Lecture Outline Nucleophilic aromatic substitution (NAS)

Lecture outline Nucleophilic aromatic substitution (NAS) involves replacement of a leaving group by a nucleophile. There are two common mechanisms by which NAS takes place — SN2 is not one of them — why? SN1 is not one of them — why? 1. The Addition–Elimination mechanism This occurs by addition of a nucleophile (usually hydroxide, an alkoxide, and amine, to the aromatic ring to make an anionic intermediate (the "Meisenheimer complex"), followed by loss of the leaving group (usually a halogen; F is especially good!) in a separate step. X OR NO2 NO2 RO NO2 NO2 –X mech: RO X OR X OR NO2 NO2 X OR NO2 NO2 NO2 NO2 Benzene itself does not do this reaction under normal conditions (but perhaps under extreme conditions?). And most simple derivatives of benzene do not do this reaction. In addition to a suitable leaving group, the reaction requires resonance-electron-withdrawing groups ortho or para to the site of attack. How is this nucleophilic substitution mechanism related to the SN2 and SN1 mechanisms? (Hint: think about the timing of the steps.) In what other cases might you expect to see a nucleophilic substitution take place by this type of mechanism? Is an aromatic ring required? Is a π-bond required? Can this happen at an sp3 C? Are substituents important? Is a nucleophilic substitution possible in each case below? If so, by what mechanism? Draw the product(s). F O2N CH3 EtNH2 ∆ CN Br KOH NO2 I CH3O Et–OH 2. The Benzyne mechanism (elimination-addition) This typically happens with a super-strong base like amide ion at low temp or with a weaker base like hydroxide or alkoxides at high temp. Cl NH2 Na NH2 NH3 (liq) Now, you probably think that’s just going by one of the usual mechanisms, don’t you? SN2 perhaps? Addition-elimination maybe? Ha. If you think it’s that simple, explain the one below. The p and m products are formed in roughly equal amounts. Cl NH2 Na NH2 + CH3O NH3 (liq) CH3O CH3O Here’s the mechanism that was proposed to explain the first reaction. How does this explain the formation of both p and m amines from p-chloroanisole? NH2 What products would you expect from m-chloroanisole, and in what ratio? Now, if you still don't believe such a crazy molecule can be involved, even as an intermediate, here some more evidence. If chlorobenzene is treated with sodamide (NaNH2) in the presence of 1,3-cyclopentadiene, the following product is formed (instead of aniline)... This is a “Diels-Alder” reaction. We’ll study those toward the end of the semester. Let's think a little about the structure of benzyne... this is probably best thought of as a "2.5-bond" Keeping in mind that benzyne has a cycle of 6 p-orbitals, perpendicular to the plane of the ring, sketch the orbitals that make up that extra goofy-looking “π”-bond. Perhaps we should draw this with one “dot” in each orbital — maybe the thing is really a biradical — how good does the overlap need to be to have a “bond”??? We can get an idea of how strong that “bond” is from gas-phase thermochemical measurements. The BDE for benzene is well known to be 111 kcal/mol. Remember, this is the energetic cost of chopping off an H to make phenyl radical. BDE = 111 kcal/mol H – H• The BDE of the H ortho to the “dot” can be measured in a round-about way via a combination of data — this turns out to be only 79 kcal/mol (not 111! Hmmmm...) H ortho-H BDE = 79 kcal/mol or – H• So what's the strength of the goofy π-bond? (cf. a normal π-bond has a BDE of 60 - 65 kcal/mol) Now here's something really weird... the BDEs for the meta and para Hs of phenyl radical can also be measured — those are 89 and 101 kcal/mol, respectively. What do those imply about “meta-benzyne” and “para-benzyne”? In other words, how chummy are the electrons? Can they be considered weakly bonded? Should we represent them be drawing Lewis structure-type “lines”? And if we did, would people think we were insane? Or at least mildly disturbed? Should we care? Should we say instead that those things are biradicals with strongly interacting electrons (strongly interacting for a biradical, that is)? And if they’re interacting, doesn’t that mean they’re “bonded”, at least weakly?