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Nucleophile attacks Electrophile

My Ph.D supervisor’s Ph.D. supervisor was quoted once as saying, “basically, all organic chemistry reactions boil down to nucleophile attacks electrophile.”

Think about it for a minute. When you expand your concept of nucleophile beyond those species that will react with an alkyl halide in an SN2 reaction to include aromatics and alkenes as well, pretty much every reaction you learn in introductory organic chemistry follows this principle.

Acid base reactions – nucleophile (base) attacks electrophile (acid).

Bromination: nucleophile (alkene) attacks electrophile (bromine) to give a new electrophile (the bromonium ion) and a new nucleophile (bromide ion) which react further to give your vicinal dibromide. For that matter, look at all the alkene addition reactions: alkene (nucleophile) plus the electrophiles BH3, H2SO4, Hg(OAc)2, OsO4, ozone, and so forth.

The Friedel Crafts and related reactions are another example: nucleophile (aromatic) attacks electrophile (alkyl or acyl carbocation generated through addition of FeCl3 or AlCl3).

Look at the Aldol reaction: nucleophile (enolate) attacks electrophile (aldehyde). Enolates are versatile nucleophiles. Part of the challenge of mastering carbonyl chemistry is understanding how the “flavor” of both nucleophilic enolates and electrophilic carbonyls changes as you adjust functional groups next to the carbonyls.

Even the Diels-Alder reaction can be thought of in this context : diene (nucleophile) attacks dienophile (electrophile).

In more technical terms, what’s just been described in all these cases is the formation of new bonds by the overlap of the highest-occupied molecular orbital (HOMO) of the nucleophile with the lowest unoccupied molecular orbital (LUMO) of the electrophile. In short then,  the essence of most reactions in organic chemistry involves the flow of electrons from electron rich (nucleophilic) sites to electron poor (electrophilic) sites.

Can you think of any exceptions?

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