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Reactions of Aromatic Compounds

Br

Simple alkenes tend to undergo addition reactions: Br Br2 HBr
C3 H6 Br2 C3 H6

Br C3 H7 Br

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: Br Br2 / FeBr3

C6 H6 C6 H5 Br 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: BE E E H E+ H H

E

The benzene acts as a nucleophile, attacking the electrophile with a pair of its !-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: !!+ Br2 Br3 Fe Br Br FeBr3 Fe

It is this highly polarized bromine that becomes a source of “Br+.” The reaction proceeds by the mechanism shown above to give brominated benzene: Br Br2 FeBr3 Chlorine: The same chemistry shown for bromine also works with chlorine to generate + “Cl . .” A mixture of benzene. What good are aromatic halides? The halogens are excellent synthetic “handles” – they can be easily converted into other functional groups... where a mild source of “I+” is required. For relatively activated compounds. For example. chlorine and iron(III)chloride yields the chlorobenzene: Cl Cl2 FeCl3 Iodine: It is a little more difficult to make iodine sufficiently electrophilic. to give iodinated benzenes. with I+ as the electrophile. and the reacted with aldehydes.. or when more than one iodine needs to be added to the ring. bromobenzenes can be turned into Grignard reagents. ketones. For more de-activated systems. copper salts are often used as a catalyst: I2 + 2 Cu++ --> 2 "I+" + 2 CuI I2 I CuCl2 Reaction then proceeds by the standard mechanism. etc. a harsher reagent exists: I Br Br H2SO 4 / I2 H5IO6 Br Br I Br Br I Why? You should always ask this question.

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). N O O Why? There are a couple of good reasons to nitrate things. it is easy to make a solution of highly electrophilic SO3. aromatic nitro compounds are about the only precursors to aromatic amines: 1) SnCl2 / H+ NH2 NO 2 2) HOSulfonation Just as with nitration. The second reason is that nitro-groups are generally easy to reduce to amines.. O O N etc. The first is in the manufacture of explosives – highly nitrated organic molecules are frequently used as explosives (trinitrotoluene(TNT). This solution can be used to sulfonate aromatic compounds: HSO 4 H H O N O . etc.).Br Mg BrMg COOH CO2 O O OMe HO HO NITRATION We can also make a highly electrophilic form of NO2: O O O N O N H H O O Which can then react with aromatic compounds via the standard mechanism to give nitrated aromatics. nitroglycerine..

cyano) attached. 2) Because alkyl groups are activating. ol’ Friedel & Crafts came up with another reaction without so many drawbacks. Alkylation first: The basic premise of this reaction is the electrophilic addition of alkyl groups to an aromatic ring.alkylation and acylation. over-alkylation is a significant problem. any carbonyl.) Friedel-Crafts Reactions: This reaction comes in two flavors . the reaction is REVERSIBLE!!! Cook it up in hot AQUEOUS acid. aromatic sulfonic acids were used as the first antibiotics . Second. The general scheme: R-Cl + AlCl3 R+ + AlCl4- R+ + (R = alkyl) R A simple example: Cl AlCl3 There are a number of drawbacks to this reaction: 1) Does not work at all on aromatic rings with de-activating groups (nitro. For example: Cl AlCl3 H H Major product AlCl3 A MESS! Cl However.) They can also be used in making detergents (oh. etc. rearrangements tend to take place. The Friedel-Crafts acylation generally proceeds without complication: . and the SO3 group falls right off again.O O S OH OH O S lose proton SO3H HO Why? First of all. what fun. 3) Because a carbocationic intermediate is involved.the so-called “sulfa” drugs (sulfanilamide.

and their main function is stabilizing the positive charge formed after the attack on the electrophile: .O Cl R AlCl3 O R O O R R O R For example: Cl O AlCl3 Note the only significant restriction is that we still can’t have any de-activating groups on the ring. OH. 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. the very nature of the activation requires ortho-para direction! Alkyl groups work somewhat differently. Alkyl The oxygen and nitrogen-based activating groups increase reactivity by a resonance effect: A A A A (A = OR. NR2. They are not as strong at activating the ring.they will often even react without a catalyst! Some examples of activating groups are: OH. NH2. A very efficient! O Substituent Effects Most of what I’ve talked about so-far has involved the addition of a compound to an unsubstituted benzene ring. rings substituted with strong electron-donating groups (particularly !-electron donating) are considered “activated” . NH2. only one can add! There is also no problem with rearrangements. Over-acylation cannot be a problem – because an acyl group is de-activating. NR2) As you can see. OR.

Cyano (CN) Acid Halide (COCl) However. Strongly electron-withdrawing groups de-activate the ring towards electrophilic substitution. COR). They are VERY electron withdrawing. the incoming electrophile must attach to the meta carbons (see below). Nitro (NO2). However. in order to avoid putting the charge that develops (after attacking an electrophile) on the carbon attached to the electron-withdrawing group. Ketone (or acyl.R R R Stable tertiary carbocation! E+ E H E H (R = alkyl) Note well: All activating groups direct ortho-para! The Halogens: The halogens are in a class by themselves. their multiple lone-pairs are able to stabilize the cation formed after electrophilic addition. with a strong enough electrophile. and thus direct ortho-para: Br Br Br E+ E H E H Meta-Directing De-activators.the charge delocalizes over all of the ortho and para positions!) O O O O H E+ Other considerations: E E H E H . Examples of such groups are: Ester (COOR). the rings often will react. and thus DE-ACTIVATE the ring towards electrophilic substitution. and behave in an unusual manner. Acid (COOH). Aldehyde (CHO). However. Note that the charge cannot be delocalized onto the carbon containing the acyl group (also note .

p directors (OR.Sterics. Sterics. The resulting phenol was found to have arisen from an elimination/re-addition reaction: H Cl OH H2O HO Because benzyne is such a useful intermediate. a method has been discovered which allows it to be prepared by much milder means. It starts with anthranilic acid. 1) If the effects of two substituents point to reactivity at one particular carbon. 4) And of course. 16. keep a close eye on the steric environment. Nucleophilic Aromatic Substitution Your text has a good description of this phenomenon (Sec. Sterics.g. Benzyne Benzyne was discovered when some crazed scientists mixed chlorobenzene and sodium hydroxide at high temperature and pressure. which then decomposes to benzyne. but it would be a good idea to be familiar with the mechanism. 2) The strongest directing group almost always prevails (e. OH over alkyl. diazotizes the amine. forcing addition to the para positions: Br2 / Fe HNO3 H2SO 4 Br NO ORTHO! NO 2 Multi-functional compounds: What if the ring has several substituents? Your text has a rather detailed description of what to do. This sort of reaction is not very common. The benzyne can then be used in many ways: . NR2) b) Alkyl groups and halogen c) All meta-directors. This is particularly a problem with bulky ortho-para directors the ortho positions are blocked. you’re in luck! That’s where the electrophile will go (providing the sterics are not horrible). NR2 over Br) 3) The order of precedence is a) Strong o. so here I’ll just supplement that data.8). carbon dioxide and nitrogen.

O OH NH2 HNO2 H2SO 4 ("diazotization") O O H N N B- mild base OR ROH Diels-Alder Slow Decomposition Biphenylene Reactions on the Aromatic Side Chain: Alkyl groups attached to a benzene ring are surprisingly reactive. for example: O H N Br O (NBS) Br (PhCO)2 O CCl4 . The hydrogens on a carbon atom attached to the benzene ring are called benzilic. Notice a similarity to allylic systems? Benzilic Hydrogens H H H H Allylic hydrogens Benzilic hydrogens show a reactivity similar to allylic hydrogens: They can be brominated with NBS.

the benzilic position is not oxidized (in this case. H2 HOOC COOH EtOH HOOC COOH Kemp's Triacid COOH (molecular recognition) COOH COOH COOH It is also extremely easy to hydrogenate a side-chain. it is possible to hydrogenate the aromatic system to a completely saturated system. Hydrogenation: With a sufficiently active catalyst. Because aromatic chemistry is so rich & diverse.if there are NO benzilic hydrogens (last example). this is one method to prepare highly substituted cyclohexanes: COOH Rh / C. As a simple example. Pd / C Ethyl Acetate 100% O . only the alcohol on the side chain gets oxidized. take ethyl cinnamate: OEt OEt O H2.Aromatic compounds with benzilic hydrogens are also susceptible to oxidative degradation: Potassium permanganate (KMnO4) decomposes these to the benzoic acid (caution you loose the WHOLE side-chain on this one!): COOH CH3 KMnO4 HO COOH (!) KMnO4 H HO O OH KMnO4 Note .

After the reaction is finished. Pd Aromatic amines Preparation There is basically one method commonly used to prepare aromatic amines. therefore additions usually go para first): . the amide can be cleaved to give back the amine with NaOH / water (note: an amide is a bulky group. or for Friedel-Crafts reactions to work at all(!). thus leaving the ring a bit less activated. the one I would remember is SnCl2 / HCl followed by NaOH in water: NO 2 NH2 HNO3 H2SO 4 Cl Cl 1) SnCl2 / HCl 2) NaOH / H2 O Cl So.Along with hydrogenation. While there are a number of methods that can be used. The reduction of aromatic nitro compounds leads to the aromatic amine under quite mild conditions. in order to get only monosubstitution. and is a PERFECT way to turn a Friedel-Crafts Acylation into an Alkylation: O R R R AlCl3 R!H Cl O H2. and you have already seen it. It is frequently necessary to “tone down” the reactivity of an aromatic amine. we can also do a different kind of reduction . The absolute best way to do this is to turn the amine into an amide (usually by allowing it to react with acetic anhydride / pyridine). an amino group is powerfully activating – can this cause problems? Of course. The lone pair on nitrogen becomes a bit more strongly delocalized out the amide end.a deoxygenation! This reaction ONLY works on Aryl Ketones (R " H).

3. you’re now looking at a benzene ring with nitrogen gas stuck onto it. First. if you add hypophosphorous acid (H3PO2) to a diazonium salt.NH2 Cl No reaction (actually. Basically. HCl CuBr There are a couple of fairly cool modifications that you can do here. The Sandmeyer proceeds in two stages. a simpler example: N NH2 N Br NaNO2 aq. This reaction is probably the neatest thing about aromatic compounds in general.you just use it for its activating and directing effects. then you throw it away. and voila! Instant substitution! First.halogens are o. Warm that puppy up for a few minutes. you’d dump in some CuBr.pdirecting!): N NH2 NH2 N I I I NaNO I I I I2 2 H3PO 2 aq. HCl I I I This is one of the best (and most common) ways to “abuse” an aromatic amine . a foul mess) AlCl3 O NH2 O O Pyridine O HN O HN NaOH NH2 Cl AlCl3 H2O The next cool reaction you can do with aromatic amines it the Sandmeyer. dump in CuCN. etc). the aromatic ring just gets “protonated. If you wanted to add cyanide. First. Who could ask for a better leaving group? Next. reaction with sodium nitrite to give the diazo compound. Another modification can be used to make phenols: If you just add water to the diazonium salt. you add an OH group to the ring: .5-trihalobenzenes (remember . you add your favorite nucleophile as a copper salt (for example.” This is usually the best way to make 1. if you wanted to add bromide.

so first substitute the aromatic amine as you want. Preparation: The best way to make phenols is to use the cool reaction you learned with aromatic amines. the Sandmeyer. However. HCl H2O Reactivity . This reaction is usually done last in a sequence. aromatic alcohols (called phenols) are very easy to deprotonate (no surprise here . then make the diazo compound and heat it up with water: N NH2 N OH NaNO2 aq. and thus make the phenol more acidic (for example. trinitrophenol is VERY acidic). Electron-donating groups have the opposite effect. The acidity of the phenolic proton is also highly dependent on the other substituents on the aromatic ring. HCl I HOOC N N I COOH I CuCN NaCN I HOOC N C I H2SO 4 COOH I Phenols and Quinones Aromatic alcohols are not quite as reactive as aromatic amines: The lone pair is not nearly so hyperactive. leading to an anion that is mildly basic and very nucleophilic.the resulting negative charge is delocalized over the ring!).N N H2O OH Cyanide is also pretty easy to add: NH2 I HOOC I I COOH NaNO2 aq. Electron withdrawing groups stabilize the anion.

Or with methyl bromide and a base. Thus. and as alcohols. The main problem is that they react both as highly activated aromatic rings. However. However. it is usually easy to control the degree of substitution: OH OH OH Br2 CCl4 Br Br2 / HBr Br 1) Br2 / H2 O 2) NaHSO4 OH Br Br Br Br Carbon dioxide is also sufficiently electrophilic to react with phenols. with an acid chloride you can form an ester.Reactions of phenols can get a bit tricky. and this is a great way to prepare phenolic acids. Thus. the ring is easily substituted. you can form an ether: O OH H3C O Cl O CH3 OH K2CO3 CH3Br OCH 3 The aromatic ring is also highly activated (as you might expect). the ortho isomer is formed. since the lone pairs on oxygen are not as “hyperactive” as those on nitrogen. with a sufficiently good electrophile. if the product is heated under basic conditions. it isomerizes to the para isomer: OH OH OH O K2CO3 CO2 150°C O- 240°C (proton transfer) O O C O O O H OO O O- O O- . Under normal conditions.

g.Some alkyl cations are also susceptible to addition to phenol. However. ortho and para dihydroxybenzenes oxidize to quinones VERY easily. Frequently. They are also easily reduced back to the dihydroxybenzene: . Friedel Crafts reactions work QUITE well: OCH 3 OH OCH 3 O O O K CO 2 3 CH3Br AlCl3 O OH O Oxidation of Phenols Phenols undergo a rather unusual oxidation to compounds called quinones: OH (KSO3 )2 NO H2O O O The oxidation of a phenol (monohydroxybenzene) to a quinone requires rather harsh conditions (Fremy’s salt). However. these react without the need of any metal catalysts (e. aluminum): OH OH H2SO 4 H+ OH OH H The aluminum catalyzed Friedel-Crafts reaction WILL NOT WORK WITH PHENOL. if you simply “protect” the alcohol as an ether.

Allyl phenyl ethers rearrange in a rather unique way: OH O 1) NaH 2) BrCH2CHCH 2 An Allyl Phenyl Ether O O H OH This rearrangement involves a 6-membered ring intermediate. and pushes 6 electrons in a “circle. This rearrangement is kinda cool.” The initial result is a cyclic ketone. but what happens if both positions ortho to the hydroxy group are blocked? The allyl group then migrates again. to the para position! O O O OH H Be sure you understand the stereo and regiochemistry of this reaction . This is generally a good method for the preparation of phenols with allyl groups substituted on the ring. time to look at electrocyclic stuff again. which rapidly tautaumerizes to regain aromaticity. . . .OH Na2Cr2 O7 O HO OH (KSO3 )2 NO H2O NaBH4 O O SnCl2 OH O The Claisen Rearrangement Okay.