Nucleophilic attack initiation characteristics

As mentioned earlier, nucleophilic attack at ring carbon atoms a and y to a heteroatom is a reaction characteristic of the ir-deficient six-membered heterocycles. Within this context we do not regard hydrogen atoms attached to ring carbon atoms as substituent groups, and hence proton removal to generate a carbanionic centre is classified as a reaction at a ring carbon atom. There are thus six major reaction types, summarized in equations (21)—(26) in terms of the initial mechanistic steps. 

Recent model studies strongly support the proposed mechanism. The first crystal structures of Fe(II) complexed to benzoylformate show that an a-keto acid can coordinate to the iron as either a monodentate or didentate ligand [236]. Exposure of these [Fe(II)(L)(bf)]+ complexes (L = tmpa or 6-Me3-tmpa) to 02 results in the quantitative conversion of benzoylformate to benzoic acid and C02, modeling the oxidative decarboxylation reaction characteristic of this class of enzymes. As with the enzymes, the use of 1802 in the model studies results in the incorporation of the label into the benzoate product. For [Fe(6-Me3-tmpa)(bf)]+, the rate of the oxidative decarboxylation increases as the substituent of the benzoylformate becomes more electron-withdrawing, affording a Hammett p of +1.07. This suggests that the oxidative decarboxylation involves a nucleophilic attack, most plausibly by the iron-bound 02, on the keto carbon of benzoylformate to initiate decarboxylation as proposed in Figure 27. 

Nucleophilic addition is the characteristic mechanism for addition reactions of aldehydes and ketones. It can be base-initiated in which a negative or neutral nucleophile attacks the carbonyl carbon generating a negative carbonyl oxygen that is subsequently neutralized. In the acid-initiated mechanism, hydrogen ion bonds to the carbonyl oxygen a carbocation results which is neutralized by the nucleophile. 

Treatment of pristinamycin IIa with meta-chloroperbenzoic acid afforded a compound to which the structure (79) was initially assigned, resulting from epoxidation of the more substituted double bond (12,13-C). This material did not display chemical properties characteristic of an epoxide as the assumed epoxide moiety remaining after treatment with nucleophilic reagents. Michael-type addition products on the dehydroproline ring were observed after treatment with thiols or amines (see Sect. 5.4.5). 2D-NMR analysis of the product from reaction of pristinamycin IIa with mCPBA showed that a transannular oxidative cyclization had taken place leading to formation of (80). The reaction can be considered to involve initial epoxidation of the 12,13-double bond followed by an intramolecular nucleophilic attack by the 37-hydroxy of the enol ether (Scheme 19). A similar transannular oxidative cyclization reaction has been reported for the reaction of l,5-dimethylcyclooct-4-en-l-ol with meta-chloroperbenzoic acid [125]. 

An interesting feature of gallium(III) compounds as classified Lewis acids is their ability to interact with unsaturated bonds particularly with alkynes. GaCl3 formed a tt complex with alkynes, which strongly activated the triple bond toward nucleophilic attack. Carbometalation (carbogallation) with alkynes is another characteristic reaction of organogallium(III) compounds, and it is likely that the initial step for this reaction is the interaction of the tt electrons of alkynes with the Lewis acid gallium (III) center. 

The pair of electrons in the n orbital are more diffuse and less firmly held by the carbon nuclei, and so more readily polarisable, than those of the a bond, leading to the characteristic reactivity of such unsaturated compounds. As the it electrons are the most readily accessible feature of the carbon-carbon double bond, we should expect them to shield the molecule from attack by nucleophilic reagents and this is indeed found to be the case (cf. p. 198, however). The most characteristic reactions of the system are, hardly surprisingly, found to be initiated by electron-deficient species such as X and X (radicals can be considered electron-deficient species as they are seeking a further electron with which to form a bond), cations inducing heterolytic, and... 

Another stereochemical characteristic of these cyclizations is the equatorial disposition of both the entering electrophile and nucleophile, as expected for overall anti addition to both double bonds (727—123). The anti mode of addition appears to be followed in the initial electrophilic attack in all cases. However, the stereoselectivity in the approach of the nucleophile is evidently less since minor amounts of axial acetates are formed in the additions to the above model cyclodecadienes (73) and (74) (722). 

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