Primary Cyclization Research Articles

ChemInform Abstract: Synthesis of 2,3‐Dihydroselenophene and Selenophene Derivatives by Electrophilic Cyclization of Homopropargyl Selenides.

AbstractDehydrogenation of the primary cyclization products affords aromatic iodoselenophenes.

Synthesis of Bicyclic σ Receptor Ligands with Cytotoxic Activity

All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonan-2-ol) and methyl ethers (6-benzyl-2-methoxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane) are prepared from (R)- and (S)-glutamate. A Dieckmann analogous cyclization, which makes use of trapping the primary cyclization product with Me3SiCl, generates the bicyclic framework. Stereoselective LiBH4 reduction and Mitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high sigma1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 muM the four methyl ethers stop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target in this cell line. The IC50-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugs cisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerable amounts of sigma1 and sigma2 receptors.

Chapter 3 Chemical and Biological Aspects of Narcissus Alkaloids

Publisher SummaryThis chapter discusses the chemical and biological aspects of Narcissus alkaloids. Numerous alkaloids have been isolated from Narcissus speciesasaresult of the continuing search for novel alkaloids with pharmacological activity in the Amaryllidaceae family. The alkaloids isolated from this genus, classified in relation to the different skeleton types. The different Narcissus wild species and intersectional hybrids, grouped into subgenera and sections, with their corresponding alkaloids, arranged according to their ring system are listed. The biosynthetic pathways of Narcissus alkaloids includes: (1) enzymatic preparation of the precursors, (2) primary cyclization mechanisms, (3) enzymatic preparation of intermediates, (4) secondary cyclization, diversification, and restructuring. The chapter discusses proton nuclear magnetic resonance (1H NMR), carbon nuclear magnetic resonance (13C NMR), and mass spectrometry (MS) for Narcissus alkaloids. A list of the different Narcissus alkaloids, their spectroscopic properties, and literature with the most recent spectroscopic data is given. Several Narcissus extracts shows the following activities: antiviral, prophage induction, antibacterial, antifungal, antimalarial, insecticidal, cytotoxic, antitumor, antimitotic, antiplatelet, hypotensive, emetic, acetylcholine esterase inhibitory, antifertility, antinociceptive, chronotropic, pheromone, plant growth inhibitor, and allelopathic.

Surprising fenchone induced cyclization: synthesis of the new chiral diol biphenyl-2,2′-sulfone-3,3′-bisfenchol (BISFOL)

The new chiral diol BISFOL (biphenyl-2,2′-sulfone-3,3′-bisfenchol) is surprisingly formed by cyclization of diphenylsulfone after treatment with n-buthyllithium at −78 °C and subsequent addition of (−)-fenchone. Formation of fenchyl alcohol as byproduct points to a Meisenheimer intermediate as primary cyclization product, which transfers lithium hydride yielding the cyclic sulfone. As a chiral and chelating ligand, BISFOL catalyzes enantioselective diorganozinc additions to aldehydes and forms with dimethylzinc an unprecedented, macrocyclic, dimeric methylzinc complex.

Semibatch operation and primary cyclization effects in homogeneous free-radical crosslinking copolymerizations

A theoretical analysis is presented on the use of semibatch reactors for producing non-linear copolymers through the homogeneous free-radical polymerization of mono- and divinyl-monomers. The kinetic scheme distinguishes two kinds of pendant double bonds and five kinds of polymer radicals, as it also takes into account the primary cyclization of terminal divinyl units. In spite of the fairly large number of groups and reactions, the generating function of vector chain length distribution of polymer species can still be accurately computed by a numerical implementation of the method of characteristics and thus average molecular weights before and after gelation can be reliably obtained. The influence of feed policies of the monomers, initiator and transfer agent on gelation, average chain lengths and weight fraction of sol is discussed, as well as their sensitivity to some kinetic parameters.

Seeded Semicontinuous Emulsion Copolymerization of Butyl Acrylate with Cross-Linkers

The seeded semicontinuous emulsion copolymerization of butyl acrylate (BA) with divinyl monomers (butanediol diacrylate, BDA, and allyl methacrylate, AMA), at 80 °C and using potassium persulfate as initiator was investigated. Particularly, the study of the influence of the type and amount of cross-linkers on the kinetics, level of branching, cross-linking density, gel fraction, sol molecular weight, and latex film mechanical properties (i.e., glass transition temperature, Tg, storage modulus, and molecular weight between entanglements, Me) produced during the polymerizations was considered. The results showed that the most reactive cross-linker, BDA, produced the less cross-linked, branched, and gel-containing polymer. Mechanical property data confirmed this unexpected trend as the copolymer made with BDA exhibited the weakest mechanical properties. These results were explained by the higher occurrence of primary cyclization reactions in the case of BDA.

Structure and swelling of poly(acrylic acid) hydrogels: effect of pH, ionic strength, and dilution on the crosslinked polymer structure

The network formation of crosslinked polymer hydrogels made via a free radical polymerization mechanism is significantly influenced by the polymerization conditions. In particular, the crosslinked structure of ionic networks like poly(acrylic acid) copolymers is affected by the monomer concentration, the pH, and ionic strength during the polymerization. In this work experimental data as well as theoretical analysis are used to investigate how these factors control the degree of crosslinking and primary cyclization during the network formation of multifunctional monomers. It was found that the amount of water present during the polymerization increases primary cyclization rates, and this change affects the subsequent swelling behavior of the acrylic acid hydrogel. The effects of ionic strength and pH on the network structure are interrelated. An increase in the pH decreases the degree of primary cyclization while an increase in the ionic strength increases cyclization. To investigate further the effect of pH, a cationic polymer was formed that contained a monovinyl amine monomer and a novel diamine crosslinking agent synthesized in our laboratory. The combined effect of the ionizing backbone chain and crosslinking agent cause the degree of primary cyclization in this material to be extremely sensitive to the pH during polymerization. This result confirms the significant role of pH on the network formation in ionic materials.

Structure and swelling of poly(acrylic acid) hydrogels: effect of pH, ionic strength, and dilution on the crosslinked polymer structure

The network formation of crosslinked polymer hydrogels made via a free radical polymerization mechanism is significantly influenced by the polymerization conditions. In particular, the crosslinked structure of ionic networks like poly(acrylic acid) copolymers is affected by the monomer concentration, the pH, and ionic strength during the polymerization. In this work experimental data as well as theoretical analysis are used to investigate how these factors control the degree of crosslinking and primary cyclization during the network formation of multifunctional monomers. It was found that the amount of water present during the polymerization increases primary cyclization rates, and this change affects the subsequent swelling behavior of the acrylic acid hydrogel. The effects of ionic strength and pH on the network structure are interrelated. An increase in the pH decreases the degree of primary cyclization while an increase in the ionic strength increases cyclization. To investigate further the effect of pH, a cationic polymer was formed that contained a monovinyl amine monomer and a novel diamine crosslinking agent synthesized in our laboratory. The combined effect of the ionizing backbone chain and crosslinking agent cause the degree of primary cyclization in this material to be extremely sensitive to the pH during polymerization. This result confirms the significant role of pH on the network formation in ionic materials.

Asymmetric synthesis of fused bicyclic alpha-amino acids having a hexahydro-cyclopenta[c]pyridine skeleton via intramolecular Pauson-Khand reaction of 1-sulfonimidoyl-substituted 5-azaoct-1-en-7-ynes.

An asymmetric synthesis of fused bicyclic amino acids having a hexahydro-cyclopenta[c]pyridine skeleton and carrying besides an enone structural element a substituent at the beta-position is described. The key steps of the synthesis are a highly selective allylation of N-tert-butylsulfonyl imino ester with bis(allylsulfoximine)titanium complexes and a highly diastereoselective Pauson-Khand cycloaddition of sulfonimidoyl-substituted gamma,delta-unsaturated alpha-amino acid esters carrying a substituent at the beta-position and a propargyl group at the N-atom. The cyclization is accompanied by a reductive cleavage of the sulfoximine group of the primary cyclization product. Surprisingly, the removal of the sulfoximine group proceeds with inversion of the configuration at the S-atom and gives N-methyl-phenylsulfinamide with >/=98% ee. Deprotection of the bicyclic N-tert-butylsulfonyl-protected amino acid ester was accomplished through treatment with CF(3)SO(3)H under anhydrous conditions. The enantio- and diastereomerically pure sulfoximine-substituted gamma,delta-unsaturated alpha-amino acid esters used as starting material were obtained through a highly regio- and diastereoselective allylation of N-tert-butylsulfonyl imino ester with acyclic bis(allylsulfoximine)titanium complexes, described previously.

Kinetic Gelation Modeling: Kinetics of Cross-Linking Polymerization

A kinetic gelation model that simulates free-radical network polymerization on a lattice with a stochastic kinetic approach to enable real time calculation was used to assess how initiation rate and primary cyclization affect the overall kinetics of polymerization of difunctional monomers. Changes that cause a more uniform distribution of reacted siteshigher initiation rate or less primary cyclizationincrease the accessibility of free radicals to functional groups, lower the fraction of trapped radicals, and consequently raise the apparent propagation rate constant. On the other hand, the final conversion, determined by kinetic chain length at a given initiator concentration, drops when termination becomes more severe such as under higher initiation rate or when radical trapping worsens such as under enhanced cyclization. In addition, the model simulates the contribution of pendant functional groups to the formation of different structures. The higher the radical concentration brought by higher initiation rate or by less preferred primary cyclization, the lower the fraction of pendant functional groups to form primary cycles and the higher the fractions of pendant functional groups to form cross-links and secondary cycles.

The effect of primary cyclization on free radical polymerization kinetics: experimental characterization

Free radical polymerization kinetics are influenced by many factors including solvent concentration during polymerization, monomer structure, and comonomer composition. This study isolates the effects of the balance between primary cyclization and crosslinking on the polymerization kinetics. Isomeric crosslinking agents, 1,2-cyclohexanediol dimethacrylate (1,2-CHDDMA), 1,3-cyclohexanediol dimethacrylate (1,3-CHDDMA), and 1,4-cyclohexanediol dimethacrylate (1,4-CHDDMA), were utilized for the study because they have differing cyclization rates due to the conformation of the two methacrylate groups in the monomer, but they are otherwise similar. In copolymerizations of 1, 2, 5, and 10% crosslinking agents with 2-methoxyethyl methacrylate (MEMA), the 1,4-CHDDMA samples were always found to have an earlier onset of autoacceleration than 1,2-CHHDMA samples. 1,3-CHDDMA copolymerized with MEMA had a polymerization rate between the 1,2-CHDDMA and 1,4-CHDDMA, as expected. Mechanical property data showed that copolymer samples made with the 1,4-CHDDMA crosslinking agent exhibited a lower M c and higher T g than the analogous 1,2-CHDDMA copolymers. It is concluded that reduced mobility from greater crosslinking than cyclization causes the earlier onset of autoacceleration in the 1,4-CHDDMA copolymers.

First Preparation of Spacer‐Linked Cyclic Neooligoaminodeoxysaccharides.

The preparation of novel cyclic 1,4-butanediol-linked oligoamino-deoxysugars 3-5 and 7 is described which are potential binders to polynucleotides. Neooligosaccharides 3-5 are assembled by two consecutive metathesis protocols. In the first phase metathesis-mediated dimerization of an aminodeoxymonosaccharide which was either allylated at the anomeric center or at C4 led to E/Z mixtures of C 2 -symmetric homodimers which were transformed into the corresponding 1,4-butanediol linked disaccharides by catalytic hydrogenation of the central olefinic double bond. Double O-allvlation of the head-to-head dimer set the stage for macrocyclization by means ol' ring-closing metathesis. This ring-closing process was highly dependent of the configuration in the carbohydrate moieties. arabino-Configured homodimer 15 directly yielded the macrocycle 32 which contains two sugar units while under the same metathesis conditions the corresponding ribo-configured starting homodimer 19 afforded cyclic neotetra- and neohexasaccharides 34 and 35 after a preceding dimerization and trimerization step, respectively. In addition, homodimer 23 was coupled with silylglycoside 14a under Lewis-acid promoted glycosidation conditions to furnish the doubly glycosylated homodimer 31. Ring-closing metathesis afforded the macrocyclic neoaminodeoxyoligosaccharide 36 with alternating 1,4-butanediol linkage and glycosidic bond. The primary cyclization products were finally transformed into the respective cyclic neoaminodeoxyoligosaccharides 3-5 and 7 by catalytic hydrogenation and standard deprotection conditions.

Effect of Primary Cyclization on Free Radical Polymerization Kinetics: Modeling Approach

A modified kinetic model is developed which captures how the cross-linked network structure and its evolution in loosely cross-linked polymers affects the polymerization kinetics. In our previous work, diffusion-controlled kinetics has been modeled through the change in free volume of the system as monomer converts to polymer.1,2 Here, the additional effect of the resistance caused by the need to diffuse through the cross-linked network is incorporated into a model of the polymerization kinetics. With this model, the effects of cross-linking and cyclization observed in experimental systems are predicted. The model quantitatively predicts experimental results for varying concentrations of 1,4-cyclohexanediol dimethacrylate and 1,2-cyclohexanediol dimethacrylate copolymerized with methoxy ethyl methacrylate.

First preparation of spacer-linked cyclic neooligoaminodeoxysaccharides.

The preparation of novel cyclic 1,4-butanediol-linked oligoaminodeoxysugars 3-5 and 7 is described which are potential binders to polynucleotides. Neooligosaccharides 3-5 are assembled by two consecutive metathesis protocols. In the first phase metathesis-mediated dimerization of an aminodeoxymonosaccharide which was either allylated at the anomeric center or at C4 led to E/Z mixtures of C2-symmetric homodimers which were transformed into the corresponding 1,4-butanediol linked disaccharides by catalytic hydrogenation of the central olefinic double bond. Double Q-allylation of the head-to-head dimer set the stage for macrocyclization by means of ring-closing metathesis. This ring-closing process was highly dependent of the configuration in the carbohydrate moieties. arabino-Configured homodimer 15 directly yielded the macrocycle 32 which contains two sugar units while under the same metathesis conditions the corresponding ribo-configured starting homodimer 19 afforded cyclic neotetra- and neohexasaccharides 34 and 35 after a preceding dimerization and trimerization step, respectively. In addition, homodimer 23 was coupled with silylglycoside 14a under Lewis-acid promoted glycosidation conditions to furnish the doubly glycosylated homodimer 31. Ring-closing metathesis afforded the macrocyclic neoaminodeoxyoligosaccharide 36 with alternating 1,4-butanediol linkage and glycosidic bond. The primary cyclization products were finally transformed into the respective cyclic neoaminodeoxyoligosaccharides 3-5 and 7 by catalytic hydrogenation and standard deprotection conditions.

Effects of Solvent Quality during Polymerization on Network Structure of Cross-Linked Methacrylate Copolymers

Processing conditions during free radical polymerization strongly affect the polymer network evolution. This work focuses on how the solvent quality during solution polymerization alters the mechanical and structural properties of the resulting polymer hydrogel network in methacrylate copolymerizations. Two copolymer systems were analyzed: 2/98 diethylene glycol dimethacrylate/methoxyethyl methacrylate and 2/98 diethylene glycol dimethacrylate/octyl methacrylate. Copolymerizations were performed in varying amounts of either hexanol or ethylene glycol diacetate. The equilibrium swelling of bulk DEGDMA was also measured to ascertain how the cross-linking agent interacts with the solvent. To compare the solvent quality of the two solvents, the equilibrium swelling of the copolymer samples was measured in each solvent. The results of dynamic mechanical analysis illustrate that changes in solvent concentration and solvent quality affect the extent of primary cyclization during the polymerization. The results ...

PREDICTING NETWORK FORMATION OF FREE RADICAL POLYMERIZATION OF MULTIFUNCTIONAL MONOMERS

Free radical polymerization of multifunctional monomers leads to the formation of crosslinked polymer materials. These crosslinked polymers are heterogeneous networks caused by varying pendant reactivity and primary cyclization reactions. A kinetic model was utilized to probe the manner in which pendant double bonds react throughout the polymerization and to characterize the cycle size. The effects of crosslinking agent size, copolymerization, and solution polymerization were each examined. Increasing crosslinking agent size causes fewer small cycles to form and diminishes the total number of cycles that are created. Increasing the solvent concentration during polymerization has the converse effects of increasing the number of cycles that form within the first couple of repeat units and increasing the total fraction of pendants that form cycles. The model was further used to predict the molecular weight between crosslinks as a function of polymerization conditions.

Kinetic modeling of the effect of solvent concentration on primary cyclization during polymerization of multifunctional monomers

Controlling the swelling ratio, diffusion rate, and mechanical properties of a crosslinked polymer is important in hydrogel design for biomedical applications. Each of these factors depends strongly on the degree of crosslinking. Primary cyclization, where a propagating radical reacts intramolecularly with a pendant double bond on the same chain, decreases the crosslinking density and increases the molecular weight between crosslinks. Processing conditions, specifically the solvent concentration, strongly affect the extent of primary cyclization. In this work the effects of solvent concentration and comonomer composition on primary cyclization are investigated using a novel kinetic model and experimental measurement of mechanical properties. Two divinyl crosslinking agents were investigated, diethyleneglycol dimethacrylate (DEGDMA) and polyethyleneglycol 600 dimethacrylate (PEG(600)DMA), and each was copolymerized with hydroxyethyl methacrylate (HEMA) and octyl methacrylate (OcMA). The model is further used to predict the gel point conversion and swelling ratio of PAA hydrogels polymerized in the presence of varying amounts of water. Model results show how increasing the solvent concentration during the polymerization increases the molecular weight between crosslinks by nearly a factor of three and more than doubles the swelling ratio. Where possible, experimental results provide quantitative agreement with model predictions.

Primary cyclization in the polymerization of bis-GMA and TEGDMA: a modeling approach to understanding the cure of dental resins

An optimal dental restorative polymeric material would have a homogeneous cross-linking density giving it consistent mechanical strength throughout the material. When multifunctional monomers are polymerized, a pendant double bond can react intramolecularly with the radical on its propagating chain to form a loop, which results in a primary cyclization reaction. Primary cyclization does not contribute to overall network structure, causes microgel formation, and leads to heterogeneity in the polymer. Knowledge of how cure conditions control the degree of primary cyclization and cross-linking in the polymer is important in developing better dental materials. To gain more understanding about the evolving polymer network, the photopolymerization of a typical dental resin (75/25 wt% bis-GMA/TEGDMA) is modeled using a first principals approach. The overall polymerization rate behavior of 75/25 wt% bis-GMA/TEGDMA is predicted using experimentally obtained propagation and termination kinetic rate constants. The effect of chain stiffness and light intensity on the polymerization kinetics is also explored. Furthermore, the model predicts the extent of cross-linking and primary cyclization in the growing polymer network. At 45% conversion, the fraction of bis-GMA and TEGDMA pendant double bonds created that have cycled is 11 and 33%, respectively. The model shows that using a stiff monomer, like bis-GMA, in dental resins diminishes the extent of cyclization and increases the cross-linking density of the polymer. Therefore, better mechanical properties are obtained than if more flexible monomers were used.

Kinetics of Primary Cyclization Reactions in Cross-Linked Polymers: An Analytical and Numerical Approach to Heterogeneity in Network Formation

It is difficult to characterize the kinetics of cyclization reactions during free radical photopolymerization of multivinyl monomers because of the varying pendant double bond reactivities and inhomogeneities in the system. Primary cyclization, where a pendant double bond reacts intramolecularly with the propagating active center that formed it, leads to formation of microgels in the network. A new analytical and numerical approach is presented that solves the differential kinetic equations and can be used to investigate the factors influencing cyclization versus cross-linking reactions. Data are presented comparing two approaches, one based on numerical integration of the appropriate balances and one based on an analytical solution.

Kinetics and Mechanism of the Formation and Decomposition of Imidazolin-4-ones from 2-(N-Benzoylamino)alkanamides in Aqueous Medium

The cyclization reactions of substituted 2-(N-benzoyl-N-methyl)aminoalkanamides 1a-1g have been studied in aqueous medium. The Hammett reaction constant is ρ = 1.4 for the cyclization reactions of compounds 1a-1e in sodium hydroxide solutions. 2-[N-Methyl- N-(4-nitrobenzoyl)amino]-2-(4-nitrophenyl)propanamide (1g) is cyclized to imidazolinone 2g in aqueous amine buffers of pH 9-11.5; the reaction is subject to specific base catalysis in these media, and the rate-limiting step is the formation of a tetrahedral intermediate. In sodium hydroxide solution, the primary cyclization product is hydrolyzed to give an intermediate M which is subsequently decomposed to sodium 4-nitrobenzoate and 2-methylamino- 2-(4-nitrophenyl)propanamide. At low sodium hydroxide concentration, the rate-limiting step of the opening of imidazoline ring of compound 2g is non-catalyzed decomposition of the intermediate. At higher sodium hydroxide concentrations, the other reaction path begins to make itself felt: hydroxide-ion-catalyzed decomposition of the intermediate. The dependence of observed rate constant of cyclization of compound 1f on sodium hydroxide concentration was used to determine kinetically the value of pKa = 13.5 ± 0.1. The kinetic deuterium isotope effect of cyclization of compounds 1f giving 2f (kCH/kCD = 1.7) was determined in solutions of NaOD in D2O.