Solubility of heterocyclic compounds

In general, the solubility of heterocyclic compounds in water (Table 36) is enhanced by the possibility of hydrogen bonding. Pyridine-like nitrogen atoms facilitate this (compare benzene and pyridine). In the same way, oxazole is miscible with water, and isoxazole is very soluble, more so than furan. 

The effect of amino, hydroxy or mercapto substituents is to increase hydrogen bonding properties. However, if stable hydrogen bonds are formed in the crystal, then this can decrease their solubility in water (63PMH(l)177), e.g. indazole and benzimidazole are less soluble than benzoxazole. 

Other solvents can be divided into several classes. In hydrogen bond-breaking solvents (dipolar aprotics), the simple amino, hydroxy and mercapto heterocycles all dissolve. In hydrophobic solvents, hydrogen bonding substituents greatly decrease the solubility. Ethanol and other alcohols take up a position intermediate between water and the hydrophobic solvents (63PMH(1)177). 

Compound Parts soluble in 1 part of water Compound Parts soluble in 1 part of water 

Structure of Five-membered Rings with Two or More Heteroatoms 

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The Solubility of Heterocyclic Compounds , W. Pfleiderer, in Physical Methods in Heterocyclic Chemistry , ed. A. R. Katritzky, Academic Press, New York, 1963, vol. 1, pp. 177-188. 

Oxirane (1) and methyloxirane (3) are miscible with water, ethyloxirane is very soluble in water, while compounds such as cyclopentene oxide and higher oxiranes are essentially insoluble (B-73MI50501) (for a discussion of the solubilities of heterocycles, see (63PMH(l)l77)). Other physical properties of heterocycles, such as dipole moments and electrochemical properties, are discussed in various chapters of pmh. The optical activity of chiral oxiranes has been investigated by ab initio molecular orbital methods (8UA1023). 

Of the substances studied the most abundant in the Paleozoic rocks of the area are furfurals presumably derived from carbohydrates, higher molecular weight hydrocarbons, and in a few samples, amino acids. Acid and base soluble, low boiling substances having some properties of heterocyclic compounds, phenols, and organic acids exist in smaller amounts. 

The NMR spectra of heterocyclic betaines and compounds with a betaine character 1 may lead to a deeper insight into their dipolar nature. Both H and C NMR results have proved to be crucial for structural proof and also for providing evidence of charge distribution within the molecule the choice of the solvents was dictated by the solubility of the compounds 1. N NMR and high-resolution solid-state CNMR spectroscopy have not been yet used to study the betaines referred to above. 

Early studies on the chemistry of the bryophytes have been summarized by Benesova and Herout 86), Hegnauer 141), Huneck 150 —153,156), Martensson and Nilsson 205a), Spencer 303) and Suire 307). A review of heterocyclic compounds found in the bryophytes was also presented (37). Recently, Markham and Porter 199) have reviewed the chemical constituents of the bryophytes their review includes sesquiterpenoids, water soluble flavonoids, lignins, lipids and bibenzyls published prior to 1978, flavonoid chemistry and chemosystematic approaches to the Marchantiales being discussed in detail. In the three years since publication of this review, 121 papers on the chemistry of the Hepaticae have been published. 

These compounds show the typical reactions of heterocyclic N-oxides and their structure was proved by methylation which takes place on N-1. Quinazoline 3-oxide is soluble in water and melts at 155°C. It has basic properties and its pKa value in water is 1.47. ... 

Colby J, DI Stirling, H Dalton (1977) The soluble methane mono-oxygenase of Methylococcus capsulatus (Bath). Its ability to oxygenate -alkanes, -alkenes, ethers, and alicyclic, aromatic and heterocyclic compounds. Biochem J 165 395-401. 

Levonantradol (8.4) was synthesized with the intention to introduce a basic amino function into the heterocycle in the hope of obtaining water-soluble salts. Although the solubility of the hydrochloride is not good it was possible to get stable aqueous micellar solutions with the aid of emulsifiers [145] and the compound made its way as an injectable into clinical trials, but never was approved. 

The peripheral selenodiazole rings of porphyrazine (169) can be opened upon treatment with H2S with the proposed formation of the octaaminoporphyrazine (184), which was not isolated and instead converted into the tetrakis(pyrazino)porphyrazine (185) (Scheme 34) (171). Other heterocycles have been fused on the periphery of porphyrazines, such as l,3-dithiol-2-thione in order to extend the aromatic core (172). Macrocyclization of 4,5-dicyano-l,3-dithiole-2-thione (186) under Linstead conditions in the presence of magnesium butoxide produced the symmetrically substituted tetrakis(l,3-dithiol-2-thiono)porphyrazine (187) (Scheme 35). Due to the low solubility of porphyrazine 181, a consequence of the planar aromatic molecular structure, a full characterization of this compound could not be accomplished. 

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