Aromatic Substitution électrophile

The aromatic substitution électrophile (or SEA ) is a Chemical reaction field of the Organic chemistry, during which a Atome, in general of Hydrogène, fixed at a aromatic cycle is substituted by a grouping électrophile. It is a very important reaction in organic chemistry, as well in industry as in laboratory. It makes it possible to prepare aromatic compounds substituted by a large variety of functional groupings according to the assessment:

ArH + EX → Are + HX

with Ar a aromatic Compound and E a grouping électrophile.

General mechanism of the reaction

The first stage of the mechanism is an addition during which the compound électrophile A⁺ reacts with an electronic doublet of the aromatic cycle. This stage generally requires a Catalyze by a Acide of Lewis. This addition leads to the formation of a intermediate Carbocation cyclohexadiénil known under the name of of Wheland (or complex σ ). This carbocation is unstable, since it corresponds at the same time to the presence of a load on the Molécule and to a loss of aromaticity. It nevertheless is stabilized by Mésomérie: the load is actually delocalized on several Atome S of Carbone.

During the second stage, the combined base of the acid of Lewis (or an anion present in the reactional medium, for example in the case of sulphonation) attacks the atom of Hydrogène related to carbon having undergone the électrophile addition. The electron which was used for the connection CH then makes it possible the system to find its aromaticity.

Principal aromatic substitutions électrophiles

This chapter details the principal aromatic substitutions électrophiles used in industry and in laboratory. For each one of them, the mechanism of the reaction is given in the particular case of the Benzène. This mechanism is of course similar for other types of aromatic compounds, in the operating conditions (Température, Solvant…) near.

Aromatic nitration

The aromatic nitration is a particular substitution électrophile aromatic during which a Atome of Hydrogène related to an atom of Carbone of the aromatic cycle is substituted by a grouping nitro - NR O₂ to form Nitrobenzène. The électrophile used for substitution is NO₂⁺ (Ion Nitronium), produced in-situ.

In practice to carry out substitution, the Benzène is heated with backward flow (with 50°C approximately) in a sulphuric mixture of Acid and Acid nitric. The reaction pathway is the following:

(1) 2:00 ₂SO₄ + HNO₃ → 2HSO₄^- + NO₂⁺ + H₃O⁺

(2) C₆H₆ + NO₂⁺ → C₆H₅NO₂ + H⁺

(3) H⁺ + H₃O⁺ + 2HSO₄^- → H₃O⁺ + H₂SO₄ + HSO₄^-

The sulphuric Acid plays to some extent the part of catalyst for the formation of the ion Nitronium. The reaction is also possible with the nitric Acid only, but it is then much slower. Among the other reagents usable for aromatic nitration, one can quote the Tetrafluoroborate of nitronium, which is a salt of Nitronium obtained starting from Hydrofluoric acid, of Acid nitric and Trifluorure of boron.

If the reaction is catalyzed in the presence of Acid sulphuric, the stage kinetically determining is the nitration of the benzene cycle to form the intermediary of Wheland. In the presence of Acid nitric only, it acts of the formation of the ion Nitronium.

The Nitrobenzène formed during this reaction can in particular be used to manufacture Aniline by reduction:

C₆H₅NO₂ + 3:00 ₂ → C₆H₅NH₂

Aromatic sulphonation

The aromatic sulphonation is a particular substitution électrophile aromatic during which a Atome of Hydrogène related to an atom of Carbone of the aromatic cycle is substituted by a grouping Sulfonic acid. In the case of the Benzene, the reaction makes it possible to form Acide sulphonic benzene.

Substitution can be realized in two manners:

the benzene is maintained with 25 °C in a oleum , solution of SO₃ in the sulphuric Acid (H₂SO₄) or mixes of SO₃ and water (with majority SO₃). The assessment of the reaction is then:

C₆H₆ + SO₃ → C₆H₅SO₃H

the benzene is heated in the sulphuric Acid concentrated. SO₃ is then formed in-situ by reaction of the sulphuric acid on itself. The assessment of the reaction is then:

C₆H₆ + 2:00 ₂SO₄ → C₆H₅SO₃H

In both cases, the mechanism of the reaction is the following:

For sulphonation, the elimination of the hydrogen atom is done by an intramolecular reaction.

This reaction does not have a stage kinetically determining.

It is interesting to note that it is about a reversible reaction: it is possible to eliminate the grouping Sulfonic acid and to regenerate the Benzène by heating the Acide sulphonic benzene in a diluted solution of Acid sulphuric in water. The assessment is then:

C₆H₅SO₃H + H₂O_(vapor) → C₆H₆ + HSO₄^- + H₃O⁺

The Acide sulphonic benzene formed during this reaction is an important intermediary of synthesis in industry, used in the manufacture of dyes and medicinal products . In addition, it is possible it to reduce in the presence of Soude melted to form phenol.

Aromatic halogenation

The aromatic halogenation is an aromatic substitution électrophile during which a Atome of Hydrogène related to an atom of Carbone of the aromatic cycle is substituted by a element Halogène according to the following assessment:

C₆H₆ + X₂ → C₆H₅X + HX

The reaction is not spontaneous, but requires the presence of a catalyst of the type Acide of Lewis. It is thus carried out in medium Anhydre. It is possible without catalyst (but is then slow) in the case of activated cycles, such as for example the phenol. Aromatic halogenation makes it possible to substitute a hydrogen atom by an atom of Chlore, Brome or Iode. On the other hand, it is not possible with the Fluor. This one is indeed a powerful Oxydant which involves a degradation of the aromatic Composé. The mechanism of the reaction is the following (example in the case of a chlorination):

During the first stage of the mechanism, the Acide of Lewis used like catalyst form a complex with the dichlore, which makes the connection Cl-Cl polarized. One of the two chlorine atoms thus becomes électrophile, and can undergo the nucleophilic attack of the aromatic cycle, thus leading to the formation of the intermediary of Wheland. The Anion formed contributes then in the second phase to the elimination of the hydrogen atom and the restoration of the aromaticity.

The catalyst used is generally consisted of the same halogenous element as that acting in substitution. The acid of the Lewis most usually employed are thus ZnCl₂, AlCl₃ and FeCl₃ in the case of chlorination, and FeBr₃ in the case of bromination. In the case of the Iodine, the mechanism of the reaction is slightly different. Indeed, the Diiode I₂ is too not very reactive. It must initially react with an agent of Oxydation (for example the nitric Acid ) to form the Ion I⁺, électrophile, which will intervene in the iodation.

The halogens are elements slightly decontaminating for the aromatic cycle. Consequently, if the reaction is catalyzed and that the halogen is present in excess, it can occur polysubstitutions.

Reactions of Friedel-Crafts

The reactions of Friedel-Crafts are aromatic substitutions électrophiles particular to the course of which a cycle aromatic is alkylated (substitution of a Atome of Hydrogène by a grouping Alkyle) or acylé (substitution of a hydrogen atom by a grouping Acyle).

detailed Article: Reaction of Friedel-Crafts.

Alkylation

The alkylation of Friedel-Crafts is a reaction of Alkylation of an aromatic compound. This reaction requires a Catalyze by a Acide of Lewis.

Acylation

The acylation of Friedel-Crafts is a reaction of Acylation of an aromatic compound. Like alkylation, it requires a Catalyze by a Acide of Lewis. Principal the Catalyseurs used is the aluminum chloride and the aluminum bromide. There requires in general more for catalyst that the stoechiometric quantities, because it complexes with the product formed, from where the need for hydrolysis after the reaction to destroy the complex.

Other substitutions

Reaction of Kolbe-Schmitt

The reaction of Kolbe-Schmitt (or proceeded of Kolbe ) is a reaction of carboxylation developped at the point by A. Kolbe and R. Schmitt. During this aromatic substitution électrophile, sodium phenolate (salt of phenol) is heated with 125°C in the presence of Carbon dioxide under a Pression of 100 atm, then treated by sulphuric Acid . The assessment of the reaction is the following:

C₆H₅OH + NaOH + H₂SO₄ → C₆H₄OHCOOH + HSO₄^-

During the first stage (not shown on the diagram), the phenol reacts with Soude to form the sodium phenolate and Ion S OH^-. Phenolate reacts then with the Carbon dioxide by aromatic substitution électrophile, the center électrophile being here the atom of Carbone of CO₂. The Ion S OH^- formed during the first stage assist the restoration of the aromaticity. The compound obtained being the combined Base of the Carboxylic acid , the last stage consists of a reaction acid-bases with the sulphuric Acid .

The product obtained during this reaction is hydroxy-acid aromatic (here the Salicylic acid , precursor of the Aspirine).

Reactions with already substituted aromatic cycles: polysubstitutions

The product of an aromatic reaction of substitution électrophile is itself a aromatic Composé: the elimination of an atom of Hydrogène makes it possible to restore the aromaticity of the intermediary of Wheland (the intermediate Carbocation). Nothing is thus opposed so that this product, which is substituted aromatic cycle, undergoes an aromatic substitution électrophile again, first of all as long as it remains hydrogen atoms related to carbon atoms. Actually, all the substituted aromatic compounds will not be able to undergo a new aromatic substitution électrophile, and the product resulting from one second reaction will be depend on the starting product: the grouping present on the substituted starting compound influences at the same time the reactivity of this compound (it can or not undergo the second substitution), as well as the Régiosélectivité of the reaction (all the possible products are not formed).

Reactivity with respect to the polysubstitution

The grouping present on the substituted starting compound strongly influences its reactivity. These groupings are classified in two categories: groupings activators and groupings decontaminating . An aromatic compound substituted by an activating grouping is thus more reactive than the aromatic compound not substituted. Contrary, an aromatic compound substituted by a decontaminating grouping is less reactive .

Groupings activators

A grouping activating is grouping whose presence increases the reactivity of the aromatic cycle with respect to aromatic substitution électrophile compared to the cycle for which this grouping is absent. A substitution of an aromatic cycle not substituted by an activating grouping will frequently lead to a polysubstitution. The reactivity of the aromatic cycle will be increased if it is necessary to provide less energy to pass from made up of departure to the reactional intermediary (intermediate of Wheland), in other words if the energy gap between the starting compound and the reactional intermediary is weaker. It will be in particular the case of made up the mésomères donors, such as for example the grouping alcohol - OH. The figure below watch stabilization by Mésomérie of the phenol and the intermediary of corresponding Wheland:

The phenol and the intermediary of Wheland are both stabilized by mesomery by delocalizing the electron S of the aromatic cycle. In addition, it is possible to write formulas mésomères bringing into play a doublet of electron of the atom of Oxygène. In the case of the phenol, these forms mésomères reveal formal loads on oxygen and an atom of carbon, they thus induce only one weak stabilization. On the contrary, in the case of the intermediary of Wheland, no additional expenditure appears: stabilization is important. The intermediary of Wheland is thus stabilized more than phenol by the presence of the grouping - OH.

This situation is summarized on the figure opposite, by comparison with the Benzène (aromatic cycle not substituted). The fictitious states (dotted lines) correspond to a situation where the presence of the grouping - OH would be neutral, i.e. a situation where it would not intervene via the doublets carried by oxygen. In this case, the energy of the phenol and intermediary of Wheland would be the same one as in the case of benzene. The full features correspond to the real situation: the intermediary of Wheland is stabilized more than phenol (its energy is lowered). Consequently, the energy gap between the phenol and the intermediary of Wheland ΔE₂ are weaker than this variation in the case of the ΔE₁ benzene. The phenol is thus more reactive than benzene with respect to aromatic substitution électrophile.

All in all, will be activators all the groupings which will be able to stabilize the positive load of the intermediary of Wheland, either by Mésomérie, or by inductive Effet, therefore the groupings mésomères donors and inductive donors.

Decontaminating groupings

A grouping decontaminating is grouping whose presence decreases the reactivity of the aromatic cycle with respect to aromatic substitution électrophile compared to the cycle for which this grouping is absent. A substitution of an aromatic cycle not substituted by an activating grouping will only lead very seldom to a polysubstitution. The reactivity of the aromatic cycle will be decreased if it is necessary to provide more energy to pass from made up of departure to the reactional intermediary (intermediate of Wheland), in other words if the energy gap between the starting compound and the reactional intermediary is more important. It will be in particular the case of made up the mésomères attractile, such as for example the grouping nitro - NO₂. The figure below watch stabilization by Mésomérie of the Nitrobenzine and the intermediary of corresponding Wheland:

The Nitrobenzine and the intermediary of Wheland are both stabilized by mesomery by delocalizing the electron S of the aromatic cycle. However in the case of the form mésomère 3 of the intermediary of Wheland, the atom of carbon related to the grouping nitro (very electronegative) is positively charged. It is form mésomère is thus very little stabilizing: the intermediary of Wheland is stabilized less than nitrobenzine, and the presence of the grouping nitro induces a destabilization compared to a situation where it would be absent. In addition, it is possible to write formulas mésomères bringing into play a doublet of electron of the atom of Azote ( has , B , C and a' , b' , it ). However in the case of the forms mésomères b' and it of the intermediary of Wheland, two positive loads are carried by united carbon atoms, which corresponds to a configuration far from stable. Again, the intermediary of Wheland is stabilized less than nitrobenzine.

This situation is summarized on the figure opposite, by comparison with the Benzène (aromatic cycle not substituted). The fictitious states (dotted lines) correspond to a situation where grouping - NO₂ would not intervene via the doublets carried by the Azote. The fictitious state of the intermediary of Wheland is destabilized compared to benzene (because positive load in the formula mésomère 3 ). On the other hand, nitrobenzine is not destabilized compared to the Benzène. The full features correspond to the real situation: the intermediary of Wheland is stabilized month that nitrobenzine (its energy is lowered) because of the loads carried by the carbon atoms united in the formulas mésomères b' and it . Consequently, the energy gap between the Nitrobenzine and the intermediary of Wheland ΔE₂ are higher than this variation in the case of the ΔE₁ benzene. Nitrobenzine is thus less reactive than benzene with respect to aromatic substitution électrophile.

All in all, will be decontaminating all the groupings which will be able to destabilize the positive load of the intermediary of Wheland, either by Mésomérie, or by inductive Effet, therefore the attractile and inductive groupings mésomères attractile.

Assessment: relative reactivity of some substituted compounds

The reactivity of a aromatic Composé substituted with respect to a new aromatic substitution électrophile thus depends strongly on the nature of the substituent already present. The reactivity is all the more large as the substituent brings electron S to the system and stabilizes the positive loads (effect mésomère donor and inductive donor). The table below thus gives some orders of magnitude of reactivity (paid to that of the Benzène, fixed at 1) of some substituted benzenes. The phenol is thus 1000 times more reactive than the Benzène, and the Nitrobenzène 10.000 times less.

Regioselectivity

When a aromatic Composé substituted undergoes the one second aromatic substitution électrophile, the attack can be done a priori since five positions. Among these positions, two are positions ortho , two of the positions méta and a position para (see figure of right-hand side).

First of all, one could thus think that the product of the reaction is a mixture made up with 40 % of isomer ortho, with 40 % of isomer méta and with 20 % of isomer para, according to a Statistical distribution (2 - 2 - 1). Actually, it is not at all the case, and the Régiosélectivité of the reaction (and thus the nature of the finished product) strongly depend on the grouping already present on the substituted aromatic cycle. According to the nature of this grouping, the second substitution could be done quasi exclusively in meta , or according to a mixture ortho + para .

Groupings ortho-para orientators

In experiments, an aromatic substitution électrophile using as starting product an aromatic cycle substituted by a grouping donor (mésomère inductive donor or donor) will lead to a mixture of isomers ortho and para, with a very small quantity of isomer méta. This result is explained by simple energy considerations.

To pass from made up of departure to a reactional intermediate during a Chemical reaction, it is necessary to provide energy to cross a barrier of potential. The reaction speed will be all the more large as this barrier will be weak, and thus that the reactional intermediary will be stable. In the case of aromatic substitution électrophile, one can consider with a good approximation that the formed finished product most quickly will be that whose intermediary of Wheland will be formed most quickly (reaction under kinetic control). It must thus correspond to the most stable intermediary of Wheland.

The figure of right-hand side shows the intermediaries of Wheland corresponding made up the ortho, méta and to para if the starting product is the phenol (mésomère donor). In the three cases, the intermediary of Wheland is stabilized by Mésomérie by delocalizing the positive load on three atoms of Carbone. In the case of the compounds ortho and para, the load is also stabilized by a mesomery bringing into play a doublet of electron S of the atom of Oxygène. These two intermediaries are thus definitely more stable than the intermediary meta, and the reaction leads to a mixture made up mainly of the isomers ortho and para.

All in all, a grouping donor (mésomère inductive donor or donor) will be thus ortho para orientator. If this grouping is very bulky, the final compound will be mainly para (the positions ortho will be difficult to reach). On the contrary if it is slightly bulky, made up ortho will be statistically favoured for it (2 positions ortho for only one para position). Thus for example, the nitration of the Toluène (φ-CH₃) will lead to a mixture of isomers ortho (60 %), para (37 %) and méta (2 %) (the substituent is not very bulky), whereas the nitration of the methoxybenzene (φ-O-CH₃) leads to a mixture of isomers ortho (34 %), para (65 %) and méta (1 %) (the substituent is relatively bulky).

Groupings méta orientators

In experiments, an aromatic substitution électrophile using as starting product an aromatic cycle substituted by an attractile grouping (mésomère attractile or inductive attractile) will lead mainly to the isomer méta, with a small quantity of isomers ortho and para.

As in the case of the groupings ortho-para orientators, this result is explained by simple energy considerations while reasoning on the stability of the intermediary of Wheland. The figure of right-hand side shows the intermediaries of Wheland corresponding made up the ortho, méta and to para if the starting product is the Nitrobenzène (mésomère attractile). In the three cases, the intermediary of Wheland is stabilized by Mésomérie by delocalizing the positive load on three atoms of Carbone. The grouping nitro being attractile, it never stabilizes the positive load by mesomery. For one of the shapes mésomères of the intermediaries ortho and para, the atom of Carbone related to the grouping nitro carries a positive load. The grouping nitro being very electronegative, this situation is very unstable, and this form mésomère is almost not stabilizing. The intermediaries ortho and para are thus less stable than the intermediary méta, which will thus be formed more quickly.

All in all, an attractile grouping (mésomère attractile or inductive attractile) will be thus méta orientator. Thus for example, the one second nitration of the Nitrobenzène will lead to 92 % of isomer méta, 7 % of ortho and 1 % of para.

Particular cases of the halogens

The Halogène S (mainly Chlorine, Bromine and Iodine) constitutes a particular case, being at the same time slightly mésomère donor and slightly inductive attractile. These groupings are slightly decontaminating (the Chlorobenzène is approximately 3 times less reactive than the Benzène) but ortho-para orientators.

Summary table

In short, the groupings donors are activators (the reactivity is more important) and ortho-para orientators, and the attractile groupings are decontaminating and méta orientators. In general, the activating or decontaminating effect is all the more important as the grouping is more donor or attractile. The table below indexes the effects on the reactivity and the regioselectivity of some groupings frequently used.

Substitutions bringing into play heterocyclic compounds

The aromatic compounds heterocyclic, such as for example the Furan, the Pyrrole or the Pyridine, can also react by aromatic substitution électrophile. Their behaviors with respect to polysubstitutions (reactivity and regioselectivity) are determined by the same energy considerations as in the example of the Benzène.

References

; Reaction of Kolbe-Schmitt

H. Kolbe, Annalen der Chemie und Pharmacy 113,1860, p. 125;
R. Schmitt, “Beltrag zu Kenntniss der Kolbe' schen Salicylsaüre-Synthesis”, in Newspaper für praktische Chemie 31, 1885, p. 397 HTTP: /visualiseur.bnf.fr/Visualiseur?Destination=Gallica&O=NUMM-90794 text on Gallica .

; Presentations of the SEA

Peter Vollhardt, '' Traité organic chemistry '', chap. 15-8;
the SEA, site of the university Bordeaux I;
the SEA, site of the university of Orleans.

See too

aromatic Compound;
Mésomérie ;
inductive Effect.

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