Acyl Substitution Reaction Research Articles

Synthesis of N-Acyl-N′-Sulfonyl Hydrazides from Sulfonyl Hydrazides and Activated Amides

AbstractA methodology was developed for synthesizing N-acyl-N'-sulfonyl hydrazides through acyl substitution reactions between activated amides and arylsulfonyl hydrazides. Optimization of the reaction conditions revealed that using Cs₂CO₃ as a base and 1,4-dioxane as a solvent at 25 °C for 12 hours produced the highest yields. Among various amides tested, N-benzoylsuccinimide was found to be the most reactive, with reduced reactivity observed for N-mesityl-, N-tosyl-, and N-Boc-substituted tertiary benzoyl amides. Cross-reactions between a diverse range of N-benzoylsuccinimides and arylsulfonyl hydrazides successfully produced the corresponding N-acyl-N′-sulfonyl hydrazides with yields ranging from 63% to 94%.

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.

Native Chemical Ligation-Based Fluorescent Probes for Cysteine and Aminopeptidase N Using meso-thioester-BODIPY.

meso-Carboxyl-BODIPY responds to small electronic changes resulting from acyl substitution reactions with a marked change in fluorescence. Herein, the minute changes that accompany the thioester to amide conversion encountered in native chemical ligation (NCL) are exploited in the construction of fluorescent "turn-on" probes. Two fluorogenic probes, 1 a and 4, derived from a meso-thioester-BODIPY scaffold, were designed for the selective detection of cysteine (1 a) and aminopeptidase N (4), respectively. The aromatic (1 a) and aliphatic (4) thioesters of meso-carboxyl-BODIPY are nonfluorescent. However, specific analyte-induced conversion to the meso-amide derivative caused significant spectral changes and a dramatic fluorescence enhancement. Probe 1 a exhibited a large fluorescence "turn-on" response with high selectivity toward cysteine via a tandem NCL reaction. Probe 4 was successfully applied to the monitoring and imaging of endogenous aminopeptidase N in live cancer cells.

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.

Synthesis of Substituted Phthalimides via Ultrasound-Promoted One-Pot Multicomponent Reaction.

In this work, a novel strategy for the straightforward synthesis of substituted phthalimides is described, which includes base-mediated Michael addition/intramolecular cyclization/[1,5]-H shift/cleavage of CS2/aromatization/nucleophilic acyl substitution reaction of 2-(4-oxo-2-thioxothiazolidin-5-ylidene)acetates and α,α-dicyanoolefines under ultrasound (US) irradiation. Some advantages of this method are as follows: having simple operation, easily accessible starting materials, chemoselective cascade process, synthetically useful yields, and green conditions by utilizing US irradiation as a source of energy and using ethanol as solvent.

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.

Degradable and curable poly(conjugated ester)s prepared by acryl- and conjugate-substitutions of the ‘smallest’ monomer

α-(Chloromethyl)acryloyl chloride was polymerized with various bisphenols and diamines to yield poly(conjugated ester)s. The polymer prepared from bisphenol Z underwent curing by heating at 170 °C, while copolymerization with methyl methacrylate afforded a crosslinked polymer. The poly(conjugated ester)s were chemically decomposed via main-chain scission by the conjugate substitution with benzyl mercaptan. Moreover, the treatment with 5 wt% aqueous ammonia resulted in complete main-chain scission to the monomeric units by conjugate substitution and acyl substitution reaction, recovering bisphenol Z. Although curing and main-chain scission resulted in contractive changes on polymer properties, both reactions were achieved by a same skeleton, α-(aryloxymethyl)acrylate. Thus, α-(chloromethyl)acryloyl chloride is the smallest monomer to incorporate such a curable and degradable skeleton.

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.

Designing Reactions with Post-Transition-State Bifurcations: Asynchronous Nitrene Insertions into C–C σ Bonds

Summary Discoveries of chemical reactions with potential energy surfaces with post-transition-state bifurcations are increasing in frequency. Although such potential energy surface features are often discovered accidentally, we demonstrate here that they can be designed rationally. We describe a process for designing such reactions and apply it to the design of a nitrene addition/alkyl-shift reaction with a post-transition state bifurcation. We examine substituent effects on this reaction and propose a dynamics-based model for selectivity control.

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.

Regioselective 1,4-Conjugate Addition of Grignard Reagents to α,β-γ,δ-Dienones and α,β-γ,δ-Dienyl Thiol Esters.

Alkyl Grignard reagents (Et, nBu, iPr, cyclohexyl), with the exception of tBuMgCl, undergo exclusive or exceptionally highly regioselective 1,4-addition reactions to α,β-γ,δ-unsaturated ketones, while aryl and heteroaryl Grignard reagents give mixed results ranging from exclusive 1,4-addition (1-naphthyl, 2-N-methylpyrrolyl) to regioselective 1,2-addition (2-furyl, 2:1). All alkyl, aryl, and heteroaryl Grignard reagents examined gave exclusive 1,4-addition reactions with α,β-γ,δ-unsaturated thiol esters, with the exception of tBuMgCl, which gave an 80:20 mixture of 1,4:1,6-addition products. The high chemo- and regioselectivity observed for these reactions is attributed to a radical or radical-like pathway for the alkyl Grignard reagents and possibly a carbanion pathway for aryl Grignard reagents. The α,γ-dienyl thiol esters provide for a one-pot tandem 1,4-addition-nucleophilic acyl substitution reaction sequence to afford 3-substituted 4-enone moieties.

Enhanced Reactivity in Nucleophilic Acyl Substitution Ion/Ion Reactions Using Triazole-Ester Reagents.

The acyl substitution reactions between 1-hydroxy-7-aza-benzotriazole (HOAt)/1-hydroxy-benzotriazole (HOBt) ester reagents and nucleophilic side chains on peptides have been demonstrated in the gas phase via ion/ion reactions. The HOAt/HOBt ester reagents were synthesized in solution and ionized via negative nano-electrospray ionization. The anionic reagents were then reacted with doubly protonated model peptides containing amines, guanidines, and imidazoles in the gas phase. The complexes formed in the reaction cell were further probed with ion trap collision induced dissociation (CID) yielding either a covalently modified analyte ion or a proton transfer product ion. The covalent reaction yield of HOAt/HOBt ester reagents was demonstrated to be higher than the yield with N-hydroxysuccinimide (NHS) ester reagents over a range of equivalent conditions. Density functional theory (DFT) calculations were performed with a primary amine model system for both triazole-ester and NHS-ester reactants, which indicated a lower transition state barrier for the former reagent, consistent with experiments. The work herein demonstrates that the triazole-ester reagents are more reactive, and therefore less selective, than the analogous NHS-ester reagent. As a consequence, the triazole-ester reagents are the first to show efficient reactivity with unprotonated histidine residues in the gas phase. For all nucleophilic sites and all reagents, covalent reactions are favored under long time, low amplitude activation conditions. This work presents a novel class of reagents capable of gas-phase conjugation to nucleophilic sites in analyte ions via ion/ion chemistry. Graphical Abstract ᅟ.

Synthetic upcycling of polyacrylates through organocatalyzed post-polymerization modification.

The direct transformation of commercially available commodity polyacrylates into value-added materials was achieved. We demonstrate how 1,5,7-triazabicyclo[4.4.0]dec-5-ene, serving as a nucleophilic catalyst, can be used to catalyze acyl substitution reactions of acrylic polymers in the presence of alcohol and amine nucleophiles. Furthermore, we found that organocatalytic transesterification exhibits high selectivity towards sterically unhindered esters, thus providing a new route towards site-selective acyl substitution of macromolecular materials. Combining this methodology with reversible-deactivation radical polymerization (RDRP) techniques such as reversible addition-fragmentation chain-transfer (RAFT) polymerization allowed for the precise functionalization of sterically-differentiated acrylic copolymers and polymeric chain ends. We envision this approach to expedite functional polymer synthesis and provide access to functional macromolecules prepared from inexpensive, hydrolytically-stable polymeric precursors.

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.