Nucleophilic Displacement Reactions Research Articles

Kinetic Study on Nucleophilic Displacement Reactions of Phenyl Y‐Substituted Phenyl Carbonates with 1,8‐Diazabicyclo[5.4.0]undec‐7‐ene: Effects of Amine Nature on Reaction Mechanism

Second‐order rate constants (k N) for nucleophilic displacement reactions of phenyl Y‐substituted phenyl carbonates (7a–7l) with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in 80 mol % H2O/20 mol % DMSO at 25.0 ± 0.1 oC have been measured spectrophotometrically. The Brønsted‐type plot for the reactions of 7a–7l with DBU is linear with βlg = –0.48, indicating that the reactions proceed through a concerted mechanism, which is in contrast to the stepwise mechanism reported previously for the corresponding reactions with ethylamine (a primary amine) and piperidine (a secondary amine). The Hammett plots correlated with σ − and σ o constants exhibit many scattered points. In contrast, the Yukawa–Tsuno plot results in an excellent linear correlation with ρY = 1.27 and r = 0.57, implying that a negative charge develops partially on the O atom of the leaving group in the transition state. The bulky DBU is less reactive than the primary and secondary amines toward substrates possessing a weakly basic leaving group. It has been concluded that steric hindrance exerted by DBU in the plausible intermediate (T±) forces the reactions to proceed through a concerted mechanism because expulsion of the leaving group from T± could reduce the steric hindrance.

Multifunctional Pt(II) Reagents: Covalent Modifications of Pt Complexes Enable Diverse Structural Variation and In-Cell Detection.

To enhance the functionality of Pt-based reagents, several strategies have been developed that utilize Pt compounds modified with small, reactive handles. This Account encapsulates work done by us and other groups regarding the use of Pt(II) compounds with reactive handles for subsequent elaboration with fluorophores or other functional moieties. Described strategies include the incorporation of substituents for well-known condensation or nucleophilic displacement-type reactions and their use, for example, to tether spectroscopic handles to Pt reagents for in vivo investigation. Other chief uses of displacement-type reactions have included tethering various small molecules exhibiting pharmacological activity directly to Pt, thus adding synergistic effects. Click chemistry-based ligation techniques have also been applied, primarily with azide- and alkyne-appended Pt complexes. Orthogonally reactive click chemistry reactions have proven invaluable when more traditional nucleophilic displacement reactions induce side-reactivity with the Pt center or when systematic functionalization of a larger number of Pt complexes is desired. Additionally, a diverse assortment of Pt-fluorophore conjugates have been tethered via click chemistry conjugation. In addition to providing a convenient synthetic path for diversifying Pt compounds, the use of click-capable Pt complexes has proved a powerful strategy for postbinding covalent modification and detection with fluorescent probes. This strategy bypasses undesirable influences of the fluorophore camouflaged as reactivity due to Pt that may be present when detecting preattached Pt-fluorophore conjugates. Using postbinding strategies, Pt reagent distributions in HeLa and lung carcinoma (NCI-H460) cell cultures were observed with two different azide-modified Pt compounds, a monofunctional Pt(II)-acridine type and a difunctional Pt(II)-neutral complex. In addition, cellular distribution was observed with an alkyne-appended difunctional Pt(II)-neutral complex analogous in structure to the aforementioned difunctional azide-Pt(II) reagent. In all cases, significant accumulation of Pt in the nucleolus of cells was observed, in addition to broader localization in the nucleus and cytoplasm of the cell. Using the same strategy of postbinding click modification with fluorescent probes, Pt adducts were detected and roughly quantified on rRNA and tRNA from Pt-treated Saccharomyces cerevisiae; rRNA adducts were found to be relatively long-lived and not targeted for immediate degradation. Finally, the utility and feasibility of the alkyne-appended Pt(II) compound has been further demonstrated with a turn-on fluorophore, dansyl azide, in fluorescent detection of DNA in vitro. In all, these modifications utilizing reactive handles have allowed for the diversification of new Pt reagents, as well as providing cellular localization information on the modified Pt compounds.

Synthesis and Characterization of Poly(Amideimide)S from Ab Monomers by Direct Polycondensation Using Triphenyl Phosphite

Poly(amideimide)s were prepared by the reaction of two new AB monomers, N-(4-aminophenyl)-4-(p-carboxyphenoxy)phthalimide and N-(3-aminophenyl)-4-(p-carboxyphenoxy)phthalimide. The monomers were synthesized by nucleophilic displacement reaction of the corresponding nitrophthalimides with p-hydroxybenzoic acid. The monomers were characterized by IR and NMR. Poly(amideimide)s were prepared from AB monomers by direct polycondensation using triphenyl phosphite. The polymers obtained had high inherent viscosities. The polymers showed high solubility in polar aprotic solvents. The polymers showed good thermal stability and had high glass transition temperatures. X-ray diffraction pattern of the polymers indicate amorphous nature of these polymers.

One-pot odourless synthesis of thioesters via in situ generation of thiobenzoic acids using benzoic anhydrides and thiourea.

An efficient and odourless procedure for a one-pot synthesis of thioesters by the reaction of benzoic anhydrides, thiourea and various organic halides (primary, allylic, and benzylic) or structurally diverse, electron-deficient alkenes (ketones, esters, and nitriles) in the presence of Et3N has been developed. In this method, thiobenzoic acids were in situ generated from the reaction of thiourea with benzoic anhydrides, which were subjected to conjugate addition with electron-deficient alkenes or a nucleophilic displacement reaction with alkyl halides.

Chlorine Functionalization of a Model Phenolic C8-Guanine Adduct Increases Conformational Rigidity and Blocks Extension by a Y-Family DNA Polymerase

Certain phenoxyl radicals can attach covalently to the C8-site of 2'-deoxyguanosine (dG) to afford oxygen-linked C8-dG adducts. Such O-linked adducts can be chemically synthesized through a nucleophilic displacement reaction between a phenolate and a suitably protected 8-Br-dG derivative. This permits the generation of model O-linked C8-dG adducts on scales suitable for insertion into oligonucleotide substrates using solid-phase DNA synthesis. Variation of the C8-aryl moiety provides an opportunity to derive structure-activity relationships on adduct conformation in duplex DNA and replication bypass by DNA polymerases. In the current study, the influence of chlorine C8-dG functionalization on in vitro DNA replication by Klenow fragment exo(-) (Kf(-)) and the Y-family polymerase (Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4)) has been determined. Model O-linked C8-dG adducts derived from the pentachlorophenoxyl radical ([PCP]G) and 2,4,6-trichlorophenoxyl radical ([TCP]G) were inserted into the reiterated G3-position of the NarI sequence (12-mer, NarI(12); and 22-mer, NarI(22)), which is a known hotspot for frameshift mutations mediated by N-linked polycyclic C8-dG adducts in bacterial mutagenesis. Within the NarI(12) duplex, the unsubstituted C8-phenoxy-dG ([PhO]G) adduct adopts a minimally perturbed B-form helix. Chlorination of [PhO]G to afford [PCP]G does not significantly change the adduct conformation within the NarI(12) duplex, as predicted by molecular dynamics simulations. However, when using NarI(22) for DNA synthesis in vitro, the chlorinated [PCP]G and [TCP]G lesions significantly block DNA replication by Kf(-) and Dpo4, whereas [PhO]G is readily bypassed. These findings highlight the impact that chlorine substituents impart to bulky C8-dG lesions.

Nanoparticle Formulation of AEA and BAEA Cellulose Carbamates Increases Biocompatibility and Antimicrobial Activity.

Antimicrobially active polymers with a cationic moiety gain increasing interest in health care providing a biocompatible alternative to commonly used products. They adhere to the polyanionic bacterial surface, disrupt cell membranes and kill bacteria. An efficient path to obtain amino group-containing cellulose is nucleophilic displacement reaction of p-toluenesulfonic acid ester and amines leading to 6-deoxy-6-(ω-aminoalkyl) aminocellulose carbamates. Spherical nanoparticles of the obtained 6-deoxy-6-(2-aminoethyl) amino (AEA) and 6-deoxy-6-{2-bis[N',N'-(2-aminoethyl)]aminoethyl}amino (BAEA) cellulose carbamate with a size range of 80-120 nm were produced. The AEA and BAEA cellulose carbamates exhibited significant antimicrobial activity with moderate cell compatibility. Nanoparticle formulation enhanced biocompatibility.

Design, synthesis, characterization, and applications of diol monomers, polyimides, and co-polyimides

Two aromatic diimide-diol monomers N,N′-bis(4-hydroxynaphthyl)oxydiphthalic diimide and N,N′-bis(4-hydroxynaphthyl)biphenyl tetracarboxylic diimide were synthesized from aromatic dianhydrides and 5-amino1-naphthol. Polyimides (PIs) and co-polyimides (co-PIs) were synthesized from these new diols and 4,4′-dichlorodiphenyl sulfone through nucleophilic displacement reaction. The structures of the monomers and PIs and co-PIs were characterized by FT-IR and NMR analysis. The PIs and co-PIs were characterized by X-ray diffraction (XRD), thermogravimetry, differential scanning calorimetry, solution viscosity, solubility test, and dielectric properties test. XRD studies indicated that these PIs and co-PIs were amorphous in nature and were soluble in organic solvents. The PIs and co-PIs showed excellent thermal stability and the 10% weight loss occurred in the range 390–452 °C. The limiting oxygen index values of these PIs and co-PIs were in the range 37.9–42.3 and the value suggests that these PIs and co-PIs can be used as self-extinguishing polymers. These PIs and co-PIs found to have a dielectric constant in the range 3.88–4.56 and have excellent electrical insulation character and can be used as high temperature electrical insulation materials.

Chiral (SO)–N–(SO) Sulfoxide Pincer Complexes of Mg, Rh, and Ir: N–H Activation and Selective Sulfoxide Reduction upon Ligand Coordination

Multigram quantities of the optically pure amino–bis-sulfoxide ligand (S,S)-bis(4-tert-butyl-2-(p-tolylsulfinyl)phenyl)amine ((S,S)-3) are accessible by in situ lithiation of bis(2-bromo-4-tert-butylphenyl)amine (1) followed by a nucleophilic displacement reaction with Andersen’s sulfinate 2. Deprotonation of (S,S)-3 with MgPh2 yields the magnesium amido–bis-sulfoxide salt (S,S)-4 quantitatively. Metathetical exchange of (S,S)-4 with [RhCl(COE)2]2 affords the optically pure pseudo-C2-symmetric Rh(I)–amido bis-sulfoxide pincer complex mer-(R,R)-[Rh(bis(4-(tert-butyl)-2-(p-tolylsulfinyl)phenyl)amide)(COE)] (mer-(R,R)-5). This complex reacts with 3 equiv of HCl to give the facial Rh(III) complex fac-(S,R,R)-[Rh(bis(4-(tert-butyl)-2-(p-tolylsulfinyl)phenyl)amine)Cl3] (fac-(S,R,R)-6), in which one of the sulfoxide functions has been reduced to the sulfide and in which the resulting sulfoxide–sulfide–amine ligand is facially coordinated. The same complexes 5 and 6 form in a 1:2 ratio in a disproportionation reaction when [RhCl(COE)2]2 is treated with 2 equiv of neutral ligand 3. N–H activation is directly observed in the reaction of [IrCl(COE)2]2 with 3, affording the amido–hydrido–Ir(III) complex [Ir(bis(4-(tert-butyl)-2-(p-tolylsulfinyl)phenyl)amide)(Cl)(H)(COE)] (8).

Synthesis of a novel naphthyl-based self-catalyzed phthalonitrile polymer

Abstract A novel naphthyl-based self-catalyzed phthalonitrile monomer was prepared via nucleophilic displacement reaction. The structure was characterized by Fourier infrared spectrum (FT-IR) and nuclear magnetic resonance (1H NMR). The polymerization mechanism was explored. Thermal properties were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), which demonstrated self-promoted behavior and excellent heat resistance.

Homogeneous tosylation of agarose as an approach toward novel functional polysaccharide materials

The homogeneous tosylation of agarose was studied with respect to the effects of reaction parameters, such as reaction medium, time, and molar ratio, on the reaction course, the degree of substitution (DS) with tosyl/chloro deoxy groups, and the molecular structure. Tosyl agaroses (TOSA) with DStosyl≤1.81 could be obtained in completely homogeneous reactions by using N,N-dimethylacetamide (DMA)/LiCl or 1,3-dimethyl-2-imidazolidinone (DMI) as solvents. The products were characterized by FT-IR and NMR spectroscopy and it was demonstrated that two types of substitution pattern can be achieved: (i) non-preferential substitution at position 6 of the 1→3-linked β-d-galactose unit (G-6) and position 2 of the 1→4-linked 3,6-anyhdro-α-l-galactose unit (LA-2) and (ii) regioselective tosylation at G-6, depending on whether the reaction is performed with or without LiCl. Finally, the nucleophilic displacement reaction of TOSA was studied using azide and ethylenediamine as representative nucleophiles. Novel deoxy-agarose derivatives were obtained that showed an interesting solubility behavior and will be used for creating functional polysaccharide materials.

Synthesis of diol monomers and organosoluble fluorinated polyimides with low dielectric

Four diimide–diol monomers were synthesized from 4,4′-(hexafluoroisopropylidene)diphthalic dianhydride and aminophenol/aminonaphthol. The structures of the monomers were characterized by spectroscopic analysis. A series of fluorinated polyimides (FPI-1 to FPI-8) were synthesized from these new diols and 4,4′-difluorobenzophenone/4,4′-dichlorodiphenyl sulphone, through nucleophilic displacement reaction. The FPIs were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance, X-ray diffraction, thermogravimetry, differential scanning calorimetry, solution viscosity, solubility test, and dielectric properties test. FPIs were amorphous and showed good solubility due to the presence of >C(CF3)2 unit and flexible groups in the polyimides backbone. These FPIs also showed good thermal stability and the 10% weight loss occurred in the range 353–505°C. The limiting oxygen index values of FPIs were in the range of 31.5–39.1 and such FPIs can be used as self-extinguishing polymers. These FPIs have a dielectric constant in the range of 3.10–4.23 and can be used as high temperature electrical insulation materials.

Nucleophilic displacement versus electron transfer in the reactions of alkyl chlorosilanes with electrogenerated aromatic anion radicals

Anion radicals of a series of aromatic compounds (C6H5CN, C6H5COOEt, anthracene, 9,10-dimethyl-, 9,10-diphenyl- and 9-phenylanthracene, pyrene and naphthalene) react with trialkyl chlorosilanes R1R2R3SiCl (R1-3=Me, Et; R1,2=Me, R3=t-Bu) in multiple ways, following classical bimolecular schemes. The ratio of one-electron transfer (ET) to a two-electron process (SN2-like nucleophilic attack of the reduced form of mediator on the chlorosilane, with k2≅102-108M−1s−1) is inversely related to the steric availability of Si for nucleophilic displacement reactions. The nucleophilic substitution pathway mainly results in mono- and disilylated aromatic products. Paralleling the electrochemical data with DFT calculations, the role of silicophilic solvent (DMF) in SN process was shown to be quite complex because of its involvement into coordination extension at silicon, dynamically modifying energetics of the process along the reaction coordinate. Although 2,2'-bipyridine also forms delocalized persistent anion radicals, they do not induce neither ET nor SN reactions in the same manner as aromatic mediators. Silicophilicity of 2,2'-bipyridine being superior to that of DMF, a R3SiCl·bipy complex of hypercoordinated silicon with electroactive ligand was formed instead, whose reduction requires about 1V less negative potentials than bipyridine itself.

Effect of Cosolvent in a Nucleophilic Substitution Reaction Using Organoclay in Triphase Catalytic System

A remarkable rate enhancement technique has been devised for a typical nucleophilic displacement reaction by using triphase catalytic materials based on tetraoctylammonium exchange forms of hectorite clay. Pseudo-first order rate constants (kobs) for the conversion of 1-bromobutane to the corresponding chloride under triphase conditions using the clay catalyst in the presence of various polar cosolvents have been observed. The results here have shown that the addition of a cosolvent increases the catalytic activity of the triphase system by several fold. In addition, the results have demonstrated that each cosolvent has a unique concentration for achieving an optimum reaction rate.

Synthesis and antimicrobial activities of 1-(3-benzyl-4-oxo-3H-quinazolin-2-yl)-4-(substituted)thiosemicarbazide derivatives

A series of 1-(3-benzyl-4-oxo-3H-quinazolin-2-yl)-4-(substituted) thiosemicarbazides (AS1-AS10) were obtained by the reaction of 2-hydrazino- 3-benzyl quinazolin-4(3H)-one (6) with different dithiocarbamic acid methyl ester derivatives. The key intermediate 3-benzyl-2-thioxo-2,3-dihydro-1Hquinazolin-4-one (4) was obtained by reacting benzyl amine (1) with carbon disulphide and sodium hydroxide in dimethyl sulphoxide to give sodium dithiocarbamate, which was methylated with dimethyl sulfate to yield the dithiocarbamic acid methyl ester (2) and condensed with methyl anthranilate (3) in ethanol yielded the desired compound (4) via the thiourea intermediate. The SH group of compound (4) was methylated for the favorable nucleophilic displacement reaction with hydrazine hydrate, which afford 2-hydrazino-3- benzyl-3H-quinazolin-4-one (6). The IR, 1H, and 13C NMR spectrum of these compounds showed the presence of peaks due to thiosemicarbazides, carbonyl (C=O), NH and aryl groups. The quinazolin-4-one moiety molecular ion peaks (m/z 144) were observed all the mass spectrum of compounds (AS1-AS10). Elemental (C, H, N) analysis satisfactorily confirmed purity of the synthesized compounds and elemental composition. All synthesized compounds were also screened for their antimicrobial activity against selective gram positive and gram negative by agar dilution method. In the present study compounds AS8 and AS9 were emerged as the most active compounds of the series.

2-Oxo promoted hydrophosphonylation & aerobic intramolecular nucleophilic displacement reaction.

Highly efficient catalyst free methods for the synthesis of α-hydroxy-β-oxophosphonates and α-oxoesters have been described. The existence of a 2-oxo group in α-oxoaldehydes is a key factor in promoting the reaction of the tervalent phosphite form towards 2-oxoaldehydes in the synthesis of α-hydroxy-β-oxophosphonates. The in situ activated α-C-H atom of α-hydroxy-β-oxophosphonates sustains aerobic intramolecular nucleophilic displacement in a curious way to produce α-oxoester.

Impact of sulfur heteroatoms on the activity of quaternary ammonium salts as phase transfer catalysts for nucleophilic displacement reactions

The application of a new class of alkylammonium salts as phase-transfer catalysts was investigated. These salts are tetra(4-thiaalkyl) ammonium bromides, and the key questions of the study focus on how the incorporation of a sulfur atom in the alkyl chains affects the efficacy of the salts as phase-transfer catalysts. Employing the nucleophilic substitution of cyanide for bromide on 1-bromopentane as a model reaction, reaction rate constants and activation energies are evaluated. The kinetic parameters obtained using the tetrathiaalkylammonium salts are compared to those obtained using their tetraalkylammonium analogs. The general trend is that the presence of sulfur in the alkyl chains reduces the reaction rates and increases activation energies. This trend is analyzed both in terms of computational modeling and experimental distribution coefficients to determine the cause of the slower reaction rates. Thiaquats are shown to distribute more into the aqueous phase than traditional quat salts of similar chain length, resulting in lower organic phase concentrations. Quantum calculations indicate stronger ion pairing for the thiaquats, increasing activation energies and slowing reaction rates. Thus, differences in rate enhancements are attributable both to phase distribution and ion pairing effects.

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs.

Methyl and ethyl thioether groups were introduced at all primary positions of α-, β-, and γ-cyclodextrin by nucleophilic displacement reactions starting from the corresponding per-(6-deoxy-6-bromo)cyclodextrins. Further modification of all 2-OH positions by etherification with iodo terminated triethylene glycol monomethyl ether (and tetraethylene glycol monomethyl ether, respectively) furnished water-soluble hosts. Especially the β-cyclodextrin derivatives exhibit very high binding potentials towards the anaesthetic drugs sevoflurane and halothane. Since the resulting inclusion compounds are highly soluble in water at temperatures ≤37 °C they are good candidates for new aqueous dosage forms which would avoid inhalation anaesthesia.

The Novel Route to Prepare Immobilized Macrocyclic Compound on 6-OH of Chitosan with Good Solubility and Prime Study on Its Applications

β-cyclodextrin (β-CD) immobilization of a chitosan derivate on C6-OH (CTS-6-CD) with good solubility was prepared through a novel method. During the process the amino group of the chitosan was protected by phthalic anhydride and deprotected in the hydrazine hydrate solution. β-CD was immobilized onto the C6 position of chitosan by a nucleophilic displacement reaction. The prepared derivate can be dissolved in hydrazine hydrate (v:v = 1:1), ethylenediamine/ethanol (v:v = 1:1), 1% aqueous acetic acid, DMSO and DMAc. The application of the 6-OH cyclodextrin-immobilized chitosan derivatives in an electrochemical biosensor was examined in a preliminarily manner.

Role of choline and glycine betaine in the formation of N,N-dimethylpiperidinium (mepiquat) under Maillard reaction conditions

This study is the first to examine the role of choline and glycine betaine, naturally present in some foods, in particular in cereal grains, to generate N,N-dimethylpiperidinium (mepiquat) under Maillard conditions via transmethylation reactions involving the nucleophile piperidine. The formation of mepiquat and its intermediates piperidine – formed by cyclisation of free lysine in the presence of reducing sugars – and N-methylpiperidine were monitored over time (240°C, up to 180 min) using high-resolution mass spectrometry in a model system comprised of a ternary mixture of lysine/fructose/alkylating agent (choline or betaine). The reaction yield was compared with data recently determined for trigonelline, a known methylation agent present naturally in coffee beans. The role of choline and glycine betaine in nucleophilic displacement reactions was further supported by experiments carried out with stable isotope-labelled precursors (13C- and deuterium-labelled). The results unequivocally demonstrated that the piperidine ring of mepiquat originates from the carbon chain of lysine, and that either choline or glycine betaine furnishes the N-methyl groups. The kinetics of formation of the corresponding demethylated products of both choline and glycine betaine, N,N-demethyl-2-aminoethanol and N,N-dimethylglycine, respectively, were also determined using high-resolution mass spectrometry.

Novel metal(III) and metal free soft phthalocyanine metal ion sensors bearing (1-hydroxyhexan-3-ylthio)-substituents: Synthesis, characterization, aggregation behavior

A new substituted phthalonitrile derivative, 4-(1-hydroxyhexan-3-ylthio) phthalonitrile, was prepared by the nucleophilic displacement reaction between 1-hydroxyhexan-3-ylthio and 4-nitrophthalonitrile. The highly soluble novel metallo phthalocyanines [M: 2H (2), Ga(III) (3), In(III) (4)] with four peripheral 1-hydroxyhexan-3-ylthio groups were synthesized by cyclotetramerization. Purification of these compounds was tedious because of their high solubility and they were purified by column chromatography. They were characterized by elemental analysis, FTIR, 1H and 13C NMR, MALDI-TOF and UV–Vis spectral data. The complexes were soluble in both polar solvents and non-polar solvents, such as MeOH, EtOH, CHCl3, CH2Cl2, benzene, toluene and even hexane. Absorption spectral changes of the functional MPcs during addition of Ag(l) and Pd(ll) soft-metal ions were evaluated by UV–Vis spectroscopy, with monomer-dimer formation.