Diazohydroxides

When carried out in dilute acid, diazotization of 2-aminothia2ole may provide unstable diazohydroxides (164, 335, 336), differing in that respect from 2-aminopyridines which give 2-pyridones when the reaction is carried out in weak acids (337). 

Radicaloid substitution has not been extensively studied in the thiophene series. Molecular orbital calculations indicate that substitution should occur in the a-position. This has been found to be the case in the Gomberg-Bachmann coupling of diazohydroxides with thiophenes which has been used for the preparation of 2-(o-nitro-phenyl) thiophene, 2-(p-toluyl) thiophene, " " and 2-(p-chloro-phenyl)thiophene. " Coupling in the /8-position has been used for the preparation of 1,3-dimethyl-4,5-benzisothionaphthene (148) from 2-amino-tt-(2,5-dimethyl-3-thienyl)cinnamic acid (149). A recent investigation describes the homolytic phenylation of 2- and 3-phenyl-... 

Arenediazonium ions are stable in acidic or slightly alkaline solution in moderate to strong alkaline medium they are converted into diazohydroxides 4 ... 

The cation 5 loses a proton to give the more stable nitrosoamine 6, which is in equilibrium with the tautomeric diazohydroxide 7. Protonation of the hydroxy group in 7 and subsequent loss of H2O leads to the diazonium ion 3. 

An arenediazonium ion 1 in aqueous alkaline solution is in equilibrium with the corresponding diazohydroxide 4 The latter can upon deprotonation react with diazonium ion 1, to give the so-called anhydride 5. An intermediate product 5 can decompose to a phenyl radical 6 and the phenyldiazoxy radical 7, and molecular nitrogen. Evidence for an intermediate diazoanhydride 5 came from crossover experiments " ... 

Research into the mechanism of diazotization was based on Bamberger s supposition (1894 b) that the reaction corresponds to the formation of A-nitroso-A-alkyl-arylamines. The TV-nitrosation of secondary amines finishes at the nitrosoamine stage (because protolysis is not possible), but primary nitrosoamines are quickly transformed into diazo compounds in a moderately to strongly acidic medium. The process probably takes place by a prototropic rearrangement to the diazohydroxide, which is then attacked by a hydroxonium ion to yield the diazonium salt (Scheme 3-1 see also Sec. 3.4). 

We now know that Hammett s explanation is correct in all its aspects. This result is especially noteworthy because Hammett arrived at his conclusions not through extensive experimentation in his laboratory, but by the consistent application of the newer theories of organic chemistry to kinetic results already published by others. This is not the only example of such anticipation of views (now generally accepted) to be found in Hammett s book, and it is worth remembering that Hammett expressly postulates the diazonium ion as the reactive form of the diazo compound in coupling, in contrast to the then current opinion that the diazohydroxide was the effective species. 

Unfortunately there have been no more recent investigations using fast kinetic methods such as stopped flow, by adding methanol or even methanol with some water to the ether solution obtained by the procedure of Muller and Haiss, so as to check whether an equilibrium mixture of nitrosoamine and diazohydroxide is formed. 

It is worth noting, however, that the prototropic equilibrium between the N-nitrosoamine (3.7) and the diazohydroxide (3.9) has been determined semiquan-titatively for the analogous diazotization of an aliphatic amine. Fishbein and coworkers (Hovinen et al., 1992) determined an upper limit for the nitrosoamine equilibrium concentration (<1.5% see also Zollinger, 1995, Sec. 7.2). 

Despite these critical remarks, this discussion may be summarized by saying that the participation of the nitrosoamine (3.7), of its conjugate O-acid (3.8), of the (Z)-or (i -diazohydroxide (3.9), and of their conjugate acids (3.10) in the system of Scheme 3-36 remains more or less conjectural, but at least the nitrosoamine (3.7) does appear to be reasonable well documented as an intermediate on the pathway to the diazonium ion. 

The reversibility of aromatic diazotization in methanol may indicate that the intermediate corresponding to the diazohydroxide (3.9 in Scheme 3-36), i. e., the (Z)-or (is)-diazomethyl ether (Ar — N2 — OCH3), may be the cause of the reversibility. In contrast to the diazohydroxide this compound cannot be stabilized by deprotonation. It can be protonated and then dissociates into a diazonium ion and a methanol molecule. This reaction is relatively slow (Masoud and Ishak, 1988) and therefore the reverse reaction of the diazomethyl ether to the amine may be competitive. Similarly the reversibility of heteroaromatic amine diazotizations with a ring nitrogen in the a-position may be due to the stabilization of the intermediate (Z)-diazohydroxide, hydrogen-bonded to that ring nitrogen (Butler, 1975). However, this explanation is not yet supported by experimental data. 

According to Scheme 5-4 the diazonium ion (as a Lewis acid) is in equilibrium with its conjugate base, the diazohydroxide, and according to Scheme 5-5 the diazohydroxide (this time as acid) is in equilibrium with its conjugate base, the diazoate. This treatment applies only to those reaction steps that are moderately or very rapid and are reversible. 

We will introduce the (Z)/(E) isomeric equilibria of diazohydroxides and diazoates in Section 5.2. In the present section the formulas ArN2OH and ArN20 in Schemes 5-1 to 5-12 refer only to the (Z) isomers that are formed initially. 

Davidson and Hantzsch (1898) and later Engler and Hantzsch (1900) investigated this system on the supposition that it corresponds to that of the common dibasic acids. From conductivity measurements they calculated basic dissociation constants for the diazohydroxides, but it is now known that their assumptions were incorrect. In fact, at the turn of the century it was practically impossible to reach the right solution. On the one hand, Hantzsch did not have at his disposal the current poten-tiometric technique for protolytic equilibria, and on the other hand, the system of Scheme 5-1 is a special case for a dibasic acid, the principle of which was not grasped in Hantzsch s time. 

The condition K2>KX has far-reaching consequences. Consider the diazonium ion during neutralization one hydroxide ion is taken up but, unlike the oxalate ion, it cannot rest after the first stage. The diazohydroxide formed must lose a proton immediately to yield the diazoate, a second hydroxide ion acting as proton acceptor. In other words, the diazohydroxide is not a stable intermediate and is not present in aqueous solution in appreciable concentration. It follows that the diazohydroxide... 

Figure 5-2 shows schematically the dependence of the relative concentration of the diazo equilibrium forms on the pH (for the diazoanhydride mentioned in this figure see Sec. 5.2). The relative concentrations of the two major equilibrium forms, the diazonium ion and the diazoate ion, decrease on the right and left sides, respectively, of the pH value corresponding to equal concentrations of these two forms ([ArNj] = [ArN20-]). The gradients correspond to a factor of 100 per pH unit, compared with only 10 per pH unit in the case of dibasic Bronsted acids. The equilibrium concentrations of the diazohydroxide and the diazoanhydride (except for very reactive diazonium ions such as the benzene-1,4-bisdiazonium dication mentioned above) are very small at all pH values, with a maximum at pH = pKm. 

The main problem of interest, however, is that of finding a way to determine Kx and K2 separately for cases where Kx < K2. Such a separation of Kx and K2 is possible by taking advantage of the fact that the addition of hydroxide ion to the diazonium ion (rate constant kx in Scheme 5-1) is slower than the deprotonation of the diazohydroxide (rate constant k2). An analogous relationship holds for the two reverse reactions (k 2>k i). From the values of kx and k x one can, of course, calculate Kx and, if KXK2 is known, K2. Such measurements of Kx and K x were, however, difficult in the 1950s. 

For the first six substituents in Table 5-1 K2 is 3 to 5 powers of 10 greater than Kx. At pH = pATm the maximum equilibrium concentration of the (Z)-diazohydroxide (last column) is very small. For the 2,6-dichloro-4-nitrobenzenediazonium ion, however, Kx is smaller than K2 by a factor of only 101 67 = 37. This factor results in a significantly higher maximum concentration of the (Z)-diazohydroxide. Finally, the benzene-l-diazonium-4-diazohydroxide cation reaches a maximum equilibrium concentration of approximatively 80% at pH = pKm because, as mentioned before, Ki is larger than K2 by a factor of ten. 

The complexity of the system consisting of the diazonium ion and the four reaction products shown in Scheme 5-14 is evident. In contrast to the two-step reaction sequence diazonium ion <= (Z)-diazohydroxide <= (Z)-diazoate (Scheme 5-1 in Sec. 5.1), equilibrium measurements alone cannot give unambiguous evidence for the elucidation of the mechanistic pathway from, for example, diazonium ion to ( )-diazoate. Indeed, kinetic considerations show that, depending on the reaction conditions (pH etc.) and the reactivity of a given diazonium ion (substituents, aromatic or heteroaromatic ring), different pathways become dominant. 

Scheme 5-14 may be called a two-dimensional system of reactions, in contrast to Scheme 5-1 which consists of a one-dimensional sequence of two acid-base equilibria. In Scheme 5-14 the (Z/E) configurational isomerism is added to the acid-base reactions as a second dimension . The real situation, however, is yet more complex, as the TV-nitrosoamines may be involved as constitutional isomers of the diazohydroxide. In order not to make Scheme 5-14 too complex the nitrosoamines are not included, but are shown instead in Scheme 5-15. The latter also includes the addition reactions of the (Z)- and ( )-diazoates (5.4 and 5.5) to the diazonium ion to form the (Z,Z)-, (Z,E)- and (2 2i)-diazoanhydrides (5.6, 5.7 and 5.8) as well as proto-de-nitrosation reactions (steps 10, 11 and 12). This pathway corresponds to the reverse reaction of diazotization, as amine and nitrosating reagent (nitrosyl ion) are formed in this reaction sequence.

The rapid formation of the (Z)-diazoate is followed by the slower (Z/J )-isomeri-zation of the diazoate (see Scheme 5-14, reaction 5). Some representative examples are given in Table 5-2. Both reactions are first-order with regard to the diazonium ion, and the first reaction is also first-order in [OH-], i.e., second-order overall. So as to make the rate constants k and k5 directly comparable, we calculated half-lives for reactions with [ArNj ]0 = 0.01 m carried out at pH = 9.00 and 25 °C. The isomerization rate of the unsubstituted benzenediazonium ion cannot be measured at room temperature due to the predominance of decomposition (homolytic dediazoniations) even at low temperature. Nevertheless, it can be concluded that the half-lives for (Z/ )-isomerizations are at least five powers of ten greater than those for the formation of the (Z)-diazohydroxide (reaction 1) for unsubstituted and most substituted benzenediazonium ions (see bottom row of Table 5-2). Only for diazonium ions with strong -M type substituents (e.g., N02, CN) in the 2- or 4-position is the ratio r1/2 (5)/t1/2 (1) in the range 6 x 104 to 250 x 104 (Table 5-2). 

Basically the kinetic results are consistent with the first (rapid) reaction being the addition of a hydroxide ion to the diazonium ion followed by the very fast deprotonation of the (Z)-diazohydroxide to give the (Z)-diazoate (steps 1 and 2 in Scheme 5-14). In addition, however, the stopped-flow experiments showed that the diazonium ion also reacts with the water molecule, initially forming the conjugate acid of the (Z)-diazohydroxide (ArN2OH2), which is then very rapidly deprotonated (reaction 1 in Scheme 5-14). The rate of the relatively slow (Z/E)-isomerization (reaction 5 in Scheme 5-14) can in general be measured by conventional spectrophotometry. 

Each of the curves in Figure 5-3 exhibits two or three pH regions in which the slope of the logarithmic plot is approximately —1, with intermediate regions where the slope is small or zero. Lewis and Hanson (1967) showed that in the case of (E,)-4-nitrobenzenediazoate the portion of the curve with slope —1 at relatively high pH was consistent with the acidity constant K3 of the (E )-diazohydroxide determined either by titration or spectrophotometrically, the relevant results being (by... 

The curve for the conversion of the unsubstituted ( -benzenediazoate in Figure 5-3 is consistent with the (ii)-diazoate-diazohydroxide pre-equilibrium followed by the slow and pH-independent elimination of the hydroxide ion from the ( )-diazohydroxide (rate constant 6 in Scheme 5-14) as found by Lewis and Suhr. Below pH 3 the acid-catalyzed dissociation of ( >diazohydroxide (k 6) is observable. Electron-withdrawing substituents such as N02 in the 2- or 4-position reduce the rate of dissociation of diazohydroxides and increase the rate of (E) (Z)... 

Jahelka et al. (1972 b) emphasize that Scheme 5-17 was derived assuming a steady state condition for all the intermediates of Scheme 5-14. The same authors (Jahelka et al., 1973a) found, however, in their investigation of the diazonium ion (Z)-diazoate equilibria (reactions 1 and 2) that the concentration of the intermediate (Z)-diazohydroxide may reach several percent, in one case even 25% (see Table 5-1). The very good fit of the calculated curves with the experimental data in Figure 5-3 is therefore rather surprising to the present author. 

Nitrobenzenediazoate can be considered as an azo compound comparable to an azobenzene having one electron acceptor and one donor on each side of the azo group the acceptor-donor relationship is more dominant in the (Z) -> (E) diazoate pair than in the diazohydroxide pair. The N=N rotation mechanism of the diazoate pair is therefore the favored process (E = 84 kJ mol-1 Lewis and Hanson, 1967). On the other hand, 4-C1 is not a substituent with a —M effect therefore it does not reduce the double-bond character of the N = N bond and the mechanism involving inversion at the N((3)-atom becomes dominant. The activation energy of the latter process (E = 104 kJ mol-1 Schwarz and Zollinger, 1981) is higher than that of the N = N rotation mechanism for the 4-nitro derivative, but it is reasonable to assume that it is lower than that for N = N rotation in the 4-chloro derivative. Furthermore, one can conclude that N-inversion is more favorable in the diazohydroxide than in the diazoate. ... 

An alternative mechanism which cannot be excluded with these data involves the isomerization of the diazohydroxide into TV-nitroso-4-chloroaniline, rotation about the N —N bond, and deprotonation. 

In Sections 5.2 and 5.3 it was shown that experimental data are consistent with a direct rearrangement of the (Z)- to the (ii)-diazohydroxide rather than with a recombination after a primary dissociation of the (Z)-isomer into a diazonium ion. Positive evidence for direct formation of the (ii)-diazohydroxide from the diazonium ion and a hydroxide ion (or water) is still lacking (see Scheme 5-15 in Sec. 5.2). For diazo ethers, however, Broxton and Roper (1976) came to the conclusion that there is no direct (Z) >(E) conversion, but rather that in the system ArNj + OCH3/(Z)-diazo ether/(Zi)-diazo ether the (Z)-ether is the kinetically determined product and the (iE )-isomer the thermodynamic product, as shown in Scheme 6-3. 

Certain problems, for example, the differentiation between the (is)-diazohydroxide (7.3) and the nitrosoamine (7.4), were quite insoluble in Hantzsch s day because of the lack of appropriate methods. The observation that the sodium salt of the anti-diazoate reacts with methyl iodide to yield the TV-derivative (A-methylnitrosoamine), whereas the silver salt gives the O-ether (diazo ether) was often taken to support the presence of constitutional isomerism, but Hantzsch, quite rightly, disagreed. 

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