Bio-inspired quinone catalysis

Inspired by quinone-redox enzymes, small molecular quinone catalysts have been developed to promote C-H functionalization of amines. Recent efforts in this area have been summarized.     

Model Studies of TTQ-Containing Amine Dehydrogenases

The reactions of a TTQ model compound [1, 3-methyl-4-(3'-methylindol-2'-yl)indole-6,7-dione] with several amines have been investigated in organic media to obtain mechanistic information on the action of quinoprotein methylamine and aromatic amine dehydrogenases. It has been found that compound 1 acts as an efficient catalyst for the autorecycling oxidation of benzylamine by molecular oxygen in CH(3)OH. In order to evaluate the oxidation mechanism of amines by 1, the product analyses and kinetic studies have been carried out under anaerobic conditions. In the first stage of the reaction of 1 with amines, 1 is converted into an iminoquinone-type adduct (so-called substrateimine), which was isolated and characterized by using cyclopropylamine as a substrate. The observed NOE of the isolated product indicates clearly that the addition position of the amine is C-6 of the quinone. The molecular orbital calculations suggest that the thermodynamic stability of the carbinolamine intermediate is a major factor to determine such regioselectivity; the C-6 carbinolamine is more stable than the C-7 counterpart by 2.9 kcal/mol. The reactivity of several primary amines and the electronic effect of the p-substituents of benzylamine derivatives in the iminoquinone formation suggest that the addition step of the amine to the quinone is rate-determining. When amines having an acidic alpha-proton such as benzylamine derivatives are employed as substrates, formation of the iminoquinone adduct was followed by rearrangement to the productimine. The kinetic analysis has revealed that this rearrangement consists of noncatalyzed and general base-catalyzed processes. Large kinetic isotope effects of 7.8 and 9.2 were observed for both the noncatalyzed and general base-catalyzed processes, respectively, since these steps involve a proton abstraction from the alpha-position of the substrate. In the reaction with benzhydrylamine, the product imine was isolated quantitatively and well characterized by several spectroscopic data. In the case of benzylamine, the product imine is further converted into the aminophenol derivative by the imine exchange reaction with excess benzylamine. These results indicate clearly that the amine oxidation by compound 1 proceeds via a transamination mechanism as suggested for the enzymatic oxidation of amines by TTQ cofactor.     

Iridium complex-catalyzed allylic amination of allylic esters

Iridium complex-catalyzed allylic amination of allylic carbonates was studied. The solvent strongly affected the catalytic activity. The use of a polar solvent such as EtOH is essential for obtaining the products in high yield. The reaction of (E)-3-substituted-2-propenyl carbonate and 1-substituted-2-propenyl carbonate with pyrrolidine in the presence of a catalytic amount of [Ir(COD)Cl](2) and P(OPh)(3) (P/Ir = 2) gave a branch amine with up to 99% selectivity. Both secondary and primary amines could be used for this reaction. When a primary amine was used, selective monoallylation occurred. No diallylation product was obtained. The reaction of 1,1-disubstituted-2-propenyl acetate with amines exclusively gave an alpha,alpha-disubstituted allylic amine. This reaction provides an alternative route to the addition of an organometallic reagent to ketimines for the preparation of such amines. The reaction of (Z)-3-substituted-2-propenyl carbonate with amines gave (Z)-linear amines with up to 100% selectivity. In all cases, no (E)-linear amine was obtained. The selectivities described here have not been achieved in similar palladium complex-catalyzed reactions.     

Efficient ruthenium-catalyzed aerobic oxidation of amines by using a biomimetic coupled catalytic system

Efficient aerobic oxidation of amines was developed by the use of a biomimetic coupled catalytic system involving a ruthenium-induced dehydrogenation. The principle for this aerobic oxidation is that the electron transfer from the amine to molecular oxygen occurs stepwise via coupled redox systems and this leads to a low-energy electron transfer. A substrate-selective ruthenium catalyst dehydrogenates the amine and the hydrogen atoms abstracted are transported to an electron-rich quinone (2a). The hydroquinone thus formed is subsequently reoxidized by air with the aid of an oxygen-activating [Co(salen)]-type complex (27). The reaction can be used for the preparation of ketimines and aldimines in good to high yields from the appropriate corresponding amines. The reaction proceeds with high selectivity, and the catalytic system tolerates air without being deactivated. The rate of the dehydrogenation was studied by using quinone 2a as the terminal oxidant. A catalytic cycle in which the amine promotes the dissociation of the dimeric catalyst 1 is presented.     

Similarities and differences between azomethines and ketimines: synthesis, materials characterization and structure of novel imines compounds

Imines (ketimines and azomethines) derived from p-dibenzoylbenzene (DB) and terephthalic aldehyde (TA) and two aromatic amines: aniline and 2,6-dimethylaniline have been investigated. Compounds were synthesized via condensation of amines with carbonyl monomers in DMA or amine solution. When using DMA as a solvent, azomethines with high yields were obtained. On the other hand, the amines used as a monomers served also as an effective solvent for the synthesis of the ketanils. This different reactivity of the aldehyde and ketone groups in DMA and in amine depends on the dehydration mechanism being dominated by a kinetic process or thermodynamic one. On the basis of FTIR, 13C and 1H NMR, UV-vis spectra, thermal characteristic and theoretical calculations conclusions are drawn regarding the similarities and differences between azomethines and ketimines.     

Quantitative determination of 22 primary aromatic amines by cation-exchange solid-phase extraction and liquid chromatography–mass spectrometry

Primary aromatic amines (PAAs) have been broadly studied due to their high toxicity. In this work a method for the analysis of 22 PAAs in aqueous simulants has been developed. The method is based on a solid-phase extraction step using cation-exchange cartridges and the subsequent analysis of the extracts by ultra-high-performance liquid chromatography with mass spectrometric detection. The recoveries obtained for all the amines analyzed ranged between 81 and 109%, linear range was between 0.03 and 75 μg L⁻¹, with the RSD values between 4.5 and 13.4% and an average value of 7.5% and limits of detection at μg L⁻¹ level. The method has been applied to two real samples obtained from migration experiments of polyurethane based laminates to simulant B (water with 3% (w/v) acetic acid) which represents the worst case for the migration of aromatic amines. The main amines found in both samples were methylenedianiline isomers, obtained from the corresponding residual diisocyanates used during polyurethane adhesive polymerization. The total amine concentration found was 26 and 6.3 μg of aniline equivalents per kg of food simulant.     

Quinone‐Catalyzed Selective Oxidation of Organic Molecules

Quinones are common stoichiometric reagents in organic chemistry. Para‐quinones with high reduction potentials, such as DDQ and chloranil, are widely used and typically promote hydride abstraction. In recent years, many catalytic applications of these methods have been achieved by using transition metals, electrochemistry, or O₂ to regenerate the oxidized quinone in situ. Complementary studies have led to the development of a different class of quinones that resemble the ortho‐quinone cofactors in copper amine oxidases and mediate the efficient and selective aerobic and/or electrochemical dehydrogenation of amines. The latter reactions typically proceed by electrophilic transamination and/or addition‐elimination reaction mechanisms, rather than hydride abstraction pathways. The collective observations show that the quinone structure has a significant influence on the reaction mechanism and has important implications for the development of new quinone reagents and quinone‐catalyzed transformations.     

脂肪胺的高效液相色谱分离及质谱鉴定

 采用新型荧光试剂1,2-苯并-3,4-二氢咔唑-9-乙酸(BCAA)为柱前衍生化试剂,在Hypersil BDS-C18色谱柱上,通过梯度洗脱对12种游离脂肪胺进行了分离和在线质谱定性。以乙腈为溶剂,1-乙基-3-(3-二甲氨基丙基)环己碳二亚胺(EDAC)为缩合剂,在50 ℃条件下衍生反应15 min后获得稳定的荧光产物。激发波长和发射波长分别为333 nm和390 nm。采用大气压化学电离源(APCI)的正离子模式,实现了土壤和污水中脂肪胺的定性及其含量的测定。脂肪胺的线性相关系数大于0.9993,检测限为12~28 fmol。     

Inhibition of polymerization of methyl methacrylate by an ortho-benzoquinone-amine system

The kinetic features of the bulk polymerization of MMA in the presence of sterically hindered ortho-benzoquinones and the tertiary amines N,N-dimethylaniline and N,N-dimethylisopropanolamine have been studied. The irradiation of solutions of quinones and amines in MMA with visible light causes inhibition of the thermal polymerization of MMA, with the effects of quinones and amines being synergistic. The effect of inhibition is enhanced as the steric shielding of carbonyl groups of ortho-benzoquinone by substituents becomes weaker. The dependence of the induction period on the redox potentials of quinones passes through a maximum. It is shown that inhibition involves oxyphenoxyl radicals arising from the interaction of the original quinone with the product of its photoreduction in the presence of amines, pyrocatechol. The inhibiting effect depends on the concentration ratio of quinone and pyrocatechol and the nature of amine. When quinone is in excess with respect to pyrocatechol, additional inhibition of polymerization is observed and the rate of quinone consumption during the induction period is increased.     

Fluorimetric method for the determination of long-chain amines in water

A method is presented for the determination of long-chain quaternary ammonium salts, tertiary amines and secondary amines in water or aqueous raffinates, based on their extraction and fluorimetric determination as amine salts with Eosine Yellowish in toluene-hexanol (4:1) as solvent. No interferences were obtained from metal ions, or chloride, nitrate or phosphate ions when a back-washing method was applied to the sample extract. The method allows the determination of long-chain tertiary amines down to 4 ppM.     

Effect of amine nature on reaction mechanism: aminolyses of o-4-nitrophenyl thionobenzoate with primary and secondary amines

Pseudo-first-order rate constants (k(obs)) have been measured spectrophotometrically for reactions of O-4-nitrophenyl thionobenzoate (2) with a series of primary and acyclic secondary amines. The plots of k(obs) vs amine concentration are linear for the reaction of 2 with primary amines. The slope of the Br?nsted-type plot for the reaction of 2 with primary amines decreases from 0.77 to 0.17 as the amine basicity increases, indicating that the reaction proceeds through a zwitterionic addition intermediate in which the rate-determining step changes from the breakdown of the intermediate to the reaction products to the formation of the intermediate as the amine basicity increases. On the other hand, for reactions with all the acyclic secondary amines studied, the plot of k(obs) vs amine concentration exhibits an upward curvature, suggesting that the reaction proceeds through two intermediates, e.g., a zwitterionic addition intermediate and an anionic intermediate. The microscopic rate constants (k(1), k(-)(1), k(2), and k(3) where available) have been determined for the reactions of 2 with all the primary and secondary amines studied. The k(1) value is larger for the reaction with the primary amine than for the reaction with the isobasic acyclic secondary amines, while the k(-)(1) value is much larger for the latter reaction than for the former reaction. The k(3) value for the reaction with secondary amine is independent of the amine basicity. The small k(2)/k(-)(1) ratio is proposed to be responsible for the deprotonation process observed in aminolyses of carbonyl or thiocarbonyl derivatives.     

Sensitive determination of aliphatic amines in water by high-performance liquid chromatography with chemiluminescence detection

A sensitive method has been developed for liquid chromatographic determination of short aliphatic amines in water samples. Analytes are preconcentrated and dansylated on solid sorbents (C18 solid-phase extraction cartridges). The dansyl derivatives are chromatographed and post-column mixed with peroxyoxalate (TCPO) and H2O2 in order to perform chemiluminescence detection. Optimal results have been obtained using a sample volume of 5 ml. The method has been applied to the quantification or screening of several aliphatic amines: methylamine, ethylamine, butylamine, diethylamine, pentylamine and hexylamine. The screening procedure has been developed including also polyamines (putrescine, cadaverine, spermidine and spermine). The results obtained by using chemiluminescence (CL) detection have been compared with other detection systems (fluorescence and UV). The sensitivity can increase from 3 to 75 times respect UV detection and from 2 to 10 times respect fluorescence detection depending on the amine. The detection limits achieved were between 0.15 and 0.9 microg/l.     

Spectrophotometric determination of some aromatic amines

A method for spectrophotometric determination of four aromatic amines is described. The method is based on the reaction between the amine and the colorless Fe(III)-ferrozine complex. The amine reduces iron from Fe(III) to Fe(II) which forms a violet colored complex with ferrozine. The method is suitable for to the determination of 1,4-phenylenediamine, 2,4-diaminotoluene, 8-aminoquinoline and 2-amino-3-hydroxypyridine. The effect of different factors such as; pH, stability of the complex, temperature, ferrozine concentration, Fe(III) concentration and methanol concentration have been studied. The composition of the complex as well as the tolerance amount of other amines have been reported. Maximum absorbance is at 562 nm and Beer's law is obeyed over the ranges 0.17-1.6 ppm for 1,4-phenylenediamine, 0.45-3.7 ppm for 2,4-diaminotoluene, 0.51-3.4 ppm for 8-aminoquinoline and 0.53-4.4 ppm for 2-amino-3-hydroxypyridine. The obtained molar absorbtivities were 4.7x10(4), 2.0x10(4), 1.6x10(4), 1.5x10(3) l mol(-1) cm(-1) respectively.     

Monitoring of aromatic amines by HPLC with electrochemical detection: comparison of methods for destruction of carcinogenic aromatic amines in laboratory wastes

A new chemical method for destruction of carcinogenic aromatic amines in laboratory wastes has been developed. The method is based on enzymatic oxidation of the amines in solution (with hydrogen peroxide and horseradish peroxidase), followed by oxidation of the solid residues with permanganate in sulphuric acid medium. To monitor the efficiency of destruction, a reversed-phase HPLC system has been developed, with voltammetric detection with a carbon-fibre detector, which is substantially more sensitive (detection limits from a few ng down to a few pg of amine) than the commonly used ultraviolet photometric detection. It has been demonstrated that the proposed method of destruction is highly efficient (99.8% destruction).     

Preparation and characterization of novel hyperbranched poly(amido amine)s from Michael addition polymerizations of trifunctional amines with diacrylamides

Novel hyperbranched poly(amido amine)s containing tertiary amines in the backbones and acryl as terminal groups were synthesized via the Michael addition polymerizations of trifunctional amines with twofold molar diacrylamide. The hyperbranched structures of these poly(amido amine)s were verified by ¹³C NMR (INVGATE). The polymerization mechanisms were clarified by following the polymerization process with NMR method, and the results show that the reactivity of secondary amine formed in situ is much lower than that of the secondary amine in 1‐(2‐aminoethyl) piperazine (AEPZ) ring and the primary amine. The secondary amine formed in situ was almost kept out of the reaction before the primary and secondary amines in AEPZ were consumed, leading to the formation of the AB2 intermediate, and the further reaction of the AB2 yielded the hyperbranched polymers. The molecular weights and properties of poly(amindo amine)s obtained were characterized by GPC, DSC, and TGA, respectively. Based on the reaction of active acryl groups in the polymers obtained with glucosamine, hyperbranched polymers containing sugar were formed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5127–5137, 2005     

Determination of biogenic amines in wines by pre-column derivatization and high-performance liquid chromatography coupled to mass spectrometry

A new HPLC method for determining biogenic amines in wines is developed. This method is based on pre-column amine derivatization, further separation of derivatives and on-line hyphenation of HPLC to atmospheric pressure chemical ionization mass spectrometry (APCI-MS). Biogenic amines have been derivatized with 1,2-naphthoquinone-4-sulfonate at 65 °C and pH 9.2 for 5 min. The separation of derivatives has been accomplished in a C₁₈ analytical column using an elution gradient based on increasing the percentage of methanol. Derivatives have been ionized in positive mode and detected by selected ion monitoring. The operating conditions of the APCI-MS system (voltages, temperatures and gases) have been thoroughly optimized to obtain the maximum sensitivity for all analytes. In the selected conditions, APCI-MS spectra display little fragmentation and good signal-to-noise ratio. Depending on the amine characteristics, the main spectral peaks are due to mono- and di-derivative products. Figures of merit of the method have been established under the selected conditions using red wine samples. Recoveries ranging from 94% to 106% have been obtained which prove excellent accuracy of the method in the determination of histamine, putrescine, cadaverine, tryptamine, phenylethylamine, tyramine and serotonin in red wines. The proposed method has been applied to the analysis of commercial wines from different Spanish regions.     

可多重N-羟甲基化的Mannich反应机理研究

用MNDO法全优化了20多个Mannich反应中间体-N-羟甲基胺和亚甲胺碳正离子的平衡几何构型, 计算了它们的电子结构。根据N-羟甲基胺脱水反应的能量变化(△E)、亚甲胺碳正离子的净电荷(Q~C~+)和几何构型, 分类讨论比较了N-羟甲胺脱水的难易、亚甲胺碳正离子的稳定性以及对反应历程的影响。以脲素、甲醛和硝仿之间的mannich反应为例, 建议在可多重N-羟甲基化情形下Mannich反应的机理。此外还对硝基脲的N-羟甲基胺及其亚甲胺碳正离子进行了计算研究。     

Tailoring D‐Amino Acid Oxidase from the Pig Kidney to R‐Stereoselective Amine Oxidase and its Use in the Deracemization of α‐Methylbenzylamine

The deracemization of racemic amines to yield enantioenriched amines using S‐stereoselective amine oxidases (AOx) has recently been attracting attention. However, R‐stereoselective AOx that are suitable for deracemization have not yet been identified. An R‐stereoselective AOx was now evolved from porcine kidney D ‐amino acid oxidase (pkDAO) and subsequently use for the deracemization of racemic amines. The engineered pkDAO, which was obtained by directed evolution, displayed a markedly changed substrate specificity towards R amines. The mutant enzyme exhibited a high preference towards the substrate α‐methylbenzylamine and was used to synthesize the S amine through deracemization. The findings of this study indicate that further investigations on the structure–activity relationship of AOx are warranted and also provide a new method for biotransformations in organic synthesis.     

8-Phenyl-(4-oxy-acetic acid N-hydroxysuccinimidyl ester)-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene as a new highly fluorescent-derivatizing reagent for aliphatic amines in disease-related samples with high-performance liquid chromatography

A novel fluorescent-activated ester, 8-phenyl-(4-oxy-acetic acid N-hydroxysuccinimidyl ester)-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene (TMPAB-OSu) has been designed and synthesized for amine labeling in HPLC. Being used 11 aliphatic amines as the models, the derivatization conditions were optimized. In 0.2 mol/l borate buffer (pH 8.8), amines reacted with TMPAB-OSu at 30 °C to form the derivatives in 10 min. The fluorescent quantum yield of TMPAB-OSu and its amine derivatives are high even compared with fluorescein. The separation of these amine derivatives was achieved with a C₈ column and gradient elution by using 0.1 mol/l sodium acetate buffer (pH 5.0) and methanol. With fluorescence detection at an emission wavelength of 509 nm and an excitation wavelength of 497 nm, the detection limits of aliphatic amines were 2–18 fmol, at a signal-to-noise ratio of 3:1. The proposed TMPAB-OSu-based HPLC method has been applied to the analysis of urine samples of health, hepatic and renal patients and lake water. Recoveries from different matrices are from 96 to 104%, depending on the sample investigated.     

一种新型用于原子转移自由基聚合过程的Cu(I)络合物的研究

将以三齿2,6 双(苯并咪唑)吡啶为配体的Cu(I)离子络合物用作A TRP引发体系的组分之一,并成功地实现了对烯类单体的自由基聚合.聚合过程具有明显的ATRP聚合特征.和几种具不同结构胺配体构成的Cu(I)络合物的聚合速度结果相比较,本工作的结果基本符合烷基胺≈吡啶>亚胺>芳基胺的序列关系.