Nucleophilic Acyl Substitution Reaction Research Articles

Real-Time Monitoring of Reactions by Headspace Sampling under Ambient Mass Spectrometric Conditions

The helium-plasma (HePI) ionization mass spectrometry method was used to track the formation of reaction products and consumption of reactants by continually monitoring the vapors in the reaction headspace in real time. Two examples of the application procedure are presented here: a nucleophilic acyl substitution reaction and a 1,4-nucleophilic addition process. For the purposes of the work, a specially constructed helium-plasma ionization (HePI) source was mounted on a single-quadrupole benchtop mass spectrometer. However, any electrospray source is easily convertible to an ambient HePI source. This setup has the potential to be used in the teaching of organic and analytical chemistry laboratories, as well as for demonstrations. Because the procedure requires only the headspace of the reaction vessel to be sampled by an easily prepared Venturi suction device (pump), the experiments can be quickly set up and adapted for any available mass spectrometer equipped with an electrospray source. For sampling, students can be shown how to prepare their own Venturi pumps and conduct reactions at different temperatures.

Synthesis and preliminary pharmacological profile of some new 3,5-dihydro-4H-imidazol-4-one and α,β-dehydroamino acid derivatives

A new series of 3,5-dihydro-4H-imidazol-4-one derivatives incorporating thiazole moiety have been readily prepared through the nucleophilic acyl substitution reactions of 5(4H)-oxazolones derivatives (2A-2J) with 4-(benzo[d]thiazol-2-yl) aniline (3) using a simple synthetic strategy under mild condition. Furthermore, the ring opening reaction of same components were examined to afford a new series of α,β-dehydroamino acid derivatives (4A-4J) in good yield. The preliminary pharmacological profile of all newly synthesized compounds were evaluated in vitro for their antibacterial and antifungal activities using micro broth dilution assay method, and it was revealed that most of the synthesized derivatives were exhibiting promising pharmacological activities against both strains. The structures of the newly synthesized 3,5- dihydro-4H-imidazol-4-one (5A-5J)) and α,β-dehydroamino acid derivatives (4A-4J) were expounded and elucidated on the bases of their FT-IR, 1H- and 13C –NMR spectral data.

Synthesis and evaluation of newly E-octadec-9-enoic acid derivatives as sustainable corrosion inhibitors for mild steel in 1.0 M HCl

Several new amide derivatives having varied aromatic characteristics prepared efficiently via nucleophilic acyl substitution reactions are tested for corrosion inhibition of mild steel in 1 M HCl at 20, 40, and 60 °C range by gravimetric methods. All compounds have shown very good inhibition efficiency (IE%) in acidic solutions. Increasing the temperature (in the presence of the inhibitor in the higher concentration (100–1000 μM) are found to increase the inhibition efficiency of the amide’s derivatives. Results from gravimetric measurements further revealed that Inh. 4 shows excellently at 60 °C giving IE% of 91.88 at 1000 μM. Thermodynamic parameters (ΔG º ads, ΔH º ads, and ΔS º ads) for the adsorption process and kinetic parameters for the metal dissolution (or hydrogen evolution) reaction in the presence of the new derivatives were determined. Experimental results agree with the Temkin adsorption isotherm. The inhibition of corrosion in 1 M HCl, influenced by both physi- and chemisorption, was found to be under mixed control but predominantly under cathodic control as revealed by the potentiodynamic polarization measurements for Inh. 4. Frontier molecular orbital calculations predicted that the newly synthesized inhibitors with aromatic characteristics serve as donor-centers to the empty d-orbital of the metal atoms and would exhibit higher corrosion IE%.

Synthesis and characterization of 2-Benzamido-NBenzylbenzamide Derivative

Anthranilamide derivatives exhibit anti-inflammatory, antipyretic, antibacterial, antiangiogenic, and anticoagulant properties. With an early in silico examination of its analgesic capabilities, this study aimed to generate a novel anthranilamide molecule by altering 2-Benzamido-N-Benzylbenzamide. Modification of anthranilamide with 1/2/3-chloro benzoyl chloride by acylation resulted in the design, synthesis, characterization, and research of the analgesic effects of 2-benzamido-N-benzoylbenzamide derivatives. 2-(2-chlorobenzamido)-N-(2-chlorobenzoyl)benzamide, 2-(3-chlorobenzamido)-N-(3-chlorobenzoyl)benzamide, and 2-(4-chlorobenzamido)-N-(4-chlorobenzoyl)benzamide were prepared. The nucleophilic acyl substitution reaction method was used to prepare these three chemicals by interaction with anthranylamide and benzoyl chloride molecules. Melting point and thin-layer chromatography were used to check the purity of the synthesis fi ndings. The structure was confi rmed by UV-Vis and infrared spectrophotometry.

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects.

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Stereoselective Synthesis of Multisubstituted α-fluoro-β-lactams

β-Lactams, found in β-lactam antibiotics, are the structurally distorted cyclic compounds being subjected to nucleophilic acyl substitution reaction. α-Fluorination of β -lactams is a simple and expedient approach to control the reactivity of β-lactam ring toward nucleophilic attack, which would hopefully lead to the new design of future antibiotics. From the viewpoint of obtaining multisubstituted α-fluoro-β-lactams, α-bromo-α- fluoro-β-lactams are considered as key compounds for structure functionalization, including nucleophilic substitution reaction, aldol-type reaction and metal-catalyzed crosscoupling reaction. All the reactions can be conducted smoothly to afford a variety of multisubstituted α-fluoro-β-lactams. During the course of the examination, chiral α,α-difluoro- β-lactams and α -bromo-β-fluoro-α-lactams are successfully obtained, which are considered potent precursors for making stereocontrolled multisubstituted α-fluoro-β-lactams.

Halide-Accelerated Acyl Fluoride Formation Using Sulfuryl Fluoride

Herein, we report a new one-pot sequential method for SO2F2-mediated nucleophilic acyl substitution reactions starting from carboxylic acids. A mechanistic study revealed that SO2F2-mediated acid activation proceeds via the anhydride, which is then converted to the corresponding acyl fluoride. Tetrabutylammonium chloride or bromide accelerate the formation of acyl fluoride. Optimized halide-accelerated conditions were used to synthesize acyl fluorides in 30-80% yields, and esters, amides, and thioesters in 72-96% yields without reoptimization for each nucleophile.

Preparation, carbonic anhydrase enzyme inhibition and antioxidant activity of novel 7-amino-3,4-dihydroquinolin-2(1H)-one derivatives incorporating mono or dipeptide moiety

New dipeptide–dihydroquinolinone derivatives were successfully synthesised by benzotriazole mediated nucleophilic acyl substitution reaction and their structures were elucidated by spectroscopic and analytic techniques. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. While all compounds showed moderate to good in vitro CA inhibitory properties against hCA IX and hCA XII with inhibition constants in the micromolar level (37.7–86.8 and 2.0–8.6 µM, respectively), they did not show inhibitory activity against hCA I and hCA II up to 100 µM concentration. The antioxidant capacity of the peptide–dihydroquinolinone conjugates was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Most of the synthesised compounds showed low antioxidant activities compared to the control antioxidant compounds BHA and α-tocopherol.

Crystal structures of two bis-carbamoyl-methyl-phosphine oxide (CMPO) compounds.

Two bis-carbamoyl-methyl-phosphine oxide compounds, namely {[(3-{[2-(di-phen-yl-phosphino-yl)ethanamido]-meth-yl}benz-yl)carbamo-yl]meth-yl}di-phenyl-phos-phine oxide, C36H34N2O4P2, (I), and diethyl [({2-[2-(di-eth-oxy-phosphino-yl)ethanamido]-eth-yl}carbamo-yl)meth-yl]phospho-nate, C14H30N2O8P2, (II), were synthesized via nucleophilic acyl substitution reactions between an ester and a primary amine. Hydrogen-bonding inter-actions are present in both crystals, but these inter-actions are intra-molecular in the case of compound (I) and inter-molecular in compound (II). Intra-molecular π-π stacking inter-actions are also present in the crystal of compound (I) with a centroid-centroid distance of 3.9479 (12) Å and a dihedral angle of 9.56 (12)°. Inter-molecular C-H⋯π inter-actions [C⋯centroid distance of 3.622 (2) Å, C-H⋯centroid angle of 146°] give rise to supra-molecular sheets that lie in the ab plane. Key geometric features for compound (I) involve a nearly planar, trans-amide group with a C-N-C-C torsion angle of 169.12 (17)°, and a torsion angle of -108.39 (15)° between the phosphine oxide phospho-rus atom and the amide nitro-gen atom. For compound (II), the electron density corresponding to the phosphoryl group was disordered, and was modeled as two parts with a 0.7387 (19):0.2613 (19) occupancy ratio. Compound (II) also boasts a trans-amide group that approaches planarity with a C-N-C-C torsion angle of -176.50 (16)°. The hydrogen bonds in this structure are inter-molecular, with a D⋯A distance of 2.883 (2) Å and a D-H⋯A angle of 175.0 (18)° between the amide hydrogen atom and the P=O oxygen atom. These non-covalent inter-actions create ribbons that run along the b-axis direction.

Microwave-assisted synthesis of novel 5-aminouracil-based compound with DFT calculations

In this investigation, microwave assisted synthesis of novel pyrazole ring formation via three reaction steps. In the beginning, nucleophilic acyl substitution reaction of the 5-aminouracil with ethyl cyanoacetate to afford 2-cyano-N-(2,4-dioxo-1,2,3,4-tetrahydropyridine-5-yl)acetamide (3). Knoevenagel Condensation of acetamide 3 with benzaldehyde afforded the corresponding acrylamide derivative 6 under microwave irradiation. Finally, Michael addition reaction of acrylamide with hydrazine hydrate to afford the novel 5-aminouracil-based compound 9. Computational studies for the three reactions have been carried out utilizing DFT/B3LYP/6-31 + G(d) theory level. The regioselectivity elucidated in terms of frontier molecular orbital (FMO), local electrophilicity, global electrophilicity and nucleophilicity indexes. The analysis of FMO showed the selectivity of these reactions was controlled through HOMO–LUMO interaction. Also, the molecular electrostatic potential (ESP) associated the hydrogen bonding interactions between electrophiles and nucleophiles. The IR of the optimized structures were examined by DFT/B3LYP/6 + 31G(d) and compared with experimental FT-IR. Furthermore, comparative study between experimental UV–Vis and calculated utilizing TD-DFT.

Reactions of aminopyrimidine derivatives with chloroacetyl and isophthaloyl chlorides

Abstract1‐Aminopyrimidine‐2‐one derivatives (1a‐c) were prepared in two steps from furan‐2,3‐diones and semicarbazones in toluene/benzene. Pyrimidin‐[1(2H)‐yl] acetamide derivatives and isophthalimide derivatives were synthesized from the nucleophilic acyl substitution reactions of compounds 1a‐c with chloroacetyl chloride. The structures of compounds 2a‐f were verified by IR, 1H NMR, 13C NMR and elemental analyses. The obtained final organic compounds were tested as catalysts in the Mizoroki‐Heck coupling reaction. They mostly exhibited very high catalytic activity results for the coupling reaction of styrene with different aryl bromide derivatives.

Propargyl-Assisted Selective Amidation Applied in C-terminal Glycine Peptide Conjugation.

Alkyl esters, such as propargyl esters, typically lack the electron-withdrawing inductive effects needed to participate in nucleophilic acyl substitution reactions. Herein, we report an unusual observation in which glycine propargyl ester derivatives displayed selective, base-independent reactivity towards linear alkylamines under mild, metal-free conditions. Through global reaction route mapping (GRRM) modeling calculations, it is predicted that these observations may be governed by factors related to hydrogen-bonding and intermolecular interactions, rather than electron-withdrawing inductive effects. Based on this concept of propargyl-assisted selective amidation, a direct application was made to develop a novel site-specific C-terminal glycine peptide bioconjugation technique as a proof-of-concept, which relies upon the selective reactivity of glycine propargyl esters over that of aspartate and glutamate side-chain-linked propargyl esters.

Soft Matter Nanoparticles with Reactive Coronal Pentafluorophenyl Methacrylate Residues via Non-Polar RAFT Dispersion Polymerization and Polymerization-Induced Self-Assembly

Soft matter nanoparticles exhibiting rich polymor- phism with reactive pentafluorophenyl methacrylate (PFPMA) units in their coronae were prepared via non-polar reversible addition-fragmentation chain transfer dispersion polymerization and polymerization-induced self-assembly. Poly(stearyl methac- rylate-stat-PFPMA) macro-CTAs, containing up to 12 mol % PFPMA, were used in n-octane and n-tetradecane for the subse- quent copolymerization of 3-phenylpropyl methacrylate. Both formulations gave the full, common family of nanoparticles (spheres, worms, and vesicles) as determined by transmission electron microscopy. Reaction of the PFP ester repeating units in the coronal layer of spherical nanoparticles with benzylamine, tetrahydrofurfurylamine, N,N-dimethylethylenediamine, and an amine functional methyl red dye yielded a new library of func- tional spherical nano-objects. The success of the nucleophilic acyl substitution reactions was confirmed using a combination of 1 H/ 19 F NMR and Fourier transform infrared spectroscopies as well as dynamic light scattering. V C 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 00, 000-000

An Integrated Laboratory Approach toward the Preparation of Conductive Poly(phenylenevinylene) Polymers

Poly(phenylene vinylene) (PPV) represents an important class of conjugated, conducting polymers that have been readily exploited in the preparation of organic electronic materials. In this experiment, students prepare a PPV polymer via a facile multistep synthetic sequence with robust spectroscopic evaluation of synthetic intermediates and the final product. The synthetic sequence could be applied by university instructors as a capstone project for an undergraduate organic chemistry laboratory or as a centerpiece project for either a polymer or integrated laboratory course. The initial synthetic step could be segmented and used as a modular piece in the traditional introductory organic chemistry laboratory. In either case, the resultant PPV polymer is analyzed by UV–vis and fluorescence spectroscopy to determine the quantum yield which promotes enhanced student understanding of the photophysical properties of the material. In addition, GPC analysis is completed to reveal the molecular weight and polydispersity of the polymer. Students completing this experiment gain valuable experience in organic/polymer synthesis and structural characterization utilizing GC/MS, GPC, NMR, UV–vis, and fluorescence spectroscopy, as well as in the mechanistic aspects and practical application of some of the classic transformations in organic chemistry including the SN2 reaction, nucleophilic acyl substitution, organometallic chemistry, and Wittig reaction.

Synthesis of Potent CERT Inhibitor HPA-12 Featuring a Tandem Corey-Link and Intramolecular Nucleophilic Acyl Substitution Reaction

A novel preparation of the potent CERT protein inhibitor (1<i>R</i>,3<i>S</i>)-HPA-12 is described. The synthesis is accomplished in five steps from (<i>S</i>)-Wynberg lactone and features a diastereoselective tandem Corey–Link and intramolecular nucleophilic acyl substitution reaction in a key step.

Factors influencing the synthesis and the post-modification of PEGylated pentafluorophenyl acrylate containing copolymers

Copolymerization reactions involving oligoethylene glycol acrylate (OEGA) or diethylene glycol acrylate (DEGA) with pentafluorophenyl acrylate (PFPA) have been performed by reversible addition fragmentation transfer (RAFT) polymerization. The effect of the reaction conditions on the nucleophilic acyl substitution reactions of PFPA was studied using a model amine (furfuryl amine). The resulting PEG/PFP functional copolymers were then used as scaffolds to produce a library of polymers by reaction with a range of amines.

Fabrication of Photofunctional Nanoporous Membrane and Its Photoinactivation Effect of Vesicular Stomatitis Virus

Fabrication and photophysical study of photofunctional nanoporous alumina membrane (PNAM) were performed, and its application of photodynamic antimicrobial chemotherapy (PACT) was investigated. Nanoporous alumina membrane (NAM) was fabricated by two-step aluminium anodic oxidation process. Surface of the fabricated NAM was modified with organo-silane agent to induce covalent bonding between NAM and a photosensitizer (PtCP: [5,10,15-triphenyl-20-(4-methoxycarbonylphenyl)-porphyrin] platinum). PtCP was covalently bonded to the surface of the modified NAM by nucleophilic acyl substitution reaction process. The morphology and the photophysical properties of the fabricated PNAM were confirmed with field emission scanning electron microscope (FE-SEM), steady-state spectroscopies, and nanosecond laser-induced time-resolved spectroscopy. For the efficacy study of PNAM in PACT, an enveloped animal virus, vesicular stomatitis virus (VSV), was utilized as a target organism. Antiviral effect of the PNAM-PACT was measured by the extent of suppression of plaque-forming units (PFU) after the light irradiation. In the cultures inoculated with PACT-treated VSV, the suppression of PFU was prominent, which demonstrates that PNAM is a potential bio clean-up tool.

Total Synthesis of (−)-Przewalskin B

The first total synthesis of (-)-Przewalskin B has been accomplished with an intramolecular nucleophilic acyl substitution (INAS) reaction and an intramolecular aldol condensation as key steps.

ChemInform Abstract: Addition of Photosensitivity to Engineering Plastics by a Novel Pattern‐Forming Method Using Reactions of the Polymers with Developers: Reaction Development Patterning

AbstractReview: 40 refs.

Total Synthesis of the Aspidosperma Alkaloid (±)-Subincanadine F via a Titanium-Mediated Intramolecular Nucleophilic Acyl Substitution Strategy

The total synthesis of the bridge-fused Aspidosperma indole alkaloid (±)-subincanadine F has been accomplished in seven steps. The synthetic utility of a titanium-mediated intramolecular nucleophilic acyl substitution (INAS) reaction for the construction of the bridge-fused ring system was demonstrated.