HDA Reaction Research Articles

Responsive Microgels through RAFT-HDA Dynamic Covalent Bonding Chemistry.

This paper developed a method for preparing ultrasound-responsive microgels based on reversible addition fragmentation chain transfer-hetero Diels-Alder (RAFT-HAD) dynamic covalent bonding. First, a styrene cross-linked network was successfully prepared by a Diels-Alder (DA) reaction between phosphoryl dithioester and furan using double-ended diethoxyphosphoryl dithiocarbonate (BDEPDF) for RAFT reagent-mediated styrene (St) polymerization, with a double-ended dienophile linker and copolymer of furfuryl methacrylate (FMA) and St as the dienophile. Subsequently, the microgel system was constructed by the HDA reaction between phosphoryl disulfide and furan groups using the copolymer of polyethylene glycol monomethyl ether acrylate (OEGMA) and FMA as the dienophore building block and hydrophilic segment and the polystyrene pro-dienophile linker as the cross-linker and hydrophobic segment. The number of furans in the dienophile chain and the length of the dienophile linker were regulated by RAFT polymerization to investigate the effects of the single-molecule chain functional group degree, furan/dithioester ratio, and hydrophobic cross-linker length on the microgel system. The prepared microgels can achieve the reversible transformation of materials under force responsiveness, and their preparation steps are simple and adaptive to various potential applications in biomedical materials and adaptive electrical materials.

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids.

Tropolone sesquiterpenoids (TS) are an intriguing family of biologically active fungal meroterpenoids that arise through a unique intermolecular hetero Diels–Alder (hDA) reaction between humulene and tropolones. Here, we report on the combinatorial biosynthesis of a series of unprecedented analogs of the TS pycnidione 1 and xenovulene A 2. In a systematic synthetic biology driven approach, we recombined genes from three TS biosynthetic gene clusters (pycnidione 1, xenovulene A 2 and eupenifeldin 3) in the fungal host Aspergillus oryzae NSAR1. Rational design of the reconstituted pathways granted control over the number of hDA reactions taking place, the chemical nature of the fused polyketide moiety (tropolono‐ vs. monobenzo‐pyranyl) and the degree of hydroxylation. Formation of unexpected monobenzopyranyl sesquiterpenoids was investigated using isotope‐feeding studies to reveal a new and highly unusual oxidative ring contraction rearrangement.

Molecular mechanism of Hetero Diels-Alder reactions between (E)-1,1,1-trifluoro-3-nitrobut-2-enes and enamine systems in the light of Molecular Electron Density Theory

The molecular mechanism of the reaction of (E)-1,1,1-trifluoro-3-nitrobut-2-ene 1 with 3,3-dimethyl-2-morpholinobutene 2 has been studied within the Molecular Electron Density Theory (MEDT). This theoretical study confirm the possibility of the formation of zwitterionic structures in the first reaction stage. Interestingly, that localized zwitterions are however not common intermediates for identified in the postreaction mixture products. The further Bonding Evolution Theory (BET) study show, that the key, HDA reaction takes place in one-step but in a non-concerted manner since three stages are clearly identified. First the C5–C6 double bond breaks, then the C1–C2 bond breaks, and in the last phase we observed the formation of the C1–C6 single bond and V(C2) and V’ (C2) pseudoradical centers in Z1 molecule. In turn, the molecular mechanism of the conversion of zwitterion Z1 to product 3 can be divided also in three groups in which we observed the disappearance of the two pseudoradical centers and formation O4–C5 single and C3–N3 double bonds, respectively.

Intermolecular Hetero-Diels-Alder Reactions of Photogenerated aza-ortho-Quinone Methides with Aldehydes.

A visible-light-driven, perfluoroalkyl radical-mediated strategy for in situ formation of aza-o-QMs from readily available precursors is reported. Combination of this method with a Brønsted base thus enables an efficient and highly diastereoselective HDA reaction between such photogenerated aza-o-QMs and π-electron-poor systems, aldehydes, providing high yielding and rapid access to valuable, diversely substituted dihydrobenzoxazines. DFT calculation elucidated the origins of stereochemistry of the products and disclosed the concerted property of the process.

Hetero-Diels-Alder Reactions in the Synthesis of Biologically Active Nitrogen Compounds: A Review

Background: The Hetero-Diels-Alder reaction (HDAR) is a method extensively used in organic chemistry as a tool in the synthesis of innumerous polycyclic compounds in particular nitrogen compounds, presents in many natural products, medicinally relevant substances and organic materials. The literature describes innumerable studies of HDAR using classic methods and modern developments such as reactions on the solid phase, the use of catalysts, transformations in aqueous solution and under microwaves. Objective: This review describes a variety of HDAR focused on obtaining nitrogen-containing compounds of considerable chemical and biological interest, and highlighting reported biological activity. Conclusion: This review has shown the importance of the HDA reaction as a tool of organic chemistry in the synthesis of nitrogen compounds. This type of reaction presents important properties including bond-forming economy, high regio- and stereoselectivities and thus provides highly efficient routes to access a wide range of polycyclic compounds. In addition to the variety of nitrogen compounds synthetized successfully by this method, they present relevant biological properties.

A New Synthetic Route to Acylnitroso Intermediates and Their Applications in HDA and Ene Reactions

A New Synthetic Route to Acylnitroso Intermediates and Their Applications in HDA and Ene Reactions

Mixed NiMo, NiW and NiMoW sulfides obtained from layered double hydroxides as catalysts in simultaneous HDA and HDS reactions

NiMoAl, NiWAl and NiMoWAl hydrotreating catalysts were prepared from NiAl-terephthalate layered double hydroxides (LDHs), by ion exchange of the therephthalate anion by heptamolybdate (Mo7O246−) and/or metatungstate (H2W12O406−). The Mo- and/or W-containing LDHs were sulfided, either by direct sulfidation (DS route) or after previous calcination (PC route).

Reaction‐Based Mechanistic Investigations of Asymmetric Hetero‐Diels–Alder Reactions of Enones with Isatins Catalyzed by Amine‐Based Three‐Component Catalyst Systems

AbstractReaction‐based mechanistic investigations were performed for the hetero‐Diels–Alder (hDA) reactions of enones with isatins that were catalyzed by an amine‐based catalyst system composed of three molecules (an amine, an acid, and a thiourea). The results indicated that the hDA product obtained from the reaction between hept‐3‐en‐2‐one and isatin using the amine‐based catalyst system was generated via a kinetically controlled [4+2] cycloaddition reaction of the in situ‐generated enamine of the enone as the diene and isatin as the dienophile. The amine of the three‐component catalyst system was essential for the catalysis and stereocontrol, but the other components of the catalyst system also played important roles. Based on the results, plausible transition states are discussed, and the system was further improved by altering the loadings of the catalyst components for faster reactions with high stereoselectivities. The three‐component catalyst systems are flexible and can be tuned to obtain better results.

Mechanical activation of a dithioester derivative-based retro RAFT-HDA reaction

A new mechanophore was synthesized from a dithioester derivative 1 and an open-chain diene 2 by the HDA reaction. It was embedded in the polymer chain by initiating the polymerization of methyl acrylate (MA). It was found that the PMA with Mn > 30 kDa could undergo a mechanically induced retro RAFT-HDA reaction rapidly at ambient temperature. The released species was evidenced chemically and spectroscopically, and the liberated dithioester derivative 1 maintained the activity to react with cyclopentadiene (Cp) or to copolymerize with styrene (St).

Pyridine synthesis by [4 + 2] cycloadditions of 1-azadienes: hetero-Diels Alder and transition metal-catalysed approaches

Cycloaddition reactions are powerful tools in synthetic chemistry. Incorporation of a nitrogen-containing component via cycloaddition represents an attractive strategy for assembling aza-heterocycles. One approach takes advantage of [4 + 2] cycloaddition reactions of 1-azadiene derivatives and 2-carbon π-components to access pyridines, a particularly significant subset of aza-heterocycles. This highlight discusses two distinct modes of reactivity within this class: the thermal pericyclic or hetero-Diels Alder (hDA) reaction and the transition metal-catalysed formal [4 + 2] cycloaddition reaction.

Searching for zwitterionic intermediates in Hetero Diels–Alder reactions between methyl α,p-dinitrocinnamate and vinyl-alkyl ethers

DFT calculations indicate that reactions of methyl α,p-dinitrocinnamate with vinyl-alkyl ethers are of a polar nature, and zwitterionic structures may arise during their course. However, these zwitterions are beyond of cycloadditions paths. On the other hand, HDA reactions of addents carried out according to “two-stage one-step” cycloaddition mechanism. It should be also remarked, that the M062x functional overestimates activation energies.

Simultaneous tetralin HDA and dibenzothiophene HDS reactions on NiMo bulk sulphide catalysts obtained from mixed oxides

Large selectivity differences were found between supported and unsupported NiMoS catalysts in dibenzothiophene HDS and tetralin HDA.

Unsupported NiMoAl hydrotreating catalysts prepared from NiAl-terephthalate hydrotalcites exchanged with heptamolybdate

Unsupported NiMoAl hydrotreating catalysts were prepared starting from NiAl-terephthalate layered double hydroxides (LDHs) with x values (Al/(Al+Ni) ratios) in the 0.3–0.8 range by ion exchange with ammonium heptamolybdate, followed by calcination at 723K. Mixed oxides containing ca. 33–43wt% molybdenum and Ni/Mo atomic ratios in the 0.5–1.4 range were obtained. There was loss in the long-range ordering of the LDHs in the c direction during the ion-exchange, but the local structure of the brucite layers was maintained. The calcined mixed-oxides had surface areas ranging from 26 to 122m2g−1. The catalysts were sulphided in situ and subsequently tested in the simultaneous dibenzothiophene (DBT) HDS and tetralin (THN) hydrogenation reactions in a high pressure batch reactor at 613K and 70bar. The catalysts had higher specific activity for both the HDS and the HDA reactions and much higher selectivity for the ring hydrogenation (HYD) route in the HDS of DBT than a conventional NiMo/Al2O3 catalyst. Their activities in both reactions were similar to those of an Al-free unsupported NiMo catalyst, but their preference for the HYD route was higher than that of the latter.

An efficient oxidative coupling method for synthesis of novel diastereomeric biaryl diols derived from estrone

An efficient oxidative coupling of estrogen derivatives was developed. Several 2-substitutent-17-deoxyestrones were applied to the aerobic oxidative coupling reactions catalyzed by CuCl2/TMEDA. The products were obtained as diastereoisomers with moderate to good yields. As chiral ligands, three couples of diastereoisomers were applied to the asymmetric HDA reaction to investigate their chemical properties.

Modular Ligation of Thioamide Functional Peptides onto Solid Cellulose Substrates

AbstractHetero Diels‐Alder (HDA) cycloaddition – as an effective modular conjugation approach – is employed to graft thioamide endfunctional oligopeptides onto solid cyclopentadienyl (Cp) functional cellulose substrates generating cellulose‐peptide hybrid materials. The highly reactive Cp moieties serve as diene functionality in the consecutive HDA reaction on the biosubstrate surface. Oligopeptides (i.e., the model peptide Gly‐Gly‐Arg‐Phe‐Pro‐Trp‐Trp‐Gly and the antimicrobial peptide tritrpticin) are functionalized at their N‐termini employing strongly electron deficient thiocarbonyl thio compounds resulting in biomacromolecules bearing a thioamide endgroup. The dienophile‐ functional peptides readily undergo HDA reactions at ambient temperature and under mild conditions in solution with synthetic polymers as well as on solid (bio)substrates. An in‐depth investigation is provided of the influence of the temperature, the Lewis acid catalysis and the side group exchange of thioamide functional oligopeptides reacting with Cp terminated poly(methyl methacrylate) (Mn = 2100 g·mol−1, PDI = 1.1) in homogenous solution as well as Cp functionalized cellulose in a heterogeneous system. To assess the success of the grafting reaction, the soluble samples were subjected to characterization methods such as size exclusion chromatography (SEC) and SEC‐electrospray ionization mass spectrometry (SEC‐ESI‐MS). The heterogeneous “grafting‐to” reactions were monitored using high resolution attenuated total reflection (ATR) Fourier transform infrared microscopy (HR‐FTIRM) imaging, X‐ray photoelectron spectroscopy (XPS) and elemental analysis. Evaluation via elemental analysis leads to quantitative peptide cellulose surface loading capacities.

A B3LYP/6-31G(d) study of Diels-Alder reactions between cyclopentadiene and (E)-2-arylnitroethenes

AbstractThe B3LYP/6-31G(d) simulations of competing CDA and HDA reactions between cyclopentadiene and (E)-2-arylnitroethenes prove that regardless of the medium polarity, the processes leading to respective 5-nitro-6-aryl-bicyclo-[2,2,0]-hept-2-enes 3,4 (paths A and B) should be most favoured, and the more electrophilic (E)-2-(p-nitrophenyl)-nitroethene should be more reactive than the less electrophilic (E)-2-(p-methoxyphenyl)-nitroethene. Asymmetry of the transition complexes on the favoured pathways increases with increase of medium polarity, but not sufficiently to enforce the zwitterionic mechanism. Analysis of competing pathways leading to HDA adducts proves that not all these compounds can be formed directly from the adducts. In particular, on the path C, the initially formed 5-nitro-6-aryl-bicyclo-[2,2,0]-hept-2-enes 3 is converted to 2-phenyl-4-aza-5-oxy-bicyclo-[3,4,0]-nona-3,7-diene N-oxides 5 as a result of a [3.3]-sigmatropic shift. On the paths D–F leading to 2-phenyl-4-aza-5-oxy-bicyclo-[3,4,0]-nonadienes N-oxides 6–8, the reaction proceeds according to a one-step mechanism.

Real-time electrochemical monitoring of isothermal helicase-dependent amplification of nucleic acids

We described an electrochemical method to monitor in real-time the isothermal helicase-dependent amplification of nucleic acids. The principle of detection is simple and well-adapted to the development of portable, easy-to-use and inexpensive nucleic acids detection technologies. It consists of monitoring a decrease in the electrochemical current response of a reporter DNA intercalating redox probe during the isothermal DNA amplification. The method offers the possibility to quantitatively analyze target nucleic acids in less than one hour at a single constant temperature, and to perform at the end of the isothermal amplification a DNA melt curve analysis for differentiating between specific and non-specific amplifications. To illustrate the potentialities of this approach for the development of a simple, robust and low-cost instrument with high throughput capability, the method was validated with an electrochemical system capable of monitoring up to 48 real-time isothermal HDA reactions simultaneously in a disposable microplate consisting of 48-electrochemical microwells. Results obtained with this approach are comparable to that obtained with a well-established but more sophisticated and expensive fluorescence-based method. This makes for a promising alternative detection method not only for real-time isothermal helicase-dependent amplification of nucleic acid, but also for other isothermal DNA amplification strategies.

High-Pressure Hetero-Diels−Alder Route to (±)-6,6,6-Trifluoro-β-C-Naphthyl Glycosides

The first de novo synthesis of a beta-C-naphthyl glycoside displaying a convenient functionality for subsequent transformations into complex C-aryl glycosides is reported. The synthesis of this (+/-)-beta-C-1,5-dibenzyloxynaphthyl 6,6,6-trifluoro-3-amino glycoside relies on a hyperbaric HDA reaction involving a new 2-vinylnaphthalenic dienophile.

Hydrodesulfurization of dibenzothiophene and a SRGO on sulfide Ni(Co)Mo/Al 2O 3 catalysts. Effect of Ru and Pd promotion

Commercial Ni(Co)Mo/γ–Al 2O 3 catalysts were modified by the addition of Pd and Ru in order to enhance their hydrogenation function as required for the simultaneous elimination of sulfur, nitrogen and aromatics from a gasoil. The ternary catalysts were prepared by wet impregnation of the commercial samples with Ru and Pd salt solutions. The oxide precursors were characterized by S BET, TPR, XRD, XPS and IR of adsorbed pyridine. The catalysts were tested in their sulfided forms to evaluate their activity in the hydrodesulfurization (HDS) of dibenzothiophene (DBT) and in the hydrotreating (HDT) of a straight run gas oil (SRGO; 0.11, 0.55 and 1.16 wt% of S). Catalyst screening in the HDS of DBT showed that: (i) the presence of isolated RuS 2 phases located on the catalyst surface contributed to overall catalytic activity and improved the catalyst hydrogenation function, (ii) catalyst doping with Ru was more effective than its doping with Pd, (iii) maximum activity was obtained at a Ru loading of 0.5 wt%, (iv) the NiMo catalyst formulation was more effective than its CoMo counterpart, and (v) a life test (87 h) performed on the 0.5%Ru/NiMo catalyst showed that this catalyst was less prone to deactivation than the NiMo reference sample. In the hydrotreatment of a SRGO ( S = 0.55 wt%), the sulfide 0.5%Ru/NiMo/Al 2O 3 catalyst proved to be more active in the HDS and HDA reactions than a commercial NiMo/Al 2O 3 one.

Integrated design and control for robust performance: Application to an MSMPR crystallizer

The interplay of different types of performance constraints in an integrated design and control problem is studied by means of a case study. This integrated problem is based on a recent method for robust process design [M. Mönnigmann, W. Marquardt, Normal vectors on manifolds of critical points for parametric robustness of equilibrium solutions of ODE systems, J. Nonlinear Sci. 12 (2002) 85–112; M. Mönnigmann, W. Marquardt, Steady state process optimization with guaranteed robust stability and feasibility, AIChE J. 49 (12) (2003) 3110–3126; M. Mönnigmann, W. Marquardt, Steady state process optimization with guaranteed robust stability and flexibility: application to HDA reaction section, Ind. Eng. Chem. Res. 44 (2005) 2737–2753; W. Marquardt, M. Mönnigmann, Constructive nonlinear dynamics in process systems engineering, Comput. Chem. Eng. 29 (2005) 1265–1275; M. Mönnigmann, Constructive nonlinear dynamics methods for the design of chemical engineering processes, Ph.D. Thesis, RWTH Aachen University, 2003]. The design is found by means of a steady-state optimization problem accounting for process economics and performance requirements. In particular, the latter are represented by constraints which guarantee a user-specified performance of the design in spite of parametric uncertainties. For the first time, two types of dynamic performance constraints are used simultaneously within the adopted framework. These are constraints on time-domain performance indicators as well as on the asymptotic dynamic process behavior. Furthermore, the effect of uncertainty in both, design and model parameters, is accounted for. A key strength of the suggested framework is the direct quantification of the trade-offs between economics and dynamic performance requirements for a selection of uncertainty scenarios. A series of different integrated design and control problems are formulated and solved for a continuous mixed-suspension mixed-product removal (MSMPR) crystallizer. The process exhibits a complex nonlinear behavior and represents a challenging example. The results of the case study allow an in depth understanding of the interactions of design and control for the underlying process.