Internal Cyclization Research Articles

Preparation of hyperbranched macromolecules with aryl fluoride and phenol terminal functionalities using new monomers and Cs2CO3 or Mg(OH)2 as the condensation agent

New A2B monomers were synthesized for preparation of hyperbranched aryl ether sulfone macromolecules with aryl fluoride and phenol terminal functionalities. The macromolecules, which possess high thermal stability, were prepared using the divergent approach. A masked phenol with two aryl fluoride groups and a bisphenol with an aryl fluoride group were the monomers used to synthesize these polymers. In both cases, the aryl fluoride group is activated by a sulfone moiety. The synthetic method used for the preparation of the hyperbranched macromolecules gave a fast reaction and a high yield. These methods include, e.g., the use of Cs2CO3 and Mg(OH)2 to generate the phenolate ion in situ. Use of the latter results in the formation of insoluble magnesium fluoride. The best conditions for the reaction utilized the more active nucleophilic polycondensation agent, Cs2CO3, and an aryl carbonate as a masked phenol. NMR, SEC, and MALDI-TOF-MS were used to characterize the samples. MALDI-TOF-MS allowed us to identify the different oligomeric species present, and it also indicated that an internal cyclization competes with the polymerization. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 2015–2033, 1997

Unimolecular Chemistry of Protonated Diols in the Gas Phase: Internal Cyclization and Hydride Ion Transfer

Unimolecular dehydration of protonated α,ω-diols in the gas phase has been examined by both tandem mass spectrometry experiments, including metastable ions decompositions, collisional activation, and neutralization−reionization techniques, and molecular orbital calculations up to the MP2/6-311G**//MP2/6-31G*+ZPE level. Two reaction mechanisms were found to explain the experimental observations: one leading to a protonated cyclic ether via an internal nucleophilic substitution and one giving a protonated carbonyl species after hydride ion transfer from the α-carbon to the ω-position. Our major findings are the following: (i) protonated 1,2-ethanediol exclusively leads to protonated acetaldehyde via a concerted pinacol rearrangement with the calculated critical energy equaling 99 kJ/mol; (ii) protonated 1,3-propanediol gives protonated oxetane at low internal energy and protonated propanal at high internal energy with the calculated critical energies of the reactions equaling 144 and 163 kJ/mol, respectively, and the competition between the two reactions being explained by the internal energy effect upon dissociation rate constants; (iii) for 1,4-butanediol and 1,5-pentanediol, the dehydration produces only the corresponding protonated cyclic ether with calculated critical energies equal to 110 and 107 kJ/mol, respectively.

Directed approaches to reactive maillard intermediates: Formation of a novel 3-alkylamino-2-hydroxy-4-hydroxymethyl-2-cyclopenten-1-one (“Cypentodine”)

Dehydration of the 4- and 5-hydroxyls of an Amadori product would lead to a reactive potential cross-linker, 1,4,5-trideoxy-1-alkylamino-2,3-hexulos-4-ene (AP-ene-dione) which has as yet only been isolated in low yield as a triacetylated 1,2-enol. We have prepared a 4,5-di- O-tosyl Amadori product as an activated precursor to AP-ene-dione. Incubation of this precursor under physiological conditions yields a novel cyclopentenone aminoreductone, 3-alkylamino-2-hydroxy-4-hydroxymethyl-2-cyclopenten-1-one, presumably derived from internal cyclization of AP-ene-dione.

SINDO1 study of the photochemical synthesis of azacyclobutadiene from 1,4‐oxazin‐2‐one

AbstractThe mechanism of the photochemical decomposition of 1,4‐oxazin‐2‐one to azacyclobutadiene and carbon dioxide was investigated by the semi‐empirical MO method SINDO1. The relevant singlet and low‐lying triplet potential energy hypersurfaces were studied and intermediates and transition structures were optimized with limited configuration interaction. The first step transforms 1,4‐oxazin‐2‐one into a bicyclic lactone via internal cyclization. Then a stepwise bond breaking mechanism on the first excited triplet state yields azacyclobutadiene and CO2, whereas a reaction on the first excited singlet state is not common. It is shown that a simultaneous bond‐breaking mechanism on the first excited singlet or on the first excited triplet is possible.

Structure-induced Strain Determining the Internal Cyclization Site in the Yeast cobI5 Autocatalytic Intron: Theory and Experimental Tests

The terminal intron of the apocytochrome b gene of yeast is endowed with autocatalytic potential in vitro and has been also shown to be capable of internal circularization at the linkage 236-237 from the 5′ extremity. The aim of this work is to identify the secondary interaction responsible for shaping and activating the internal cyclization site (ICS). This is done by simulating the sequential folding of an abnormally large fragment of 237 nucleotides which starts at the 5′ cleavage site and contains the internal guide sequence (IGS) starting 220 nucleotides into the intron. The resulting portion of the overall structure features the conserved interaction P1 and is compatible with the complete consensus secondary structure for this intron. The structural motif which emerges from sequential folding and is responsible for shaping the ICS is confirmed by analyzing the localization of structure-induced strain in the RNA backbone. It is shown that after the conserved stem P1 has been dismantled, the highest strain in a phosphodiester linkage is localized internally precisely at the experimentally determined cyclization site. Moreover, it is shown that our dynamical model of folding is compatible with the actual reaction pathways. Thus, internal cyclization becomes feasible only after conserved interaction P1 has been dismantled. This last event, in turn, might take place as a consequence of either of the following events: (i) 5′ cleavage caused by nucleophilic attack by the GTP-cosubstrate or (ii) excision of the 3′ exon after prior formation of P10. This last event, in turn, requires dismantling helix P1. Moreover, event (ii) is necessary for internal circularization since it habilitates the 3′ terminal guanosine as a nucleophilic agent.

Modeling of Free-Radical Polymerization Kinetics with Crosslinking for Methyl Methacrylate/Ethylene Glycol Dimethacrylate

A model has been developed to represent polymerization kinetics with crosslinking up to, and past, the gelpoint. Based upon the method of moments, the representation predicts the changes in polymer molecular weight (MW) as branching occurs, and provides a measure of the MW increase caused by the crosslinker. Loss of pendant double bonds by internal cyclization and decrease in branching rate due to diffusion limitations are included. The Ross-Laurence correlation for diffusion-controlled termination has been modified to predict the faster rate acceleration that occurs in lightly crosslinked systems and the delayed Trommsdorff effect observed upon addition of chain transfer agent. The model successfully represents gelpoint and rate data for methyl methacrylate (MMA) polymerization for a wide range of ethylene glycol dimethacrylate (EGDMA) levels, with and without the presence of chain transfer agent.

Thermal degradation of polymethacrylonitrile

The thermal degradation properties of polymethacrylonitrile (PMAN) have been studied by isothermal heating and thermogravimetric analysis. There are two initiation processes for weight loss from PMAN degraded in nitrogen, namely chain-end and random scission initiation. There is also an internal cyclization reaction which forms a thermally stable residue during the thermal degradation process. The activation energies of the weight loss and formation of stable residues have been calculated. X-ray photoelectron spectroscopy has been used to investigate the structure of the stable residue and thus to confirm the degradation mechanism.

Oxidation of monohydric phenol substrates by tyrosinase. An oximetric study.

The purity of commercially available mushroom tyrosinase was investigated by non-denaturing PAGE. Most of the protein in the preparation migrated as a single band under these conditions. This band contained both tyrosinase and dopa oxidase activity. No other activity of either classification was found in the preparation. Oxygen consumption by tyrosinase during oxidation of the monohydric phenol substrates tyrosine and 4-hydroxyanisole (4HA) was monitored by oximetry in order to determine the stoichiometry of the reactions. For complete oxidation, the molar ratio of oxygen: 4HA was 1:1. Under identical conditions, oxidation of tyrosine required 1.5 mol of oxygen/mol of tyrosine. The additional oxygen uptake during tyrosine oxidation is due to the internal cyclization of dopaquinone to form cyclodopa, which undergoes a redox reaction with dopaquinone to form dopachrome and dopa, which is then oxidized by the enzyme, leading to an additional 0.5 mol of oxygen/mol of original substrate. Oxygen consumption for complete oxidation of 200 nmol of 4HA was constant over a range of concentrations of tyrosinase of 33-330 units/ml of substrate. The maximum rate of reaction was directly proportional to the concentration of tyrosinase, whereas the length of the lag phase decreased non-linearly with increasing tyrosinase concentration. Activation of the enzyme by exposure to citrate was not seen, nor was the lag phase abolished by exposure of the enzyme to low pH. Michaelis-Menten analysis of tyrosinase in which the lag phase is abolished by pre-exposure of the enzyme to a low concentration of dithiothreitol gave Km values for tyrosine and 4HA of 153 and 20 microM respectively.

Ｏ‐グリコシドの合成手法における最近の進歩

The present article deals with a short review on the recent methodological progress in O-glycoside synthesis. Particular stress is laid on the design of newer classes of glycosyl donor, which allow the selective activation/O-glycoside formation under specific reaction conditions. Based on the anomeric leaving group, glycosyl donors are classified into nine classes, 1) fluoride, 2) thioglycoside, 3) O-acylate, 4) O- and S-carbonate derivatives, 5) phosphate derivatives, 6) trichloroacetimidate, 7) 1-hydroxyl sugar, 8) 4-pentenyl glycoside, 9) glycal, and their selective activation methods are tabulated. Also described are the other approaches based on different principles, e.g., glycosylidene carbene, anomeric O-alkylation, internal cyclization or glycoside synthesis based on physical means;light, electric, thermal, and high pressure. Recent topics in this field are also included, 1) new protecting groups, 2) stereochemical control in manno- and 2-deoxy-sugars, and 3) the armed/disarmed concept.

Solid-State Carbon-13 Studies of Vulcanized Elastomers. VIII. Accelerated Sulfur-Vulcanized Butyl Rubber at 75.5 MHz

Abstract The chemical microstructural changes of an accelerated sulfur cure of IIR with TMTD/ ZnO/sulfur have been elucidated. No reaction occurs in the isobutylene units. Isomerization occurs at the initial stages of vulcanization and reaches an equilibrium at 30–35 min. Sulfurization initially results in III and VI and is polysulfidic in nature. At cure times greater than 75 min, desulfurization of III and VI occurs and mono- and poly-sulfidic sulfurization giving IV and VII occurs. The reaction rate of III and VI is much greater than that of IV and VII. Equilibrium swelling measurements have been shown to correlate with rheometry measurements for this system and have shown that polysulfldic III and VI correlate with an increase in properties, while mono- and poly-sulfldic IV and VII correlate with reversion. No migration of the double bond, saturation, internal cyclization, or sulfurization resulting in V and VIII were observed.

Acid-catalysed rearrangement of 1-oximinoacridine-1,9-diones. synthesis of novel 4,5-dihydro-3H-isoxazolo[3,4,5-kl]acridines

A polyphosphoric acid (PPA) catalysed internal cyclization of 1 -oximinoacridine-1,9-diones 2 to novel isoxazolo[3,4,5-kl]acridines 3 is reported. Some of the compounds displayed antimalarial activity in animal models

αβ-Dehydro-3,4-dihydroxyphenylalanine derivatives: Rate and mechanism of formation

The amino acid l-3,4-dihydroxyphenylalanine (DOPA), when present in the primary sequence of proteins, does not form melanin upon oxidation to the quinone, since its amine moiety participates in a peptide bond and cannot undergo internal cyclization. Instead, peptidyl DOPA quinone is available for other reactions. We have investigated the oxidation chemistry of a low molecular weight peptidyl DOPA analog, N-acetylDOPA ethyl ester (NAcDEE), and have shown that a major product of oxidation is an unsaturated DOPA derivative, N-acetyl-α,β-dehydroDOPA ethyl ester (NAcΔDEE) (see companion paper, Rzepecki et al., Arch. Biochem. Biophys. (1991) 285, 17–26 . In the present study, we have explored kinetic and mechanistic features of the conversion of NAcDEE to NAcΔDEE and found that the reaction requires: (i) oxidation of NAcDEE to the quinone, (ii) the presence of a Lewis base as a catalyst (phosphate anion was the best of those tried in the pH range 6.0–8.0), and (iii) prevention of competing reactions such as Michael additions. Conversion efficiencies in the presence of Lewis bases ranged between 12 and 19% at pH 8.0 and 35 and 90% at pH 6.0. At least two separate reaction mechanisms appeared necessary to explain the kinetic data: (i) a pseudo-first-order mechanism at pH 6.0 and above, and (ii) an additional second-order mechanism at higher pH which involved both NAcDEE catechol and quinone. The apparent pseudo-first-order rate constants increased with pH from 2.36 × 10 −4 s −1 at pH 6.0 to about 30 × 10 −4 s −1 at pH 8.0 in 0.1 m sodium phosphate. Tautomerization of DOPA quinone to dehydroDOPA may thus be a factor in the sclerotization of natural structures incorporating DOPA containing proteins.

Synthesis of technetium-99m labeled diaminodithiol for bifunctional chelating agents

Diaminodisulfide analogs ( 2a–b) were prepared by reduction of the intermediate Schiff's bases ( 1a–b) with sodium cyanoborohydride (NaBH 3CN) in dry diethyl ether under acidic condition without inducing internal cyclization reaction. The less sterically hindered NH proton of the diaminodisulfide ( 2b) could be successfully displaced by functional groups. The diaminodulfides ( 2a–b, 4c) were quickly converted to diaminodithiol (DADT; 5a–b, 6c) by reduction with a small amount of lithium aluminium in refluxing dry diethyl ether for 20 min, whereas reduction of bicyclic diaminodisulfides ( 3a–b) with excess LiAlH 4 did not produce the desired DADT ( 5a–b). Reduction of the other bicyclic diaminodisulfide including a functional group (methyl group) ( 3′c) with excess LiAlH 4 produced the DADT including a functional group in the sterically hindered nitrogen atom ( 8). Diaminodiathiol analogs including an N-functional group, such as N- p-iodophenethyl ( 6d), were synthesized without deiodination by a new revised procedure. The chelating ability of these ligands ( 5a–b, 6c–d, 8c) for Tc-99m was determined by thin-layer chromatography (TLC). The radiochemical yield of the Tc-99m labeled 5a–b, 6c–d, 8c was more than 95%. These results indicated that the DADTs including a functional group in the less sterically and the sterically nitrogen atom prepared by our new method have high chelating ability and high stability of Tc-99m and appear to be an attractive candidate as a useful chelator for bifunctional chelating agents.

Coupling of electronic and nuclear motion in the photochemical internal cyclization of pyrrole

The importance of coupling between electronic and nuclear motion for the photochemical internal cyclization of pyrrole and 2-cyanopyrrole is illustrated by generalized potential curves along the reaction pathway. After the generation of CI surfaces with the SINDO1 method, the scalar portion of electronic-nuclear coupling is included in the potential surfaces. The curves show significant coupling at two intermediates and demonstrate the feasibility of internal conversion in these regions.

PQQ: Biosynthetic studies inMethylobacterium AM1 andHyphomicrobium X using specific13C labeling and NMR

Using 13C labeling and NMR spectroscopy we have determined biosynthetic precursors of pyrroloquinoline quinone (PQQ) in two closely related serine-type methylotrophs, Methylobacterium AM1 and Hyphomicrobium X. Analysis of the 13C-labeling data revealed that PQQ is constructed from two amino acids: the portion containing N-6,C-7, 8, 9 and the two carboxylic acid groups, C-7' and 9', is derived-intact -from glutamate. The remaining portion is derived from tyrosine; the phenol side chain provides the six carbons of the ring containing the orthoquinone, whereas internal cyclization of the amino acid backbone forms the pyrrole-2-carboxylic acid moiety. This is analogous to the cyclization of dopaquinone to form dopachrome. Dopaquinone is a product of the oxidation of tyrosine (via dopa) in reactions catalyzed by monophenol monooxygenase (EC 1.14.18.1). Starting with tyrosine and glutamate, we will discuss possible biosynthetic routes to PQQ.

Detection and quantification of non-steroidal anti-inflammatory agents by gas chromatography/mass spectrometry: diclofenac.

A sensitive and reliable gas chromatography/mass spectrometric assay for diclofenac in plasma using selected ion monitoring is described. The procedure is based on the acidic extraction of diclofenac and ketoprofen (internal standard) with toluene. Both compounds are converted into their ethyl ester derivatives with ethanol containing 0.5% (v/v) sulphuric acid. No internal cyclization to indolone side product is produced in these conditions. The ions monitored are m/z 214 for diclofenac and m/z 209 for ketoprofen. The main recovery of diclofenac added to plasma has been estimated around 84.6% (120 ng ml-1, n = 4). The intra-assay and inter-assay variability were 1.9% and 10.3%, respectively. The sensitivity was lower than 2 ng ml-1. The applicability of the assays to study the bioavailability of two formulations in a multiple-dosage trial is described. The method has been used in more than 600 determinations without any interference.

Carbonyl ylide formation from the rhodium (II) acetate catalyzed reaction of a α-diazoketone

Reaction of the α-diazoketone derived from 7-carboxyphthalide with rhodium acetate results in an internal cyclization to give a six-ring carbonyl ylide which is subsequently converted to 7-carbomethoxyphthalide.

Cyclization of methacrylate–functional silane on particulate clay

AbstractPhysically absorbed γ‐methacryloxypropyltrimethoxysilane (γ‐MPS) deposited from aqueous alcohol on particulate clay exists as low‐molecular‐weight cyclic, caged polysilsesquioxanes. These structures are incapable of forming high‐molecular‐weight chains or networks because of this internal cyclization tendency. The behavior is extremely different from that found in bulk solutions or when organofunctional silanes are adsorbed on low‐surface‐area glass or metal substrates. Fourier‐transform infrared spectroscopy and gel permeation chromatography were used to characterize the silane species deposited in bulk and on the surface of particulate clay. The cyclization tendency is postulated from analysis of the behavior of hydrolyzed γ‐methacryloxypropyltrimethoxysilane upon cocondensation with other organofunctional silanes and under variable cure conditions.

Chemical intermediates in α-methylnoradrenaline oxidation by tyrosinase—II. Kinetic study of process

1. 1. The pathway for α-methylnoradrenaline oxidation to α-methylnoradrenochrome by tyrosinase. has been studied as a system of various chemical reactions coupled to an enzymatic reaction. 2. 2. A theoretical and experimental kinetic approach was proposed for such a system, we named this type of mechanism as a mechanism enzymatic-chemical-chemical (E 2CC). 3. 3. Rate constants for the implied chemical steps at different temperature and pH values, were evaluated from measurement of the lag period, arising from the accumulation of aminochroine, that took place when α-methylnoradrenaline was oxidized at acid pH. 4. 4. The thermodynamic activation parameters of the chemical steps, the deprotonation and the internal cyclization of o-quinone into leukoaminochrome, were also calculated.

Chemical intermediates in dopamine oxidation by tyrosinase, and kinetic studies of the process

A minor pathway for dopamine oxidation to dopaminochrome, by tyrosinase, is proposed. Characterization of intermediates in this oxidative reaction and stoichiometric determination have both been undertaken. After oxidizing dopamine with mushroom tyrosinase or sodium periodate in a pH range from 6.0 to 7.0, it was spectrophotometrically possible to detect o-dopaminoquinone-H + as the first intermediate in this pathway. The steps for dopamine transformation to dopaminochrome are as follows: dopamine → o-dopaminequinone-H + → o-dopaminequinone → leuko-dopaminochrome → dopaminochrome. No participation of oxygen was detected in the conversion of leukodopaminochrome to dopaminochrome. Scanning spectroscopy and graphical analysis of the obtained spectra also verified that dopaminequinone-H + was transformed into aminochrome in a constant ratio. The stoichiometry equation for this conversion is 2 o-dopaminequinone-H + → dopamine + dopaminochrome. The pathway for dopamine oxidation to dopaminochrome by tyrosinase has been studied as a system of various chemical reactions coupled to an enzymatic reaction. A theoretical and experimental kinetic approach is proposed for such a system; this type of mechanism has been named “Enzymatic-chemical-chemical” (E ZCC). Rate constants for the implied chemical steps at different pH and temperature values have been evaluated from the measurement of the lag period arising from the accumulation of dopaminochrome that took place when dopamine was oxidized at acid pH. The thermodynamic activation parameters of the chemical steps, the deprotonation of dopaminequinone-H + to dopaminequinone, and the internal cyclization of dopaminequinone to leukodopaminochrome have been calculated.