Of pseudobases

Transition state pKn values may also be estimated for reactions which involve nucleophilic attack by water and by hydroxide ion (Kurz, 1963, 1972). Such may be the case in the formation of pseudobases from quaternary heterocyclic cations (32a,b), a number of which have rates of... 

Alkaline solutions of alkylpyridinium salts contain increasing amounts of pseudobases (106 equation 83) in equilibrium with the charged form as the series 1-methylquinolinium, 2-methylisoquinolinium, 10-methylphenanthridinium and 10-methylacridinium is traversed. Such species were first postulated as a result of the observation that alkaline solutions of quaternary salts do not obey the Beer-Lambert law. Pseudobase formation at... 

Photolysis of 2-hydroxy-1-indanones 11 leads to a mixture of pseudobase ether 12 and 1,5-dicarbonyl compound 13 (76JA5581), which are precursors of 2-benzopyrylium salts and should be convertible to the latter compounds under strongly acidic conditions. 

The study of the enamine structure may be associated, to a certain degree, with the problem of the so-called pseudobases an instructive, but somewhat specialized, review of these compounds was contributed by the late Professor Beke 47 to the first volume of this series. The name pseudobases was given by Hantzsch,48 towards the end of the last century, to those a-aminocarbinols which undergo a structural change during salt formation and yield salts with the loss of one molecule of water. The liberation of pseudobases from their salts is accompanied by rehydration. This behavior has been observed with a,/3-unsaturated heterocyclic compounds and, to a certain degree, with aromatic heterocyclic pyridine derivatives. As formulated by Gadamer,49 the pseudobases represent a potential tautomeric system of three components, the quaternary hydroxide A, the carbinolamine B, and the open-chain amino-carbonyl derivative C, in which all three components exist in a mobile equilibrium ... 

Despite the fact that the concept of pseudobase formation has entered the folklore of heterocyclic chemistry, 15 the example presented by most heterocyclic chemistry texts of a reaction involving this phenomenon has recently been shown to be incorrect (Section V,C). It is only recently that systematic quantitative studies on pseudobase stability have been attempted or that the kinetics of pseudobase-cation equilibration have been investigated in detail. Thus, the current review covers a period in which extensive quantitative studies of pseudobase formation have become available. In addition, work in this area since Beke s earlier review4 has been characterized by the detailed application of spectroscopic techniques to the determination of pseudobase structure and tautomerism. 

The concept of pseudobase formation by heteroaromatic cations is intimately related to the covalent hydration of heteroaromatic molecules16-19 and to Meisenheimer complex formation,20-25 although this relationship has not generally been emphasized in the literature until recently26,27. All such reactions involve the formation of -complexes by nucleophilic addition to electron-deficient aromatic species, and yet, extensive reviews of covalent hydration16-19 and of Meisenheimer complex formation20-25 have neither explicitly recognized their mutual relationship nor considered pseudobase formation. 

Other cation-pseudobase equilibrations that have received detailed spectral investigation include quaternary isoquinoline alkaloids and related isoquinolinium derivatives,910 naphthyridinium mono- and dications,26,38,42 44 50 pyridinium cations,51,52 isobenzopyrylium (isochro-mylium) cations,53 benzothiopyrylium (thiochromylium) cations,40 and 1,3-dithiolium cations.54 PMR spectroscopy has also been useful in the identification of pseudobases as reaction intermediates in several reactions in solution.55-57 While 13C-NMR spectroscopy is also potentially useful for the assignment of pseudobase structure, at present there do not appear to... 

Heterocycle P. P Cr. for N—Me cation Resonance energy" of heterocycle (kcal mol-1) Pseudobase reference molecule Resonance energy6 of pseudobase reference A R (kcal mol-1)... 

In general, cation-pseudobase equilibration is quite rapid in aqueous solution, and the use of the stopped-flow or temperature-jump techniques is usually required for the measurement of the rates of pseudobase formation from, and decomposition to, the cation. The presence of a large substituent, such as a phenyl ring, at the site of hydroxide ion addition does slow the rate of equilibration sufficiently to allow kinetic measurements by normal spectrophotometric techniques.92... 

The empirical equations (26) and (27) suggest that two kinetically distinguishable pathways are available for each of pseudobase formation and decomposition in aqueous solution.92 The pH-independent term kHl0 for pseudobase formation is interpretable either as a rate-determining attack of a water molecule on the heterocyclic cation followed by a rapid deprotonation (transition state C) or alternatively as the general-base-catalyzed attack (by another water molecule) of a molecule of water on the heterocyclic cation (transition state D). In more basic solutions, this mechanism becomes unimportant compared with the direct attack of hydroxide ion (kOH[OH-]) on the heterocyclic cation (transition state A), or alternatively the kinetically... 

Detailed studies of the temperature dependence of the kinetics of cation-pseudobase equilibration have been reported92 for three cations, and activation parameters have been evaluated for each of k0H, kH20, kt, and k2 in these cases. Whereas entropies of pseudobase formation from the cation are positive (Section III), the entropies of activation associated with k0H are quite negative (-11 to -17 cal mol-1 deg-1). For direct hydroxide ion attack on the cation via transition state A, one would predict an entropy of activation similar to the entropy of formation of the pseudobase from heterocyclic cation and hydroxide ion. Interpretation of k0H in terms of transition state B in which hydroxide ion acts as a general-base catalyst for the attack of a water molecule seems to be more consistent with the observed entropies of activation. The k2 step, which is the microscopic reverse of fcoH would then be interpreted as general-acid-catalyzed (by a water molecule) decomposition of the neutral pseudobase to the cation. These interpretations of /cqH and k2 are also consistent with the observed solvent isotope effects for the reactions in HzO and DzO and with the presence of general... 

In Section II, a strategy was described for the investigation of the ring opening of pseudobases in aqueous solutions on the basis of a comparison of the electronic absorption spectra of the pseudobases formed by a particular heterocyclic cation in aqueous and alcoholic solutions. Similar... 

The following sections will emphasize those systems in which reasonable attempts have been made to conduct detailed investigations of ring-opening reactions of pseudobases in aqueous solution. In addition, there are numerous reactions of heterocyclic molecules, under a wide variety of reaction conditions, which have been postulated to proceed via ring-opening of a pseudobase intermediate.100-194-20 3... 

While quantitative measurements of pseudobase formation in aqueous alcoholic solutions may be used as indications of the relative susceptibilities to nucleophilic attack for closely related cations,9,53,75,218 such data are not directly comparable with equilibrium and rate data for pseudobase formation in either water or the pure alcohol (or even with data in aqueous alcoholic solutions of other compositions). Several workers218,257,261,262 have reported rate constants for hydroxide ion attack on heterocyclic cations in aqueous alcoholic solutions without any apparent attempt to consider the complications that arise in such media as a result of the competition between hydroxide and alkoxide ions as nucleophiles. The only attempt to measure the relative reactivities of hydroxide and alkoxide ions toward a heterocyclic cation appears to be the work of Gravitz and Jencks306 for the IV,0-trimethylenephthalimidium cation (158). In this study, product analysis indicated the relative proportions of hydroxide and alkoxide adduct... 

It is unfortunate that there has been so little work devoted to quantitative measurements of cation-pseudobase equilibria in methanol and ethanol since these media have several advantages over water for the determination of the relative susceptibilities of heterocyclic cations to pseudobase formation. The enhanced stability of the pseudobase relative to the cation in alcohols compared to water is discussed earlier this phenomenon will permit the quantitative measurement of pseudobase formation in methanol (and especially ethanol) for many heterocyclic cations for which the equilibrium lies too far in favor of the cation in aqueous solution to allow a direct measurement of the equilibrium constant. Furthermore, the deprotonation of hydroxide pseudobases (Section V,B) and the occurrence of subsequent irreversible reactions (Sections V,C and D), which complicate measurements for pKR+ > 14 in aqueous solutions, are not problems in alcohol solutions. Data are now available for the preparation of buffer solutions in methanol over a wide range of acidities.309-312 An appropriate basicity function scale will be required for more basic solutions. The series of -(substituted phenyl)pyridinium cations (163) studied by Kavalek et al.i2 should be suitable for use as indicators in at least some of the basic region. The Hm and Jm basicity functions313 should not be assumed90 to apply to methoxide ion addition to heterocyclic cations because of the differently charged species involved in the indicators used to construct these scales. 

Meisenheimer complex formation as separate reactions. Meisenheimer complexes can be considered as the anionic pseudobases derived from neutral aromatic molecules, and in this light it is clear that heterocyclic Meisenheimer complexes are appropriately considered in the current Review. By so doing, it is hoped that attention can be drawn to potentially mutual benefits that may be derived from comparative studies of neutral and anionic pseudobases. Certainly, the spectroscopic techniques applicable to the study of pseudobase and Meisenheimer complex formation are identical. Quantitative studies of substituent effects and structural effects on rates and equilibria for nucleophilic addition should be relevant both to neutral and to anionic e-complex formation. The general rules enunciated by Strauss23,318 and Fendler319 for the prediction of the relative stabilities of Meisenheimer complexes should be directly applicable to analogous pseudobases. Terrier et al.2n have made an important contribution in this area with a detailed comparison of kinetic and thermodynamic parameters for formation of a benzofuroxan Meisenheimer complex and an isoquinoline pseudobase. 

The equilibria between cation and pseudobase are established rapidly at temperatures above -50°, and in each of the cases (190-197), the equilibrium lies heavily in favor of the pseudobase. An enhanced stability of pseudobase relative to the cation is quite apparent in liquid ammonia... 

Analogously, although the enhanced reactivity of quinoline derivatives (relative to pyridine counterparts) in nucleophilic additions such as the formation of pseudobases and Reissert compounds probably relates to the relatively lower energy of the LUMO in the quinoline derivatives, the radicals from these heterocycles, in which the corresponding orbitals are singly occupied, are anionic thus, reactivity toward nucleophiles is also unlikely to be important. 

Imino-4-substituted-6,7-dihydropyrimido[6,l-a]isoquinolines yield an equilibrium system involving the tautomeric forms of pseudobases 48, 49, and 50 and anhydro base 51 (see Scheme 8) [90CB493 91CB111 94H(37)2051]. 

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