Quinone methide <9-protonation

Scheme 10. Mechanislic possibililies for PF condensalion. Mechanism a involves an SN2-like attack of a phenolic ring on a methylol. This attack would be face-on. Such a mechanism is necessarily second-order. Mechanism b involves formation of a quinone methide intermediate and should be Hrst-order. The quinone methide should react with any nucleophile and should show ethers through both the phenolic and hydroxymethyl oxygens. Reaction c would not be likely in an alkaline solution and is probably illustrative of the mechanism for novolac condensation. The slow step should be formation of the benzyl carbocation. Therefore, this should be a first-order reaction also. Though carbocation formation responds to proton concentration, the effects of acidity will not usually be seen in the reaction kinetics in a given experiment because proton concentration will not vary.

SCHEME 7.17 Electrostatic potential map of the protonated pyrido[l,2-<2]indole-based cyclopropyl quinone methide. The two possible nucleophile-trapping paths with the respective products are shown. 

FIGURE 7.20 Potential-density maps for the O-protonated pyridoindole quinone methide and the corresponding neutral species. The charge density color codes are anionic (red), cationic (blue) and neutral (green). 

Foster, K. L. Baker, S. Brousmiche, D. W. Wan, P. o-Quinone methide formation from excited state intramolecular proton transfer (ESIPT) in an o-hydroxystyrene. J. Photochem. Photobiol. A Chem. 1999, 129, 157-163. 

Fischer, M. Wan, P. m-Quinone methides from m-hydroxy-1,1-diaryl alkenes via excited-state (formal) intramolecular proton transfer mediated by a water trimer. J. Am. Chem. Soc. 1998, 120, 2680-2681. 

To account for the effects of specific acid catalysis, the calculations were also carried out in the presence of an additional proton. The resulting potential energy surface at PCM-B 3LYP/6-311 G(2df,p)//B 3LYP/6-31 G(d, p) level of theory suggested that the p-O-4-linked quinone methide ((3-O-QM) is a fairly stable species and its... 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

The third primary intermediate in the oxidation chemistry of a-tocopherol, and the central species in this chapter, is the orr/zo-quinone methide 3. In contrast to the other two primary intermediates 2 and 4, it can be formed by quite different ways (Fig. 6.4), which already might be taken as an indication of the importance of this intermediate in vitamin E chemistry. o-QM 3 is formed, as mentioned above, from chromanoxylium cation 4 by proton loss at C-5a, or by a further single-electron oxidation step from radical 2 with concomitant proton loss from C-5a. Its most prominent and most frequently employed formation way is the direct generation from a-tocopherol by two-electron oxidation in inert media. Although in aqueous or protic media, initial... 

For over 35 years, the quinone methide species has been invoked as a reactive intermediate in bioreductive alkylation and in other biological processes.8 29 Generally, there is only circumstantial evidence that the quinone methide species forms in solution. Conceivably, the O-protonated quinone methide (i.e., the hydroquinone carbocation) could be the electrophilic species. If so, bioreductive alkylation may simply be an SN1 reaction. Also, there are questions concerning the mechanism of quinone methide... 

Illustrated in Scheme 7.8 are the mechanisms that give rise to the products shown in Scheme 7.7. These mechanisms involve either electrophilic attack or an internal redox reaction. The internal redox reaction shown in Scheme 7.8 involves proton trapping from the solvent or from the hydroquinone hydroxyl group as shown. This process has been documented for the mitomycin system50 and also occurs in many quinone methide systems.25,30,31... 

The product structures shown in Fig. 7.14 indicate that the cyclopropyl quinone methide traps protons and nucleophiles like the classic quinone methides, see mechanisms in Scheme 7.15. However, the cyclopropyl quinone methides can also... 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

We studied the reactions shown in Scheme 7.18 using the global fitting methodology described in Section 7.2.1. The quinone methide species rapidly built up in solution upon quinone reduction and trapped by either water or a proton to afford the final products shown in Scheme 7.18. global fitting provided the rates of quinone methide... 

The rate constants associated with the conversion of the pyrrolo[ 1,2-c/Jindole hydroquinone to its quinone methide were fit to the rate law equation (7.1), see Fig. 7.17 for rate data and the fit. The solid line in Fig. 7.17 was generated with Eq. 7.1 where k0 = 0.09min-1 and k 1.5 x 105M min The mechanism consistent with the pH-rate profile is the spontaneous elimination of acetate (kf) process) and the proton assisted elimination of acetate (kx process) from the electron-rich hydroquinone. The k0 process is independent of pH and exhibits a zero slope while the kx process exhibits a — 1 slope consistent with acid catalysis. 

Equation 7.2 represents the rate law for quinone methide disappearance. This equation was derived using material balance where reactions occur from and equilibrating mixture of neutral and protonated quinone methide. Both the protonated (k2 process) and neutral equivalent (k2 and k4 processes) react to afford the observed major products shown in Scheme 7.18. Alternatively, the quinone methide can be protonated... 

The mechanistic interpretation of the pH-rate profiles for quinone methide disappearance relied on Hartree-Fock calculations with 6-31G basis sets as well as on product studies. In Fig. 7.20, we show the potential-density maps of the protonated and neutral pyridoindole quinone methide with negative charge density colored red and positive charge density colored blue. Inspection of the methide... 

The global fitting studies revealed that the hydroquinone species shown in Scheme 7.5 affords the quinone methide at rates of 1-2 x 10 3 min-1 that are independent of both pH (from 7 to 9.5) and the concentration of buffers used to hold pH. We interpreted this observation as protonation of the C-5 center followed by the slow loss on the nitrogen-leaving group. The anionic C-5 center of the electron-rich hydroquinone ring would be very basic resulting in complete protonation near neutrality. 

The results enumerated above indicate that the quinone methide species must be protonated, by either a specific or general acid, to afford a cation before it can trap a nucleophile. The pK.A determined from pH-rate profile (pKA = 6.66) is consistent with (9-protonated quinone methide pKA values of 6-7 discussed in Section 7.3.5. 

Scheme 7.25 shows the role of quinone methide energy on the cation-quinone methide equilibrium. A high pKa value for this equilibrium is expected if the energy of the quinone methide approaches that of the carbocation. To construct this cycle, we used the Ka values that we determined for the protonated ketone (pKa — —0.9) and quinone methide (pKa = 6.6). This pKa difference requires that the keto form be more stable than the quinone methide by — 10.2kcal/mol. We obtained the calculated energy difference of lO.lkcal/mol from Hartree-Fock calculations using 6-31G and STO-3G basis sets, inset of Scheme 7.25. 

CONCLUSIONS AND FUTURE PROSPECTS 7.4.1 Quinone Methide O-Protonation... 

The most important conclusion of this research program is that quinone methide O-protonation is required for alkylation to occur. The quinone methide species is often referred to in the literature as an electrophilic species. Actually, the quinone methides obtained from reductive activation possess a slightly electron-rich methide center. There is electron release to the methide center by the hydroxyl, which is balanced by electron... 

Fig. 12.7a,e) it is important to realize that a protonated quinone methide QM1H + is actually a benzylic carbocation (Fig. 12.7a). Water will also add to the quinone methide under fairly neutral conditions.86-88 The isomer distribution of the resulting compounds, PI can be determined directly from or 13C (or 2D 13C/1H correlation)... 

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