Reactions of Arenes - Organic Chemistry - Lecture Notes, Study notes of Organic Chemistry

Download Reactions of Arenes - Organic Chemistry - Lecture Notes and more Study notes Organic Chemistry in PDF only on Docsity! 1 Reactions of Arenes Electrophilic Aromatic Substitution Electrophiles add to aromatic rings in a fashion somewhat similar to the addition of electrophiles to alkenes. Recall: C C R4 R1 R3 R2 + E Y δ+ δ− R1 C R2 C E R3 R4 Y R1 C R2 C E R3 R4 Y In aromatic rings, however, we see substitution of one of the benzene ring hydrogens for an electrophile. H + E Y δ+ δ− E + Y H The mechanism is the same regardless of the electrophile. It involves two steps: (1) Addition of the electrophile to form a high-energy carbocation. (2) Elimination of the proton to restore the aromatic ring system. H H + E Y δ+ δ− H H E slow + Ystep 1 step 2 H H E + Y fast E + Y H high energy arenium ion The first step is the slow step since the aromaticity of the benzene ring system is destroyed on formation of the arenium ion intermediate. This is a high energy species but it is stabilized by resonance with the remaining two double bonds. The second step is very fast since it restores the aromatic stabilization. docsity.com 2 H H E H H E H H E There are five electrophilic aromatic substitution reactions that we will study. (1) Nitration H + HNO3 H2SO4 NO2 (2) Sulfonation H + H2SO4 SO3H (3) Halogenation with bromine or chlorine H + X2 X FeX3 X = Br, Cl (4) Friedel-Crafts Alkylation H + RX R AlX3 (5) Friedel-Crafts Acylation H + C AlX3 Cl C O R R O docsity.com 5 H H CH3CH2 Cl + Cl Al Cl Cl CH3CH2 Cl Al Cl Cl Cl CH3CH2 Cl Al Cl Cl Cl+ H H CH2 CH3 Cl Al Cl Cl Cl H CH2CH3 + Cl Al Cl Cl We do see rearrangements so as to form the more stable carbocations so it is not possible to make straight chain alkyl benzene derivatives having more than two carbons in the chain. The secondary derivative is always formed as the major product. H H + CH3CHCH2 Cl Al Cl Cl Cl H CH3 C H CH3 H H H H CH CH3 CH3 H CH CH3 CH3 OH2 CH3 C CH3 H CH2 Cl + Cl Al Cl Cl Cl Al Cl Cl ClCH2C H CH3 CH3 CH3 C CH3 CH3 H H H H C CH3 CH3 CH3 OH2H C CH3 CH3 CH3 We can also generate carbocations for Friedel-Crafts alkylations from alkenes in acidic conditions. We protonate the alkene to form the more stable carbocation according to Markovnikov’s rule. docsity.com 6 H H + CH2 CH CH3 H2SO4 CH3 CH CH3 H H H H CH CH3 CH3 H CH CH3 CH3 OH2 Friedel-Crafts Acylations Friedel-Crafts acylations use a carboxylic acid chloride (or acid chloride for short) and catalysis by a Lewis Acid such as aluminum trichloride, AlCl3, to give acyl benzene derivatives. We do not see rearrangements with Friedel-Crafts acylations. H H + Cl C O CH2CH2CH3 AlCl3 C O CH2CH2CH3 + HCl The mechanism involves the formation of a quite stable acylium ion. The Lewis acid is attacked by the chlorine lone pair. The chlorine is then removed to form the acylium ion. This is an sp2 carbocation but is reasonably stable since one of the lone pair of the oxygen donates electrons to form a resonance structure in which all of atoms have an octet. Due to this stabilization of the carbocation by the oxygen lone pair, no rearrangements occur. The acylium ion is attacked by the benzene π−system to give an arenium ion, which then loses a proton to restore the aromatic system. docsity.com 7 CH3CH2CH2 C O Cl AlCl3 CH3CH2CH2 C O Cl Al Cl Cl Cl CH3CH2CH2 C O Cl Al Cl Cl Cl+ CH3CH2CH2 C O Fairly stable resoance structure since all atoms have an octet of electrons. H H H H C H C Cl O CH2CH2CH3 O CH2CH2CH3 We can also do Friedel-Crafts acylations using anhydrides. CH3 C O O C O CH3+ AlCl3 C O CH3 The mechanism is similar to that using the acid chloride. We first form an acylium ion, which is attacked by the π−system of the benzene ring. CH3 C O O C O CH3 AlCl3 CH3 C O O C O CH3 Al Cl Cl Cl C OCH3 H H C H C O CH3 O CH3 + O C AlCl3 CH3 Synthesis of Straight Chain Alkyl Benzenes In order to synthesize benzene rings with straight chain alkyl substituents with more than two carbons in the alkyl chain, we can not simply use Friedel-Crafts alkylation because there will be a rearrangement reaction and we will get a 2-substituted derivative. docsity.com 10 The methyl group is an activating group and ortho/para directing. We need to understand why this is the case and in order to do this we need to look at the mechanism and to examine the effect of the substituent on the initially formed carbocation or arenium ion. Formation of the carbocation is the slow, rate determining step and as we have seen, the more stable carbocation is formed faster because it is lower in energy. Therefore, in order to understand the directing group effects, we need to look at the relative stabilities of the carbocations involved. First consider ortho attack in the nitration of toluene. We see that if nitration occurs in the ortho position, there will be a relatively stable tertiary carbocation as one of the resonance structures. CH3 O N O CH3 H NO2 CH3 H NO2 CH3 H NO2 Ortho Nitration Particularly stable resonance structure with tertiary carbocation. For attack at the para position, we get a similar result. CH3 O N O Para Nitration CH3 NO2 H CH3 NO2 H CH3 NO2 H Particularly stable resonance structure with tertiary carbocation. For attack at the meta position, we do not see the stabilized carbocation. We have only secondary carbocations that skip the tertiary carbocation that is observed in the ortho and para cases. docsity.com 11 CH3 O N O Meta Nitration CH3 NO2H CH3 NO2H CH3 NO2H None of these resonance structures have a teriary carbocation. The net effect of this is that the carbocation formed in the first step of nitration of toluene is lower in energy if it occurs in the ortho and para positions. And, since the methyl group is an activating group, the carbocation formed by nitration in any of the three positions is lower in energy than that formed by nitration of benzene. CH3 H NO2 CH3 NO2 H H H NO2 CH3 En er gy NO2H The trifluoromethyl group is strong electron withdrawing group. The central carbon has a partial (+) charge due to the strong electronegativity of the three fluorines. The trifluoromethyl group will destabilize a carbocation. The more stable resonance structures will have the trifluoromethyl group on a carbon away from the carbocation. The high energy structures will have the trifluoromethyl group on a carbon directly attached to the trifluoromethyl group. Look at ortho substitution. Attack at the ortho position is disfavored because in one of the resonance structures, the (+) charge is on the carbon that bears the trifluoromethyl group. This is a very high energy resonance structure docsity.com 12 CF3 O N O CF3 H NO2 CF3 H NO2 Ortho Nitration Particularly unstable resonance structure since the (+) charge is directly attached to the strong electron withdrawing group. CF3 H NO2 We see the same situation in attack at the para position. Para attack puts the (+) charge on the carbon bearing the trifluoromethyl group. Again, this is a very high energy resonance structure. CF3 O N O Para Nitration CF3 NO2 H CF3 NO2 H CF3 NO2 H Particularly unstable resonance structure since the (+) charge is directly attached to the strong electron withdrawing group. CF3 O N O Meta Nitration CF3 NO2H CF3 NO2H CF3 NO2H Nitration at the meta position avoids the unstable resonance structure. We see that meta nitration avoids the very high energy resonance structure where the positive charge is on the carbon that is directly attached to the electron withdrawing trifluoromethyl group. Nitration at all three positions of trifluoromethylbenzene is slower than for benzene but it is less slow at the meta position. Looking at an energy diagram showing the relative stabilities of the carbocations intermediates involves illustrates this. The carbocation formed from addition of the nitronium ion at the meta position is lower in energy than the carbocation formed from addition at the ortho or para positions and therefore the meta product forms faster. docsity.com 15 O H H O H Particularly stable resonance structure because all atoms have an octet. Para Bromination Br Br BrH O H BrH O H BrH O H BrH Attack at the meta position would result in a higher energy arenium ion because there would be no carbocation that is directly stabilized by the oxygen lone pair. O H O H Meta attack misses the particularly stable resonance structure because the (+) charge is never on the carbon bearing the oxygen. Meta Bromination Br Br H Br O H H Br O H H Br Amines are even stronger activating groups since the resonance overlap of the lone pair is even more effective than with oxygen and inductive effect is less than with oxygen since nitrogen is less electronegative than oxygen. Deactivating Substituents – Meta Directors All substituents in which a carbonyl group is attached directly to the benzene ring are deactivating. This includes the following compounds: C O H Aldehyde R C O R' R C O OH R C O OR' R C O Cl R ketone carboxylic acid ester acid chloride The carbonyl carbon has a partial (+) charge (δ+) that withdraws electrons from the benzene ring in an inductive effect. docsity.com 16 C O H C O H C O Hδ+ δ− There is also a resonance delocalization of the benzene π−system onto the carbonyl. This also withdraws electrons from the benzene ring and is deactivating. This is shown below for benzaldehyde. C O H C H O C H O C H O The cyano group (-CN) has a similar effect. C N C N C N C N C N And also the sulfonyl group. S O O OH S O O OH S O O OH S O O OH S O O OHS O O OH Halogens Halogens (I, Br, Cl, F) are the exception to the general rule. They are electron withdrawing substituents and deactivating but they direct to the ortho and para positions. This is a combination of the two factors, the inductive effect and the resonance effect. Since they are electronegative, they with draw electrons from the benzene π−system (inductive effect) but they are also good at stabilizing the arenium ion intermediate through resonance donation of the lone pair. This is similar to the situation with oxygen and docsity.com 17 nitrogen substituents but in the case of the halogens, the inductive effect is stronger than the resonance effect (With oxygen and nitrogen it is the opposite; the resonance effect is larger than the inductive effect.). X The inductive effect withdraws electrons from the π−system. X X The resonance effect donates electrons to the ring and helps to stablize the arenium ion intermediate in the ortho and para positions. etc. For nitration of bromobenzene, the intermediate arenium ion is more stable (lower in energy) when the nitronium ion adds in the ortho and para positions. This allows for a resonance structure in which the positive charge ends up on the carbon that bears the bromine. Lone pair donation from the benzene π−system helps to stabilize it and all atoms have an octet of electrons. This direct donation cannot occur when addition of the nitronium ion electrophile occurs at the meta position. Br O N O Br Ortho Nitration H NO2 Br H NO2 Br H NO2 Br H NO2 Particularly stable resonance structure because all atoms have an octet. Br O N O Br Para Nitration Particularly stable resonance structure because all atoms have an octet. NO2H Br NO2H Br NO2H Br NO2H docsity.com 20 CH3 CH3 HNO3 H2SO4 CH3 CH3 NO2 98% Synthesis of Disubstituted Derivatives When preparing disubstituted benzene derivatives, attention must be paid to the correct order of adding the substituents so that the directing groups effects will give the desired product. For example, in synthesizing 3-bromoacetophenone, we want to do the acylation step first because the acetyl group is a meta director. C O CH3 Br Cl C O CH3 AlCl3 C O CH3 Br2 FeBr3 C O CH3 Br If the steps were done in the reverse order, the wrong isomer would be obtained. Br2 FeBr3 Br Cl C O CH3 AlCl3 Ortho/para director Br C O CH3 + Br C H3C O Another important consideration when planning syntheses is that both Friedel-Crafts alkylation and acylation are relatively difficult reactions and do not work well if there is a docsity.com 21 strong deactivating group on the benzene ring. The strongest deactivating group allowable for a Friedel-Crafts reaction to work well is a halogen. For example of make 3-nitroacetophenone, it is best to put the acetyl group on first. Cl C O CH3 AlCl3 C O CH3 C O CH3 NO2Meta director HNO3 H2SO4 If the nitro group were put on first, then the Friedel-Crafts acylation step would not work, even though the directing group effects are correct. HNO3 H2SO4 NO2 Cl C O CH3 AlCl3 No reaction Monohalogenated benzene rings will undergo Friedel-Crafts reactions. For the following synthesis we want a 1,3-(or meta) relationship between an ethyl group and a chlorine. This is achievable if the molecule is acylated first to give a meta directing acetyl group. The chlorine can then be added and then the acyl group is reduced. Cl C O CH3 AlCl3 C O CH3 Meta director Cl2 AlCl3 C O CH3 Cl Zn(Hg) HCl CH2CH3 Cl Another synthetic example where the order of steps is critical is synthesis of 4-nitrobenzoic acid from toluene. The methyl group of toluene is an ortho/para director while the carboxylic acid is a meta director so the correct order of steps is to nitrate toluene first and then oxidize the methyl group to the carboxylic acid. docsity.com 22 CH3 CO2H NO2 CH3 CO2H NO2 HNO3 H2SO4 CH3 NO2 H2CrO4 H2SO4 Substitution in Naphthalene Polycyclic systems react with the same reagents as benzene and they are generally more reactive than benzene itself. In naphthalene, the C1 carbon is the more reactive site. 1 2 Cl C O CH3 AlCl3 C CH3O 90% The preference for reaction at C1 rather than C2 can be seen by looking at the resonance structures involved. When the electrophile adds to the C1 position, it forms a more stable carbocation that is lower in energy since in resonance structure B there is both benzylic stabilization and allylic stabilization and the full aromaticity of the benzene aromatic system is preserved. E HE HE Here in this resonance structure we have allylic and benzylic type resonance stabilization of the carbocation in which the benzene aromatic system in the other ring is fully intact. C1 Addition 1 2 A B docsity.com