Bicyclic Bisureas Research Articles

Glycoluril and Its Chemical Properties

In the chemistry of heterocyclic compounds, bicyclic bisureas — glycolurils, have a special place. Glycolurils are used as a basis for the industrial production of substances that have found application in many areas of human life. The variety of glycoluril derivatives and their properties is primarily due to various substituents in the bicyclic structure. In this review, 2,4,6,8-tetraazabicyclo[3.3.0.]octane-3,7-dione (glycoluril), as the main representative of bicyclic bisureas, its physico-chemical properties, and methods for the synthesis of derivatives based on it are considered. In particular, the main physico-chemical characteristics of glycoluril and the data obtained from its spectral analysis by IR, NMR spectroscopy and X-ray diffraction analysis are presented and discussed. The paper briefly outlines the known methods for the synthesis of glycolurils and related compounds, also highlights the chemical properties of glycoluril and its derivatives, as well as the ways to modify them. Coordination compounds based on N-alkylglycolurils as ligands are briefly considered. The reaction products of N-halogenation and N-acylation of glycolurils are presented and discussed. Reactions for obtaining phosphorus-, nitro- and nitroso derivatives of glycolurils; alkylation methods, Mannich reactions, thionization, alkaline hydrolysis and reduction reactions at the carbonyl group of glycolurils are also shown. There is a discussion of the macromolecules formation in the condensation reaction of glycoluril with formaldehyde as precursors for the synthesis of cucurbit[n]urils.

Study of glycoluril and its derivatives by 1H and 13C NMR spectroscopy

Bicyclic bisureas, especially 2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione (glycoluril), have a special place in chemistry of heterocyclic compounds. The carbamide fragment in glycoluril structure determines the properties of the molecule, which are due to the presence of two reaction centers (NH-groups and C=O-groups) in the molecule. In this work, we analyzed the proton and carbon chemical shifts of glycoluril and its derivatives (86 compounds) in the NMR spectra to reveal the effect of the donor-acceptor substituents on the changes in the electron density in the bicyclic framework from the position of symmetry and asymmetry. A general analysis of the 1H and 13C NMR spectra of glycolurils makes it possible to accurately determine the spatial configurations of molecular symmetry, in the presence of which (σ1 and / or σ2) the enantiotopic hydrogen and carbon atoms of the bicyclic framework are manifested by equivalent signals. Also, according to the 1H and 13C chemical shifts in the NMR spectra, glycolurils with electron-acceptor substituents can be clearly distinguished by the shielding of carbon atoms of C=O-groups, and with electron-donating substituents by the deshielding of CH-CH-carbons, due to the rearrangement of electron density and the occurrence of local paramagnetic contributions owing to anisotropy.

BIS-DEACETYLATION OF TETRAACETYLGLYCOLURYL UNDER ACTION OF UREAS

It is established that tetraacetylglycoluril under the action of urea, some N-substituted ureas and benzylidenebisurea in the acid-catalyzed conditions undergoes only bis-deacetylation with the formation of syn- and anti-regio-substituted N,N-diacetylglycolurils, rather than N-acetylation as it was previously shown in a similar reaction for a number of aromatic and heterocyclic amines. In the course of individual experiments, the absence of independent effect of organic solvents during boiling for several hours (alcohols, dioxane, tetrahydrofuran, dimethylsulfoxide) on the deacetylation of tetraacetylglycoluril was revealed, since in these conditions the original substrate remained unchanged. Based on the NMR spectroscopy data, by comparison the integrated intensities of methine and acetyl protons of glycoluryl fragments, we found that the bis-deacetylation of tetraacetylglycoluril in the studied conditions occurs regioselectively with an overwhelming majority of anti-N,N-diacetylglycoluril (up to 92-94%) except for benzylidenebisurea, when the content of the trans-isomer reaches 75%. A marked increase in the cis-isomer (up to 25%) of N,N-diacetylglycoluril in the case of benzylidenebisurea seems to be dictated by the specific effect on the intermediates of reaction of phenylmethylureido carbocation from eliminating urea molecule in acid-catalyzed conditions. It is shown that N,N-diacetylglycoluril in similar conditions under the action of urea and its derivatives does not undergo further deacetylation to the progenitor of bicyclic bisureas – glycoluril, primarily related to the high hydrolytic and steric resistance of these compounds. On the basis of the above research results, the reaction mechanisms of bis-deacetylation of tetraacetylglycoluril in the acid-catalyzed conditions under the action of urea and its N-methyl (phenyl) derivatives through an intermediate process of nucleophilic addition of ureas is proposed.Forcitation:Hoang N.P., Bakibaev A.A., Malkov V.S. Bis-deacetylation of tetraacetylglycoluryl under action of ureas. Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 2018. V. 61. N 7. P. 49-53

Standard volumetric characteristics of N-dimethyl-substituted bicyclic bisureas (glycolurils) in water at T = (278.15 to 318.15) K and p ~ 0.1 MPa

Densities of aqueous solutions of achiral cis-dimethylglycoluril (2,8-DMGU) and chiral (in the racemic form) trans-dimethylglycoluril (2,6-DMGU) were measured using a hermetically sealed vibrating-tube densimeter, with an uncertainty of ~1×10−5g∙cm−3, at T=(278.15, 288.15, 298.15, 308.15, and 318.15) K and p=(99.6±0.4) kPa. The solution molality was ranged from (0.037 to 0.396) mol·kg−1 for aqueous 2,6-DMGU and from (0.046 to 0.202) mol·kg−1 for aqueous 2,8-DEGU. The standard (at infinite dilution) molar volumes and isobaric molar expansibilities for the specified N-dimethyl-substituted heterocyclic compounds in water were computed and discussed in comparison with previously derived results for the equimolecular 2,4-dimethylglycoluril (2,4-DMGU) whose isomeric molecules contain simultaneously both the unsubstituted and fully methylated five-membered rings. It was established that the compared glycoluril-derivatives are the prevailingly structure-breaking solutes in water despite of presence of two methyl groups in each of heterocyclic molecules. In other words, the hydrophobic hydration effect is being less pronounced than the hydrophilic hydration or H-bonding effect (via amide and carbonyl groups). The temperature-dependent behavior of packing-related hydration effects was described taking into account the structural (stereochemical) features of a solute molecule.

Effect of glycoluril and its derivatives on the flame resistance and physico-mechanical properties of rubber

The effect of bicyclic bisureas (glycolurils) and their derivatives functionalized with hydroxymethyl, halomethyl, and dimethoxyphoshorylmethyl groups on the flame resistance and physico-chemical properties of synthetic isoprene and divinyl rubbers was studied, and the procedures for preparing these agents were suggested. The rubbers with the addition of the synthesized bicyclic bisureas demonstrated satisfactory levels of flame resistance and physico-mechanical parameters.

ChemInform Abstract: New Condensation Methods in the Synthesis of Bicyclic Bisureas.

For the first time, synthetic approaches to bicyclic bisureas of the octane series bearing three alkyl substituents at nitrogen atoms have been developed.

New condensation methods in the synthesis of bicyclic bisureas

For the first time, synthetic approaches to bicyclic bisureas of the octane series bearing three alkyl substituents at nitrogen atoms have been developed.

Analysis of the variety of effects of the tranquilizer mebicar in experimental and clinical medicine

The drug mebicar, which gave rise to a new class of chemicals with psychotropic activity - derivatives of bicyclic bisureas, has been experimentally studied for more than 20 years, and clinical experience with its use has been accumulating since 1979. During this short time on the scale of pharmacology, experimental substantiation and clinical confirmation of its effectiveness have been obtained in a number of ways. new indications in various fields of medicine: psychiatry, narcology, cardiology, anesthesiology, neuropathology, gynecology, gerontology, dentistry, sports medicine, etc. The versatility of the therapeutic effects of the drug has created a precedent that attracts the attention of specialists. The question arises about the fundamental possibility of such a variety of therapeutic activity of the drug and the mechanisms for its implementation.

Synthetic anticonvulsants, antihypoxics, and inducers of the liver monooxygenase system based on amides and ureas. XVI. Studies of the antihypoxic properties of bicyclic bis-ureas

Synthetic anticonvulsants, antihypoxics, and inducers of the liver monooxygenase system based on amides and ureas. XVI. Studies of the antihypoxic properties of bicyclic bis-ureas

Geometrical aspects of complex formation by bicyclic bisureas

Geometrical characteristics of complexes of bicyclic bisureas (BBUs) of the octane series with biological metals (Co, Li, and Zn) have been studied using molecular mechanics. It was established that formation of the complexes [Co(BBU)2-(H2O)2-X2], [Li·BBU·(H2O)3]·X, [Zn·BBU·Cl2·(H2O)], and [Li2·(μ-BBU)2·(H2O)4]·X2 is not sterically hindered.

ChemInform Abstract: Synthesis of Bicyclic Bisureas and Imidazole Derivatives from Aromatic α‐Hydroxy Ketones and Ureas.

AbstractThe aromatic α‐hydroxy ketones (I) and (VI) are coupled with urea (IIa) in the presence of sulfuric acid on exposure to air to give the bicyclic bisureas (IIIa) and (VII) respectively.

Spatial structure of bicyclic bisureas

The method of molecular mechanics has been used to examine the spatial structure of bicyclooctane, bicyclononane, bicyclodecane, purone, and spiran bicyclic bisureas (BBU). Bicyclononanediones have been shown to exist in a planar form with planar urea groups, whereas spiro[5,5]undecanedione exists in the chair-chair form. On introducing N-alkyl groups, steric hindrance in bicyclooctane and bicyclononane BBU is eliminated by reorientation of the urea fragment NCN, and in bicyclodecane BBU, by reorientation of the CNCNC fragment.

Electronic structure of bicyclic bisureas

1. A CNDO/2 calculation gave the electronic parameters of representative bicyclic bisureas of the bicyclooctane, bicyclononane, purone, and spirane series. 2. A comparison of the electron densities on the atoms, which are potential coordination sites with biometals, showed that the coordination of the BBM at the oxygen atoms is preferable to coordinaton at the nitrogen atoms. 3. The relative changes in the charges on the oxygen and nitrogen atoms indicate that not only the carbonyl group oxygen atoms but also the ring nitrogen atoms are possible coordination sites, and substituents affect the charges on the atoms capable of coordination with metals.

Dication ethers. 7. Dication ether salts from cyclic bisureas

AbstractThe bicyclic bisureas 2 react with triflic anhydride to give the dication ether salts 4. Further transformation of the remaining carbonyl groups of 4 into bis‐carbenium ether linkages was not possible. The monocyclic bisurea 8 yields the dicationic heterocycle 9 in an intramolecular fashion. The structure of 9, which is the first dication ether salt with an endocyclic ether linkage, was established by independent synthesis from 10 as well as by its hydrolysis to give the hemi‐protonated bisurea 11.

The chemistry of bicyclic bisureas. 4. Reduction of bicyclic bisureas and their O-alkyl derivatives

1. When LiAlH4, is allowed to react with unsubstituted, di-, and tetra-N-alkylated bicyclic bisureas (BBU) of the octane and nonane series, reduction takes place only in the case of tetra-N-alkyl BBU, reduction of one or both carbonyl groups taking place according to the structure of the BBU. 2. Reaction of non-N-alkylated O-alkyl BBU with nucleophilic reagents results in deprotonation with the formation of bicyclic isoureas.

The chemistry of bicyclic bisureas. 3. The synthesis and hydrolytic stability of the difluoroborate salts of 3,7-diethoxy-2,6-diaza-4,8-diazoniabicyclo[3.3.0]octane-3,7-dienes and 3,7-diethoxy-2,6-diaza-4,8-diazoniabicyclo[3.3.1]non-ane-3,7-dienes

1. Unsubstituted and tetra-N-methyl-substituted bicyclic bisureas (BBU) of the octane and nonane series on reaction with triethyloxonium fluoroborate form O-alkylation products at both carbonyl groups, namely the difluoroborates of 3,7-diethoxy-2,6-diaza-4,8-diazoniabicyclo[3.3.0]octane-3,7-dienes and 3,7-diethoxy-2,6-diaza-4,8-diazoniabicyclo[3.3.1]nonane-3,7-dienes. 2. On hydroylsis of the O-alkylation products of tetra-N-methyl-substituted BBU, the reaction resulting in the fission of one of the rings predominates.

The chemistry of bicyclic bisureas

A general preparative method has been developed for the alkylation of BBU with various structures using alkyl iodides and liquid ammonia by the action of sodium amide in the presence of alkali halide salts.

The chemistry of bicyclic bisureas 1. Synthesis of 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones and 2,4,6-8-tetraazabicyclo[3.3.1]nonane-3,7-diones by the reaction of ureas with ?- and ?-dicarbonyl compounds

1. The monooximes of alkyl- and aryl-α-dicarbonyl compounds gave 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione only with the unsubstituted urea. 2. The most favorable conditions for the preparation of tetra-N-methyl derivatives of 2,4,6,8-tetraaza-bieyclo[3.3.1]nonane-3,7-diones by the condensation of N,N'-dimethylurea with malonic aldehyde tetraacetal and its substituted derivatives were established.