Reactivity with nucleophiles

Quinone methides are electron-deficient at C7, as readily understood via the resonance forms of QM1 shown in Fig. 12.7. They are therefore susceptible to nucleophilic attack at that position. Although reactions during high-temperature pulping demonstrate that 8- 9-4-aryl ether quinone methides QM1 are rearomatized by attack with hard nucleophiles such as HO- and HS, 81 these reactions do not readily occur at ambient temperatures.41,85 Thus, HO will not add to quinone methide QM1 under any conditions that we have tried (including with cosolvents, and using phase-transfer conditions). Of course water will add to quinone methides under acidic conditions 

Cleavage of 8-0-4-ethers in alkaline pulping is also facilitated by HS as used in kraft pulping.98 The major mechanisms (Fig. 12.8b) are via addition to the quinone methide QM1 to give adduct 19, followed by anchimerically assisted fragmentation via a thioepoxide 20. 

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Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

Alkyltrifluorosilanes and disubstituted difluorosilanes are themselves quite reactive with nucleophiles such as lithium amide bases [102, 103 104], alkyl-lithium reagents [1051, Gngnard reagents [105], or alkoxides [105] (equations 82 and 83)... 

Oxetanes are significantly less reactive with nucleophiles due to diminished ring strain. Under certain conditions, however, amines can open oxetanes to give amino alcohols. tert-Butylamine reacts with oxetanes in the presence of Yb(OTf)3 to give 3-hydroxy amines. Lithium tetrafluorohorate has also been used for this... 

In this review, the chemical properties of these electrophilic metabolites (i-XIIl) are discussed in terms of their metabolic formation and reactivity with nucleophiles, solvolysis and redox characteristics, reaction mechanisms, and their role as ultimate carcinogenic metabolites. 

For N-methyl arylamines, electrophilic N-sulfonyloxy esters appear to be strong candidates for the ultimate carcinogenic metabolites. However, additional studies are required as these conclusions are circumstantially based on their comparative reactivity with nucleophiles and on the failure of other metabolic conjugation systems to esterify N-hydroxy-N-methyl arylamines (9,187). 

As in the case of pyrimidine bases discussed previously, adenine and guanine are subject to nucleophilic displacement reactions at particular sites on their ring structures (Figure 1.50). Both compounds are reactive with nucleophiles at C-2, C-6, and C-8, with C-8 being the most common target for modification. However, the purines are much less reactive to nucleophiles than the pyrimidines. Hydrazine, hydroxylamine, and bisulfite—all important reactive species with cytosine, thymine, and uracil—are almost unreactive with guanine and adenine. 

The regioselectivity of ring opening of 4a-c is successfully controlled by the choice of reaction conditions. Lewis acid in dichloromethane and hydrogen chloride in alcohol are suitable conditions for generation of an alkylideneallyl cation, which was employed for studying its reactivity with nucleophiles such as... 

Just as protonation of the O-acylisourea enhances its electrophilicity, and consequently its consumption, it can be postulated that the reactivity with nucleophiles of any 2-alkoxy-5(4//)-oxazolone that is formed is enhanced by its protonation. Thus, it is reasonable to assert that a beneficial effect of HOBt in improving efficiency in couplings of /V-alkoxycarbonylamino acids is protonation of the oxazolone (see Section 2.25) that facilitates its consumption.432... 

Comparison with the reported reactivity of the spiro[2.5]octa-l,4-dien-3-one 110 and 4-(hexafluoroisopropylidene)cyclohexa-2,4-dien-l-one 111 have suggested that the conjugated cyclopropane ring of compounds 108 and 109 imparts a strong acid dependence to its reactivity with nucleophiles, Eq. (45). This property is likely to be relevant for the exceptional reactivity of these antibiotics toward DNA [148]. 

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