Gas-Phase Nucleophilic and Elimination Reactions in Simple Alkyl Nitrates

There has been increasing interest in the gas-phase reactivity of alkyl nitrates because of their well-known applications as explosives and because of then role in atmospheric and in marine processes This manuscript describes an experimental study by FT-ICR techniques of the gas-phase reactions of OH(-) and F(-) with methyl and ethyl Innate For methyl nitrate, the main reaction channel is found to be an elimination process promoted by abstraction of an a proton from the methyl group. Nucleophilic displacement of nitrate anion through an S(N)2 process at the carbon center Is also found to he an important reaction channel with methyl nitrate In ethyl nitrate, Ruination of NO(3)(-) is greatly enhanced and this is attributed to the ease of an E2-type elimination process promoted by proton abstraction at the beta position of the ethyl group. Theoretical calculations at the MP2/6-311+G(3df,2p)//MP2/6-31+G(d) level of theory ale consistent with the relative importance of the reaction channels and suggest that these reactions proceed through a double well potential The calculations also predict that nucleophilic attack by OH(-) at the nitrogen center (Sn2@N) is energetically the rueful ad pathway but experiments with (18)OH(-) showed no evidence for this channel. Single-point calculations reveal a strong preference for approach to the emboli center and may explain the lack of reactivity at the nitrogen center. Calculations were also carried out or NH(2)(-) and SH(-) to establish the reactivity pattern to provide a better understanding of environmentally relevant nitrate esters.

Stereoselective Nucleophilic Addition of Potassium Alkyltrifluoroborates to Cyclic N-Acyliminium Ions: a Simple and Mild Approach to Chiral 5-Alkyl-pyrrolidin-2-ones

The stereoselective nucleophilic addition of potassium alkyltrifluoroborates to cyclic N-acyliminium ions derived from N-benzyl-3,4,5-triacetoxy-pyrrolidin-2-one, which affords 5-substituted-pyrrolidin-2-ones, is described. The products are obtained in moderate to good yields and are produced predominantly as the anti diastereomer.

Electrooxidation of [(η5-C5H5)Fe(CO)2]2 as a probe of the nucleophilic properties of ionic liquid anions

The oxidative electrochemistry of [CpFe(CO)2]2, 1 (Cp = [η5-C5H5]–), was examined in detail in ionic liquids (ILs) composed of ions of widely varying Lewis acid−base properties. Cyclic voltammetric responses were strongly dependent on the nucleophilic properties of the IL anion, but all observations are consistent with the initial formation of 1+ followed by attack from the IL anion. In [NTf2]–-based ILs ([NTf2]– = bis(trifluoromethylsulfonyl)amide), the process shows nearly ideal chemical reversibility as the reaction between 1+ and [NTf2]– is very slow. This is highly significant, as 1+ is known to be highly susceptible to nucleophilic attack and its stability indicates a remarkable lack of coordinating ability of these ILs. In 1-methyl-3-butylimidazolium hexafluorophosphate, [bmim][PF6], the oxidation of 1 is still largely reversible, but there is more pronounced evidence of [PF6]– coordination. In contrast, 1 exhibits an irreversible two-electron oxidation process in a dicyanamide-based IL. This overall oxidation process is thought to proceed via an ECE mechanism, details of which are presented. Rate constants were estimated by fitting the experimental data to digital simulations of the proposed mechanism. The use of [NTf2]–-based ILs as a supporting electrolyte in CH2Cl2 was examined by using this solvent/electrolyte as a medium in which to perform bulk electrolyses of 1 and 1*, the permethylated analogue [Cp*Fe(CO)2]2 (Cp* = [η5-C5(CH3)5]–). These cleanly yielded the corresponding binuclear radical-cation species, 1+ and 1*+, which were subsequently characterized by electron paramagnetic resonance (EPR) spectroscopy. In addition to the above oxidation studies, the reduction of 1 was studied in each of the ILs; differences in cathodic peak potentials are attributed, in part, to ion-pairing effects. This study illustrates the wide range of electrochemical environments available with ILs and demonstrates their utility for the investigation of the redox properties of metal carbonyls and other organometallic compounds.

Suicide nucleophilic attack: Reactions of benzohydroxamate anion with bis(2,4-dinitrophenyl) phosphate

(Chemical Equation Presented) The reaction between the benzohydroxamate anion (BHO-) and bis(2,4-dinitrophenyl)phosphate (BDNPP) has been examined kinetically, and the products were characterized by mass and NMR spectroscopy. The nucleophilic attack of BHO- follows two reaction paths: (i) at phosphorus, giving an unstable intermediate that undergoes a Lossen rearrangement to phenyl isocyanate, aniline, diphenylurea, and O-phenylcarbamyl benzohydroxamate; and (ii) on the aromatic carbon, giving an intermediate that was detected but slowly decomposes to aniline and 2,4-dinitrophenol. Thus, the benzohydroxamate anion can be considered a self-destructive molecular scissor since it reacts and loses its nucleophilic ability. © 2009 American Chemical Society.

New insights on reaction pathway selectivity promoted by crown ether phase-transfer catalysis: Model ab initio calculations of nucleophilic fluorination

Crown ethers have the ability of solubilizing inorganic salts in apolar solvents and to promote chemical reactions by phase-transfer catalysis. However, details on how crown ethers catalyze ionic S(N)2 reactions and control selectivity are not well understood. In this work, we have used high level theoretical calculations to shed light on the details of phase-transfer catalysis mechanism of KF reaction with alkyl halides promoted by 18-crown-6. A complete analysis of the of the model reaction between KF(18-crown-6) and ethyl bromide reveals that the calculations can accurately predict the product ratio and the overall kinetics. Our results point out the importance of the K* ion and of the crown ether ring in determining product selectivity. While the K* ion favors the S(N)2 over the E2 anti pathway, the crown ether ring favors the S(N)2 over E2 syn route. The combination effects lead to a predicted 94% for the S(N)2 pathway in excellent agreement with the experimental value of 92%. A detailed analysis of the overall mechanism of the reaction under phase-transfer conditions also reveals that the KBr product generated in the nucleophilic fluorination acts as an inhibitor of the 18-crown-6 catalyst and it is responsible for the observed slow reaction rate. (C) 2012 Elsevier B.V. All rights reserved.

Iron-Promoted Nucleophilic Additions to Diimine-Type Ligands: A Synthetic and Structural Study

We report here three examples of the reactivity of protic nucleophiles with diimine-type ligands in the presence of FeII salts. In the first case, the iron-promoted alcoholysis reaction of one nitrile group of the ligand 2,3-dicyano-5,6-bis(2-pyridyl)-pyrazine (L1) permitted the isolation of an stable E-imido−ester, [Fe(L1‘)2](CF3SO3)2 (1), which has been characterized by spectroscopic studies (IR, ES-MS, Mössbauer), elemental analysis, and crystallographically. Compound 1 consists of mononuclear octahedrally coordinated FeII complexes where the FeII ion is in its low-spin state. The iron-mediated nucleophilic attack of water to the asymmetric ligand 2,3-bis(2-pyridyl)pyrido[3,4-b]pyrazine (L2) has also been studied. In this context, the crystal structures of two hydration−oxidation FeIII products, [Fe(L2‘)2](ClO4)3·3CH3CN (2) and trans-[FeL2‘‘Cl2] (3), are described. Compounds 2 and 3 are both mononuclear FeIII complexes where the metals occupy octahedral positions. In principle, L2 is expected to coordinate to metal ions through its bipyridine-type units to form a five-membered ring; however, this is not the case in compounds 2 and 3. In 2, the ligand coordinates through its pyridines and through the hydroxyl group attached to the pyrazine imino carbon after hydration, that is, in an N,O,N tridentate manner. In compound 3, the ligand has suffered further transformations leading to a very stable diamido complex. In this case, the metal ion achieves its octahedral geometry by means of two pyridines, two amido N atoms, and two axial chlorine atoms. Magnetic susceptibility measurements confirmed the spin state of these two FeIII species:  compounds 2 and 3 are low-spin and high-spin, respectively.

The arginine finger of RasGAP helps Gln-61 align the nucleophilic water in GAP-stimulated hydrolysis of GTP

The Ras family of GTPases is a collection of molecular switches that link receptors on the plasma membrane to signaling pathways that regulate cell proliferation and differentiation. The accessory GTPase-activating proteins (GAPs) negatively regulate the cell signaling by increasing the slow intrinsic GTP to GDP hydrolysis rate of Ras. Mutants of Ras are found in 25–30% of human tumors. The most dramatic property of these mutants is their insensitivity to the negative regulatory action of GAPs. All known oncogenic mutants of Ras map to a small subset of amino acids. Gln-61 is particularly important because virtually all mutations of this residue eliminate sensitivity to GAPs. Despite its obvious importance for carcinogenesis, the role of Gln-61 in the GAP-stimulated GTPase activity of Ras has remained a mystery. Our molecular dynamics simulations of the p21ras–p120GAP–GTP complex suggest that the local structure around the catalytic region can be different from that revealed by the x-ray crystal structure. We find that the carbonyl oxygen on the backbone of the arginine finger supplied in trans by p120GAP (Arg-789) interacts with a water molecule in the active site that is forming a bridge between the NH2 group of the Gln-61 and the γ-phosphate of GTP. Thus, Arg-789 may play a dual role in generating the nucleophile as well as stabilizing the transition state for P—O bond cleavage.

Direct Nucleophilic Substitution of Free Allylic Alcohols in Water Catalyzed by FeCl3⋅6 H2O: Which is the Real Catalyst?

The allylic substitution reaction, and particularly the direct allylic amination reaction, of free allylic alcohols in water catalyzed by FeCl3⋅6 H2O is described. This novel environmentally-friendly methodology allows the use of a wide variety of nitrogenated nucleophiles such as sulfonamides, carbamates, benzamides, anilines, benzotriazoles, and azides, generally giving good yields of the corresponding substitution products. The synthetic applicability of the process is also demonstrated because the reaction can be performed on gram-scale. Additionally, carbon nucleophiles such as silylated nucleophiles, aromatic compounds, and malonates also proved to be suitable for this transformation. Finally, the nature of the catalytic species present in aqueous media is unveiled, pointing towards the formation of hexaaquo iron(III) complexes.

Nucleophilic substitution reactions of pyranose polytosylates

The 2,3,4-tri-toluenesulfonate ester derivatives of the methyl pyranosides of L-arabinose, D-ribose, D-lyxose, and D-xylose have been prepared, and their substitution reactions with various nucleophiles have been examined. For arabinose, xylose, and ribose, highly regioselective monosubstitutions were observed with benzoate, nitrite, and azide anions. These reactions have led to short and simple routes from D-xylose to L-arabinose derivatives, from L-arabinose to D-xylose derivatives, and from D-ribose to L-lyxose derivatives. The tritosylate derived from methyl alpha-D-lyxopyranoside was unreactive toward nucleophilic substitution reactions, giving instead a dihydropyran product arising from an initial E2 elimination reaction of the 2-tosylate.

Organic reactions in ionic liquids: ionic liquid-accelerated nucleophilic substitution reaction of alpha-tosyloxyketones with potassium salts of aromatic acids

The room temperature ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) is used as a ‘green' recyclable alternative to classical molecular solvents for the nucleophilic substitution reaction of a-tosyloxy ketones with potassium salts of aromatic acids. Significant rate enhancement and improved yields have been observed.

Biological fluorination from the sea : discovery of a SAM-dependent nucleophilic fluorinating enzyme from the marine-derived bacterium Streptomyces xinghaiensis NRRL B24674

We thank Prof. David O’Hagan and Dr Qingzhi Zhang (University of St Andrews, UK) for their helpful discussion and for providing the synthetic 50 -FDA sample. This work is supported by National Natural Science Foundation of China (No. 81503086), a starting funding (No. 20140520) from Tianjin University of Science & Technology, a research funding of “1000 Talents Plan” of Tianjin (to LM) and Foundation of Key Laboratory of Industrial Fermentation Microbiology of Ministry of Education and Tianjin Key Lab of Industrial Microbiology (No. 2015IM106)

Nucleophilic addition of Nitrones to Electron deficient acetylenes and related studies

Nitrones or azomethine-N-oxides are important precursors for the synthesis of several heterocyclic systems. They belong to the allyl anion type 1,3-dipoles and possess unique structural features which make them extraordinarily useful synthons. They behave as 1,3-dipoles in 1,3-dipolar cycloaddition reactions and as electrophiles in reactions with organometallic reagents. These are the two basic reactions given by nitrones. Nitrones also act as ‘spin traps’ in which they react with short-lived radicals to furnish stable nitroxide radicals which can be detected and identified by electron paramagnetic resonance (EPR) spectroscopy. Recently SmI2 catalysed reductive cross-coupling reactions of nitrones have gained significant interest in which the reactions are initiated by single electron transfer (SET) to nitrones. Apart from these reactions, nitrones are also known to participate in reactions which are initiated by the nucleophilic attack of nitrone-oxygen. In our group, we have also explored the nucleophilic character of nitrones through various reactions. The results obtained enabled us to develop a novel two-step one-pot strategy for quinolines and indoles - the heterocycles renowned for their pharmacological applications, from nitrones and electron deficient acetylenes. Using dibenzoylacetylene and phenylbenzoylacetylene as dipolarophiles, we could introduce a desired functional group at a predetermined position of the quinolines or indoles to be synthesised. In this context, the thesis entitled “NUCLEOPHILIC ADDITION OF NITRONES TO ELECTRON DEFICIENT ACETYLENES AND RELATED STUDIES” portrays our attempt to expand the scope of our x novel synthetic protocol using ester functionalised acetylenes: dimethyl acetylenedicarboxylate (DMAD) and methyl propiolate. The thesis is organised in to five chapters. The first chapter briefly describes the different classes of reactions that nitrone functionality can tolerate. The research problem is defined at the end of this chapter. The second chapter describes the synthesis of different nitrones used for the present study. The optimisation and expansion of scope of the novel strategy towards quinoline synthesis is discussed in the third chapter. The fourth chapter portrays the synthesis of indole-3-carboxylates using the novel strategy. In the fifth chapter, the reaction of N-(2,6-dimethylphenyl) and N-(2,4,6-trimethylphenyl)nitrones are discussed. Here we also discuss the mechanistic reinvestigation of Baldwin’s proposal in the isoxazoline-oxazoline rearrangement. The major outcome of the work is given at the end of the thesis. The structural formulae, schemes, tables and figures are numbered chapter-wise since each chapter of the thesis is organized as an independent unit. All new compounds (except two compounds reported in fourth chapter) are fully characterised on the basis of spectral and analytical data and single crystal X-ray analysis on representative examples. Relevant references are included at the end of individual chapters.

Recent Advances in the Direct Nucleophilic Substitution of Allylic Alcohols through SN1-Type Reactions

Direct nucleophilic substitution reactions of allylic alcohols are environmentally friendly, since they generate only water as a byproduct, allowing access to new allylic compounds. This reaction has, thus, attracted the interest of the chemical community and several strategies have been developed for its successful accomplishment. This review gathers the latest advances in this methodology involving SN1-type reactions.

Oligodeoxynucleotide synthesis using protecting groups and a linker cleavable under non-nucleophilic conditions

Oligodeoxynucleotides (ODNs) containing latent electrophilic groups can be highly useful in antisense drug development and many other applications such as chemical biology and medicine, where covalent cross-linking of ODNs with mRNA, protein and ODN is required. However, such ODN analogues cannot be synthesized using traditional technologies due to the strongly nucleophilic conditions used in traditional deprotection/cleavage process. To solve this long lasting and highly challenging problem in nucleic acid chemistry, I used the 1,3-dithian-2-yl-methoxycarbonyl (Dmoc) function to protect the exo-amino groups on the nucleobases dA, dC and dG, and to design the linker between the nascent ODN and solid support. These protecting groups and linker are completely stable under all ODN synthesis conditions, but can be readily cleaved under non-nucleophilic and nearly neutral conditions. As a result, the new ODN synthesis technology is universally useful for the synthesis of electrophilic ODNs. The dissertation is mainly comprised of two portions. In the first portion, the development of the Dmoc-based linker for ODN synthesis will be described. The construction of the dT-Dmoc-linker required a total of seven steps to synthesize. The linker was then anchored to the solid support―controlled pore glass (CPG). In the second portion, the syntheses of Dmoc-protected phosphoramidites ODN synthesis monomers including Dmoc-dC-amidite, Dmoc-dA-amidite, Dmoc-dG-amidite are described. The protection of dC and dA with 1,3-dithian-2-yl-methyl 4-nitrophenyl carbonate proceeded smoothly giving Dmoc-dC and Dmoc-dA in good yields. However, when the same acylation procedure was applied for the synthesis of Dmoc-dG, very low yield was obtained. This problem was later solved using a highly innovative and environmentally benign procedure, which is expected to be widely useful for the acylation of the exo-amino groups on nucleoside bases. The reactions to convert the Dmoc-protected nucleosides to phosphoramidite monomers proceeded smoothly with high yields. Using the Dmoc phosphoramidite monomers dA, dC, dG and the commercially available dT, and the Dmoc linker, four ODN sequences were synthesized. In all cases, excellent coupling yields were obtained. ODN deprotection/cleavage was achieved by using non-nucleophilic oxidative conditions. The new technology is predicted to be universally useful for the synthesis of ODNs containing one or more electrophilic functionalities.