The ipso protonation

The ipso protonation deserves a special scrutiny is discussed earlier. Here we show that the additivity rule is operative for the ipso protonation too, if proper reference level is found. Let us consider multiply substituted fluorobenzenes. They are schematically depicted in Fig.7. It is obvious that the proton affinity of benzene cannot serve as a gauge value for the ipso protonation. Instead, we shall employ once again homodesmic reactions and proceed as follows. Protonation at position 1 of 1,2,3-trifluorobenzene will provide an illuminating example in this respect. The corresponding homodesmic reactions read  

Proton affinities of some polysubstituted benzenes obtained by the MP(I) model (f l[MP2(I)]) and by the additivity rule (PA(add)). Deviations from the additivity are given by A in kcal/mol 

Taking a difference (16)-(17) and rearranging the resulting terms one obtains  

the ipso protonation at position 1 of 1-fluorobenzene is denoted by the subscript 1, whereas ortho and meta signify positions of other substituent(s) relative to the proto-nation site. The difference A = (c5 - 6+) determines deviations from strict additivity. It will appear that S and cancel to a large extent, although their particular values are sometimes not negligible. Relation (18) is easily generalized to encompass polyfluorinated benzenes  

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A series of substituted anthracenium monocations were generated by van der Griendt and Cerfontain (only proton data are available).15 A noteworthy feature is the anisotropic shielding of methyl in i/wo-protonated ethyl-substituted carbocations. A similar effect is seen in one of the methyl groups for the ipso-protonated isopropyl derivative. 

It is interesting to point out that the lowest proton affinity in polyfluorinated naphthalenes is found for ipso protonation (viz. systems 33, 35 and 36). It is a consequence of the out-of-plane shift of fluorine and the accompanying ring puckering. However, this is at the same time a manifestation of the rr-electron fluoro effect put forward by Liebman et al. [45]. It is very well known that multiply fluorinated compounds possess considerably stabilized a-MOs if the systems are planar, the 7r-manifold being almost unaffected [46]. However, in nonplanar systems all MOs at the carbon skeleton are significantly stabilized [45,46] which is exactly the ceise for the ipso protonation. Now, it can be easily shown... 

First, a ring-closure barrier ( TS3,4) leads to arene oxide products directly. Second, a proton-shuttle mechanism transfers the ipso-proton from the substrate in Icat to one of the nitrogen atoms of the porph5rrin ring to give the proton-transfer intermediate ( PT) via a barrier TSa s. In PT, the aromaticity has come back into the ring, and the structme can be seen as a phenolate... 

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

The acid-catalyzed rearrangements of substituted pyrroles and thiophenes consequent on ipso protonation have been referred to previously (Section 3.02.2.4.2). There is some evidence that these rearrangements are intramolecular in nature since in the case of acid-induced rearrangement of 2-acylpyrroles to 3-acylpyrroles no intermolecular acylation of suitable substrates could be demonstrated (Scheme 10) (8UOC839). 

In some instances the attack of the arene on the nitrilium salt occurs at the ipso carbon rather than the ortho carbon. For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2 1 mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ipso aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a proton vields product 12. ... 

Path c. The electrophilic group (in this case NOj) can undergo a 1,2 migration, followed by loss of the proton. The product in this case is the same as that obtained by direct attack of NOj at the ortho position of PhZ. It is not always easy to tell how much of the ortho product in any individual case arises from this pathway, though there is evidence that it can be a considerable proportion. Because of this possibility, many of the reported conclusions about the relative reactivity of the ortho, meta, and para positions are cast into doubt, since some of the product may have arisen not from direct attack at the ortho position, but from attack at the ipso position followed by rearrange-... 

The work of Coombes and coworkers20 on the formation of the 4-methyl-4-nitro intermediate has already been discussed above. Here the solvent was aqueous sulphuric acid with acid concentration ranging from 55% to 90%. The final product, 4-methyl-2-nitrophenol, was formed by the expected two routes about 40% via the ipso-intermediate and 60% directly. Their kinetic studies enabled the acidity dependence of the ipso-rearrangement to be examined they argued that this dependence demonstrated that the rate-limiting stage of the conversion involved the protonated /pso-intermediate (43). They... 

While donor substituents assist in ortho and meta protonation, acceptor substituents direct protonation of the primary anion-radicals to the ipso and para positions. It should be emphasized that water treatment of the naphthalene anion-radical in THF leads to 1,4-dihydronaphthalene. Notably, the same treatment of this anion-radical, but o-bound to rhodium, leads to strikingly different results. In the rhodium-naphthalene compound, an unpaired electron is localized in the naphthalene, but no protonation of the naphthalene part takes places on addition of water. Only evolution of hydrogen was observed (Freeh et al. 2006). Being a-bound to rhodium, naphthalene acts as an electron reservoir. The naphthalene anion-radical part reacts with a proton according to the electron-transfer scheme similar to the anion-radicals of aromatic nitro compounds (see Scheme 1.14). 

Benzoyl-3-diazo-4-phenylpyrazole, decomposed in hot sulfuric acid (50%) with evolution of nitrogen but no pure product, could be isolated [60CI(L)659]. By contrast, 4-diazopyrazoles were very stable in strong acids [60CI(L)659], especially the unconventional diazo 22a in which, due to the particular mesomeric structure, protonation at the ipso carbon is not... 

These addition reactions require formation of an imino-cyclohexadiene intermediate (Fig. 13.41). In cases where the ipso substituent is a proton, tautomeriza-tion to form the substituted aniline derivative is fast, and such intermediates have not been isolated. On the other hand, in situations where the nucleophile adds to a substituted ring position, the intermediate can undergo further secondary reactions. For example Novak et al. showed that the 4-biphenylylnitrenium ion reacts with water forming the imine cyclohexadiene intermediate 74, which in turn experiences an acid-catalyzed phenyl shift reaction to 76 via 75 (Fig. 13.42). 

There is an alternate mechanism for halide replacement, following the sequence of nucleophile addition, protonation and elimination of HX (Scheme 9). In this pathway, the addition of the nucleophile need not be at the ipso position it can be ortho to halide leading to cine substitution or it can be at the meta or para positions, leading to tele substitution.69,70 The mechanism is the same for both cine and tele substitution and the different names reflect a differentiation in the IUPAC naming schemes. 

In an analogous way, electron transfer to an acceptor-substituted aromatic like 25 produces a radical anion ot type 26. This is proto-naled in the ipso position to give intermediate 27. A second electron transfer and prolonation leads similarly to product 28. In most cases BuOH proves to be a good source of protons. 

Product formation was interpreted in terms of transalkylation of substituted triphenylmethanes. Protonation at the ipso position of the substituted phenyl ring to form arenium ion 64 followed by the C—C bond breaking yields the diphenylmethyl cation, which alkylates benzene or is stabilized by hydride transfer (Scheme 5.30). The protonated intermediate 64 is highly unstable when the ring has an electron-withdrawing substituent. Consequently, its transformation is extremely slow and the primary product triphenylmethane can be isolated. 

While donor substituents assist the ortho and meta protonation, acceptor substituents direct the protonation of the primary anion radicals to the ipso and para positions. 

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