Isothiazoles basicity

Although isothiazole (pK = 1.90) is less basic than thiazole, its rale of quaternization by dinitrophenyl acetate in water at 52°C is approximately 2.5 times higher (447). This deviation from the Bronsted relationship (A log k - 0.ApK, with positive) is interpreted as a consequence of the or effect of the adjacent sulfur lone pair in isothiazole that is responsible for its higher nucleophilicity (448, 449). 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

The relative basicity and acidity of isothiazole and its methyl derivatives have been compared by IR spectroscopy (77MI41702). The isothiazoles, dissolved in inert solvents (e.g. CCI4, CS2) containing traces of butanol (a proton donor), interact with the butanol OH... 

Isothiazole-4,5-dicarboxylic acid, 3-phenyl-dimethyl ester synthesis, S, 150 Isothiazole-5-glyoxylic acid ethyl ester reduction, 6, 156 Isothiazole-4-mercurioacetate reactions, 6, 164 Isothiazole-5-mercurioacetate reactions, 6, 164 Isothiazoles, 6, I3I-I75 acidity, 6, 141 alkylation, 6, 148 aromaticity, S, 32 6, 144-145 basicity, 6, I4I biological activity, 6, 175 boiling points, 6, I43-I44, 144 bond fixation, 6, 145 bond orders, 6, I32-I34 calculated, 6, 133 bromination, S, 58 6, 147 charge densities, 6, 132-134 cycloaddition reactions, 6, 152 desulfurization, S, 75 6, 152 deuteration, S, 70... 

In contrast with the reaction of the chloropyridine, but in keeping with its observed reactions with diethyl malonate under classical procedures, 3-chloro-l,2-benzoisothiazole produces not only the SNAr products, (1) and (2) (Scheme 2.3), but also products arising under the basic conditions from ring opening of the isothiazole... 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

The isothiazoles possess the typical properties of a heterocyclic aromatic system without the ring lability so characteristic of the analogous isoxazoles.87 The chemistry reflects the relative inertness of the 3-position, the susceptibility of the 4-position to electrophilic attack, and the susceptibility of the 5-position to nucleophilic attack. The ring nitrogen is only weakly basic, but can be induced to form quaternary derivatives, and the N-S bond may be cleaved under certain circumstances. 

The fate of isocyanosulfide (70) depends on the nature of the substituent originally at C-4 of the isothiazole ring. If R is aryl, as in 55, the extended conjugation of the sulfide and the aryl group is expected to lower the basicity of the sulfide resulting in reprotonation at the isocyano carbon to yield 71. Protonation at this site renders the carbon more susceptible to nucleophilic attack by the negative sulfur. As a result, these substituted isocyanides spontaneously cyclize to 4-arylthiazoles 73 (R=Ar). 

Pyrazole is a much weaker base than imidazole. Both have resonance-stabilized conjugate acids (Figure 14) but in the case of the pyrazolium cation 64 the direct linking of the quaternary nitrogens has a base-weakening effect. This additional effect also contributes to the low basicities of isothiazoles and isoxazoles (65 and 66). 

Of the substituted pyridines, the halogenated derivatives have been the most intensively studied.144,145 Treatment of 3,5-dichloropyridine A-oxide at 74° with 0.1 A NaOD led to exchange in three positions of the molecule, whereas with 3-chloropyridine iV-oxide relative rates of exchange were position 2>6>4>5. In l-methyl-4-pyridone, 1,3,5-trimethyl-4-pyridone, and 3,5-dibromo-l-methyl-4-pyridone, deuteration in basic D20 at 100° gives 2- and 6-substitution.146 With the poly-azaindenes (45) -(47) already discussed in the acid exchange section,141 base-catalyzed deuteration occurs in the positions indicated 45 3 and 5 46 2, 3, 5, and 6 and 47 2, 5, 6, and 7. In other isolated heterocycles some selectivity is observed in base-catalyzed exchange, e.g., certain imidazoles,147 thiazole,148 isothiazole,148 benzothiazole,149 and benzoxazole.149... 

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25)147). Many transition metal cations form complexes with imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thiazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(21)323). Isothiazoles react with hexacarbonyls M(CO)6 to give iV-coordinate M(CO)5 derivatives. 

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