Effect Of N-substituents Research Articles

Tailoring amide N-substitution to direct liquid crystallinity in benzanilide-based dimers

The design of liquid crystalline dimers containing tertiary benzanilide groups has proved challenging due to their strong preference for the E amide conformation. In this work we have investigated the effect of different N-substituents on the amide conformation of model benzanilide monomers and found this had effectively no effect on conformation. Based on this observation, we investigated the effect of introducing large, flexible decyl chains at the amide nitrogen and compare their properties to the corresponding benzanilide-based dimers with lateral methyl substituents. The introduction of the decyl chain decreases the melting temperatures, and the tendency to crystallise, promoting glassy behaviour. This allows for nematic behaviour to be seen to much lower temperatures.

Oxidopyridinium Cycloadditions Revisited: A Combined Computational and Experimental Study on the Reactivity of 1-(2-Pyrimidyl)-3-oxidopyridinium Betaine.

To investigate the effect of N-substituents on their reactivity and selectivity of oxidopyridinium betaines, we performed density functional theory (DFT) calculations of model cycloadditions with N-methylmaleimide and acenaphthylene. The theoretically expected results were compared with the experimental results. Subsequently, we demonstrated that 1-(2-pyrimidyl)-3-oxidopyridinium can be used for (5 + 2) cycloadditions with various electron-deficient alkenes, dimethyl acetylenedicarboxylate, acenaphthylene, and styrene. In addition, a DFT analysis of the cycloaddition of 1-(2-pyrimidyl)-3-oxidopyridinium with 6,6-dimethylpentafulvene suggested the possibility of pathway bifurcations involving a (5 + 4)/(5 + 6) ambimodal transition state, although only (5 + 6) cycloadducts were experimentally observed. A related (5 + 4) cycloaddition was observed in the reaction of 1-(2-pyrimidyl)-3-oxidopyridinium with 2,3-dimethylbut-1,3-diene.

Selective and Efficient Gold Extraction from E-Waste by Pyrrolidinium-Based Ionic Liquids with Various N-Substituents

With environmental problems and a shortage of resources, it is urgent to recover gold from electronic waste (e-waste). Meanwhile, it is necessary to explore the relationships between the structures and extraction performances of ionic liquids (ILs) to further improve the extraction capacities of ILs for gold. Herein, three pyrrolidinium-based ILs with various N-substituents were synthesized for solvent-free extraction of Au(III). The three pyrrolidinium-based ILs exhibited ultrahigh extraction capacities for Au(III) with the order of [Pyr-EA][NTf2] (524.6 mg·g–1) > [Pyr-Bu][NTf2] (457.3 mg·g–1) > [Pyr-C2OC2][NTf2] (403.5 mg·g–1). The effects of N-substituents on extraction performances were quantitatively investigated by electrostatic potential (ESP) and quantitative NMR. Among them, the ester group (−COOR) is the most beneficial to the extraction process, which is associated with an increased ESP value and boosted hydrophobicity. Notably, [Pyr-EA][NTf2] displayed outstanding selectivity in multimetal solutions; especially, it could selectively and efficiently extract Au(III) from the actual CPU. Furthermore, [Pyr-EA][NTf2] possesses significant reuseability and can maintain superior extraction efficiency of 84.3% after five cycles. These excellent performances together with low cost ($0.44·g–1 [Pyr-EA][NTf2]) and considerable profit ($29.72·g–1 [Pyr-EA][NTf2]) confirmed that [Pyr-EA][NTf2] is a promising prospect for sustainable recovery of gold from e-waste.

Deciphering the cooperative effect of base and N-substituents on the origin of enantioselectivity switching for Mannich reactions of glycinate by carbonyl catalysts

Chiral carbonyl catalysis has developed rapidly in recent years and provided reliable methods for the preparation of chiral molecules, while the effective catalyst model remains unclear, and the size effect of catalyst substituents on the reversal of enantioselectivity needs to be clarified. Herein, the N-quaternized pyridoxals catalyzed asymmetric Mannich reactions of glycinate were studied to obtain fundamental understanding on these issues. The calculations show that the dual activation model aided by base NaHCO3, which contributes additional beneficial OH···N and Na···O/N interactions, is energetically more favorable than the base-free models, and the multiple interactions among the three entities, the base NaHCO3, the catalyst, and the imine substrate, in the enantiocontrolling transition states (TS) are responsible for the high enantioselectivity, rendering the preferred chiral product of (R,R)-4 in reaction I and (S,S)-4 in reaction II. The origin of the reversed enantioselectivity upon the substitution of a methyl for the H on the N-functional group in the catalyst was analyzed, and was attributed to the variation of the preferred orientation of NaHCO3 from facing-up to facing-down owing to the substitution, which created governing interactions to drive the reversal of the enantioselectivity in the such asymmetric Mannich reactions. This understanding of the activation model and the reversed stereoinduction sheds light on the effective chiral N-quaternized pyridoxal catalyst form and role of base on the enantioselectivity, and offers new insights for the future design of related asymmetric catalysts and Mannich reactions.

Deciphering the Cooperative Effect of Base and N-Substituents on the Origin of Regioselectivity Switching for Mannich Reactions of Glycinate by Carbonyl Catalysts

Deciphering the Cooperative Effect of Base and N-Substituents on the Origin of Regioselectivity Switching for Mannich Reactions of Glycinate by Carbonyl Catalysts

Electronic effects on protective mechanism of electropolymerized coatings based on N-substituted aniline derivatives for mild steel in saline solution

Polyaniline (PANI), poly(N-methylaniline) (PNMA) and poly(N-formylanilide) (PNFA) coatings were fabricated over mild steel via chronoamperometric strategy in oxalate electrolyte. Scanning electron microscope (SEM), attenuated total reflection infrared spectroscopy (ATR-IR) and X-ray photoelectron spectroscopy (XPS) evidenced the polymerization of monomers. Anticorrosive effects of PANI, PNMA and PNFA coatings for steel substrate were evaluated during long-term immersion in 3.5% NaCl solution by potentiodynamic polarization, electrochemical impedance spectroscopy (EIS) and frequency modulation (EFM). Morphological variation for coated specimens before and after immersion in NaCl solution was also monitored by SEM and atomic force microscope (AFM). Differentiated protection capability were observed for three coatings following the sequence of PNFA > PNMA > PANI. Through electrochemical and interfacial analyses, electroactivity and physical barrier were ascertained as the critical factors, especially the former one, in the long-term protection capacity. Electroactivity was distinguished by the elevated apparent current density from non-destructive EFM measurements. Furthermore, electron-donation and -withdrawal effects of N-substituents played an essential role in coating electroactivity. In detail, N-substituents improved the anodic protection and physical barrier of PNMA and PNFA coatings. Particularly, formyl with electron-withdrawal effect reinforced the anodic protection and thus the superior the anticorrosion efficiency of PNFA for underlying steel.

Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives.

We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the N-substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially different positions compared with those in the alkylamine and amide moieties. Among the tested compounds, cyclopropylsulfonamide 9f (SYK-839) was the most potent full inverse agonist for the DOR, whereas phenethylsulfonamide 9e (SYK-901) showed full DOR agonist activity with moderate potency. These NTI derivatives are expected to be useful compounds for investigation of the molecular mechanism inducing these functional activities.

The effect of N-substituent on the relative thermodynamic stability of unionized and zwitterionic forms of α-diphenylphosphino-α-amino acids

The relative thermodynamic stability of unionized and zwitterionic forms of α-phosphino-α-amino acids is governed by the substituent R at the nitrogen atom, namely, (het)aryl substituents favour the formation of the unionized form RHNCH(PPh2)COOH, while in the case of alkyl analogues the zwitterions RH2N+CH(PPh2)COO− predominate. The experimentally observed trends have been supported by quantum-chemical calculations. The synthesis and X-ray crystal structure analysis of a new unionized α-phosphino-α-amino acid [α-diphenylphosphino-N-(2-methoxycarbonylphenyl) glycine] are reported.

Effect of N-substituent in 4-styrylpyridinium dyes on their binding to DNA

4-Styrylpyridinium dyes containing N-methyl and N-(3-pyridiniopropyl) substituents have been prepared and characterized by optical and CD spectroscopy. These compounds demonstrate affinity to calf thymus DNA, with dye–DNA binding mode being different for various N-substituents.

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities.

N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC50 41 µM and 138 µM, respectively, using DNJ as reference (IC50 134 µM). On the other hand, β-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 µM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 µM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 µM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-glucosidase inhibitors of the series with IC50 of 4 µM.

Role of N-substituents of maleimides on penultimate unit effect for sequence control during radical copolymerization

Radical copolymerization of N-substituted maleimides (RMIs) and olefins provides AAB sequence-controlled copolymers by penultimate unit (PU) control. In this study, we investigated the steric, resonance, and polar effects of N-substituents on sequence control during copolymerization of RMIs as the M2 monomer with diisobutene (DIB) and d-limonene (Lim) as the M1 monomer in chloroform at 60 °C. The monomer reactivity ratios (i.e., r2 (= k22/k21), r12 (= k122/k121), and r22 (= k222/k221)) were determined based on the terminal and PU models using a nonlinear least-squares method. For the copolymerization of RMIs with DIB, the introduction of a bulky N-alkyl group suppressed the PU effect and led to the formation of alternating copolymers. The copolymerization of N-phenylmaleimides with o- and p-substituents was also investigated to reveal the steric, resonance, and polar effects of the substituents. In conclusion, less bulky and more electron-donating substituents effectively induced the PU effect during the radical copolymerization of RMIs and olefins. Radical copolymerization of N-substituted maleimides and olefins provides AAB sequence-controlled copolymers by penultimate unit control. In this study, we investigated the steric, resonance, and polar effects of N-substituents on sequence control during copolymerization of various N-substituted maleimides with diisobutene and limonene in chloroform at 60 °C, and concluded that less bulky and more electron-donating substituents effectively induced the penultimate unit effect. We also demonstrated that 2:1 sequence-controlled maleimide copolymers was efficiently produced during radical copolymerization of limonene and N-phenylmaleimides with an electron-donating substituent.

Catalytic activity of chiral chelating N-heterocyclic carbene palladium complexes towards asymmetric allylic alkylation

The catalytic activity of a series of chiral heteroaryl coordinated chelating N-heterocyclic carbene (NHC) palladium complexes towards asymmetric allylic alkylation (AAA) were presented here. The effects of different N-substituents, NHC backbones and chelate rings on the catalytic activity and the enantioselectivity of the alkylation of (E)-1,3-diarylallyl acetates with dialkyl malonate were investigated. The results showed that, under the optimized conditions, complexes 3a, 3b, and 3i carrying the pyridinyl-coordinated five-membered chelate ring showed high catalytic activity and chiral induction efficiency. The corresponding alkylated products were obtained in high yields with moderate ee. Furthermore, it was found that the substituents of (E)-1,3-diarylallyl acetates and the type of the nucleophile affect the results as well.

Manipulation of Glutathione-Mediated Degradation of Thiol-Maleimide Conjugates.

The retro Michael-type addition and thiol exchange of thioether succinimide click linkages in response to thiol-containing environments offers a novel strategy for the design of glutathione-sensitive degradable hydrogels for controlled drug delivery. Here we characterize the kinetics and extent of the retro Michael-type addition and thiol exchange with changes in both the p Ka of the thiols and the identity of N-substituents of maleimides. A series of N-substituted thioether succinimides were prepared through typical Michael-type addition. Model studies (1H NMR, HPLC) of 4-mercaptophenylacetic acid (MPA, p Ka 6.6) conjugated to N-ethyl maleimide (NEM), N-phenyl maleimide (NPM), or N-aminoethyl maleimide (NAEM) and then incubated with glutathione showed half-lives of conversion from 3.1 to 18 h, with extents of conversion from approximately 12% to 90%. The variations in the rates of exchange and hydrolytic ring opening appear to be mediated by resonance effects, electron-withdrawing capacity of the N-substituted moiety, as well as the potential for intramolecular catalytic hydrogen bonding of amine substituents with water (particularly in the case of ring opening). Further model studies of 4-mercaptohydrocinnamic acid (MPP, p Ka 7.0) and N-acetyl-l-cysteine (NAC, p Ka 9.5) conjugated to selected N-substituted maleimides and then incubated with glutathione showed half-lives of conversion from 3.6 to 258 h, with extents of conversion from approximately 1% to 90%. A higher p Ka of the thiol decreased the rate of the exchange reaction and limited the impact of other electronic effects of N-substituents on the extents of conversion. Additional factors affecting the conversion kinetics were studied on NEM conjugates. The kinetics of the retro Michael-type addition and exchange reaction were not hindered by thiol traps of lower p Ka, but were retarded in conditions of lower pH. These studies shed light into details of thiol and maleimide design that could be used to tune the rates of degradation of drug and polymer conjugates for a variety of applications.

Combined Effects of Backbone and N-Substituents on Structure, Bonding, and Reactivity of Alkylated Iron(II)-NHCs.

Iron and N-heterocyclic carbenes (NHCs) have proven to be a successful pair in catalysis, with reactivity and selectivity being highly dependent on the nature of the NHC ligand backbone saturation and N-substituents. Four (NHC)Fe(1,3-dioxan-2-ylethyl)2 complexes have been isolated and spectroscopically characterized to correlate their reactivity to steric effects of the NHC from both the backbone saturation and N-substituents. Only in the extreme case of SIPr where NHC backbone and N-substituent steric effects are the largest is there a major structural perturbation observed crystallographically. The addition of only two hydrogen atoms is sufficient for a drastic change in product selectivity in the coupling of 1-iodo-3-phenylpropane with (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide due to resulting structural perturbations to the precatalyst. Mössbauer spectroscopy and magnetic circular dichroism enabled the correlation of covalency and steric bulk in the SIPr case to its poor selectivity in alkyl-alkyl cross-coupling with iron. Density functional theory calculations provided insight into the electronic structure and molecular orbital effects of ligation changes to the iron center. Finally, charge donation analysis and Mayer bond order calculations further confirmed the stronger Fe-ligand bonding in the SIPr complex. Overall, these studies highlight the importance of considering both N-substituent and backbone steric contributions to structure, bonding, and reactivity in iron-NHCs.

Dependence of color change of vinylethylene carbonate copolymers having N-substituted maleimides on chemical structure by acid-base switching in solution and solid state

The copolymers of vinylethylene carbonate (VEC) and N-substituted maleimide (NMI) having various N-substituents were synthesized by radical polymerization. The color of P(VEC/NMI)s changed from colorless to red reversibly based on the acid-base switching in solution and solid state. Furthermore, the color depth of P(VEC/NMI) solution and powder changed systematically depending on the electric effect of N-substituents. However, the copolymers of styrene and NMIs barely changed under the same conditions. These color change and depth behaviors of NMI copolymers were analyzed in detail by UV–vis and IR spectra, and the results were also supported by the density functional theory (DFT) calculation for the model compound of maleimide tautomers. Additionally, the powder color of P(VEC/NMI)s changed reversibly before and after exposure to cigarette smoke and vinegar.

Efficient stereochemical communication in phosphine-amine palladium-complexes: Exploration of N-substituent effects in coordination chemistry and catalysis

Six-membered chelate complexes of type [Pd(1a-e)Cl2] (2a-e) and [Pd(1a-e)(η3-PhCHCHCHPh)]BF4 (3a-e) of a series of systematically varied chiral phosphine-amine ligands (S,S)-Ph2PCH(CH3)CH2CH(CH3)NHR 1a-e (R = benzyl 1a, R = ethyl 1b, R = (S)-α-phenylethyl 1c, R = isopropyl 1d, R = methyl 1e) have been studied. The complexes 2a-e were characterized by X-ray crystallography, DFT analysis and in solution by 1D and 2D NMR spectroscopy. A very good correlation has been observed between the steric demand of the N-substituent and the distortion of the chelate. Furthermore, it has been proved that sterically more demanding N-substituents are capable of distorting the chelate to a larger extent along one single, well defined conformational pathway. The careful variation of the N-substituent thus allows a precise stereochemical fine tuning of the metal's coordination sphere. As a substantiation of this concept, the investigation of complexes 3a-e revealed that the exo/endo ratio as well as the twisting of the allyl moiety around the Pd-allyl axis can easily be modified by the proper choice of the nitrogen substituent. Furthermore, Pd-catalysts with ligands 1a-e provided high enantioselectivities (up to 96%) in asymmetric allylic alkylation reactions.

Reactions of Isocyanides with Metal Carbyne Complexes: Isolation and Characterization of Metallacyclopropenimine Intermediates.

η2-Iminoketenyl species have often been postulated as the intermediates in nucleophile-induced carbyne-isocyanide C-C coupling processes. However, such species are elusive. Here we report direct formation of η2-iminoketenyl complexes from reactions of metallapentalyne with isocyanides. Our studies show that steric effects of N-substituents of the isocyanides play an important role in the stability of the three-membered metallacycles of the η2-iminoketenyl complexes. Sterically bulky isocyanides, such as tert-butyl or 1-adamantyl isocyanides, inhibit bending at the isocyanide nitrogen atoms, a requirement for formation of η2-iminoketenyl structures. Reactions of metallapentalyne with excess isocyanide allow the metal-bridged metallaindene derivativesto be isolated as a result of the isocyanide insertion into the M-Cα σ bond of metallapentalyne.

ChemInform Abstract: A Bicyclic N‐Heterocyclic Carbene as a Bulky but Accessible Ligand: Application to the Copper‐Catalyzed Borylations of Aryl Halides.

Imidazol-2-ylidene and imidazolin-2-ylidene are frequently employed as the core structures of N-heterocyclic carbene (NHC) ligands, because these have two nitrogen sites adjacent to carbenic carbons. The electronic and steric effects of N-substituents to a bound metal have been aptly studied, and bulky substituents have commonly been introduced on nitrogen(s). However, too much bulkiness can sometimes result in an ineffectiveness of the hindered substrates. In this study, we thoroughly compared our original bicyclic NHC, which has bulky substituents on its noncarbenic carbons, with ubiquitous NHC ligands to probe its steric properties. A well-defined bicyclic NHC-CuCl complex was successfully synthesized and applied to the copper-catalyzed borylations of aryl halides at ambient temperature. A bicyclic NHC-CuCl proved to be a better catalyst than commonly used NHC ligand-Cu complexes, particularly for sterically hindered substrates, which suggested that the bicyclic NHC ligand offered a bulky but accessible environment to the bound copper.

A Bicyclic N-Heterocyclic Carbene as a Bulky but Accessible Ligand: Application to the Copper-Catalyzed Borylations of Aryl Halides.

Imidazol-2-ylidene and imidazolin-2-ylidene are frequently employed as the core structures of N-heterocyclic carbene (NHC) ligands, because these have two nitrogen sites adjacent to carbenic carbons. The electronic and steric effects of N-substituents to a bound metal have been aptly studied, and bulky substituents have commonly been introduced on nitrogen(s). However, too much bulkiness can sometimes result in an ineffectiveness of the hindered substrates. In this study, we thoroughly compared our original bicyclic NHC, which has bulky substituents on its noncarbenic carbons, with ubiquitous NHC ligands to probe its steric properties. A well-defined bicyclic NHC-CuCl complex was successfully synthesized and applied to the copper-catalyzed borylations of aryl halides at ambient temperature. A bicyclic NHC-CuCl proved to be a better catalyst than commonly used NHC ligand-Cu complexes, particularly for sterically hindered substrates, which suggested that the bicyclic NHC ligand offered a bulky but accessible environment to the bound copper.

Syntheses and Catalytic Ability of Sugar-Incorporated N-Heterocyclic Carbene Pincer Pd Complexes Possessing Various N-Substituents

Abstract Exploration of catalysts for organic reactions in water, which is a nontoxic and nonexplosive liquid, has been studied to achieve environmentally friendly chemical processes. For such a purpose, we utilized click chemistry to incorporate sugar units into transition-metal complexes affording water-soluble complexes. In this study, a series of palladium complexes with C–C–N pincer ligands, each of which consisted of two N-heterocyclic carbenes (NHCs) and a triazole moiety with a d-glucopyranosyl unit were synthesized. These complexes possess various N-substituents, namely, methyl, isopropyl, benzyl, or d-glucopyranosyl units on the terminal NHC moieties. The diastereoselectivity in the formation of the complexes and their catalytic ability toward the Suzuki–Miyaura cross-coupling reactions in water exhibited clear N-substituent effects. The tridentate ligand with an acetylated d-glucopyranosyl unit on the terminal NHC moiety led to high diastereoselectivity in the formation of its complex, while each of the other ligands with achiral substituents on the terminal NHC units afforded both of the diastereomers with low selectivity. Catalytic reactions using the complexes were examined for the Suzuki–Miyaura cross-coupling reactions of phenylboronic acid and 4′-bromoacetophenone in water. The complex possessing an isopropyl group on the terminal NHC moiety exhibited excellent catalytic activity with TON (800000), which is comparable to the best value reported for a similar reaction.