Reactions of Aromatic Compounds Simple alkenes tend to undergo addition reactions: HBrBr2BrBr BrC3H6C3H6Br2C3H7Br The elements of the reagent (HBr or Br2) are simply added to the starting material. This is called, unsurprisingly, and addition reaction. Aromatic compounds do not react in this manner. A look at a simple aromatic bromination: Br2 / FeBr3BrC6H6C6H5Br What we have done in this case is substitute a bromine for a hydrogen. Hence the term “aromatic substitution.” Because the benzene ring is quite electron-rich, it almost always behaves as the nucleophile in a reaction - which means that the substitution on benzene occurs by the addition of an electrophile -> electrophilic aromatic substitution. There is basically one simple mechanism for all electrophilic aromatic substitutions: E+HEHEHEB-E The benzene acts as a nucleophile, attacking the electrophile with a pair of its π-electrons. This initial step destroys the aromaticity of the molecule! The resulting positive charge is delocalized over the ortho and para positions. The conjugate base of the initial electrophile then assists in removing the now-extraneous proton, and restores aromaticity. Because all electrophilic aromatic substitutions proceed in this way, the only thing that matters is the preparation of a “hot’ electrophile. Why a “hot” electrophile? As you can see, the first step of the reaction involves destroying aromaticity. In order to do this, there must be a significant energetic driving force. This driving force comes in the form of a very reactive (unhappy) electrophile. How are such electrophiles generated? Halogenation As you can imagine, halogens bearing a positive charge are particularly reactive. I will focus on preparing halogen electrophiles from Br, Cl and I. Bromine: Allowing bromine to react with iron metal first generates FeBr3, which then interacts with the remaining Br2 to form a highly polarized system: FeBr2FeBr3Br3Fe Br Br!-!+It is this highly polarized bromine that becomes a source of “Br+.” The reaction proceeds by the mechanism shown above to give brominated benzene: Br2FeBr3Br Chlorine: The same chemistry shown for bromine also works with chlorine to generate “Cl+.” A mixture of benzene, chlorine and iron(III)chloride yields the chlorobenzene: Cl2FeCl3Cl Iodine: It is a little more difficult to make iodine sufficiently electrophilic. For relatively activated compounds, where a mild source of “I+” is required, copper salts are often used as a catalyst: I2CuCl2II2 + 2 Cu++ --> 2 "I+" + 2 CuI Reaction then proceeds by the standard mechanism, with I+ as the electrophile, to give iodinated benzenes. For more de-activated systems, or when more than one iodine needs to be added to the ring, a harsher reagent exists: Br BrBrH2SO4 / I2H5IO6Br BrBrI II Why? You should always ask this question. What good are aromatic halides? The halogens are excellent synthetic “handles” – they can be easily converted into other functional groups. For example, bromobenzenes can be turned into Grignard reagents, and the reacted with aldehydes, ketones, etc....BrMgBrMgOHOOMeOHOCO2COOH NITRATION We can also make a highly electrophilic form of NO2: NOOOHHSO4HNOOOHHONO Which can then react with aromatic compounds via the standard mechanism to give nitrated aromatics... ONONOOetc. Why? There are a couple of good reasons to nitrate things. The first is in the manufacture of explosives – highly nitrated organic molecules are frequently used as explosives (trinitrotoluene(TNT), nitroglycerine, etc.). The second reason is that nitro-groups are generally easy to reduce to amines. And since it is nearly impossible to make an amine electrophilic (in order to add it to an aromatic ring under electrophilic aromatic substitution conditions), aromatic nitro compounds are about the only precursors to aromatic amines: NO21) SnCl2 / H+2) HO-NH2 Sulfonation Just as with nitration, it is easy to make a solution of highly electrophilic SO3. This solution can be used to sulfonate aromatic compounds:OSOHSHOOOOHSO3Hlose proton Why? First of all, the reaction is REVERSIBLE!!! Cook it up in hot AQUEOUS acid, and the SO3 group falls right off again. Second, aromatic sulfonic acids were used as the first antibiotics - the so-called “sulfa” drugs (sulfanilamide, etc.) They can also be used in making detergents (oh, what fun.) Friedel-Crafts Reactions: This reaction comes in two flavors - alkylation and acylation. Alkylation first: The basic premise of this reaction is the electrophilic addition of alkyl groups to an aromatic ring. The general scheme: R-Cl + AlCl3R+ + AlCl4-R+ + R(R = alkyl) A simple example: ClAlCl3 There are a number of drawbacks to this reaction: 1) Does not work at all on aromatic rings with de-activating groups (nitro, any carbonyl, cyano) attached. 2) Because alkyl groups are activating, over-alkylation is a significant problem. 3) Because a carbocationic intermediate is involved, rearrangements tend to take place. For example: ClH HMajor productClAlCl3AlCl3AMESS! However, ol’ Friedel & Crafts came up with another reaction without so many drawbacks. The Friedel-Crafts acylation generally proceeds without complication:Cl ROAlCl3ROO RRORO For example: ClOAlCl3O Note the only significant restriction is that we still can’t have any de-activating groups on the ring. Over-acylation cannot be a problem – because an acyl group is de-activating, only one can add! There is also no problem with rearrangements. A very efficient! Substituent Effects Most of what I’ve talked about so-far has involved the addition of a compound to an unsubstituted benzene ring. What about additions to a substituted ring? I will summarize: Activating/de-activating groups Because the benzene ring’s electrons are acting as the nucleophile in all of the above reactions, rings substituted with strong electron-donating groups (particularly π-electron donating) are considered “activated” - they will often even react without a catalyst! Some examples of activating groups are: OH, OR, NH2, NR2, Alkyl The oxygen and nitrogen-based activating groups increase reactivity by a resonance effect: AA A A (A = OR, OH, NH2, NR2) As you can see, the very nature of the activation requires ortho-para direction! Alkyl groups work somewhat differently. They are not as strong at activating the