Aminolysis Of Esters Research Articles

Polymer Free Volume-Controlled Molecular Clock and Emitter for Multicolored Transient Data Display in Advanced Photonic Cryptography.

The booming demand on data security has aroused great interest for developing smart materials with temporal display feature and dynamic multicolor fluorescence. However, it remains challenging to implement both features on most responsive molecules. Herein, we construct a polymer free volume-controlled "molecular clock and emitter" via covalently embedding a multi-stimuli responsive molecular switch (i.e., spiropyran) into a polymer network (i.e., poly(pentafluorophenyl acrylate)) with programmable crosslink density and free volume. By the aminolysis of pentafluorophenyl ester with different amount of diamine crosslinkers, pPFPA-co-SP networks with controllable crosslink densities are generated, which have different confinement effects on the rate constant of SP/MC isomerization, thus leading to time-dependent photochromism. In addition, PTF1, a fluorescent probe that is sensitive to polymer rigidity, is introduced to further endow pPFPA-co-SP system with phototunable dynamic full-color emission. Therefore, relying on their synergistical responses to the rigidity of the polymer network, we have successfully developed a versatile molecular clock and emitter via an "one stone two birds" manner, which shows time-dependent data display along with dynamic multicolor fluorescence switching, providing great potential for advanced encryption and anticounterfeiting with a high security level.

Polymer Free Volume‐Controlled Molecular Clock and Emitter for Multicolored Transient Data Display in Advanced Photonic Cryptography

AbstractThe booming demand on data security has aroused great interest for developing smart materials with temporal display feature and dynamic multicolor fluorescence. However, it remains challenging to implement both features on most responsive molecules. Herein, we construct a polymer free volume‐controlled “molecular clock and emitter” via covalently embedding a multi‐stimuli responsive molecular switch (i.e., spiropyran) into a polymer network (i.e., poly(pentafluorophenyl acrylate)) with programmable crosslink density and free volume. By the aminolysis of pentafluorophenyl ester with different amount of diamine crosslinkers, pPFPA‐co‐SP networks with controllable crosslink densities are generated, which have different confinement effects on the rate constant of SP/MC isomerization, thus leading to time‐dependent photochromism. In addition, PTF1, a fluorescent probe that is sensitive to polymer rigidity, is introduced to further endow pPFPA‐co‐SP system with phototunable dynamic full‐color emission. Therefore, relying on their synergistical responses to the rigidity of the polymer network, we have successfully developed a versatile molecular clock and emitter via an “one stone two birds” manner, which shows time‐dependent data display along with dynamic multicolor fluorescence switching, providing great potential for advanced encryption and anticounterfeiting with a high security level.

Synthesis of linear polyesters bearing amino groups via lipase-catalyzed polymerization of N-protected monomer and deprotection

Linear biodegradable polyesters with a controlled number of side chains of amino groups have been synthesized. Such polyesters with a large number of amino side groups can be conjugated with a wide variety of functional molecules to obtain multi-functional biodegradable polyesters. In this study, poly(1,3-propylene-co-2-amino-1,3-propylene) adipate) (P(P-co-AP)A) was synthesized by enzymatic polymerization of divinyl adipate, 1,3-propanediol, and N-Boc-2-amino-1,3-propanediol (BocAPDO), and subsequent deprotection under strong acidic conditions. The mild reaction conditions and the specificity of the enzymatic polymerization could effectively inhibit side reactions, while the protecting groups of the monomers prevented polymer branching from the amino groups. It was found that the introduction rates of BocAPDO in the polymers could be well-controlled as the feeding rates changed from 0 to 100 mol%. After the deprotection and desalting, the ester groups in the main chain gradually converted into amide groups by intramolecular ester aminolysis at room temperature for a few days due to nucleophilic free amino groups. It was also found that the synthesized functional copolymers were all amorphous, since the random component of amino groups disrupted the crystallinity of poly(1,3-propylene adipate) (PPA). The glass transition temperature gradually increased with the increase in the content of 2-amino-1,3-propylene adipate (APA), eventually reaching −0.4 °C at the APA content of 100 mol% due to the intermolecular hydrogen bonding. Moreover, P(P-co-AP)A shows high hygroscopicity, where 3.9 wt% and 8.1 wt% of water were absorbed in the polymers with the APA contents of 50 and 100 mol%, respectively, when left in air at 60–70 % humidity for 6 h. Thus, the hydrophilicity dramatically improved with the increase in the APA content, eventually resulting in the acquisition of water solubility. The model post-polymerization modification using butyric acid was also conducted, and it was confirmed that carboxylic acids could be conjugated to the polymers by simple condensation reaction. Since polymerization of functional monomers is generally susceptible to the polarity of metal catalysts, the mild and selective reaction employed in this study could realize a higher content of various functional groups in the side chains of polyesters leading to a newly designed multi-functional polyester.

Synthesis of novel cyanopyridine compounds as potential EGFR inhibitors targeting A549 and PC3 cancer cell lines: In vitro, In vivo and ADME pharmacokinetics studies

Developing new leads for fighting cancer is a challenge for organic and medicinal chemists; hence, new functionalized pyridines have been synthesized via several transformations, including new amide bond formation, cyclization, and hydrazone synthesis. Aminolysis of the ethyl ester 2 with benzylamine affords the benzyl amide 3. Hydrazinolysis of the ester 2 afforded hydrazide 4. Hydrazide 4 used as precursor to obtain new hydrazino- and cyclized derivatives 5–10. Moreover, new series of hydrazone derivatives 11–17 were synthesized by condensation 2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 4 with aromatic aldehydes and ketones. The synthesized compounds were subjected to cytotoxic screening against A549 and PC3 cells. Compounds 6 and 15 exhibited remarkable cytotoxic activities with IC50 values of 0.85 μM and 1.88 μM against A549 cells and IC50 values of 3.63 μM and 1.58 μM against PC-3 cells. Compounds 6, 8, and 15 exhibited promising EGFR inhibition with IC50 values of 42.6, 60.36, and 89.6 nM, respectively, compared to Erlotinib (93.7 %, IC50 = 78.6 nM). Moreover, compound 6 significantly activated apoptotic cell death in A549 cells, increasing the cell apoptosis by 76.7-fold (37.6 % in treated compared to 0.48 % for control) and arresting the cell cycle at S-phase by 32.56 % compared to control 24.03 %. Additionally, compound 6 caused tumor inhibition by 50.1 % of solid tumor in the SEC-bearing mice by interfering with EGFR enzymatic activity via considerable apoptosis-induction, which make it an attractive lead compound for the development of a chemotherapeutics to treat lung cancer.

Discovery and Mechanistic Understanding of a Lipase from Rhizorhabdus dicambivorans for Efficient Ester Aminolysis in Aromatic Amines.

The formation of amide bonds via aminolysis of esters by lipases generates a diverse range of amide frameworks in biosynthetic chemistry. Few lipases have satisfactory activity towards bulky aromatic amines despite numerous attempts to improve the efficiency of this transformation. Here, we report the discovery of a new intracellular lipase (Ndbn) with a broad substrate scope. Ndbn turns over a range of esters and aromatic amines in the presence of water (2 %; v/v), producing a high yield of multiple valuable amides. Remarkably, a higher conversion rate was observed for the synthesis of amides from substrates with aromatic amine rather than aliphatic amines. Molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) studies showcase the mechanism for the preference for aromatic amines, including a more suitable orientation, shorter catalytic distances in the active site pocket and a lower reaction barrier for aromatic than for aliphatic amines. This unique lipase is thus a promising biocatalyst for the efficient synthesis of aromatic amides.

Multifunctional Poly(2-ethyl-2-oxazoline) Copolymers Containing Dithiolane and Pentafluorophenyl Esters as Effective Reactive Linkers for Gold Surface Coatings.

Surface functionalization with biological macromolecules is an important task for the development of sensor materials, whereby the interaction with other biological materials should be suppressed. In this work, we developed a novel multifunctional poly(2-ethyl-2-oxazoline)-dithiolane conjugate as a versatile linker for gold surface immobilization of amine-containing biomolecules, containing poly(2-ethyl-2-oxazoline) as antifouling polymer, dithiolane for surface immobilization, and activated esters for protein conjugation. First, a well-defined carboxylic acid containing copoly(2-ethyl-2-oxazoline) was synthesized by cationic ring-opening copolymerization of 2-ethyl-2-oxazoline with a methyl ester-containing 2-oxazoline monomer, followed by postpolymerization modifications. The side-chain carboxylic groups were then converted to amine-reactive pentafluorophenyl (PFP) ester groups. Part of the PFP groups was used for the attachment of the dithiolane moiety, which can efficiently bind to gold surfaces. The final copolymer contained 1.4 mol% of dithiolane groups and 4.5 mol% of PFP groups. The copolymer structure was confirmed by several analytical techniques, including NMR spectroscopy and size-exclusion chromatography. The kinetics of the PFP ester aminolysis and hydrolysis demonstrated significantly faster amidation compared to hydrolysis, which is essential for subsequent protein conjugation. Successful coating of gold surfaces with the polymer was confirmed by spectroscopic ellipsometry, showing a polymer brush thickness of 4.77 nm. Subsequent modification of the coated surfaces was achieved using bovine serum albumin as a model protein. This study introduces a novel reactive polymer linker for gold surface functionalization and offers a versatile polymer platform for various applications including biosensing and surface functionalization.

Carbon-Nitrogen Bond Formation Using Sodium Hexamethyldisilazide: Solvent-Dependent Reactivities and Mechanisms.

The solvent-dependent reactivity of sodium hexamethyldisilazide (NaHMDS) toward carbon-centered electrophiles reveals reactions that are poorly represented or unrepresented in the literature, including direct aminolysis of aromatic methyl esters to give carboxamides, nitriles, or amidines, depending on the choice of solvent. SNAr substitutions of aryl halides and opening of terminal epoxides are also examined. A combination of 1H and 29Si nuclear magnetic resonance (NMR) spectroscopic studies using [15N]NaHMDS, kinetic studies, and computational studies reveals the complex mechanistic basis of the preferences for simple aryl carboxamides in toluene and dimethylethylamine and arylnitriles or amidines in tetrahydrofuran (THF). A prevalence of dimer- and mixed dimer-based chemistry even starting from the observable NaHMDS monomer in THF solution is notable.

Synthesis of Anilides by Aminolysis of Unactivated Esters using MnCl2 in Combination with strong Bases as Catalyst

AbstractAnilides are often found in pharmaceuticals and active ingredients in crop protection. Although of great interest, the atom‐ and step economic formation of the amide bond between a less nucleophilic aniline with an acid or ester remains still a major challenge. Herein, we report an aminolysis of aromatic and alkyl esters with anilines catalyzed by a readily available catalytic system comprising of an earth‐abundant Mn‐salt in combination with an inexpensive base.

Synthesis of structural analogues of Reversan by ester aminolysis: an access to pyrazolo[1,5-a]pyrimidines from chalcones.

Reversan, a multidrug resistance-associated protein (MRP1) inhibitor described more than a decade ago, is a commercial drug (CAS: 313397-13-6) that has a high price and is six to eight times more potent than known drug transporter inhibitors. However, to date, a complete route for synthesizing pyrazolo[1,5-a]pyrimidine-based Reversan is yet to be published. Herein, the silica gel-mediated synthesis of Reversan and a novel family of its structural analogues (amides) via the microwave-assisted amidation reaction of 3-carboethoxy-5,7-diphenylpyrazolo[1,5-a]pyrimidine (ester) with primary amines is reported. Moreover, a set of this ester-type precursor was obtained using the NaF/alumina-mediated reaction of 5-amino-3-carboethoxy-1H-pyrazole with chalcones, implying a final removal of H2 using Na2S2O8. Both esters and amides were obtained in high yields using heterogeneous catalyst and solvent-free, highly efficient, and scalable synthetic protocols.

6-Halo-2-pyridone as an efficient organocatalyst for ester aminolysis

It was found that 6-halo-2-pyridones catalysed ester aminolysis in which not only reactive aryl esters but also relatively less reactive methyl and benzyl esters could be used as a substrate. The reaction could be performed without strictly dry and anaerobic conditions and the 6-chloro-2-pyridone catalyst could be recovered quantitatively after reaction. The method could be applied to dipeptide synthesis from methyl or benzyl esters of amino acids, where a high enantiomeric purity of the products was maintained. The mechanism involving dual activation of ester and amine substrates through hydrogen bonding between catalyst and substrates is proposed where 6-halo-2-pyridones act as a bifunctional Brønsted acid/base catalyst.

Mechanistic insights into lysine-targeting covalent inhibition through a theoretical study of ester aminolysis.

Development of targeted covalent inhibitors in drug design has a broad and important interest and many efforts are currently being made in this direction. Targeted covalent inhibitors have special relevance in oncology due to the possibilities they offer to overcome the problems of acquired resistance. In recent experiments, lysine-targeting has been envisaged for the irreversible inhibition of the heterodimeric lipid kinase phosphoinositide 3-kinase delta (PI3Kδ). Activated esters have been evaluated and shown to be promising inhibitors of this enzyme, but the reaction mechanisms display specificities that are not yet fully understood. In the present work, we have carried out a theoretical study of the aminolysis reaction of model esters in aqueous solution to gain insights into the corresponding biological processes. We have found that phenolic esters bearing electron-withdrawing groups are particularly reactive. The predicted mechanism involves the formation of a tetrahedral zwitterionic intermediate, which dissociates into an alkoxide and a protonated amide, this charge separation being the driving force for the subsequent proton transfer and final product formation. Structure-reactivity relationships are reported and shown to be a useful tool for evaluating potential inhibitor candidates.

Towards Thermally Reversible Networks Based on Furan-Functionalization of Jatropha Oil.

A novel biobased monomer for the preparation of thermally reversible networks based on the Diels-Alder reaction was synthesized from jatropha oil. The oil was epoxidized and subsequently reacted with furfurylamine to attach furan groups via an epoxide ring opening reaction. However, furfurylamine also reacted with the ester groups of the triglycerides via aminolysis, thus resulting in short-chain molecules that ultimately yielded brittle thermally reversible polymers upon cross-linking via a Diels-Alder reaction. A full-factorial experimental design was used in finding the optimum conditions to minimize ester aminolysis and to maximize the epoxide ring opening reaction as well as the number of furans attached to the modified oil. The optimum conditions were determined experimentally and were found to be 80 °C, 24 h, 1:1 molar ratio, with 50 mol % of LiBr with respect to the modified oil, resulting in 35% of ester conversion, 99% of epoxide conversion, and an average of 1.32 furans/triglyceride. Ultimately, further optimization by a statistical approach led to an average of 2.19 furans per triglyceride, which eventually yielded a flexible network upon cross-linking via a Diels-Alder reaction instead of the brittle one obtained when the furan-functionalization reaction was not optimized.

Thermally Reversible Polymeric Networks from Vegetable Oils.

Low cross-link density thermally reversible networks were successfully synthesized from jatropha and sunflower oils. The oils were epoxidized and subsequently reacted with furfurylamine to attach furan groups onto the triglycerides, preferably at the epoxide sites rather than at the ester ones. Under the same reaction conditions, the modified jatropha oil retained the triglyceride structure more efficiently than its sunflower-based counterpart, i.e., the ester aminolysis reaction was less relevant for the jatropha oil. These furan-modified oils were then reacted with mixtures of aliphatic and aromatic bismaleimides, viz. 1,12-bismaleimido dodecane and 1,1′-(methylenedi-4,1-phenylene)bismaleimide, resulting in a series of polymers with Tg ranging between 3.6 and 19.8 °C. Changes in the chemical structure and mechanical properties during recurrent thermal cycles suggested that the Diels–Alder and retro-Diels–Alder reactions occurred. However, the reversibility was reduced over the thermal cycles due to several possible causes. There are indications that the maleimide groups were homopolymerized and the Diels–Alder adducts were aromatized, leading to irreversibly cross-linked polymers. Two of the polymers were successfully applied as adhesives without modifications. This result demonstrates one of the potential applications of these polymers.

An isophorone-fused near-infrared fluorescent probe with a large Stokes shift for imaging endogenous nitroxyl in living cells and zebrafish.

Nitroxyl (HNO) plays an important role in multiple physiological and pathological processes, but the detailed generation mechanism of the endogenous HNO still remained to explore and perfect further. There is an urgent need to develop an excellent fluorescent probe for selective recognition and sensitive detection of HNO in biological systems. Near-infrared (NIR) fluorescent probes with a large Stokes shift are an ideal tool for bioimaging applications. Here, we have developed a NIR fluorescent probe with a large Stokes shift, namely, NIR-HNO, to monitor HNO in cells and zebrafish. NIR-HNO consists of an isophorone-fused NIR fluorescence reporter and a diphenylphosphinobenzoyl HNO-responsive unit. Based on an aza-ylide intramolecular ester aminolysis reaction, NIR-HNO showed a rapid selective NIR fluorescent turn-on response for HNO, high sensitivity (detection limit was 39.6 nM), and large Stokes shift (265 nm). The biological imaging results indicate that NIR-HNO is a good candidate for imaging of endogenous HNO in living systems.

Enantioselective Formal Synthesis of (+)-Cycloclavine and Total Synthesis of (+)-5-epi-Cycloclavine.

Starting from the commercially available 4-bromoindole, a concise and efficient enantioselective formal synthesis of (+)-cycloclavine (1) in 13 steps with 2.0% overall yield and a total synthesis of (+)-5-epi-cycloclavine (2) in 14 steps with 3.3% overall yield were achieved. Key features of the syntheses include the addition of a Grignard reagent to the C═N/Heck reaction sequence to construct the fused 6-5-6 ring systems, cyclopropanation, an ester aminolysis reaction, and the first example of the construction of a 3-azabicyclo[3,1,0]hexane through an intramolecular [3 + 2] cycloaddition/nitrogen extrusion.

A recoverable dendritic polyamidoamine immobilized TEMPO for efficient catalytic oxidation of cellulose

Polyamidoamine (PAMAM) dendrimers of G1.0 and 2.0 were synthesized by the repeated Michael addition and ester aminolysis of ethylenediamine and methyl acrylate. Through the reductive amination reaction of primary amines in PAMAM and carbonyl groups in 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl (4-oxo-TEMPO), the water-soluble PAMAM immobilized TEMPO (PAMAM-TEMPO) was successfully prepared. The obtained PAMAM-TEMPO was characterized by Fourier transform infrared spectroscopy (FT-IR) and ultraviolet-visible spectrophotometer (UV–vis). PAMAM-TEMPO was used as catalyst instead of free TEMPO for selective catalytic oxidation of primary hydroxyl groups in cellulose with water as reaction medium. The results showed that the catalytic performance of G1.0 PAMAM-TEMPO with 28.8% TEMPO loading was equivalent to free TEMPO. After salting out the supernatant of oxidation mixture, PAMAM-TEMPO was recovered by extraction with N,N-dimethylformamide and reused for further oxidation cycles. No significant reduction in catalytic performance was found after 4 oxidation cycles. The recovery of PAMAM-TEMPO after each cycle was about 90%. By sonication of oxidized cellulose obtained with G1.0 PAMAM-TEMPO as catalyst, the individualized cellulose nanofibers with approximately 10 nm in diameter were successfully prepared. This is the first report on the use of immobilized TEMPO catalysts comparable to the performance of free TEMPO to oxidize cellulose in water.

Amide Synthesis via Aminolysis of Ester or Acid with an Intracellular Lipase

A unique lipase (SpL) from Sphingomonas sp. HXN-200 was discovered as the first intracellular enzyme for the aminolysis of ester or acid to produce amide. Reactions of a series of esters and amines...

Facile crosslinking of polythiophenes by polyethylenimine via ester aminolysis for selective Cu(II) detection in water

Functionalization of π-conjugated polymers is dispensable for solubilization of the rigid and hydrophobic backbones in water. However, polymer aggregation is always present and leads to issues with complication and reproducibility in spectral properties. Herein, we reported a simple and robust method to make a series of conjugated polymer nanostructures by a crosslinking strategy. In favor of multivalency effect, polythionenes with various chain lengths were functionalized with branched polyethylenimine (PEI) via ester aminolysis reaction under mild conditions. Photophysical studies revealed the conjugated backbones could be well stabilized and dispersed in water. By taking advantage of intermolecular recognition interaction between copper ions and cationic PEI, we applied crosslinked polythiophenes as a nano probe at very low concentration (0.01 mg/mL) to fluorescently detect copper ions with high sensitivity up to 10 nM and selectivity over other metal ions in aqueous solutions, without occurrence of detectable aggregates. The overall performance of our nano probes outperforms reported water-soluble polymers-based probes, particularly in probe availability and manipulation as well as selective copper detection capability.

Mechanism for acetic acid-catalyzed ester aminolysis

This paper reports a computational study elucidating reaction mechanism for amide bond formation from esters and amines catalyzed by acetic acid. Two optional mechanisms (namely, classic stepwise and concerted acyl substitution mechanisms) have been studied. Calculation results establish the reaction energy profiles of both mechanisms and locate all the intermediates and transition states in both catalytic cycles. Our results propose that the concerted acyl substitution mechanism may be more likely wherein the formation of CN bond and the cleavage of CO bond occur concurrently without the need of rehybridization of the carbonyl carbon. This is also consistent with the fact that no significant racemization/epimerization were observed in the amide products when asymmetric esters and/or amines were used as the reactants, because concerted acyl substitution mechanism precludes the intermediacy of tetrahedral adducts and the accompanying generation/elimination of new chiral centers. Further discussion implies that the concerted acyl substitution mechanism may widely occur in related amidation reactions in the presence of different types of coupling reagents.

Synthesis of Cuboctahedral CeO2 Nanoclusters and Their Assembly into Cuboid Nanoparticles by Oriented Attachment

AbstractHere, we describe a simple approach to control the oriented attachment process through selective ligand scavenging from the {100} facets of CeO2 nanoclusters. Aggregates of these nanoclusters smaller than 10 nm with controlled shapes and exposed facets were obtained. For the synthesis of the cuboctahedral CeO2 nanoclusters, we developed a solvent‐controlled synthesis approach based on a non‐hydrolytic sol–gel process and used an ester aminolysis reaction to control ligand scavenging from the {100} facets. First‐principle calculations allowed us to understand and interpret, at the atomic level, the effects of shape control on the synthesis. Fine‐tuning of the desired morphologies can be achieved by controlling the values of the surface energies, which leads to the formation of morphologies that the classic growth process does not allow.