Prototropic mechanisms

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

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). 

Prototropic interconversions have been the subject of much detailed study, as they lend themselves particularly well to investigation by deuterium labelling, both in solvent and substrate, and by charting the stereochemical fate of optically active substrates having a chiral centre at the site of proton departure. Possible limiting mechanisms (cf. SNl/SN2) are those (a) in which proton removal and proton acceptance (from the solvent) are separate operations, and a carbanion intermediate is involved, i.e. an intermolecular pathway and (b) in which one and the same proton is transferred intramolecularly ... 

Halle, B. and Karlstrom, G. 1983b. Prototropic charge migration in water. 2. Interpretation of nuclear magnetic resonance and conductivity data in terms of model mechanisms. J. Chem. Soc. Faraday Trans. 7/79, 1047-1073. 

While at Leeds from 1924 to 1930, Ingold s laboratory focused on three main topics of research (1) the nature and mechanism of orienting effects of groups in aromatic substitution (mainly nitration) (2) the study of prototropic rearrangements (shifts of H+) and aniontropic rearrangements (shifts of anions) as the ionic mechanisms of tautomerism and (3) the effect of polar substituents on the velocity and orientation of addition reactions to unsaturated systems. One of Ingold s students at Leeds, John William Baker, wrote a widely read book on tautomerism. 16... 

This reaction, for which the term prototropic rearrangement is sometimes used, is an example of electrophilic substitution with accompanying allylic rearrangement. The mechanism involves abstraction by the base to give a resonance-stabilized carbanion, which then combines with a proton at the position that will give the more stable olefin 56... 

The experimental observations presented can be explained by a carbanionic mechanism with prototropic rearrangement. On heterogeneous catalysts this involves the formation of an ally lie carbanion by proton abstraction112,125 [Eq. (4.24)]. The carbanion then participates in transmetalation to yield a new anion and the isomerized product [Eq. (4.25)] ... 

The mechanisms proposed by Caspar and coworkers in their approach to the problem have a common point, the formation of the intermediate 9. This silylene then undergoes two prototropic rearrangements initial isomerization to a silene, the 2//-silole (11), followed by a second to give the 1H-silole (2)19 (equation 3). 

Prototropic isomerization of the propene molecule in the presence of hydroxide ion has been studied using ab initio and DFT methods in the gas phase and in DMSO solution 152 the mechanism involves formation of an intermediate complex of the allyl anion with a water molecule. 

A combination 13C/15N NMR and PM3 quantum-mechanical study of 7-OH-, SH-, and NH2-substituted l,2,4-triazolo[l,5-a]pyrimidines 20 has provided evidence that the former two exist as a 4H and 3H prototropic mixture in rapid equilibrium on the NMR time scale [95JMS273]. In... 

Figure 2. Proposed mechanism for theaspirane 1A/1B formation by prototropic dehydration of 4-hydroxy-7,8-dihydro-P-ionol (4) according to Ohloff et al. (Ref. 15).

The reaction of the dimethyl-derivative (27) with butoxide ion might be expected to produce the chlorocyclopropene (28) however, in practice two eliminations occur to produce (31) and the carbene (30), which can be trapped by an added alkene. Both products may be derived from (28), by a 1,4- or a formal 1,2-elimination respectively a study using a 14C-label at C-l of (27) showed that the carbene (30) was formed with the label exclusively at C-l, suggesting elimination via (29)32). However, in a related study, the isolated cyclopropene (28) labelled with 12C at C-l has been shown to react with methyl lithium to produce the carbene (30) labelled only at C-2 this suggests either that the reaction of (28) with butoxide follows a completely different course to that with methyl lithium, or that (28) is not involved in the reaction of (27) with base33). In a similar reaction the dichloride (32) has been shown to react with t-butoxide in DMSO to produce the allene (33) the product may be explained in terms of initial elimination to produce (34), followed either by rearrangement to the alkyne (35) and then elimination or by direct 1,4-elimination as in (36), followed in either case by a prototropic shift. Whatever the mechanism, a 12C-label at Ca in (32) is found at Ca in (33) 33). 

The reaction of the dichlorides (213, n = 3-7) with potassium t-butoxide in DMSO leads to the elimination of two molecules of HC1 and the formation of (214, n = 3-7) respectively. In each case the reaction can be explained by a sequence of elimination to a chlorocyclopropene, prototropic shifts, then a second elimination to a cyclo-propene followed by prototropic shifts. Thermolysis of (214, n = 3 or 4) leads to (215, n = 3 or 4), although the mechanism of this reaction is rather uncertain in contrast the larger ring species (214, n = 6 or 7) rearrange to a methylenecyclo-pentene, (2 1 6) 148,149). In the case of (213, n = 2), the analogous elimination product (214, n = 2) is not observed, presumably rearranging under the reaction conditions to the observed product (217)149). 

The key step in the first reaction is, once again, a 1,4-dehydrohalogenation followed by a stereocontrolled prototropic shift and electrocyclic closure of the derived triene to a bicy-cloheptadiene (shown below) the dichlorocyclopropane then undergoes a typical sequence of 1,2-dehydrochlorination followed by prototropic shifts to lead to the [10]annulene. The chlorodiene 45 may be produced by a similar sequence of 1,4-dehalo-genation, prototropic shift and cyclization 00b. The mechanisms of these and related reactions have been the subject of labelling studies. 

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