SALFORD 5 , LANCASHIRE ; and DEPARTMENT OF MEDICAL CHEMISTRY, AUSTRALIAN NATIONAL UNIVERSITY, CANBERRA) THIS review sets out methods for predicting the approximate thermodynamic pK, values, in water, of organic bases. With small changes, the same methods should also be applicable to organic acids. Extant compilations of published ionization constants in water, which include 1056 organic acids* and 3790 organic bases,2 cover only a small fraction of known substances in these classes. For the numerous compounds where pK measurements have not been (or cannot be) made, estimates of acidic or basic strength are often required by organic chemists and biochemists.Many examples of the importance of this information could be given. To obtain spectra of essentially pure ionic species, measurements must be made at pH values at least two units away from pK values.* Again, apparently baffling changes in products obtained under slightly different conditions of pH can sometimes be interpreted in terms of the ionic species undergoing reaction. This is also true of changes in physical properties, such as solubility and extraction by solvents, which govern conditions for the isolation, of substances. At a more sophisticated level, comparison of measured and predicted pK values frequently allows a choice to be made between alternative structures for a given compound. Allied to this are applications of pK values to the investigations of equilibria between tautomeric species, Also, a knowledge of the fraction ionized can be valuable to workers concerned with the effects of substances under physiological condition^.^ Again, an estimated pK value is useful in discussing the properties of a postulated reaction intermediate which is not available for direct measurement. Finally, for the physical-organic chemist, such ionization reactions provide probably the simplest reversible systems for studying and interpreting the effects of molecular structure on chemical reactions.Throughout this review, the strength of a base will be expressed in terms of the pK, (= -1og K,) value of its conjugate acid. That is, for the equilibrium, BH+ + B + H+, K a = (B)(H+)/(BH+),where the parentheses denote activities and all species are solvated. Except where stated, all pK, values are taken from reference 2: they have been * There are numerous instances in the literature where spectral comparisons are invalidated because this condition is not met.
Several thieno[2,3‐d]pyrimidines have been prepared by intramolecular cyclisation of 6‐(substituted methylthio)‐5‐pyrimidinecarbaldehyde and carbonitrile intermediates derived from 6‐chloropyrimidine‐5‐carbaldehydes and 5‐carbonitriles and methyl thioglycolate or 5‐formylpyrimidine‐4‐(3H)‐thiones and appropriate α‐halogeno compounds. Thienopyrimidines 18 and 5c were nitrated to the corresponding nitro compounds 23 and 24. Hydrolysis at position 4 of compound 18 also occurred during nitration. The ester 5g was hydrolysed in base to the acid 25.
M5 4WT 5-Aminothieno[2,3-d]pyrimidine-6-carboxamides or -6-carboxylic esters have been converted into thieno[2,3-d:4,5-d']dipyrimidines with the reagents formamide, triethyl orthoformate, urea, methyl isothiocyanate, phenyl isocyanate, and guanidine. A 5-aminothieno[2,3-d J pyrimidine-6-carboxannide gave, on treatment with nitrous acid, the first pyrimido [ 5',4'-4,5] thieno[3,2-d] -lr2,3-triazine. Many compounds containing the thienopyrimidine ring system have interesting pharmacological properties. Biological activity is exhibited by the simple thienopyrimidine system (see, for example, refs. 2-8) and by tri-and tetra-cyclic compounds containing a thienopyrimidine system (see, for example, refs. 9-11).This paper describes syntheses of a number of thienodipyrimidines, the work on which was prompted by a .rather than the N-phenyl derivative (4; R = Ph, X = NHMe, Y = 0). Presumably the intermediate (5) cyclised with loss of aniline rather than ammonia although similar reactions had previously given N-phenyl compounds. l 4 0
Ten P-(rn-and p-substituted pheny1)-p-oxopropionates (I and 11; X = F, CI, Br, Me, or OMe) were synthesised and condensed with thiourea to yield the corresponding 6-(m-and p-substituted pheny1)thiouracils [ (V) and (VI)], which were converted into the analogous uracils [ (VII) and (VIII)] by treatment with chloroacetic acid. Nitration of 6-(p-substituted phenyl) uracil derivatives gave 5-nitro-or m.5-dinitro-compounds according to reaction conditions. l H N.m.r. spectra of most of the compounds are recorded.
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