Barbiturate ring hydrolysis

The reaction of barbiturate and 1,3 -dimethylbarbiturate ions with 2- and 4-nitrobenzaldehyde and 2,4-dinitrobenzaldehyde represented generally in Scheme 5 involves a diffusion-controlled (viscosity effects on rates) proton transfer from hydronium ion to an addition intermediate T in the slow step.14 The addition of water and ring-opening reactions of the protonated benzoxazines (14) involves the cyclic intermediate (15). At low buffer concentrations buffer-catalysed collapse of the intermediate is rate limiting but, at high buffer concentrations, the addition of water is the rate-limiting step.15 The anionic tetrahedral intermediate (16) is involved in the hydrolysis of the 2, 2, 2,-trifluoroethyl monoester of 1,8-naphthalic acid (17).16... 

Six-membered ring heterocycles 708 are obtained in the reaction of carbodiimides with malonyl chloride. Hydrolysis of the dichlorodihydropyrimidine-diones affords barbituric acid derivatives. ... 

Stxlium salts of the barbiturates are readily prepared and are water soluble. Their aqueous. solutions generate an alkaline pH. A classic incompatibility is the addition of an agent with an acidic pH in solution, which rc.sults in formation and precipitation of the free water-insoluble disubsliluied barbituric acid. Sodium salts of barbiturates in aqueous solution decompose at varying rates by base-catalyzed hydrolysis, generating ring-opened sails of carboxylic acids. 

For 1,3,5,5-tetrasubstituted barbiturates the 1-6 versus 1-2 or 3-4 ring opening depends on the nature of the substituents and on hydrolysis conditions.312,313,354 2-Thiobarbiturates are less stable than their 2-oxo analogs in an alkaline medium.304,329,355,356 The barbituric acid ring is quite stable in an acidic medium (undissociated molecule)4 and the only barbiturates whose ring opens under these conditions are 5-allyl-5-(2 -hydroxypropyl)barbituric acid (proxibarbal)357-359 and l-benzoyl-5-ethyl-5-phenylbarbituric acid (benzonal).353... 

Only a few workers have reported photochemical reactions of barbiturates. Otsuji et al. found that hydrolysis of 5,5-diethylbarbituric acid, in alkaline solution, is accelerated by UV (254 nm) light.378 Investigations of 5,5-dialkylbarbituric acid photolysis, carried out by Bojarski and coworkers,379,380 questioned a previous photohydrolytic mechanism378 and implicated the photochemical ring-opening reaction within the malonyl moiety with the isocyanate derivative 135 as an intermediate379 (Scheme 12). 

During the photolysis of barbiturates with a-branched substituents at C-5, the ring-opening reaction is accompanied by dealkylation of these substituents.383-387 The elimination of the allyl group has also been observed in the case of photolysis of 5-allyl-5-(r-methylbutyl)barbituric acid.387 On the other hand, comparative studies on hydrolysis and photolysis of 5-allyl-5-(2 -hydroxypropyl)barbituric acid showed only an increase of the rate of hydrolysis by UV light with no differences in the isolated products.359,388... 

Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.80-81 Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents Ri, R2, and R3. For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett s o value.82... 

The cyanopyridine cation is obtained by the addition of chlorocyane to pyridine. During its hydrolysis, the pyridine ring is opened, forming gluta-cone aldehyde 0CH-CH=CH-CH2-CH0. This reacts with barbituric acid to form a colour whose intensity is proportional to the hydrogen cyanide concentration [18]. 

Example. Phenobarbital [Gardinal ]. The following scheme vividly explains the base hydrolysis of phenobarbital wherein the cyclic ureide ring (in barbiturate) undergoes cessation. Besides, it may also be seen that the aforesaid cessation strategically takes place either between C-l/C-2 and/or C-l/C-6 locations in the structure of barbiturate. However, the cleavage between C-1 and C-6 is considered to be the most preferred pathway prevailing in the ionized barbiturates , such as aqueous solutions of sodium salts. 

---