The most important reactions of this type are nitration, halogenation, sulfonation, alkylation, acylation.
Mechanism of aromatic electrophilic substitution.
Most aromatic electrophilic substitution reactions proceed according to a single mechanism:
The reaction begins with the formation of a p-complex, in which the p-electron system of the aromatic nucleus acts as an electron donor, and the electrophilic reagent (E +) acts as an acceptor. Further, the p-complex with disruption of the aromatic system slowly rearranges into an s-complex, in which the electrophile is bound by an s-bond to a certain carbon atom, and the positive charge is delocalized along the conjugate system of the former aromatic ring. The delocalization of the positive charge in the s-complex occurs mainly due to the o- and p-positions with respect to the incoming substituent, which can be shown using a set of resonance structures
At the last stage, a proton is eliminated from the s-complex under the action of a base with the restoration of the aromatic system. The rate-limiting step in the process of electrophilic substitution is the step of formation of the s-complex.
The course of the reaction and its mechanism is illustrated by the energy diagram shown in the figure:
Orientation and reactivity
If the benzene ring already contains a substituent, then:
- the reaction can proceed faster or slower than with benzene itself;
- possible formation of three different substitution products
The influence of the substituent present in the benzene ring can be explained on the basis of its electronic effects. On this basis, substituents can be divided into 3 main groups:
1. Substituents that speed up the reaction compared to unsubstituted benzene ( activating) and substitution guides in ortho,-para-positions.
2. Substituents that slow down the reaction ( deactivating) and substitution guides in ortho,-para- positions.
3. Substituents that slow down the reaction ( deactivating) and substitution guides in meta- provisions.
Substituents noted in p.p. 1.2( ortho-, para-orientators) are called substituents of the 1st kind; noted in paragraph 3 ( meta orientants) - substituents of the second kind. The assignment of commonly occurring substituents according to their electronic effects is given below.
Table 6. Effect of aromatic ring substituents on S reactions E Ar
| Orientants of the 1st kind ( ortho-, para-) | Orientants of the second kind ( meta-) | |
| activating | deactivating | deactivating |
| All alkyl groups, -OH, -OR, -O - , -OC(O)R, -NH 2 , -NHR, -NR 2 , NHC(O)R | Halogens: F, Cl, Br, I |
CHO, -C(O)R, -CN, SO 3 H, -COOH, COOR, -NO 2 CHal 3, -N + R 3, |
It is obvious that electrophilic substitution will occur the faster, the more electron-donating substituent in the nucleus, and the slower, the more electron-withdrawing substituent in the nucleus.
To explain the orientation of substitution, consider the structure of s-complexes under attack in ortho-, meta- and para- positions of monosubstituted benzene (as already noted, the formation of s-complexes is usually the rate-determining step of electrophilic substitution; therefore, the ease of their formation should determine the ease of substitution in a given position):
If the Z group is an electron donor (whether inductive or mesomeric), then at ortho- or pair-attack, it can be directly involved in the delocalization of the positive charge in the s-complex (structures III, IV, VI, VII). If Z is an electron acceptor, then these structures will be energetically unfavorable (due to the presence of a partial positive charge on the carbon atom associated with the electron-withdrawing substituent), and in this case, a meta-attack is preferable, in which such structures do not arise.
The above explanation is given on the basis of the so-called dynamic effect, i.e. electron density distributions in the reacting molecule. The orientation of electrophilic substitution in monosubstituted benzenes can also be explained in terms of static electronic effects - electron density distributions in a non-reacting molecule. When considering the shift of the electron density along multiple bonds, it can be seen that in the presence of an electron-donating substituent, the electron density is most increased in the ortho- and para-positions, and in the presence of an electron-withdrawing substituent, these positions are most depleted in electrons:
Halogens are a special case - being substituents in the benzene nucleus, they deactivate it in electrophilic substitution reactions, however, they are ortho-, pair- orientants. Deactivation (decrease in the rate of reaction with electrophiles) is due to the fact that, unlike other groups with unshared electron pairs (such as -OH, -NH 2, etc.), which have a positive mesomeric (+M) and negative inductive effect ( -I), halogens are characterized by the predominance of the inductive effect over the mesomeric one (+ M< -I).
At the same time, halogen atoms are ortho, couple-orientants, since they are able, due to the positive mesomeric effect, to participate in the delocalization of a positive charge in the s-complex formed during ortho- or pair- attack (structures IV, VII in the above scheme), and thereby reduce the energy of its formation.
If the benzene nucleus has not one, but two substituents, then their orienting action may coincide ( agreed orientation) or not match ( mismatched orientation). In the first case, one can count on the predominant formation of some specific isomers, and in the second, complex mixtures will be obtained.
The following are some examples of the coordinated orientation of two substituents; the place of preferential entry of the third substituent is shown by an arrow.
Examples of electrophilic substitution reactions.
Nitration
Nitration is usually carried out with a mixture of concentrated nitric and sulfuric acids, the so-called nitrating mixture. At the first stage of the reaction, an electrophilic agent is formed - nitronium ion + NO 2:
The nitronium cation then reacts with an aromatic substrate such as benzene:
Halogenation
In contrast to nitration, during halogenation, the attack of the aromatic substrate can be carried out by various electrophiles. Free halogens, such as Cl 2 and Br 2, can easily attack an activated aromatic nucleus (eg, phenol), but are not able to react with benzene and alkylbenzenes. Polarization of an attacking halogen molecule requires Lewis acid catalysis , such as AlCl 3 , FeBr 3 , etc.; in this case, the so-called "electrophilic end" appears in the halogen molecule (the energy required for the formation of the Hal + cation is much higher). Thus, electrophilic substitution is greatly facilitated:
Sulfonation
Arenes interact with concentrated sulfuric acid or oleum (solution of SO 3 in sulfuric acid) to form arenesulfonic acids:
ArH + H 2 SO 4 ® ArSO 3 H + H 2 O
The electrophilic species is SO 3 . The attack of the aromatic substrate is carried out by the sulfur atom, since it is strongly positively polarized, that is, it is electron-deficient:
Sulfonation is reversible process. The sulfonic group can be removed from the aromatic nucleus, which is widely used in organic synthesis.
Friedel-Crafts Alkylation
Like halogens, alkyl halides can be so strongly polarized by Lewis acids (aluminum and zinc chlorides, boron trifluoride, etc.) that they become capable of electrophilic substitution in the aromatic nucleus:
In addition to alkyl halides, alkenes or alcohols can be used for alkylation of aromatic compounds in the presence of a protic acid catalyst:
The presence of a catalyst - a protic acid - is necessary to generate an electrophilic particle - a carbocation:
Alkylation of arenes by alkenes occurs in accordance with Markovnikov's rule.
The alkylation products enter into electrophilic aromatic substitution reactions more easily than the starting compound (Alk is an electron donor group), therefore, the product is predominantly alkylated further and polyalkylation products are formed. If you want to get products of monoalkylation, then you need to take a large excess of aromatic compounds.
Friedel-Crafts acylation
Arenes interact with acid chlorides and anhydrides of carboxylic acids to form ketones:
Acid chlorides and anhydrides have a polar carbonyl group and are capable of electrophilic substitution in aromatic systems:
The electrophilic activity of these compounds, however, is low and must be increased by the action of Lewis acids. As a result, a polarized complex is formed (and, in the limit, an acyl cation), which acts as an electrophile:
Polyacylation is not observed because the resulting ketone is much less reactive than the starting compound. Aromatic compounds with strongly deactivating substituents, such as nitro or cyano groups, also do not acylate according to Friedel-Crafts.
Electrophilic substitution in condensed aromatic hydrocarbons.
Fused aromatic hydrocarbons are more reactive than benzene, since the conjugation energy per one aromatic ring is less in them than in benzene.
For substitution in naphthalene, the formation of two isomeric products is possible when an electrophile is attacked in the a- or b-position. Hydrogen atoms in the a-position have a higher reactivity and, if the reaction proceeds under kinetic control conditions (chlorination, nitration), then the a-isomer is formed:
Sulfonation of naphthalene with concentrated sulfuric acid at 80 o C leads to the a-isomer, which is formed at a higher rate (kinetic control), and at 160 o C - to the thermodynamically more stable b-isomer ( thermodynamic control).
Anthracene is even more reactive than benzene. In all cases, the attack of electrophilic reagents occurs at the central core, while peripheral benzene nuclei are preserved.
Remark 1
The most important group of reactions for aromatic compounds are the electrophilic substitution reactions. Since the aromatic ring attracts electrophilic rather than nucleophilic species, reactions proceed easily and are widely used in both laboratory and industrial synthesis.
This process consists in replacing one electrophilic particle (usually a proton) with another electron-deficient part. This reaction uses a variety of electrophilic reagents, denoted by the symbol $E^+$, and is a route to many substituted aromatic compounds. Moreover, when this reaction is applied to benzene derivatives already containing one or more substituents, the process is characterized by the phenomenon of regioselectivity (specificity and direction of substitution), as well as selective reactivity, which are explained by theory.
Types of electrophilic aromatic substitution mechanisms
For electrophilic aromatic substitution, two alternative mechanisms are proposed:
Mechanism of one-step bimolecular substitution of $S_E2$ type
According to this mechanism, the configuration in the aromatic sextet of $\pi$-electrons is preserved during the reactions, and the substitution process occurs through the interactions of LUMO of electrophiles with HOMO bonds of aromatic compounds $C - H$:
Figure 2.
In transition states, three-center two-electron bonds are formed between $C-H$ and those electrophile atoms $E^+$, on which the LUMO density is high. The formation of three-center transition states $(I)$ does not raise theoretical objections. Two-electron three-center fragments in these transition states are isoelectronic to aromatic $\pi$-systems of cyclopropenyl cations, which are aromatic. This means that the transition states $(I)$ will be "aromatic", i.e., not too high in energy.
Mechanism of SE-arenone electrophilic substitution
The second mechanism was given the name $S_E(Ar)$ - $S_E$-arenonium electrophilic substitution. According to this mechanism, aromaticity and the six-electron system in the intermediates disappear, they are replaced by non-cyclic four-electron conjugated systems of pentadienyl cations $(C=C-C=C-C^+)$, and at the second stage, aromatic systems are again restored as a result of proton elimination. The attack of the LUMO of electrophiles occurs not on the $\sigma$ bond orbitals, but on the $\pi$ HOMO, so the interactions of the boundary MOs can be represented as two alternative schemes:
Figure 3
However, in monosubstituted benzene $C_6H_5X$ the degeneracy is lifted. For example, in phenol or aniline, HOMOs have the form (a). The structure of $(II)$ arenonium ions can be represented in various ways:
Figure 4
The first formula is most often used, however, the other schematic formulas given are also relevant. Using these alternative formulas it can be shown that the positive charges of arenon ions are mainly in ortho- And pair- position to the geminal nodes of cyclohexadienyl cations. And therefore $\sigma$-complexes will be stabilized by donor substituents , which are in ortho- And pair- positions x, much better than donor substituents in the meta position. If the transition states of the slow stages of electrophilic substitution are similar to arenonium ions, then the (+M)-substituent will direct the electrophile to pair- And ortho- position, i.e. the reaction will be regioselective.
In the 1950s-70s, in two research groups - K. Ingold (University College, University of London) and O.A. Reutov (Department of Chemistry, Moscow State University named after M. V. Lomonosov), intensive studies were carried out on the mechanism of electrophilic substitution at a saturated carbon atom. As the main objects, organomercury compounds were chosen, in which the carbon-mercury bond is rather easily cleaved by the action of electrophiles (acids, halogens, metal salts, etc.).
During this period, other extremely important works in this direction were also carried out, in particular, the study of the mechanisms of addition and elimination reactions, aromatic nucleophilic substitution, which are important for modeling biological systems, mechanisms of catalysis of nucleophilic reactions of carbonyl compounds, mechanisms of inorganic reactions, reactions of organic compounds of transition metals etc.
$Se$-Reactions of organometallic compounds
$\sigma$-bonded organic compounds of various metals enter into $Se$-reactions - from alkali and alkaline earth metals to heavy intransition metals, as well as transition metals, lanthanides and actinides. The mechanism and rate of the reaction strongly depend on the nature of the metal. For example, $R_2Zn$ zinc dialkyls react with an explosion with an electrophile like water, $R_2Cd$ react slowly, and $R_2Hg$ practically does not interact, although mercury dialkyls are split under the action of $HCl$ solutions.
From the point of view of synthetic significance, organolithium and magnesium compounds are the most important, so it is necessary to know the reaction mechanisms of these compounds. However, the corresponding studies are greatly complicated due to the extremely high reactivity of lithium and magnesium compounds (they are usually used in situ, and they can be stored and handled only under anaerobic conditions). In addition, organolithium compounds in solutions are strongly associated, while organomagnesium compounds are in Schlenk equilibrium. Therefore, organolithium and magnesium compounds were recognized as not very convenient substrates for studying the quantitative patterns of electrophilic substitution. And although the mechanisms of reactions involving $RLi$ or $RMgX$ are naturally being studied, the most important role in elucidating the mechanism of $Se$ reactions was played by mercury and, to a lesser extent, organotin compounds, which are quite stable in air and react with electrophiles at rates , which can be measured by conventional methods.
Features of the mechanisms of electrophilic substitution reactions
A theoretical consideration of the stereochemistry of electrophilic substitution reactions according to the $Se2$ mechanism leads to the conclusion that, in contrast to $Sn2$-reactions, which are allowed by orbital symmetry when a nucleophile is attacked from the rear and forbidden during a frontal attack, the $Se2$ reactions are not forbidden either under a frontal attack. , nor in the rear attack of an electrophile. Nevertheless, theoretically, a frontal attack is somewhat more preferable, since the electrophile attacks the highest occupied MO (HOMO) of the $C-Z$ bond, and the electron density of this orbital is concentrated mainly in the internuclear region:
Picture 1.
The frontal attack corresponds to the three-center (5), and the rear - to the linear (6) transition states; in the first case, the stereochemical result will be the preservation of the configuration of the carbon center, and in the second case, the configuration will be inverted:
Figure 2.
The vast majority of second-order electrophilic substitution reactions proceed with configuration retention. Thus, second-order electrophilic substitution occurs very easily at the carbon atoms at the head of the bridging bridge. $Se$-reactions of neopentyl substrates $(CH_3)_3CCH_2Z$ also proceed easily, which react extremely slowly in the case of nucleophilic substitution due to spatial obstacles to rear attack.
However, examples of configuration reversal are known, which indicates a rear attack by an electrophile.
Types of electrophilic substitution mechanisms
Based on the results of the study of $Se$-reactions of $\sigma$-organometallic compounds, the concept of nucleophilic assistance to electrophilic substitution was formulated. Its essence lies in the fact that the presence of certain producers of nucleophilic particles significantly affects the rate and mechanism of $Se$-reactions in solutions. Such nucleophilic particles can be as "internal" nucleophiles $Nu^-$, which are part of the electrophilic agents $E-Nu$ (for example, $C1^-$ in $HgCl_2$ ($E = HgCl^+$), $Br^ -$ into $Br_2$ ($E = Br^+$), two $I^-$ anions into $I^(3-)$ ($E = I^+$), etc.) and ordinary nucleophilic particles.
Thus, the addition of nucleophiles capable of coordinating with metal atoms should also increase the rate of $SE1$ reactions. Assisted monomolecular reactions are denoted by $Se(N)$, and internally assisted bimolecular reactions by $Sei$. The $Sei$ mechanism is characterized by a four-center transition state 7, in which the formation of $C-E$ and $M-Nu$ bonds and the breaking of $E-Nu$ and $C-M$ bonds occur more or less synchronously. The $Se(N)$ and $SEi$ mechanisms are shown in the diagram below:
Nucleophiles can also catalyze $Se2$ reactions, coordinating exclusively with metals, for example:
Figure 5
Under the action of concentrated nitric acid or a mixture of concentrated nitric and sulfuric acids (nitrating mixture), the hydrogen atoms of the benzene ring are replaced by a nitro group:
nitrobenzene
Nitration is preceded by the formation of an electrophilic reagent NO 2 - nitronium cation.
In the reaction of benzene nitration with a nitrating mixture nitronium cation (NO 2 ) formed by protonation of nitric acid with concentrated sulfuric acid present:
Further nitration is difficult, since the nitro group is a substituent of the second kind and makes it difficult for reactions with electrophilic reagents:
nitrobenzene 1,3-dinitrobenzene 1,3,5-trinitrobenzene
Benzene homologues (toluene, xylenes) nitrate more easily than benzene, since alkyl groups are substituents of the first kind and facilitate reactions with electrophilic reagents:
1,3,5-trinitrobenzene
toluene ortho-nitrotoluene para-nitrotoluene
1,3,5-trinitrobenzene
1.2. Sulfonation reactions.
When benzene and its homologues are treated with concentrated sulfuric acid or sulfur trioxide, hydrogen atoms in the benzene nucleus are replaced by a sulfo group:
benzenesulfonic acid
reaction mechanism
Sulfonation is preceded by the formation of an electrophilic reagent HSO + 3 - hydrosulfonium ion:
3H 2 SO 4 → H 3 O + + HSO + 3 + 2HSO - 4
π-complex σ-complex
H + + HSO - 4 → H 2 SO 4
An even more active electrophilic reagent is sulfur trioxide, in which there is a deficit of electron density on the sulfur atom:
σ-complex
bipolar ion
Benzene homologues are sulfonated more easily than benzene, since alkyl groups are substituents of the first kind and facilitate reactions with electrophilic reagents:
1.3. halogenation reactions.
In the presence of Lewis acid catalysts (AlCl 3 ; AlBr 3 ; FeCl 3 ; FeBr 3 ; ZnCl 2 ) at room temperature, the hydrogen atoms of the benzene ring are replaced by halogen atoms:
Moreover, chlorine replaces hydrogen in the aromatic nucleus more actively than bromine, and it is practically impossible to carry out iodination and fluorination of arenes due to insufficient activity of iodine and excessive activity of fluorine.
The role of the catalyst is to form either a positive halogen ion or a complex of a halogen with a Lewis acid with halogen-halogen bond polarization:
1) the formation of a positive halogen ion:
2) formation of a complex of a halogen with a Lewis acid with polarization of the halogen-halogen bond:
Further halogenation is difficult, since halogens hinder reactions with electrophilic reagents, but are ortho- and para-orientants:
bromobenzene 1,2-dibromobenzene 1,4-dibromobenzene
Benzene homologues are halogenated more easily than benzene, since alkyl groups are substituents of the first kind and facilitate reactions with electrophilic reagents:
toluene ortho-chlorotoluene para-chlorotoluene
By chemical properties, arenas differ from saturated and unsaturated hydrocarbons. This is due to the structural features of the benzene ring. The delocalization of six p-electrons in the cyclic system lowers the energy of the molecule, which leads to an increased stability (aromaticity) of benzene and its homologues. Therefore, arenes are not prone to undergo addition or oxidation reactions that lead to loss of aromaticity. For them, the most characteristic reactions proceed with the preservation of the aromatic system, namely, the substitution reactions of hydrogen atoms associated with the cycle. The presence of regions of increased p-electron density on both sides of the planar aromatic ring leads to the fact that the benzene ring is a nucleophile and, therefore, tends to be attacked by an electrophilic reagent. Thus, electrophilic substitution reactions are most typical for aromatic compounds.
Let us consider the mechanism of electrophilic substitution using the example of benzene nitration.
Benzene reacts with a nitrating mixture (a mixture of concentrated nitric and sulfuric acids):
nitrobenzene
Substitution reactions in the ring proceed only through the formation of positively charged intermediate particles.
p-complex 
s-complex
The particle to be replaced is the proton.
According to this mechanism, the reactions of alkylation, halogenation, sulfonation, nitration of aromatic compounds and others proceed, differing only in the way the active particle of the reaction is formed - the electrophile E +
a) sulfonation:
HO–SO 3 H + H–SO 4 H à HSO 3 + + HSO 4 –
b) halogenation
Cl 2 + AlCl 3 a Cl + + AlCl 4 –
c) alkylation:
CH 3 -CH 2 -Cl + AlCl 3 à CH 3 -CH 2 + + AlCl 4 -
d) acylation
CH 3 COCl + AlCl 3 à CH 3 C + \u003d O + AlCl 4 -
In the unsubstituted ring of benzene, all 6 positions are equivalent for the occurrence of a substituent group. The situation is more complicated if homologues or derivatives of benzene enter into the reaction. In this case, the newly entering group enters a certain place in the ring. This place depends on the substituent already present (or present) in the ring. For example, if the ring contains an electron-donating group of the type: alkyl-, -OH, -OCH 3, -NH 2, -NHR, NR 2, -NH-COR, -X (halogen)(substituents of the first kind), then the substituting group enters ortho- or para-positions relative to the existing group:
If the ring already contains an electron-withdrawing group of the type: –NO 2 , –NO, –SO 3 H, –CX 3 , –COOH, –COH, –COR, –CN (substituents of the second kind), then the newly entering group becomes in a meta position to them:
table 2
Summary table of substituents and their electronic effects
| Substituent or group of atoms | Orientation | effects |
| CH 3 > CH 3 –CH 2 > (CH 3) 2 CH | o-, p- orientation, (halogens-deactivating) | +I, +M |
| (CH 3) 3 C | + I, M=0 | |
| An atom attached to the p-system has an unshared pair of electrons: X- (halogen), -O -, -OH, -OR, -NH 2, -NHR, -NR 2, -SH, -SR, | – I, + M | |
| the atom attached to the p-system is in turn bonded to a more electronegative atom: –N=O, –NO 2 , –SO 3 H, –COOH, –COH, –C(O)–R, –COOR, –CN, – CX 3 , –C=N=S, | m-orientation, with deactivation | -I, -M |
| sp 2 -hybridized carbon: –CH = CH–, –C 6 H 5 (phenyl) | o-, p- orientation | I=0,+M |
| An atom that does not have p-orbitals, but with a total positive charge -NH 3 +, -NR 3 +, | m - orientation, with deactivation | –I, M=0 |
If the ring has two deputies of different kind guiding substitution inconsistently, then the place of entry of the new group is determined by deputy of the first kind, For example.
