N-substituted Maleimides Research Articles

Theoretical Study on Mechanism of Initiation Reaction of Asymmetric Anionic Polymerization of N-Substituted Maleimide with a Zn catalyst

N-Substituted maleimides (RMIs) are polymerized to form optically active polymers by using asymmetric catalyst prepared from an optically active bisoxazoline (Rbox) derivative and dialkylzinc. In the present study, the mechanism of the initiation reaction for an asymmetric anionic polymerization was investigated by use of the Density Functional Theory (DFT) calculations. RMI does not coordinate to Zn2+ during the initiation reaction which proceeds via a mechanism similar to SN2 reactions. The substituents of RMIs and Rboxes give little influence on transition state geometries as well as activation energies. It was confirmed that the initiation reaction is scarcely related to the specific optical rotations experimentally observed.

Synthetic transformations of higher terpenoids: VIII. [4+2]-Cycloaddition reactions of lambertianic acid

The Diels-Alder reaction of lambertianic acid with maleic anhydride occurred in a stereoselective fashion and yielded diastereoisomeric (1R,2S,6R,7R)- and (1S,2R,6S,7S)-exo-adducts. The latter reacted with L-valinol to give the corresponding diterpenoid imides, 4-aza-9-oxabicyclo[2.2.1]dec-8-enes. Reactions of lambertianic acid with N-substituted maleimides in the presence of Lewis acids afforded diastereoisomeric adducts having both exo and endo configuration. Some transformations of the adducts were examined with a view to obtain cantharidin and dihydroisoindole analogs.

New mesogenic maleimide-styrene copolymers via N-oxyl mediated free radical copolymerization

New mesogenic N-substituted maleimide monomer was obtained starting 4-maleimido benzoic acid, hydroquinone and hexadecyloxy benzoic acid by successive Schotten-Bauman condensations. The copolymerization of this monomer in 1:1 ratio with styrene was performed both by stable free radical polymerization (SFRP) and conventional free radical polymerization (CFRP). High molecular weight polymeric material in high conversion and with low polydispersity was obtained under SFRP conditions. By using 1H- and 13C-NMR techniques, structural characteristics of the polymers were evidenced that could sustain the alternating character of the copolymers and the participation of the electron donor–acceptor complex in the propagation step. The copolymers formed a liquid crystal mesophase in the melt. This was ascribed to the strong tendency of the rod-like side groups on the stiff imide ring to order even in 1:1 dilute systems such as the alternating copolymers.

Micellar catalysis of Diels-Alder reactions: substrate positioning in the micelle.

We have studied the kinetics of the Diels-Alder reactions of cyclopentadiene, sorbyl alcohol, and sorbyltrimethylammonium bromide with a series of N-substituted maleimides in micellar media. Micellar rate constants have been determined and were found to be 20-40 times lower than the respective aqueous rate constants. Nevertheless, it was found that upon addition of sodium dodecyl sulfate the observed rate constants could be enhanced up to a factor of about 4.5. The low micellar rate constants can be attributed to the relatively apolar (water-poor) region of the micelle, in which the reactions take place. NMR experiments indicate that the reactants usually reside near the alpha- or beta-CH2 groups of the surfactant molecules in the micelle. Comparison of the micellar rate constants with rate constants in water/1-propanol mixtures suggests a concentration of water of 10-15 M in the micellar region where the diene and dienophile react.

Effect of Amine Structure on Photoreduction of Hydrogen Abstraction Initiators

The photocuring rates of acrylate monomers initiated by abstraction type photoinitiators (benzophenone, isopropylthioxanthone, and N-methylmaleimide) and a series of structurally different tertiary amine combinations are reported. Photo-DSC results confirm that transferable hydrogens on tertiary amines are essential for efficient acrylate polymerization. Laser flash photolysis experiments were carried out to define the electron/proton transfer reactions which occur between excited triplet states of the photoinitiators and tertiary amines. In the case of N-methylmaleimide, an intermediate radical anion was detected for amines with no readily transferable proton. This confirms that the photoreduction of the triplet state of N-substituted maleimides by tertiary amines occurs by an electron/proton transfer when the tertiary amine electron donor has a transferable proton.

Antifouling activities of N-substituted imides: antimicrobial activities and inhibition of Mytilus edulis phenoloxidase.

In the search for novel biodegradable antifouling agents, a series of imides (N-substituted maleimides and succinimides) have been synthesized. A large majority of N-substituted maleimides and succinimides showed an antimicrobial activity toward gram-positive and gram-negative bacteria and fungi of marine origin with minimal inhibition concentrations in the range of 6 to 24 microg/ml. The imides with an alkyl substituent showed higher activities than aromatic analogues, but structure-activity relationships were not clearly established. Some compounds were powerful inhibitors of Mytilus edulis phenoloxidase. This inhibition was noncompetitive as demonstrated with 2 maleimides, a 3-acetoxy succinimide and a succinimide. Thus, this family of products has potential interest as antifouling agents.

Strategies for Covalent Multilayer Growth. 1. Polymer Design and Characterization

We describe the synthesis and characterization of several maleimide−vinyl ether and maleimide−primary alkene alternating copolymers capable of being incorporated into covalently bound multilayer assemblies. Synthetic control over the monomer substituents allows substantial versatility in the choice of layer formation chemistry and in polymer properties. We report on the copolymerization of substituted allyl-, allyloxy-, vinyl-, and vinyloxy- monomers with a variety of N-substituted maleimides. The substituted maleimides were prepared by reaction of maleic anhydride with selected aromatic amines. Polymerization yields are typically in the range of 75−95% consumption of the monomers. 1H NMR, FTIR, and UV−visible spectroscopies were used to characterize the polymers.

Structure-Based Design of Nonpeptidic Thrombin Inhibitors: Exploring the D-Pocket and the Oxyanion Hole

Structure-activity relationships for new members of a class of nonpeptidic, low-molecular-weight inhibitors of thrombin, a key serine protease in the blood coagulation cascade, are described. These compounds, which originate from X-ray-structure-based design, feature a conformationally rigid, bi- or tricyclic core from which side chains diverge into the four major binding pockets (distal D, proximal P, recognition or specificity S1, and oxyanion hole O) at the thrombin active site (Fig. 1). Phenylamidinium is the side chain of choice for the S1 pocket, while the most active inhibitors orient an i-Pr group into the P-pocket (Table 1). The key step in the synthesis of the inhibitors is the construction of the central bi- or tricyclic scaffold by 1,3-dipolar cycloaddition of an in situ prepared azomethine ylide and an N-substituted maleimide (Schemes 1–3, and 8–10). One series of compounds was designed to explore the binding features of the large hydrophobic D pocket. This pocket provides space for lipophilic residues as bulky as benzhydryl groups. A new strategy was developed, allowing introduction of these sterically demanding substituents very late in the synthesis (Schemes 5 and 6). Benzhydryl derivative (±)-2 was found to be the most selective member (Ki (trypsin)/Ki (thrombin)=1200) of this class of nonpeptidic thrombin inhibitors, while the ‘dipiperonyl' analog (±)-3 (Ki=9 nM, 7.60-fold selectivity) displays the highest potency of all compounds prepared so far (Table 1). A second series of inhibitors features side chains designed to orient into the oxyanion hole and to undergo H-bonding with the backbone NH groups lining the catalytic site of the enzyme. Unfortunately, neither activity nor selectivity could be substantially improved by introduction of these substituents (Table 2). Presumably, the high degree of pre-organization and the rigidity of the tightly bound scaffolds prevents the new substituents from assuming a position that would allow favorable interactions in the oxyanion hole. However, the oxyanion hole and the S1′ pocket next to it were found to be capable of accommodating quite large groups, which leaves much room for further exploration.

Synthesis and antimicrobial activities of N-substituted imides

In the field of our research programs concerning novel antimicrobial agents, a series of N-substituted imides was synthesized. These compounds were obtained by cyclization of amido-acids in acetic anhydride/sodium acetate or hexamethyldisilazane/zinc bromide for the hydroxy-aromatic derivatives. The hydroxy-alkyl maleimides were directly prepared by condensation of the corresponding amino-alcohol with maleic anhydride in boiling toluene. Most of N-substituted maleimides showed an interesting antimicrobial activity towards bacteria from the ATCC collection ( Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) but the MIC values for P. aeruginosa were always high (128 μg/ml). The imides with alkyl substituents showed higher activities than aromatic analogues with MIC values in the range of 8–32 μg/ml. Comparatively, succinimides were practically inactive.

Spectrofluorimetric determination of cysteine by 5-maleimidyl-2-( m-methylphenyl)benzoxazole

A new thiol weak-fluorescence probe, 5-maleimidyl-2-( m-methylphenyl)benzoxazole (MMPB), gives a highly fluorescence product in the presence of Cys. In this paper, MMPB has been developed for the fluorimetric determination of cysteine (Cys). At λ ex/ λ em=305.6/425.6 nm, the linear range is from 0 to 3.3×10 −7 mol l −1 and the detection limit ( σ=3) of 6.2×10 −10 mol l −1. The main advantage of this method lies in the relative high selectivity compared with the methods using other N-substituted maleimide type of thiol reagents, in which 0.15-fold (molar ratio) of GSH is allowed and most of other amino acids at 100-fold (molar ratio) level had no obvious effect on the results. The proposed method has been applied to the determination of Cys in real samples.

A new tricyclic ring and a nitrogen–sulfur analogue of the tri-pentagon bowl: cycloaddition reactions of the unstablised 1,3,4-thiadiazolium-3-methanide 1,3-dipole: steric influences on the endo-effect: substituted pyrrolo[2,1-b]-1,3,4-thiadiazole systems: azolium 1,3-dipoles

1,3,4-Thiadiazolium-3-methanide 1,3-dipole 6 and the 2,5-diphenyl and 2,5-dimethyl derivatives, 4 and 5, were generated at −60 °C in dichloromethane. Cycloaddition reactions with substituted alkenes gave many new derivatives of the pyrrolo[2,1-b][1,3,4]thiadiazole ring system. The first examples of a bowl-shaped tricyclic nitrogen-sulfur analogue of the tripentagon bowl, a 3,4,10-triaza-6-thiatricyclo[6,3,0,03,7]undecane ring system were obtained from N-substituted maleimide dipolarophiles. The reactions displayed predominantly endo-stereochemistry but with decreasing size of the substituent at the incipient 7a-fusion bridgehead in the cycloaddition transition state, the extent of exo-cycloaddition increased. The cycloadduct endo ∶ exo ratio was reduced from exclusively endo to ca. 2 ∶ 1 on changing the 1,3-dipole from the 2,5-diphenyl derivative 4 to the unsubstituted case 6. X-Ray crystal structures are reported for 2,7a-diphenyl-5,6,7,7a-tetrahydropyrrolo[2,1-b][1,3,4]thiadiazole-endo-6,7-N-methyldicarboxyimide 7a, 2,7a-diphenyl-5,6,7,7a-tetrahydropyrrolo[2,1-b][1,3,4]thiadiazole-endo-6,7-N-phenyldicarboxyimide 9e and 2,7a-diphenyl-5,6,7,7a-tetrahydropyrrolo[2,1-b][1,3,4]thiadiazole-7-endo-carbonitrile 13.

Direct spectrofluorimetric determination of glutathione in biological samples using 5-maleimidyl-2-( m-methylphenyl) benzoxazole

A new thiol fluorescence probe, 5-maleimidyl-2-( m-methylphenyl)benzoxazole (MMPB) has been developed for the direct determination of reduced glutathione (GSH) in real samples. Compared to the reported N-substituted maleimide type of thiol reagents, the main advantage of MMPB is its rather high selectivity for GSH to cysteine (Cys), which often coexists with GSH in biological samples. Under mild conditions similar to the physiological environment, MMPB reacted with GSH to give a highly fluorescent derivative with the excitation and emission wavelengths of 299.2 and 355.8 nm, respectively. In the presence of 0.40-fold (molar ratio) of Cys, a linear relationship was found in the range of 0–1.62×10 −7 mol l −1 with the detection limit (3 σ) of 3.23×10 −10 mol l −1 for GSH determination. Many other amino acids (100-fold) did not interfere with the determination. Since the molar ratio of Cys to GSH in mammalian tissues and blood does not exceed the value of 0.40:1, the proposed method has been used in the direct determination of GSH in these kinds of biological samples, such as human blood, pig’s liver and heart with the recoveries of 94.3–104.5%

Theoretical Study on Asymmetric Anionic Polymerization Mechanism of N-Substituted Maleimide with Li Complex

光学活性ビスオキサゾリンとアルキルリチウムより調製した不斉触媒を用いて、N-置換マレイミドを重合すると、光学活性ポリマーが生成することが知られている。本研究では非経験的分子軌道法を用い、この不斉アニオン重合の反応機構の検討を行った。開始反応において、触媒の立体配置に基づく不斉誘起がなされるものの、成長反応では不斉触媒の立体配置に影響を受けず、開始反応の立体配置に基づき不斉重合が進行することがわかった。

Photoinitiated polymerization of vinyl ether-based systems

The photoinitiated polymerization of vinyl ether (VE)-based coatings has been studied by real-time infrared (RTIR) spectroscopy. In the presence of diaryliodonium or triarylsulfonium photoinitiators, the cationic polymerization occurs rapidly upon UV-exposure and continues to proceed upon storage in the dark. Increasing the formulation viscosity by introduction of telechelic VE oligomers was found to have a strong slowing down effect on the UV-curing, because of the reduced mobility of the reactive species. VEs proved to be very effective monomers to achieve a fast and extensive curing of dicycloaliphatic epoxides. Similar polymerization profiles have been recorded by RTIR spectroscopy for the two monomers upon UV-exposure, which argues in favor of a copolymerization process between VEs and epoxides. When associated to electron acceptor monomers, like unsaturated esters or N-substituted maleimides, VEs undergo a radical-type copolymerization upon UV-exposure. For the maleate/VE combination, the two monomers were found to disappear at the same rate, whatever the monomer feed composition. The resulting alternating copolymer was shown to be formed by homopolymerization of a donor/acceptor complex. A similar conclusion was drawn from the kinetic data obtained for the maleimide/VE combination which polymerizes readily upon UV-exposure, even in the absence of any added photoinitiator.

Crosslinkable maleimide copolymers for stable NLO properties

Second-order, nonlinear optical polymers based on epoxy-substituted methylvinylisocyanates and N-substituted maleimides were synthesized and characterized with spectral and thermal analysis. The photocrosslinking and thermal-crosslinking reactions of copolymers with different chromophore contents were studied. Thermally induced crosslinking during the poling process, performed at the glass-transition temperature (Tg), was prevented by Tg being decreased through the addition of a plasticizer. Electrooptic coefficients (r33), measured for crosslinked and noncrosslinked systems, had similar absolute values and relaxation dynamics. This behavior was explained in terms of the similar rotational mobility of the chromophore units and the paucity of crosslinking sites. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1589–1595, 2001

Synthesis and Polymerization of Poly(N-substituted maleimide) Macromonomers

Four new types of poly(N-substituted maleimide) macromonomers (RMI, R = N-substituent, phenyl and cyclohexyl) were synthesized from methacryloyloxyethyl isocyanate (MOI) and oligomaleimides. The obtained macromonomers were polymerized in tetrahydrofuran (THF) to afford the corresponding polymacromonomers with degradation temperature of 266-272°C in high yields. The radical polymerizations of the macromonomers with styrene (ST) or methyl methacrylate (MMA) were performed in THF at 60°C to give the corresponding copolymers. The obtained copolymers exhibited higher glass transition temperatures than those of poly(ST) and poly(MMA).

Endo/exo Facial selectivities in cycloaddition reactions of substituted 1,2,3-triazolium-1-methanides, unstabilised 1,3-dipoles, with some alkene dipolarophiles: models for 1,2,3-triazolium-1-aminides: new tetracyclic pyrrolo[1,2-c][1,2,3]benzotriazole structures: azolium 1,3-dipoles

endo/exo Stereochemistry in the cycloaddition reactions of substituted 1,2,3-triazolium-1-aminide and 1,2,3-triazolium-1-methanide 1,3-dipoles has been explored for the dipolarophiles acrylonitrile and N-substituted maleimides. The cycloadditions with acrylonitrile displayed predominant endo-geometry but gave mixtures of endo- and exo-isomers. In contrast N-substituted maleimides gave almost exclusive exo-cycloadducts. The cycloaddition products are novel tri- and tetracyclic structures. Factors affecting endo/exo selectivities are discussed for these systems. Generalisations are not reliable and each 1,3-dipole–dipolarophile pair needs to be carefully considered.

Prototropic Generation of Azomethine Ylides from Esters of N-benzylideneaminoacids, and 1,3-Dipolar Cycloaddition Thereof

Esters of N-benzhydrylideneglycin and -alanine undergo prototropic isomerization to yield azomethine ylides that react stereoselectively with N-substituted maleimides and fumaronitrile affording pyrrole derivatives.

Regioselectivity and endo/exo selectivity in the cycloadditions of the phthalazinium dicyanomethanide 1,3-dipole with unsymmetrical alkene and alkyne dipolarophiles. Unexpected reversals of regiochemistry: a combined experimental and DFT theoretical study

In the reactions of phthalazinium dicyanomethanide 1,3-dipole with electron-poor monosubstituted alkene and alkyne dipolarophiles the dicyanomethanide terminus bonds to the unsubstituted carbon giving 1-substituted pyrrolo[2,1-a]phthalazines. With electron-rich dipolarophiles the regiochemistry is reversed and the products are 2-substituted pyrrolo[2,1-a]phthalazines. An unexpected reversal of regiochemistry occurred with methyl methacrylate, due to a steric effect of the C–Me group, and the main product was 2-exo-methyl-2-endo-methoxycarbonyl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine, 17. endo Cycloadditions were strongly favoured with alkene dipolarophiles containing π bonds in substituents on the alkene unit. With N-substituted maleimides endo products were formed exclusively even when the N-substituent was tBu or adamantyl. Only with alkoxyvinyl ethers were exo-cycloadducts encountered. The mechanisms are discussed in conjunction with DFT calculations. An X-ray crystal structure is reported on endo-N-tert-butyl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine-1,2-dicarboximide, 25.

Functional Copolymers of N-(4-Formyl-Phenoxy-4′-Carbonylphenyl) Maleimide with Styrene

A new reactive N-substituted maleimide monomer containing an aldehyde function, N-(4-formyl-phenoxy-4′-carbonylphenyl) maleimide (MI-CHO), was synthesized. The radical copolymerization of MI-CHO with styrene was performed at 60 °C in the presence of 2,2′-azoisobutyronitrile as an initiator in dimethylsulfoxide. The copolymerization of MI-CHO with styrene yielded the ‘nearly equimolar’ alternating copolymers for the mole fractions of MI-CHO in the feed ranging from 0.2 to 0.7. The monomer reactivity ratios ( r1, r2) in the polymerization of MI-CHO ( M1) with styrene ( M2) and the Alfrey–Price Q1 and e1 parameters were determined. The thermal properties of the copolymers were investigated by using thermogravimetric analysis and differential scanning calorimetry.