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.

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

2-FC

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.

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

4-DA

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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{ 4 comments… read them below or add one }

Gloria

Sorry for such a late post on an old topic. Basically I’m a biochem student and google always helps a lot and I fall onto your site quite often, it’s been very helpful so thank you. I’ve read this post and for the life of me can’t stop thinking about the whole “nucleophile attacks electrophile” thing. I know most reactions occur that way, but what about electrophilic substitution/addition if those two things are the same. I know cations such as carbocations don’t generally exist because they’re unstable and only form as a result of some nucleophilic attack, and lately in the last few classes this has been plaguing me because all I do notice is some negative thing attacking a positive thing and I can’t for the life of me think about any exceptions. Then where does electrophilic substitutions fit in all this? Is it that in electrophilic mechanisms, the solvent does something to the molecule so that it becomes a cation first and then nucleophile attacks? Can it be said that electrophilic substitutions are basically the counterpart of nucleophilic substitutions? Then where exactly is the difference? Thanks!

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Jonathan Minkin

A big fan of your site.
Just one question about the geometry of the acylium cation intermediate of the friedel crafts acylation reaction. Since one resonance structure is linear (carbon triply bonded to carbon) and one resonance structure is depicted here as ‘bent’ (carbon doubly bonded to carbon) would you expect the resonance hybrid to be linear, bent, or somewhere in between?

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João Louçano

Hi Jonathan!

You posed a very interesting question. Allow me to contribute to the debate.
The linear resonance structure of the acylium cation is an oxonium cation: the positive charge is localized in the oxygen atom. Oxygen is very electronegative and more electronegative than carbon. Oxonium cations are thus hardly stable (although there are exemples in nature – anthocyanins) and consequently the contribution of this resonance structure to the resonance hydrid should be small.
I would expect the resonance hybride to have a slightly larger angle than the typical 120 degrees for sp2 carbons.

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Pete

I’m afraid I disagree. Why would the molecule choose to be bent? It can be sp hybridized and linear, placing the positive charge in a p-orbital on carbon, and making the C-R sigma bond lower in energy since it has more s-character, or it can be sp2 hybridized with the charge in an sp2 orbital. It seems to me there would be a steric AND electronic penalty for the acylium cation to be anything but linear.

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