Detritiation reactions

Another reaction exhibiting surprisingly high selectivity is the detritiation reaction. The available results, although somewhat... 

Stevens and Strickler (1973) obtained an a value of about 1 for the dedeuteration of naphthalene in sulphuric acid while Johnson, Katritzky and O Neill (1974) observed values of 0-83 at the 1 position and 0-64 at the 2 position for the mechanistically identical detritiation reaction. 

Dahlberg and Long also studied the detritiation reaction with acetate ion [63]. Here there are no 02 effects and they found = 1.00. 

The greater dependence of rate coefficient upon acidity for detritiation compared to dedeuteration is apparent for benzene as it was for toluene and is more marked, but in view of the errors in the benzene work (which appear to arise only from measuring the acid concentration but could possibly arise from some feature of the kinetic method) and element of doubt must remain here. Nevertheless, this phenomenon (which is understandable on the basis that when the reactions are infinitely fast they will then both take place at the same rate, and the more reactive the compound and the stronger the acid, the more closely this situation is approached) seems to be general, for Gold et a/.460 found that the log rate coefficient... 

Thus it can be seen that evidence for the A-l mechanism, even if one accepted that this followed from a linear rate coefficient-acidity function correlation, was scant. On the other hand, there have been a very large number of carefully documented studies in which general acid catalysis has been observed leading to the A-Se2 mechanism for the reaction, or it has been shown that the conclusions from an acidity function dependence are not rigorous. One such study has already been described above, and Satchell478 also found that in the detritiation of [4,6-3H2]-l,2,3-trimethoxybenzene by potassium bisulphate, dichloro- and tri-fluoroacetic acids, plots of log kl versus —H0 were linear with a slope of ca. 1.0... 

Kresge and Chiang480 measured the rate coefficients for detritiation of [1-3H]-2,4,6-trimethoxybenzene in acetate buffers and found the first-order rate coefficient (lO7 ) to increase from 2.5 at 0.01 M acetic acid to 8.3 at 0.1 M acetic acid, whereas if the reaction was specific acid-catalysed no change in rate should have been observed. A similar technique to that described above for separation of the rate coefficients due to hydronium ions and other acids was used, the values for the former being obtained using dilute hydrochloric acid at which acidities no undissociated acid was present (Table 131). Rate coefficients were then measured... 

Thomas and Long488 also measured the rate coefficients for detritiation of [l-3H]-cycl[3,2,2]azine in acetic acid and in water and since the rates relative to detritiation of azulene were similar in each case, a Bronsted correlation must similarly hold. The activation energy for the reaction with hydronium ion (dilute aqueous hydrochloric acid, = 0.1) was determined as 16.5 with AS = —11.3 (from second-order rate coefficients (102At2) of 0.66, 1.81, 4.80, and 11.8 at 5.02, 14.98, 24.97, and 34.76 °C, respectively). This is very close to the values of 16.0 and —10.1 obtained for detritiation of azulene under the same condition499 (below) and suggests the same reaction mechanism, general acid catalysis, for each. 

Katritzky et a/.511 have measured rate coefficients for deuteration of 3,5-dimethylphenol and heterocyclic analogues. As in all of the deuteration work of this group, rates of exchange were measured by the nmr method, which is useful for following exchanges at more than one position in the molecule but is, of course, much less accurate than detritiation techniques. In this study, the chemical shift for the ortho and para protons for the parent compound was too small to allow separate integration, but it was apparent that rates of exchange at these two positions did not differ by a factor > 4. From the rate-acidity profile (Table 149) reaction clearly occurs on the neutral species at pD < 3.5 (the log kl versus pD slope was 0.96) and upon the anion at pD > 3.5 (slope zero), and the reactivity of the anion to the neutral molecule was estimated as 107-8, close to the value of 107 noted above. 

Much of the kinetic work in this category has already been described under the section relating to studies of mechanism. Additional data was obtained by Ols-son569, who measured rate coefficients (lO7 ) for dedeuteration and detritiation of thiophen by 57.02 wt. % sulphuric acid at 24.6 °C as follows [2-2H], 3,890 [2-3H], 2,000 [3-2H], 3.72 [3-3H], 2.20. The ratio of reactivities at the 2 and 3 positions (ca. 1,000) is in excellent agreement (bearing in mind the larger p-factor usually obtained with trifluoroacetic acid) with the value of ca. 1,250 which may be deduced from the data in Table 158. The ratio of dedeuteration to detritiation is 1.96 at the 2 position and 1.70 at the 3 position and thus decreases with decreasing reactivity of the reaction site. 

Streitweiser et al.591 have measured rates of base-catalysed dedeuteration and detritiation and have attempted to discover details of the reaction mechanism. Second-order rate coefficients for the reaction of some polycyclics with lithium cyclohexylamide in cyclohexylamine are given in Table 179, and it can be seen... 

Although in the above work the rate spread for detritiation was greater than for dedeuteration, surprisingly, in the reaction of lithium cyclohexylamide at 25 °C with fluorobenzenes and benzotrifluorides, the relative rates for dedeuteration and detritiation were595, respectively 2-F, 6.3 xlO5 and 3.4 x10s 3-F, 107 and 86 4-F, 11.2 and 9.1 3-CF3, 580 and 390, which therefore shows the reverse. The rate enhancement for these substituents were found to correlate reasonably with a field effect model for the inductive effect. 

Thus for these reactions m is necessarily less than unity, a result that has now been widely observed in practice,117,118,120,161,180,181 and thus the m1 value offers a clear distinction between the A1 and A-SE2 mechanisms, which is not the case with the H0 correlations discussed above. A number of different excess acidity plots according to equation (56), covering a wide reactivity range, are shown in Fig. 9. These are for the hydration of oc-methylstyrene,120 equation (58), and the mechanistically similar hydration of phenylacetylene 118 for the isomerization of m-stilbene 120 and for the detritiation of tritiated benzene, equation (28) above."7 As can be seen, all four plots are good straight lines the references cited may be consulted for the details. The slopes look steep, but m values for carbon protonation approximate 1.8,36 and the nfi values are all calculated to be... 

For these more efficient reactions the rate of the intermolecular reaction (acetate-catalysed detritiation) is too slow relative to that of the intramolecular reaction to be measured accurately. These EM s are therefore based on estimated upper limits for the rates of the reference reactions Harper and Bender, 1965. The reference intermolecular reaction is the benzoate-catalysed enolization of PhCOCHMe2... 

Finally, radiochemical methods of analysis may be used to follow rates of detritiation. This method is particularly useful for very slow reactions (where it is impractical to collect data for any appreciable extent of reaction) as an initial rate approach may then be employed. Separation difficulties, at least for aqueous solutions, may be overcome by using the freeze-drying method or the more recent countercurrent dialysis and Sephadex gel filtration techniques. ... 

A comparatively large selection of thioureas can be formed from the reaction of amines with isothiocyanates, hence they are attractive starting materials for formation of guanidines. A common solution-phase approach to this reaction involves abstraction of the sulfur via a thiophillic metal salt, like mercuric chloride.10 For solid-phase syntheses, however, formation of insoluble heavy-metal sulfides can have undesirable effects on resin properties and on biological assays that may be performed on the product. A more relevant strategy, with respect to this chapter, is S-alkylation of thioureas and then reaction of the methyl carbamimidothioates formed (e.g., 5, Scheme 6) with amines. This type of process has been used extensively in solution-phase syntheses.1 Ul4 Two examples are shown in Scheme 6 11 the second is an intramolecular variant, which involves concomitant detrity-lation.15... 

Figure 26. Relative rates of detritiation of t-butylmalononitrile in aqueous salt solutions at 298 K as a function of added salt concentration k and w are rate constants for reaction in salt solution and in water respectively, all solutions containing 0-001 mol dm-3 HQ (Hibbert and Long, 1972).

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