Nucleophilic addition leaving-group effects

In response to reviewer feedback, new sections have been added on fragmentation patterns in mass spectrometry (Section 13.3) and peptide sequencing (Section 28.6). In addition, sections on splitting in NMR spectroscopy (Section 14.7) and substituent effects in substituted benzenes (Section 18.6) have been rewritten to clarify and focus the material. Some mechanisms have been modified by adding electron pairs to nucleophiles and leaving groups to more clearly indicate the course of the chemical reaction. 

The cyanide ion plays an important role in this reaction, for it has three functions in addition to being a good nucleophile, its electron-withdrawing effect allows for the formation of the carbanion species by proton transfer, and it is a good leaving group. These features make the cyanide ion a specific catalyst for the benzoin condensation. 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

The effect of the nature of ion pairs as nucleophiles in a metal-catalysed substitution reaction has been investigated by determining product ratios for the Pd-catalysed allylic alkylations of substrates (9)-(ll) under various conditions, particularly with respect to catalyst ligands, nucleophiles, and counterions. Each dienyl acetate ionizes to form initially the vinyl (7r-allyl)-Pd intermediate corresponding most closely to the leaving group, i.e. (12) from (9), (13) from (11), but (12) and (13) from (10). The initial intermediate can then either be trapped by the nucleophile or it can begin to equilibrate to some mixture of vinyl 7r-allyl intermediates. If nucleophilic addition occurs before full equilibration, the product ratio is different for each substrate if... 

If the potential leaving group is attached to unsaturated carbon, as in vinyl chloride or phenyl chloride, attack by nucleophiles is also extremely difficult, and these compounds are very unreactive in Sn2 reactions compared with simple alkyl halides. In these cases, the reason is not so much steric but electrostatic, in that the nucleophile is repelled by the electrons of the unsaturated system. In addition, since the halide is attached to carbon through an 5p -hybridized bond, the electrons in the bond are considerably closer to carbon than in an 5/ -hybridized bond of an alkyl halide (see Section 2.6.2). Lastly, resonance stabilization in the halide gives some double bond character to the C-Hal bond. This effectively strengthens the bond and makes it harder to break. This lack of reactivity is also tme for SnI reactions (see Section 6.2). 

We can also rationalize why some addition reactions simply do not occur, e.g. halide ions do not add to carbonyl groups. Although we know that a halide such as bromide can act as an effective nucleophile in Sn 1 and Sn2 reactions (see Section 6.1.2), it is also a very good leaving group (pATa value for HBr —9). This means that the reverse reaction becomes very much more favourable than the forward reaction. In cases where both forward and reverse reactions are feasible, we can often usefully disturb the equilibrium by using an excess of one reagent (see below). 

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