatic potential fields (EPFs) for controlling chemical reactivity, including ion gradients in water microdroplets, the tips of STMs, and precisely engineered crystals. These are powerful tools because EPFs can affect all reactions, even those whose mechanisms do not involve formal charges. For some time now, supramolecular chemists have become increasingly proficient in using encapsulation to control stoichiometric and catalytic reactions. However, the field has not taken advantage of the broad range of nanocontainers available to systematically explore how EPFs can affect reactions within their inner-spaces. With that idea in mind, previously, we reported on how positively and negatively charged supramolecular capsules can modulate the acidity and reactivity of thiol guests bound within their inner, yoctoliter spaces (Cai, X.; Kataria, R.; Gibb, B. C. J. Am. Chem. Soc. 2020, 142, 8291–8298; Wang, K.; Cai, X.; Yao, W.; Tang, D.; Kataria, R.; Ashbaugh, H. S.; Byers, L. D.; Gibb, B. C. J. Am. Chem. Soc.2019, 141, 6740–6747). Building on this, we report here on the cyclization of 14-bromotetradecan-1-amine inside these yoctoliter containers. We examine the rate and activation thermodynamics of cyclization (Eyring analysis), both in the absence and presence of exogenous salts whose complementary ion can bind to the outside of the capsule and hence attenuate its EPF. We find the cyclization rates and activation thermodynamics in the two capsules to be similar, but that for either capsule attenuation of the EPF slows the reaction down considerably. We conclude the capsules behave in a manner akin to covalently attached electron donating/withdrawing groups in a substrate, with each capsule enforcing their own deviations from the idealized SN2 mechanism by moving electron density and charge in the activated complex and TS, and that the idealized SN2 mechanism inside the theoretical neutral host is relatively difficult because of the lack of solvation of the TS.

The mechanism of sorbitol dehydration in hot acidic solutions.

Sugar alcohol dehydration in hot water is an important reaction that allows for environmentally friendly biomass conversion without the use of organic solvents. Here, we report a free-energy analysis by metadynamics (MTD) simulations based on ab initio density functional theory and semiempirical density-functional tight-binding method to understand the mechanism of dehydration reactions of d-sorbitol (SBT) in hot acidic water. Comparing the results of ab initio and semiempirical MTD, it was found that the latter gives a reliable free energy surface of SBT dehydration reaction, although the results vary upon the inclusion of dispersion correction. It was found that the reaction proceeds consistently via an SN 2 mechanism, whereby the free energy of protonation of the hydroxyl group created as an intermediate is affected by the acidic species. This mechanism was further verified by real-time trajectories started from the transition state using ab initio molecular dynamics simulations. The free energy barriers of the reaction pathways leading to five-membered ether products are lower than those leading to six-membered ether products, in agreement with experiment. This outcome can be ascribed, in part, to our finding that the reaction barrier of the pathway is correlated to the stability of the SBT confined conformation at the initial stage of the reaction.

Asymmetric Nucleophilic Allylation of α-Chloro Glycinate via Squaramide Anion-Abstraction Catalysis: SN1 or SN2 Mechanism, or Both?

The nucleophilic substitution mechanism of enantioselective allylation of α-chloro glycinate catalyzed by squaramide organocatalysts was studied using density functional theory. Based on a comprehensive study of SN1 and SN2 pathways of a catalyst-free reaction, we found that the catalytic reaction slightly favors the SN1 mechanism, instead of the previously proposed SN2 mechanism. Further investigation of different leaving groups and nucleophiles revealed that this is not limited to the present reaction, and the SN1 mechanism might have been generally overlooked. For the squaramide-catalyzed reactions, the SN1 mechanism was predicted to be preferred. However, the rate-determining step of the SN1 pathway has changed from the chloride-leaving step to the C-C bond-formation step. Therefore, a first-order dependence on both substrates was predicted, in agreement with the observed second-order kinetics. Intriguingly, the lowest-energy enantioselective transition states (TSs) originate from different pathways; R-inducing TS corresponds to the SN1 pathway, while S-inducing TS corresponds to SN2. The calculated enantiomeric excesses of two squaramide catalysts agree well with the experimental values. Given the ubiquity of nucleophilic substitution reactions in chemistry and biology, we believe that our finding will inspire more studies that will lead to an improved mechanistic understanding of important chemical reactions, and it may even lead to better catalysts.

An Asymmetric SN2 Dynamic Kinetic Resolution.

The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

Concise synthesis of the Taxol side chain and demethoxy-4-epi-cytoxazone via oxazoline formation through intramolecular benzylic substitution of a bis-trichloroacetimidate

A concise and efficient method for synthesizing the Taxol side chain via the corresponding oxazoline intermediate was developed. The oxazoline ring is formed via an SN1 mechanism to ensure that the trans-oxazoline stereochemistry is retained. This process was induced by intramolecular benzylic substitution of a 1,2-bis-trichloroacetimidate, which was obtained from a known, enantiomerically pure diol. Demethoxy-4-epi-cytoxazone was also obtained from the intermediary trans-oxazoline 3b.

Photophysical Properties and Kinetic Studies of 2-Vinylpyridine-Based Cycloplatinated(II) Complexes Containing Various Phosphine Ligands.

A series of cycloplatinated(II) complexes with general formula of [PtMe(Vpy)(PR3)], Vpy = 2-vinylpyridine and PR3 = PPh3 (1a); PPh2Me (1b); PPhMe2 (1c), were synthesized and characterized by means of spectroscopic methods. These cycloplatinated(II) complexes were luminescent at room temperature in the yellow–orange region’s structured bands. The PPhMe2 derivative was the strongest emissive among the complexes, and the complex with PPh3 was the weakest one. Similar to many luminescent cycloplatinated(II) complexes, the emission was mainly localized on the Vpy cyclometalated ligand as the main chromophoric moiety. The present cycloplatinated(II) complexes were oxidatively reacted with MeI to yield the corresponding cycloplatinated(IV) complexes. The kinetic studies of the reaction point out to an SN2 mechanism. The complex with PPhMe2 ligand exhibited the fastest oxidative addition reaction due to the most electron-rich Pt(II) center in its structure, whereas the PPh3 derivative showed the slowest one. Interestingly, for the PPhMe2 analog, the trans isomer was stable and could be isolated as both kinetic and thermodynamic product, while the other two underwent trans to cis isomerization.

Efficient synthesis of amine-functionalized graphene oxide by ultrasound-assisted reactions and density functional theory mechanistic insight

Herein described is a facile preparation protocol by which amino-alcohol derivatives of graphene oxide (GO) can be conveniently synthesized in high yield and short time by an ultrasound treatment of ethanol-graphite-oxide suspensions and amines. Linear primary amines of different chain length rapidly react with graphite oxides prepared from powder and flakes, leading to the formation of GO amino-alcohol derivatives. Characterization of the amine-modified materials by XRD, TGA, FTIR, and Raman spectroscopy demonstrates the proposed derivatization; the findings are corroborated by SEM and TEM observations. Additionally, quantum-chemical investigations shed additional light on the reaction, suggesting an alcohol-accelerated SN2 mechanism where the initial step, the simultaneous formation of a C–N bond (GO-amine) and rupture of an epoxide bond in GO, is rate-determining. Energy barriers lower than 8 kcal/mol are estimated, which can be overcome with the energy supplied by the sonotrode tip (ca. 2 kcal) and the use of ethanol to facilitate it.