Base-Catalyzed Exchange

Strong bases will remove sufficiently activated protons from aromatics in a rate-determining step [Eq. (2.16)]. This is followed by rapid abstraction of a proton from the solvent [Eq. (2.17)]. The reaction pathway is symmetrical, 

Since the base must attack the ring hydrogens in the plane of the ring, but away from it, one would expect steric effects to be minimal, and certainly no more than for acid-catalyzed exchange. This appears to be the case for attack by amide, but the bulkier cyclohexylamide shows evidence of some steric hindrance [72MI2(266)]. 

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There is no generally reliable rule of thumb to predict whether an axial or equatorial proton will exchange faster. For instance, in the examples discussed above, the slowest rate of exchange is found for the S -axial proton in 5a-androstan-7-one (1) [see(2)-(4)] and the 2fi-equatorial proton in 5a-androstan-l 1-one (5) [see (6)-(9)]. Furthermore, the results of base-catalyzed exchange cannot necessarily be predicted from the corresponding... 

During the course of base-catalyzed exchange in O-deuterated alcohols, the vinylic hydrogen in the a position to the ketone is replaced by deuterium, in addition to the hydrogens activated by enolization. Thus, under these conditions the exchange of androst-l-en-3-one (16, R = H) gives a trideuterio derivative (18) instead of the expected 4,4-d2 analog (16, R = D). " (For other examples see compounds 13, 19, 21, 23, 26 and 27.) Incorporation of this deuterium is due to rapidly reversible alcohol addition (16 -+17) and elimination (17 18) which competes with the enolization step. " ... 

For the 1,2-dithiolium system (35, R = CeHs, R = H) exchange was fotmd in the 3-position when carried out in CFSCOOD-D2O at 74°. The rate decreases as the concentration of acid increases, suggesting base-catalyzed exchange, the mechanism probably being analogous to isothiazolium exchange (Scheme 6). 

Base-catalyzed exchange proceeds very quickly at C-7, more slowly at C-6, and very slowly at C-2 and C-5. The proton at C-2 of the methiodides exchanges about 1000 times faster than that in the free base (68JOC1087). The results are consistent with an ylide-type intermediate. 

Experimental work in the area has thus far been limited to a few annulated members of the family. The benzo derivatives shown in 15-17 were recently synthesized for such a study, and the base-catalyzed exchange rates of their key allylic methylene groups were determined and compared to those of models 18-20 measured under comparable conditions.23 In each instance, the kinetic acidity of the C-H link was found... 

Specifically deuterated derivatives of phenols can be prepared conveniently by using appropriate combinations of acid- and base-catalyzed exchange reactions. Treating with NaOD (or NaOH) causes exclusive exchange in positions ortho and para to the phenolic group while D3P04 deuterates all available aromatic sites. As an example, the conversion of 4-hydroxy-3-methoxytoluene to 5-monodeutero- and 2,6-dideuteroderiva-tives is illustrated below. 

In the first the mode of incorporation of the amino phenol O-methyl-norbelladine 343 into 10 was examined. Thus, tritium labels were inserted ortho and para to the phenolic hydroxy groups of 343 by base-catalyzed exchange with tritiated water under conditions ensuring equal labeling in all exchangeable positions. Norpluviine biosynthetized from multiply labeled 343 in Texas daffodil was selectively degraded to locate the tritium labels. 

Scheme 2.6. Base-catalyzed exchange mechanism for pyridine involving free base and conjugate acid.

The spread of rates in base-catalyzed exchange is smaller than under acid-catalyzed conditions, and this makes direct comparison of reactions easier, so that extrapolative techniques have not been necessary. 

The effects of substituents in the benzenoid ring on the rate of exchange at the 2-position of benzothiazole have also been measured (Table 8.15) (76JHC1021). These parallel those for benzimidazole (Table 8.14) and notable is the small difference between the effects at the 5- and the 6-positions. This may be attributed to the fact that only inductive effects are important in base-catalyzed exchange, and they may be transmitted through either heteroatom with comparable facility. 

Consistent with the results for base-catalyzed exchange, are the more rapid reactions of n-butyllithium with the thienothiophenes compared to thiophene (68ACS63). 

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