1.2.4- Triazoles acidity, basicity

The acidity/basicity descriptor pH provides a useful means of identifying substances that are corrosive to the skin by disrupting its pH balance (away from a physiological value of about 5.5). In Table 18.4, three chemicals (2-bromobutane, sodium bisuffite and 4-amino-1,2,4-triazole) have borderline predictions because of the proximity of their pH values to the cut-offs (3.4 and 10.5) of the PM. 

On CNDO/2 calculations with pK (as base) = 2.30 for triazole, the basicities of H and AH tautomers are estimated to be equal, and maximum separation of protonated nitrogens i.e. N-1 and N-4 rather than N-1 and N-2) is predicted to afford the most stable cation (68TL3727). Acidity constants of 1,2,4-triazoles correlate with total and rr-electron densities but not with the lone pair character of the pyridine-type N in MO calculations (70JCS(B)i692, 70BCJ3344). 

Improved method for preparation of 173 is reported by Wang and Gu (Scheme 12.29). It comprises of four-step synthesis of 179, conversion of acid into 5-2-(5-fluoropyrimidin-4-yl)propionyl chloride, Friedel-Crafts reaction to obtain ketone 180, and the reaction with 1-methyl-17/-1,2,4-triazole under basic condition. 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

The pK values for azolediazonium ions (Scheme 12-4) refer to the heterolysis of the NH bond, not to the addition of a hydroxy group. Therefore, these heteroaromatic diazo components may react either as a cation (as shown in Scheme 12-4) or as the zwitterion (after loss of the NH proton). Diener and Zollinger (1986) investigated the relative reactivities of these two equilibrium forms (Scheme 12-5) in the azo coupling reaction of l,3,4-triazole-2-diazonium ion with the tri-basic anion of 2-naphthol-3,6-disulfonic acid. 

It appears that treatment of phenacyl bromides 1239 with methylhydrazine in refluxing acetic acid leads also to 1,4-disubstituted triazoles 1244. Fivefold excess of methylhydrazine is used in these reactions. According to the proposed mechanism, structures 1240-1243, methylhydrazine has a double role, as a condensing agent and an oxidant. In the final account, three molecules of methylhydrazine have to be used to produce one molecule of triazole 1244, two molecules of methylamine and one molecule of ammonia. The basic triazole 1244 (X = Y = H) is separated in 59% yield. The reactions go well with electron-donating substituents (for X = OH, the yield is 81%), but electron-withdrawing substituents can lower the yield dramatically (11% for X = N02) (Scheme 206) <2003JCM96>. 

It was shown that furoxans can be transformed to 1,2,3-triazoles. Thus, 4-acetylamino-3-arylazo-l,2,5-oxadiazole 2-oxides undergo two successive (cascade) mononuclear heterocyclic rearrangements in an aqueous basic medium with the formation of 4-acetylamino-2-aryl-5-nitro-2/7-l,2,3-triazoles (Equation 12) <2001MC230>, or 3,3 -disubsti-tuted 4,4 -azo-l,2,5-oxadiazole 2-oxides were found to undergo a rearrangement into 2-(furoxan-4-yl)-4-nitro-2//-1,2,3-triazole 1-oxides on heating in pertrifluoroacetic or peracetic acids (Equation 13) <2003MC272>. 

Basic hydrolysis of the [l,2,4]triazolo[5,l-3][l,3]thiazine derivative 77 was described to yield triazole-thione 78, the reaction proceeding in 59% yield <2005ZOR1092>. Related partially saturated triazolothiazines 79 were also subjected to ring-opening reaction aqueous hydrolysis afforded the acid 80 <2004KGS1256>, whereas reaction of 79 with hydrazine hydrate yielded the acid hydrazine 81 <2004ZOR260>. Both transformations took place in high yields. 

Two structurally related arylazides were also transformed similarly. Porter et al. described <1997S773> that ketone 486 can conveniently be transformed into 487 when treated with a substituted acetonitrile containing an active methylene group under basic conditions. The products were obtained in most cases in excellent yields. Cyclization to 489 proceeds in a similar manner as described by an Italian team <1996FA131, 2000EJM333> the n-azidobenzoic acid 488 yielded the fused [l,2,3]triazole 489. 

Williams investigated the reactions between 3-amino-1,2,4-triazoles and EMME or 1-ethoxyethylidenemalonate (6IJCS3046 62JCS2222). He assumed that 3-amino-1,2,4-triazoles reacted with EMME or 1-ethoxyethylidenemalonate first via the primary amino group under acidic conditions, while under basic conditions, the ring nitrogen atom was involved in the first step of the cyclocondensation (61JCS3046). 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

Oxidation of benzotriazoles and other fused triazoles by potassium permanganate is a well-established route to lif-triazole 4,5-dicarboxylic acid derivatives. Many of the triazolo[d]pyrimidines, synthesized as purine analogs, can be degraded to monocyclic triazoles by acidic or basic hydrolysis (in other triazolopyriraidines, however, the triazole ring is cleaved preferentially ), e.g. Scheme 24. 

Ab initio calculations on the equilibrium between (14a) and (14b) are carried out with the 3-21G basis set. Figure 4 shows a plot of the calculated activation energy E vs. the reaction energy AE for the cyclization reactions. The plot is linear and provides a striking confirmation of Hammond s postulate. The cyclic structures (14b) are found to be planar, while the terminal =NH group in (14a) is ca. 50° out of the plane formed by the other atoms in (14a) <90CC882>. The gas phase basicity and acidity of 1,2,3-triazole have been calculated by ab initio methods (6-31G //6-31G) and compared with experimental values <89MI 401-01 >... 

Substituted 1,2,3-triazoles are oxidized by w-chloroperoxybenzoic acid at the more basic N(3) to give the corresponding triazole A -oxides. The yield is lower if an electron-withdrawing substituent is present at the C(4) or C(5) position <87ACS(B)724>. 2-Alkyl-1,2,3-triazole-1-oxides are produced from the oxidative cyclization of alkyl hydrazono oximes <86ACS(B)262> see Section 4.01.8.1. 

The mixed hydrazones (667), prepared from diacetyl monobenzoyl hydrazone and arylhydrazines, undergo oxidative cyclization to 2-aryl-jV-benzoyl-4,5-dimethyl-l,2,3-triazol-l-ylimines (668) in 32-76% yield upon treatment with lead tetraacetate in acetonitrile (Scheme 132) <92JOC2252>. The cychzation of bishydrazones to 1,2,3-triazoles can also occur in acidic or basic media. For instance, the tetrahydrobenzo[ /]triazol-4-one (669) is prepared by the base-catalyzed cyclization of the corresponding a-hydrazono oxime (Equation (53)) <85HCA1748>. 3-Methyl-1,2-cyclohexanedione reacts... 

Acid hydrolysis of 3-methyl-6-phenyl-l,2,4-triazine 4-oxide (827) yields 4-phenyl-1,2,3-triazole through an acyclic intermediate (828) (Scheme 168) <89AHC(46)73>. 1,2,4-Triazine 2-oxides (829) undergo rearrangement in basic conditions (Equation (80)) to form 4-substituted 2//-1,2,3-triazoles <89AHC(46)73>. l-(2-Nitrophenyl)-5-aryltetrazoles (830) and l-aryl-5-(2-nitrophenyl)tetrazoles are converted into 2-arylbenzotriazoles (831) by refluxing in nitrobenzene (Equation (81)) <81AJC69l>. 

Triazole has values of 2.19 (as a base) and 10.26 (as an acid). A representative selection of acidity data Hammett treatment to the pXa values of triazoles. The Hammett equation is more satisfactory for acidic than basic values of triazoles <65ZC38l). For triazoles with only annular NH as acidic groups the Hammett a value is 6.00, while for 3-(or 5-) hydroxytriazoles it is 7.62. In both cases constants are most appropriate <65ZC304) this is also true for nitrotriazoles <70KGS558). 

Triazole reacts with a,yS-unsaturated ketones under basic conditions or the corresponding Man-nich bases under acidic conditions to give N-alkylated triazoles (Scheme 3) <87SC809>. A method for the alkylation of N(l) with the 2-phenylethyl group has been described <94JHC1421>. 

The main conclusions of this study are (86JA3237) (1) that pyrazole (6) is less basic than imidazole (4) (see Table V) is mainly due to the electrostatic repulsion NH NH in the pyrazolium cation (6H ) (2) that 1,2,4-triazole (8a) is less basic than imidazole (4) (see Table V) is mainly due to the electronegative aza effect (3) that imidazole (4) is more acidic than pyrazole (6) in the gas-phase (see Table VI) is a consequence of the lone pair/lone pair electrostatic interaction in the pyrazole anion (6 ). 

The presence of a basic amino group affords a compound that also shows some degree of antidepressant activity. Acylation of the hydrazine (16-3) with chloroacetyl chloride proceeds on the more basic nitrogen to give the hydrazide (17-1). Heating that intermediate in acetic acid closes the triazole ring to give the chloromethylated product (17-2). The displacement of chlorine by means of dimethylamine then affords adinazolam (17-3) [21]. 

The mechanistic proposal shown in Scheme 5.15 explains all of the observations above as well as the overall robust nature of the process. Under the more basic conditions of its formation, Meldrum s adduct 24 is initially obtained as its anionic form (A ), which stabilizes it and prevents its decomposihon. This also means that subsequent reactivity with 3 is enhanced by adjustment of the pH with an exogenous acid capable of shifting the equilibrium back to 24, (HA). The acid is only needed in a catalytic amount since, as decarboxylation of 24 proceeds, the triazole HCl salt 3 converts to amide 25, turning over a proton. 

Hydrolysis of 2-phenyl-[l. 2.3]triazolo[4,5-d]pyrimidine-5,7-dione N-oxides 463 in basic solution gives rise to 4-amino- and 4-ureido-2-phenyl-l,2,3-triazole-5-carboxylic acid 1-oxides 464, as well as their hydrazides and methylamide (2005JGU636) (Scheme 134). 

The 1,2,4-triazole is more important because it is the basis of the best modern agricultural fungicides as well as drugs for fungal diseases in humans. The extra nitrogen atom makes it more like pyridine and so more weakly basic, but it increases its acidity so that the anion is now easy to make. 

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