SNi Reactions Research Articles

Cooperative Diarylborinic Acid/Chloride-Catalyzed Formal SNi Reaction of cis-4-Hydroxymethyl-1,2-Cyclopentene Oxides.

A catalytic formal SNi reaction was designed to achieve stereoretentive products for cis-4-hydroxymethyl-1,2-cyclopentene oxides by using diarylborinic acid as a dual role catalyst and chloride as a catalytic transient nucleophile through a double-displacement mechanism. This reaction offers the advantages of a low catalyst loading of 0.1 mol % and wide substrate scope, even including N-substituents. The use of chiral boron acid as a catalyst for this reaction was also attempted.

A molecular electron density theory study of the bimolecular nucleophilic substitution reactions on monosubstituted methyl compounds.

The nucleophilic substitution reactions involving methyl monosubstituted compounds have been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311+G(d,p) computational level in DMSO. This study aims to characterize the electronic nature of the transition state structures (TSs) involved in the so-called SN2 and SNi reactions. Both electron localization function and atom-in-molecules topological analyses indicate that the TSs involved in these nucleophilic substitutions can be described as a central methyl CH3+ carbocation, which is strongly stabilized by the presence of two neighbouring nucleophilic species through electron density transfer. This MEDT study establishes a significant electronic similarity between the so-called SN1 and SN2 reactions. Due to the weak electrophilic character of the methyl tetrahedral carbons, the departure of the leaving group should be expected with the approach of the nucleophile. However, while along the SN1 reactions, the strong stabilization of the tertiary carbocation does not demand the participation of the nucleophile, along the SN2 and SNi reactions involving primary tetrahedral carbons, the nucleophiles should participate in the reaction to stabilize the unstable methyl carbocation.

Environmental degradation of human metabolites of cyclophosphamide leads to toxic and non-biodegradable transformation products

The present study assessed the ready biodegradability of the prodrug cyclophosphamide (CPA) and its stable human metabolites in the closed bottle test (CBT). The results of the CBT showed that only the main human metabolite, carboxyphosphamide (CXP), was biodegradable to a certain extent (23 ± 2.4 % ThODNH3). All other metabolites showed neither biodegradation under these conditions nor were any toxic effects on the inoculum observed. Yet, HRMSn results revealed partial primary elimination of all human metabolites and formation of 25 new transformation products. Abiotic degradation via SNi and SN2 reactions was proposed as the main degradation pathway during the CBT. The main degradation products were assigned as 3-(2-chloroethyl)oxazolidin-2-one (COAZ), cytotoxic N-2-chloroethylaziridine (CEZ) and nor‑nitrogen mustard (NNM), an analogue of the chemical warfare agent HN2. While the acute ecotoxicity of the detected products is widely unknown, many have already been reported in medical literature to be either mutagenic, genotoxic, cytotoxic or carcinogenic and may therefore cause a greater risk than their precursors. QSAR models predicted that 16 of them are mutagenic and genotoxic, thus classifying the majority of the chemicals as potential environmental hazards. The central intermediates during the degradation process were proposed as CEZ and its corresponding aziridinium ion. However, other degradation products may occur depending on the type and strength of nucleophiles present in the matrices. Overall, the results demonstrated the importance to include human metabolites in the evaluation of the environmental fate of pharmaceuticals and their risk assessment especially when investigating prodrugs. The results underline the importance of identifying possible degradation products of metabolites, as they can be more toxic than related parent compounds and metabolites and can cause a greater risk to the environment and humans.

DFT Analysis into the Calcium(II)-Catalyzed Coupling of Alcohols With Vinylboronic Acids: Cooperativity of Two Different Lewis Acids and Counterion Effects.

The mechanism of the calcium-catalyzed coupling of alcohols with vinylboronic acids has been analyzed by means of density functional theory computations. This study reveals that the calcium and boron Lewis acids associate to form a superelectrophile able to promote a pericyclic group transfer reaction with allyl alcohols. With other alcohols, the two Lewis acids act synergistically to activate the OH functionality and trigger a SNi reaction pathway. These two mechanisms are affected by the nature of the counterions, which has been rationalized by electronic and steric factors.

Aziridination of Aromatic Aldimines Through Stabilized Ammonium Ylides: A Molecular Electron Density Theory Study

The domino reaction between ammonium salt AS 4 and aldimine AD 2, in the presence of Cs2CO3, yielding aziridine trans‐AZ 7 was studied within the Molecular Electron Density Theory at the B3LYP (PCM, DCM)/def2‐TZVP//B3LYP (PCM, DCM)/GenECP computational level. This domino reaction begins with the proton abstraction from AS 4 by Cs2CO3 yielding ammonium ylide AY 5. The subsequent nucleophilic attack of AY 5 on AD 2 furnishes the gauche betaine‐like intermediate IN‐2Tg1, which experiences a C–C single bond rotation generating the anti betaine‐like intermediate IN‐2Ta. Finally, IN‐2Ta is converted into trans‐AZ 7 by an SNi process. Analysis of the relative Gibbs free energies indicates that conversion of IN‐2Ta into trans‐AZ 7 is the rate‐determining step. Analysis of the reactivity indices allows characterizing AY 5 as a strong nucleophile and AD 2 as a strong electrophile, in clear agreement with the high polar character of the addition step, while analysis of the electrophilic Parr functions explains the regioselectivity within the C1–C2 single bond formation. A Bonding Evolution Theory study of the bonding changes along the ring‐closure step allows understanding the mechanism of the SNi reaction, which takes place through a non‐concerted two‐stage one‐step mechanism involving zwitterionic species having a carbocationic C1 center.

A Stepwise Solvent-Promoted SNi Reaction of α-d-Glucopyranosyl Fluoride: Mechanistic Implications for Retaining Glycosyltransferases

The solvolysis of α-d-glucopyranosyl fluoride in hexafluoro-2-propanol gives two products, 1,1,1,3,3,3-hexafluoropropan-2-yl α-d-glucopyranoside and 1,6-anhydro-β-D-glucopyranose. The ratio of these two products is essentially unchanged for reactions that are performed between 56 and 100 °C. The activation parameters for the solvolysis reaction are as follows: ΔH(++) = 81.4 ± 1.7 kJ mol(-1), and ΔS(++) = -90.3 ± 4.6 J mol(-1) K(-1). To characterize, by use of multiple kinetic isotope effect (KIE) measurements, the TS for the solvolysis reaction in hexafluoro-2-propanol, we synthesized a series of isotopically labeled α-d-glucopyranosyl fluorides. The measured KIEs for the C1 deuterium, C2 deuterium, C5 deuterium, anomeric carbon, ring oxygen, O6, and solvent deuterium are 1.185 ± 0.006, 1.080 ± 0.010, 0.987 ± 0.007, 1.008 ± 0.007, 0.997 ± 0.006, 1.003 ± 0.007, and 1.68 ± 0.07, respectively. The transition state for the solvolysis reaction was modeled computationally using the experimental KIE values as constraints. Taken together, the reported data are consistent with the retained solvolysis product being formed in an S(N)i (D(N)(++)*A(Nss)) reaction with a late transition state in which cleavage of the glycosidic bond is coupled to the transfer of a proton from a solvating hexafluoro-2-propanol molecule. In comparison, the inverted product, 1,6-anhydro-β-D-glucopyranose, is formed by intramolecular capture of a solvent-equilibrated glucopyranosylium ion, which results from dissociation of the solvent-separated ion pair formed in the rate-limiting ionization reaction (D(N)(++) + A(N)). The implications that this model reaction have for the mode of action of retaining glycosyltransferases are discussed.

Triflic Acid Mediated Dealkylative Lactonisation via NMR‐Observable Alkyloxonium Intermediates

AbstractTrifluoromethanesulfonic acid (TfOH) efficiently induces the dealkylative cyclisation of pent‐4‐enoates to generate γ‐lactones with high selectivity. For primary alkyl esters bearing an additional alkene, only monolactonisation occurs, even in the presence of excess TfOH. The kinetics of the reaction have been studied by 1H NMR spectroscopy, which reveal that the TfOH acid undergoes a self‐catalysed reaction with the pent‐4‐enoate to generate an oxonium triflate intermediate (rate ≈ kobsd.[TfOH]2[ester]1), possibly via the dimer (TfOH)2. The oxonium triflate intermediate then evolves to the γ‐lactone according to unimolecular kinetics, liberating MeOTf in an SNi reaction. 2H‐labelling experiments with TfOD suggest that the acid protonates the carbonyl moiety of the ester, with subsequent intramolecular delivery of D+ to the alkene. The resulting carbocation is transient, being rapidly captured intramolecularly to generate the oxonium species. Reversibility in this step mediates equilibration of diastereomeric oxonium intermediates via the carbocation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The fragmentation of 7-norbornyloxychlorocarbene — SNi-like transition states

7-Norbornyloxychlorocarbene (15) fragments mainly to 7-norbornyl chloride (16). A C-2 deuterated analog of 15 (syn-15-d) fragments to labeled chloride 16 with 78% retention and 22% inversion. When the deuterium label is replaced by a syn-exo-2-methyl group, the resultant carbene 22 fragments to syn- and anti-7-chloro-exo-2-methylnorbornane in a ratio of 1:1.1, corresponding to 48% retention and 52% inversion. Computational studies suggest that the fragmentations proceed via competitive SNi-like transition states that lead to either retention or inversion. Key words: carbenes, carbocations, SNi reactions, stereochemistry.

Negative ion fragmentations of deprotonated peptides: backbone cleavages directed through both Asp and Glu

The collision-induced spectra of [M − H]− ions of a variety of natural and synthetic amphibian peptides containing Asp and/or Glu exhibit characteristic γ backbone cleavage ions that identify the positions of these residues in the peptide. A theoretical study suggests that the Glu cleavage involves an SNi reaction of the carboxylate anion from the Glu α side chain to form a deprotonated cyclic lactone. The presence of either Asp or Glu or other residues that effect pronounced side-chain cleavages (e.g. Ser or Thr) results in the normal α and β backbone cleavages being reduced in comparison to those cleavages which originate from side chains. Copyright © 2001 John Wiley & Sons, Ltd.

Homogeneous Zinc(II) Catalysis in Accelerated Vulcanization IV. The Mechanism of Cross-Link (De)Sulfuration

Abstract This paper reports a detailed re-examination of the mechanism of zinc-mediated cross-link desulfuration by means of Reaction-Stage Modeling. Heating the model cross-link bis(2,3-dimethyl-2-buten- 1-yl)disulfide in the presence of catalytic amounts of bis(diethyl-dithiocarbamato)zinc(II), ZDEC, results in slow but definite formation of monosulfides displaying retention and isomerization of the double-bond position. The formation of monosulfides with retained double bonds implies that cross-link desulfuration occurs according to SNi reactions; whereas, the formation of isomerized monosulfides points to the operation of SNi′- and/or thione-like desulfuration reactions. Importantly, these observations constitute the first evidence for zinc accelerators acting as homogeneous catalysts in desulfuration. The activation energy for cross-link desulfuration of SNi reaction was established to be 86(16) kJ mol−1. In addition, ZDEC is reported to sulfurate model cross-links. The required sulfur atoms may originate either from desulfuration of other sulfides, or from elemental sulfur added to the mixture. Just as for cross-link desulfuration, zinc-mediated sulfuration was found to occur both with and without double-bond isomerization.

Anionically induced decomposition of ethyl 2-(2,2-dimethylethylperoxymethyl)propenoate by amines: an easy access to amino epoxyesters and amino ester peroxides

Treatment of ethyl 2-(2,2-dimethylethylperoxymethyl)propenoate with primary and secondary amines led to amino epoxides and/or amino peroxides. These compounds were produced by the addition of the amine to the unsaturation of the peroxide to form a zwitterion, followed, respectively, by a proton transfer and an SNi reaction. The formation of one or the other amino derivative was favoured by different reaction conditions (mode of addition of the reactant, solvent). Easy separation of these compounds was possible by chromatography on silica when the reaction was unselective.

Gas phase and condensed phase SNi reactions. The competitive six and seven centre cyclisations of the 5,6-epoxyhexoxide anion. A joint experimental and ab initio study. A comparison with SNi reactions of homologous epoxyalkoxide anions †

A. Ab initio calculations [at the MP2 Fc/6-31+G(d) level of theory] indicate that the barriers to the transition states for the competitive six and seven centre SNi cyclisation processes of the 5,6-epoxyhexoxide anion are 35.0 and 39.7 kJ mol–1 respectively. Experimental studies show that (i) in solution, the 5,6-epoxyhexoxide anion cyclises (and at the same time opens the ethylene oxide ring) to give tetrahydropyran-2-methanol as the predominant product on workup, and (ii) collisional activation of the 5,6-epoxyhexoxide anion in the gas phase gives the 2-tetrahydropyranmethoxide anion as the exclusive anionic product. It is proposed that frequency factors (Arrhenius A factors) control the courses of these kinetically controlled gas phase reactions. A comparison of the calculated harmonic vibrational partition functions for the two possible transition states confirms a higher value of QVib for the reaction proceeding through the six-membered transition state.

Comparison of gas phase and condensed phase SNi reactions. The competitive four- and five-centre cyclisations of the 3,4-epoxybutoxide anion. A joint experimental and theoretical study

Ab initio calculations [at the MP2-Fc/6-31+G(d) level] indicate that the 3,4-epoxybutoxide anion should undergo competitive SNi cyclisations (through four- and five-membered transition states) to yield the (M – H)– ions of oxetan-2-ylmethanol and tetrahydrofuran-3-ol respectively. The barriers to the transition states are comparable (ca. 70 kJ mol–1) for each process, and the latter product is the more stable by 82 kJ mol–1 at the level of theory indicated. Gas phase studies of the 3,4-epoxybutoxide anion excited by collisional activation are in accord with this scenario, and show, in addition, that deprotonated 2-oxetanylmethanol can convert to the starting material. Base treatment of 2-(oxiran-2-yl)ethan-1-ol (3,4-epoxybutan-1-ol) in two different solvent systems [10% aqueous sodium hydroxide and sodium hydride–tetrahydrofuran (both at reflux)] yields the same two products observed in the gas phase studies. However, deprotonated tetrahydrofuran-3-ol is the kinetic product in both solvent systems.

Dynamic simulation, kinetics and mechanisms of surface reaction on oxides

The mechanism of SNi(Si) and SEi reactions on silica surfaces were studied by AM1 and MNDO/H methods in cluster approach. Potential energy surface profile (PESP) calculations were carried out by adiabatic and dynamic reaction coordinate (ARC, DRC) methods.

Hydrolyses of alpha- and beta-cellobiosyl fluorides by cellobiohydrolases of Trichoderma reesei.

Cellobiohydrolase II hydrolyses alpha- and beta-D-cellobiosyl fluorides to alpha-cellobiose at comparable rates, according to Michaelis-Menten kinetics. The stereochemistry, absence of transfer products and strict hyperbolic kinetics of the hydrolysis of alpha-cellobiosyl fluoride suggest that the mechanism for the alpha-fluoride may be the enzymic counterpart of the SNi reaction observed in the trifluoroethanolysis of alpha-glucopyranosyl fluoride [Sinnott and Jencks (1980) J. Am. Chem. Soc. 102, 2026-2032]. The absolute factors by which this enzyme accelerates fluoride ion release are small and greater for the alpha-fluoride than for the beta, suggesting that its biological function may not be just glycoside hydrolysis. Cellobiohydrolase I hydrolyses only beta-cellobiosyl fluoride, which is, however, an approx. 1-3% contaminant in alpha-cellobiosyl fluoride as prepared and purified by conventional methods. Instrumental assays for the various components of the cellulase complex are discussed.

Sulfur as Supporting Element in Vinylcyclopropane Formation

Abstract Vinylcyclopropanes 5,9,10 are conveniently obtained by sulfur-mediated SNi reactions.

Substitution reactions under NH3 chemical ionization conditions in cis‐/trans‐1,2‐dihydroxybenzosuberans

AbstractThe nucleophilic substitution reaction under NH3 chemical ionization (CI) conditions in cis‐ and trans‐1,2‐dihydroxybenzosuberans (1–4) has been studied with the help of ND3 CI and metastable data. The results indicate that in the parent diols 1 (cis) and 2 (trans), the substitution ion [MsH]+, is produced mainly by the loss of H2O from the [MNH4]+ ion (SNi reaction) while in their 7‐methoxy derivatives 3 and 4, the ion‐molecule reaction between [MOH]+ and NH3 seems to be the major pathway for the formation of [MsH]+. The substitution ion from 1 and 2 and the [MH]+ ion from trans‐1‐amino‐2‐hydroxybenzosuberan give similar collision‐induced dissociation mass‐analysed ion kinetic energy spectra. Interestingly, their diacetates do not undergo the substitution reaction.

Ammonium adduct ion in ammonia chemical ionization mass spectrometry: 2—Mechanism of elimination of neutrals from the ammonium adduct ion

AbstractThe mechanism of elimination of ROH (R = H or CH3) from the ammonium adduct ion, [M+NH4]+, of 1‐adamantanol and its methyl ether is examined by using linked‐scan metastable ion spectra and by measuring the dependence of the peak intensity ratio [M+NH4]+/[M+NH4ROH]+ on ammonia pressure. For 1‐adamantanol both SNi and SN1 reactions are suggested in metastable ion decomposition, while only the SN1 mechanism is operative in the ion source. For 1‐adamantanol methyl ether the SN1 reaction predominates both in metastable ion decomposition and in the ion source reaction.

ChemInform Abstract: SYMPATHOMIMETIC AMINES HAVING A 3,4‐DIHYDROCARBOSTYRIL NUCLEUS

AbstractAus den Verbindungen (I) oder (III) werden die Amine (II) hergestellt.

Sympathomimetic amines having a 3,4-dihydrocarbostyril nucleus.

A series of new sympathomimetic amines having a 3, 4-dihydrocarbostyril nucleus was synthesized. These compounds have two weakly acidic hydrogen atoms in locations similar to those of the hydroxyl groups of adrenergic agents containing catechol. One threo-isomer 1i-threo was synthesized by inversion of the corresponding erythro-isomer by the SNi reaction.