For electrophilic substitution reactions S E The most typical are those leaving groups that can exist in a state with an unfilled valence shell.
Such a group can be a proton, but its mobility depends on acidity. In saturated alkanes, hydrogen is inactive. Hydrogen substitution occurs more easily in those positions where it is sufficiently acidic, for example, the -position to the carbonyl group, or the proton at the acetylene bond. Important type of reaction S E is anionic cleavage, involving the cleavage of a carbon-carbon bond, with the leaving group being carbon. Particularly prone to reactions S E organometallic compounds.
Mechanisms of aliphatic electrophilic substitution
Aliphatic mechanism S E unlike S N insufficiently studied. There are four types of mechanisms S E : S E 1, S E 2 (from the rear), S E 2 (from the front), S i. Bimolecular mechanism S E similar S N 2 in the sense that a new connection is formed simultaneously with the rupture of the old one. However, there is a significant difference.
IN S N 2, the nucleophile approaches with its electron pair and, since electron pairs repel each other, it can only approach the outgoing electron pair from the rear. In electrophilic substitution, a vacant orbital can approach either from the rear, attracting an electron pair, or from the front. Therefore, two possible mechanisms are theoretically considered.
S E 2 (from the front)
S E 2 (from the rear)
There is a third bimolecular mechanism S E, when part of the electrophile molecule promotes the separation of the leaving group by forming a bond with it. This mechanism is called S i .
Evidence: Mechanisms S E 2 and S i not easy to distinguish. All of them correspond to second-order kinetics. S i And S E 2 (from the front) proceed while maintaining the configuration. S E 2 (from the rear) proceeds with reversal of the configuration. Mechanism confirmation S E 2 (from the front) is that electrophilic substitution can occur at the carbon atoms at the head of the bridge.
Monomolecular mechanism of electrophilic substitution S E 1 is similar S N 1 and includes two stages, slow ionization and fast recombination.
Evidence of mechanism S E 1. One of the proofs is the first order kinetics of the substrate. Stereochemical evidence in the reaction is important:
The exchange of a proton for deuterium occurs at the same rate as racemization, and a kinetic isotope effect is observed. Reaction S N 1 does not occur at the head of the bridge, but S E 1 proceeds easily, from which it follows that the carbanion does not have to be flat, it can have a pyramidal structure.
When carrying out electophilic substitution with an allylic substrate, the rearrangement product can be obtained:
This type of process is similar S N and can go two ways.
The first occurs through the formation of an allylic carbanion intermediate:
The second route involves electrophilic addition at a double bond with the intermediate formation of a carbocation and subsequent elimination of the electrofuge:
The most important reactions of aliphatic electrophilic substitution
Reactions of CH acids
If in electrophilic substitution reactions the leaving group is hydrogen, which is eliminated in the form of a proton, then such substrates are called CH-acids. The most important reactions of this type following the mechanism S E 1 :
Hydrogen isotope exchange
;
Migration of double and triple bonds
- Combination with diazonium salts
In a superacidic environment, hydrogen substitution can proceed according to the mechanism S E 2 , through the formation of carbonium ions:
Reactions of organometallic compounds
The main reactions of organometallic compounds are protodemetalation, halidedemetalation and transmetallation
Proto-demetallation is the reaction of replacing a metal in an organometallic compound with hydrogen under the action of acids
Halidedemetallation are called reactions of metal substitution with halogen under the influence of halogens or interhalogens:
Remetallation called the reaction of exchange of one metal for another. Both an inorganic metal salt and an organometallic compound can act as a regent:
Reactions involving heterolytic carbon-carbon bond cleavage
Reactions occurring with the cleavage of the carbon-carbon bond, called anionic cleavage, often occur through the mechanism S E 1 with intermediate formation of a carbanion:
Anion splitting reactions are conventionally divided into two groups. The first group includes processes in which carbonyl compounds act as the leaving group. The substrate for this reaction is hydroxyl-containing compounds. The most important reactions of this group are: retroaldol reaction, cleavage of cyanohydrins, cleavage of tertiary alcoholates. The second group of anionic cleavage reactions is called acyl cleavage, since the electrofuge is cleaved in the form of a carboxylic acid or its derivative. The substrates in this group are carbonyl compounds, and the process begins with the nucleophilic addition of a base to the carbonyl group:
The most important reactions of this type are: cleavage of β-ketoesters and β-diketones (acid cleavage under the influence of bases), haloform reaction, decarboxylation reactions of carboxylic acid salts.
Electrophilic substitution undoubtedly constitutes the most important group of reactions of aromatic compounds. There is hardly any other class of reactions that has been so thoroughly, deeply and comprehensively studied both from the point of view of mechanism and from the point of view of application in organic synthesis. It was in the field of electrophilic aromatic substitution that the problem of the relationship between structure and reactivity, which is the main subject of study in physical organic chemistry, was first posed. In general, this type of reaction of aromatic compounds can be represented as follows:
ArE+H+
1. Literature review
1.1 Electrophilic substitution in the aromatic series
These reactions are typical not only for benzene itself, but also for the benzene ring in general, wherever it is located, as well as for other aromatic rings - benzenoid and non-benzenoid. Electrophilic substitution reactions cover a wide range of reactions: nitration, halogenation, sulfonation and Friedel-Crafts reactions are characteristic of almost all aromatic compounds; reactions such as nitrosation and azo coupling are inherent only in systems with increased activity; reactions such as desulfurization, isotope exchange, and numerous cyclization reactions, which at first glance seem quite different, but which also turn out to be appropriate to classify as reactions of the same type.
Electrophilic agents E + , although the presence of a charge is not necessary, because An electrophile can also be an uncharged electron-deficient particle (for example, SO 3, Hg(OCOCH 3) 2, etc.). Conventionally, they can be divided into three groups: strong, medium strength and weak.
NO 2 + (Nitronium ion, nitroyl cation); complexes of Cl 2 or Br 2 with various Lewis acids (FeCl 3, AlBr 3, AlCl 3, SbCl 5, etc.); H 2 OCl + , H 2 OBr + , RSO 2 + , HSO 3 + , H 2 S 2 O 7 . Strong electric saws interact with benzene-series compounds containing both electron-donating and virtually any electron-withdrawing substituents.
Electrophiles of medium strength
Complexes of alkyl halides or acyl halides with Lewis acids (RCl. AlCl 3, RBr. GaBr 3, RCOCl. AlCl 3, etc.); complexes of alcohols with strong Lewis and Brønsted acids (ROH. BF 3, ROH. H 3 PO 4, ROH. HF). They react with benzene and its derivatives containing electron-donating (activating) substituents or halogen atoms (weak deactivating substituents), but usually do not react with benzene derivatives containing strong deactivating electron-withdrawing substituents (NO 2, SO 3 H, COR, CN, etc.) .
Weak electrophiles
Diazonium cations ArN +є N, iminium CH 2 =N+ H 2, nitrosonium NO + (nitrosoyl cation); carbon monoxide (IY) CO 2 (one of the weakest electrophiles). weak electrophiles interact only with benzene derivatives containing very strong electron-donating substituents of the (+M) type (OH, OR, NH 2, NR 2, O-, etc.).
1.1.2 Mechanism of electrophilic aromatic substitution
Currently, aromatic electrophilic substitution is considered as a two-step addition-elimination reaction with the intermediate formation of an arenonium ion called a σ-complex
I-Arenonium ion (
-complex), as a rule, short-lived. This mechanism is called S E Ar, i.e. S E (arenium). In this case, at the first stage, as a result of the attack of the electrophile, the cyclic aromatic 6-electron π-system of benzene disappears and is replaced in intermediate I by a non-cyclic 4-electron conjugated system of the cyclohexadienyl cation. At the second stage, the aromatic system is restored again due to the abstraction of a proton. The structure of arenonium ion I is depicted in various ways:
The first formula is most often used. The σ complex will be much better stabilized by donor substituents in the ortho and para positions than by donor substituents in the meta position.
π -Complexes
As is known, arenes are π-bases and can form donor-acceptor complexes with many electrophilic reagents. Thus, when dry gaseous HCl or DCl was passed into a solution of benzene, toluene, xylenes or other polyalkylbenzenes in n-heptane at -78 o C, it was possible to detect formation of molecular complexes of 1:1 composition (G. Brown, 1952).
These complexes are not colored, and their solutions in aromatic hydrocarbons are non-electrically conductive. When gaseous DCl is dissolved in benzene, toluene, xylenes, mesitylene, pentamethylbenzene, no exchange of H for D occurs. Since solutions of the complexes do not conduct electric current, they are not ionic particles, i.e. These are not arenonium ions.
Such donor-acceptor complexes are called π-complexes. For example, crystals of complexes of benzene with bromine or chlorine of composition 1:1, according to X-ray diffraction data, consist of chains of alternating molecules of a π-donor of composition (C 6 H 6) and an acceptor (Cl 2,Br 2), in which the halogen molecule is located perpendicular to the plane of the ring along axis passing through its center of symmetry.
σ-complexes (arenonium ions)
When HCl and DCl are added to a solution in alkylbenzenes AlCl 3 or AlBr 3, the solution begins to conduct electric current. Such solutions are colored and their color changes from yellow to orange-red when passing from para-xylene to pentamethylbenzene. In the ArH-DCl-AlCl 3 or ArH-DF-BF 3 systems, the hydrogen atoms of the aromatic ring are already exchanged for deuterium. The electrical conductivity of solutions clearly indicates the formation of ions in the ternary system of arene-hydrogen halide-aluminum halide. The structure of such ions was established using NMR spectroscopy on 1 H and 13 C nuclei in the ArH-HF (liquid) -BF 3 or ArH-HF-SbF 5 system in SO 2 ClF at low temperature.
1.1.3 Classification of substituents
Monosubstituted benzenes C 6 H 5 X may be more or less reactive than benzene itself. If an equivalent mixture of C 6 H 5 X and C 6 H 6 is introduced into the reaction, then the substitution will occur selectively: in the first case, predominantly C 6 H 5 X will enter into the reaction, and in the second case, predominantly benzene.
Currently, substituents are divided into three groups based on their activating or deactivating effect, as well as the orientation of substitution in the benzene ring.
1. Activating ortho-para-orienting groups. These include: NH 2, NHR, NR 2, NHAc, OH, OR, OAc, Alk, etc.
2. Deactivating ortho-para-orienting groups. These are the halogens F, Cl, Br and I.
3. Deactivating meta-orienting groups. This group consists of NO 2, NO, SO 3 H, SO 2 R, SOR, C(O)R, COOH, COOR, CN, NR 3+, CCl 3, etc. These are orientants of the second kind.
Naturally, there are also groups of atoms of an intermediate nature, causing a mixed orientation. These, for example, include: CH 2 NO, CH 2 COCH 3, CH 2 F, CHCl 2, CH 2 NO 2, CH 2 CH 2 NO 2, CH 2 CH 2 NR 3 +, CH 2 PR 3 +, CH 2 SR 2 + etc.
1.2 Electrophilic substitution in π-excess heterocycles
Furan, pyrrole and thiophene are highly reactive with common electrophilic reagents. In this sense, they resemble the most reactive benzene derivatives, such as phenols and anilines. The increased sensitivity to electrophilic substitution is caused by the asymmetric charge distribution in these heterocycles, resulting in a greater negative charge on the carbon atoms of the ring than in benzene. Furan is slightly more reactive than pyrrole, and thiophene is the least reactive.
1.2.1 Electrophilic substitution of pyrrole
While pyrrole and its derivatives are not prone to nucleophilic addition and substitution reactions, they are very sensitive to electrophilic reagents, and reactions of pyrroles with such reagents proceed almost exclusively as substitution reactions. Unsubstituted pyrrole, N- and C-monoalkylpyrroles and, to a lesser extent, C,C-dialkyl derivatives polymerize in strongly acidic environments, therefore most electrophilic reagents used in the case of benzene derivatives are not applicable to pyrrole and its alkyl derivatives.
However, if there are electron-withdrawing groups in the pyrrole ring that prevent polymerization, such as ester groups, for example, it becomes possible to use strongly acidic media, nitrating and sulfonating agents.
Protonation
In solution, reversible proton addition is observed at all positions of the pyrrole ring. The nitrogen atom is protonated most quickly; the addition of a proton at position 2 occurs twice as fast as at position 3. In the gas phase, when using acids of moderate strength, such as C 4 H 9 + and NH 4 +, pyrrole is protonated exclusively at carbon atoms , and the tendency to add a proton at position 2 is higher than at position 3. The most thermodynamically stable cation, the 2H-pyrrolium ion, is formed when a proton is added at position 2, and the determined pK a value for pyrrole is associated precisely with this cation. The weak N-basicity of pyrrole is due to the lack of possibility for mesomeric delocalization of the positive charge in the 1H-pyrrole cation.
Electrophilic substitution reactions are characteristic of aromatic, carbocyclic and heterocyclic systems. As a result of the delocalization of p-electrons in the benzene molecule (and other aromatic systems), the p-electron density is distributed evenly on both sides of the ring. Such shielding of the ring carbon atoms by p-electrons protects them from attack by nucleophilic reagents and, conversely, facilitates the possibility of attack by electrophilic reagents.
But unlike the reactions of alkenes with electrophilic reagents, the interaction of aromatic compounds with them does not lead to the formation of addition products, since in this case the aromaticity of the compound would be disrupted and its stability would decrease. Retention of aromaticity is possible if an electrophilic species replaces a hydrogen cation.
The mechanism of electrophilic substitution reactions is similar to the mechanism of electrophilic addition reactions, since there are general patterns of reactions.
General scheme of the mechanism of electrophilic substitution reactions S E:
At the first stage of the reaction, p-complex with an electrophilic particle (fast stage), which then turns into s-complex(slow stage) due to the formation s- bond between one of the carbon atoms and an electrophilic particle. For education s- connection with an electrophilic particle, a pair of electrons “breaks out” from conjugation, and the resulting product acquires a positive charge. IN s-complex aromaticity is disrupted, since one of the carbon atoms is in sp 3 hybridization, and four electrons and a positive charge are delocalized on the other five carbon atoms.
To regenerate a thermodynamically favorable aromatic system, heterolytic cleavage of the C sp 3 -H bond occurs. As a result, the H + ion is split off, and a pair of bonding electrons goes to restore the conjugation system, while the hybridization of atomic orbitals of the carbon atom that removed the proton changes from sp 3 to sp 2 . The mechanism of reactions of nitration, sulfonation, halogenation, alkylation, acylation of aromatic compounds includes an additional stage not indicated in the general scheme - the stage of generating an electrophilic particle.
Reaction equationnitrationbenzene has the form:
In nitration reactions, the generation of an electrophilic particle occurs as a result of the interaction of nitric and sulfuric acids, which leads to the formation of the nitronium cation NO 2 +, which further reacts with an aromatic compound:
In a benzene molecule, all carbon atoms are equivalent; substitution occurs at one of them. If a molecule contains substituents, then the reactivity and direction of electrophilic attack are determined by the nature of this substituent. Based on their influence on reactivity and the direction of attack, all substituents are divided into two groups.
Orientants of the first kind. These substituents facilitate electrophilic substitution compared to benzene and direct the incoming group to the ortho and para positions. These include electron-donating substituents that increase the electron density in the benzene ring. As a result of its redistribution to positions 2,4,6 (ortho- and para-positions), partial negative charges arise, which facilitates the addition of an electrophilic particle to these positions with the formation s-complex.
Orientants of the second kind. These substituents make electrophilic substitution reactions more difficult compared to benzene and direct the incoming group to one of the meta positions. These include electron-withdrawing substituents that reduce the electron density in the benzene ring. As a result of its redistribution in positions 3,5 (meta-positions), partial negative charges arise and the addition of an electrophilic particle with the formation s-complex goes in tough conditions.
Halogen atoms direct the electrophilic particle to the ortho- or para-position (due to the positive mesomeric effect), but at the same time complicate the reaction, since they are electron-withdrawing substituents (-I>+M). Reactions of benzene halogen derivatives with electrophilic reagents occur under harsh conditions.
In reactions sulfonation the role of an electrophilic particle is played by the SO 3 molecule formed as a result of the reaction: 2H 2 SO 4 «SO 3 +H 3 O + + HSO 4 - . The sulfur atoms in this molecule are characterized by a strong deficiency of electron density and the presence of a partial positive charge and, therefore, it is the S atom that, as an electrophile, must bind to the carbon atom of the benzene ring of toluene.
The methyl group in toluene is an orienting agent of the first kind, and as an electron-donating substituent it facilitates the substitution reaction and directs the incoming group to the ortho and para positions. In practice, substitution products are also formed in the meta position, but their amount is significantly less than the amount of substitution products in the ortho-para position.
Halogenation benzene and many aromatic compounds, the action of the halogen itself occurs only in the presence of catalysts such as ZnCl 2, AlCl 3, FeBr 3, etc. The catalysts are usually Lewis acids. A bond is formed between the metal atom and the halogen atom via a donor-acceptor mechanism, which causes polarization of the halogen molecule, enhancing its electrophilic character. The resulting adduct can undergo dissociation to form a complex anion and a halogen cation, which then acts as an electrophilic particle:
Aqueous solutions of HO-Hal in the presence of strong acids can also be used as halogenating agents. The formation of an electrophilic particle in this case can be explained by the following reactions:
The mechanism of further interaction of Br + or Cl + cations is no different from the mechanism of nitration with NO 2 + cations. Let us consider the reaction mechanism using the example of aniline bromination (we will limit ourselves to the formation of monosubstituted products). As is known, aniline decontaminates bromine water, ultimately forming 2,4,6-tribromoaniline, which is released in the form of a white precipitate:
The resulting electrophilic species attacks the p-electrons of the benzene ring, forming a p-complex. From the resulting p-complex, two main ones are formed s-complexes in which the carbon-bromine bond occurs in the ortho- and para-positions of the ring. At the next stage, proton abstraction occurs, which leads to the formation of monosubstituted aniline derivatives. In excess of the reagent, these processes are repeated, leading to the formation of dibromo and tribromo derivatives of aniline.
Alkylation(replacement of a hydrogen atom with an alkyl radical) of aromatic compounds occurs when they interact with haloalkanes (Friedel-Crafts reaction). The interaction of primary alkyl halides, for example CH 3 Cl, with aromatic compounds in the presence of Lewis acids is not much different in its mechanism from halogenation reactions. Let us consider the mechanism using the example of methylation of nitrobenzene. The nitro group, as a second-order orienting agent, deactivates the benzene ring in electrophilic substitution reactions and directs the incoming group to one of the meta positions.
In general, the reaction equation has the form:
The generation of an electrophilic species occurs as a result of the reaction of a haloalkane with a Lewis acid:
The resulting methyl cation attacks the p-electrons of the benzene ring, which leads to the formation of a p-complex. The resulting p-complex then slowly turns into s-complex (carbocation) in which the bond between the methyl cation and the carbon atom of the ring occurs primarily in positions 3 or 5 (i.e., in the meta positions in which partial negative charges arise due to the electronic effects of the nitro group). The final stage is the abstraction of a proton from s-complex and restoration of the associated system.
Alkenes or alcohols can also be used as alkylating agents in the alkylation of benzene instead of alkyl halides. For the formation of an electrophilic particle - a carbocation - the presence of an acid is necessary. The reaction mechanism in this case will differ only at the stage of generating an electrophilic particle. Let's consider this using the example of benzene alkylation with propylene and propanol-2:
Generation of an electrophilic particle:
When propylene is used as a reagent, the formation of a carbocation occurs as a result of the addition of a proton (according to Markovnikov’s rule). When propanol-2 is used as a reagent, the formation of a carbocation occurs as a result of the elimination of a water molecule from a protonated alcohol.
The resulting isopropyl cation attacks the p-electrons of the benzene ring, which leads to the formation of a p-complex, which further turns into s- complex with impaired aromaticity. The subsequent removal of a proton leads to the regeneration of the aromatic system:
Reactions acylation(replacement of the H + cation with the acyl group R-C + =O) occurs in a similar way. Let us consider the example of the acylation reaction of methoxybenzene, the equation of which can be represented as follows:
As in previous cases, the electrophilic species is generated by the reaction of acetic acid chloride with a Lewis acid:
The resulting acylium cation first forms a p-complex, from which mainly two arise s-complex in which the formation s- The bond between the ring and the electrophilic particle occurs predominantly in the ortho- and para-positions, since partial negative charges arise in these positions due to the electronic influence of the methoxy group.
Aromatic heterocycles also undergo electrophilic substitution reactions. At the same time, five-membered heterocycles - pyrrole, furan and thiophene - enter into SE reactions more easily, since they are p-excess systems. However, when carrying out reactions with these compounds, it is necessary to take into account their acidophobicity. The instability of these compounds in an acidic environment is explained by the loss of aromaticity as a result of the addition of a proton.
During reactions, an electrophilic particle replaces a proton in the a-position; if both a-positions are occupied, then the substitution occurs at the b-position. Otherwise, the mechanism of electrophilic substitution reactions is similar to the cases discussed above. Let us take the bromination of pyrrole as an example:
The reaction mechanism involving aromatic heterocycles includes all the stages discussed above - the generation of an electrophilic particle, the formation of a p-complex, its transformation into s- complex (carbocation), abstraction of a proton leading to the formation of an aromatic product.
When carrying out electrophilic substitution reactions involving p-deficient aromatic systems, such as pyridine and pyrimidine, their initially lower reactivity must be taken into account (a deficiency of p-electron density makes it difficult to form a p-complex and its conversion to s- complex), which decreases even more when reactions are carried out in an acidic environment. Although the aromaticity of these compounds is not impaired in an acidic environment, protonation of the nitrogen atom leads to an increased deficiency of p-electron density in the cycle.
Pyridine is capable of alkylation, sulfonation, nitration, acylation and halogenation. However, in most cases, the more nucleophilic nitrogen atom forms a bond with the electrophilic particle, rather than the pyridine carbon atoms.
If the reaction occurs in the pyridine ring, the substitution occurs at one of the b-positions, in which partial negative charges arise.
The most widely used reaction of benzene is the replacement of one or more hydrogen atoms by some electrophilic group. Many important substances are synthesized in this way. The choice of functional groups that can be introduced into aromatic compounds in this way is very wide, and in addition, some of these groups can be transformed into other groups after introduction into the benzene ring. The general reaction equation is:
Below are five of the most common reactions of this type and examples of their use.
Nitration:
Sulfonation:
Friedel-Crafts dikylation:
Friedel-Crafts acylation:
Halogenation (chlorination and bromination only):
The following reactions are often used to further transform compounds resulting from aromatic electrophilic substitution.
Side chain restoration:
Reduction of the nitro group:
Diazotization and further transformations
Aniline and its substitutes can be converted into highly reactive compounds called diazonium salts:
Diazonium salts serve as starting materials for the synthesis of a wide variety of aromatic compounds (Scheme 9-1). In many cases, the diazonium salt synthesis method is the only way to introduce any functional group into an aromatic compound.
The replacement of the diazonium group with chlorine and bromine atoms, as well as with a cyano group, is achieved by the interaction of diazonium salts with copper salts (1). Iodine and fluorine atoms cannot be introduced into the aromatic ring by direct halogenation. Aromatic iodides and fluorides are prepared by treating diazonium salts with potassium iodide and hydrofluoroboric acid, respectively.
Aromatic carboxylic acids can be prepared either by hydrolysis of the nitrile group or by the action of carbon dioxide on the Grignard reagent (more on this reaction will be discussed in Chapter 12). Phenols in the laboratory are most often obtained by hydrolysis of diazonium salts.
Diagram 9-2. Reactions of diazonium salts
The diazonium group (and therefore also the amino group and the nitro group) can be removed (i.e. replaced by a hydrogen atom) by the action of diazonium salts of hypophosphorous acid
Finally, the interaction of diazonium salts with activated aromatic compounds leads to the formation of azo dyes. Dyes can be of very different colors depending on the nature of the substituents on both aromatic rings.
Nitrous acid, which is used to obtain diazonium salts, is a low-stable substance and is prepared in situ (i.e., directly in the reaction vessel) from sodium nitrite and hydrochloric acid. In the reaction diagram, treatment with nitrous acid can be shown in one of two ways, which are used below:
Here are some examples of reactions of diazonium salts:
Preparation of practically important substances using electrophilic substitution reactions
Dyes. The synthesis of methyl orange is shown below. If you take the original compounds with other substituents in the aromatic rings, the color of the dye will be different.
Polymers. Polystyrene is produced by polymerization of styrene (see Chapter 6), which, in turn, can be synthesized as follows. Benzene is acylated by Friedel-Crafts using acetic anhydride instead of acetyl chloride, the resulting ketone is reduced to alcohol, which is then dehydrated using potassium hydrogen sulfate as an acid catalyst:
Medicines. in the synthesis of sulfonamide (streptocide), the first two stages are reactions that we have already encountered. The third stage is the protection of the amino group. This is necessary to prevent the interaction of chlorosulfonic acid with the amino group. After the group reacts with ammonia, the protecting group can be removed.
Streptocide was one of the first antimicrobial drugs of the sulfonamide group. It is still used today.
Electrophilic substitution reactions allow the introduction of many different groups into the aromatic ring. Many of these groups can then be transformed during synthesis.
Mechanism of aromatic electrophilic substitution
It has been established that electrophilic substitution in aromatic compounds occurs in two stages. First, an electrophile (which can be generated by various methods) is added to the benzene ring. In this case, a resonantly stabilized carb cation is formed (below in parentheses). This cation then loses a proton and becomes an aromatic compound.
Here, for clarity, the formulas of aromatic compounds are shown with double bonds. But you, of course, remember that in fact there is a cloud of delocalized electrons.
The mechanisms of the two reactions, including the electrophile generation step, are given below. Haogenation
Electrophile generation:
Substitution:
Friedel-Crafts acylation Electrophile generation:
Substitution:
Influence of deputies
When a substituted benzene reacts with an electrophile, the structure of the substituent already present on the benzene ring has a significant effect on the orientation of the substitution and its rate.
Based on their influence on the rate and orientation of electrophilic substitution, all possible substituents can be divided into three groups.
1. Activating orthopara-orientants. In the presence of a substituent of this group in an aromatic compound, it reacts faster than unsubstituted benzene, and the electrophile is directed to the ortho- and para-positions of the substituent and a mixture of ortho- and para-disubstituted benzenes is formed. This group includes the following substituents:
2. Deactivating meta-orientants. These substituents slow down the reaction compared to benzene and direct the electrophile to the meta position. This group includes:
3. Decontaminating ortho-, para-orientants. This group includes atoms of alogens.
Examples of orientation for electrophilic substitution:
Explanation of the influence of substituents
Why do different substituents have such different effects on the nature of electrophilic substitution? The answer to this question can be obtained by analyzing the stability of the intermediates formed in each case. Some of these intermediate carbocations will be more stable, others less stable. Recall that if a compound can react in several ways, the reaction will go along the path that produces the most stable intermediate.
Shown below are the resonance structures of intermediate particles formed during the electrophilic attack of a cation in the ortho- and para-positions of phenol, which has a powerful activating substituent - ortho, para-orientant, toluene, which has a substituent with the same, but much weaker properties, and nitrobenzene, which has in which the nitro group is an orienting agent and deactivates the ring:
When an electrophile attacks both the ortho and para positions of the phenol, more resonance structures can be written for the resulting intermediate than for the meta-substitution intermediate. Moreover, this “extra” structure (circled in a frame) makes a particularly large contribution
in the stabilization of the cation, since all atoms in it have an octet of electrons. Thus, with an ortho- or para-oriented attack of an electrophile, a more stable cation appears than with an attack in the meta position, so the substitution occurs predominantly in the ortho- and para-positions. Since the cation resulting from such substitution is more stable than the cation formed from unsubstituted benzene, phenol undergoes electrophilic substitution reactions much more easily than benzene. Note that all substituents that strongly or moderately activate the aromatic ring in electrophilic substitution reactions have an atom associated with the ring with lone pairs of electrons. These electrons can be fed into the ring. In this case, a resonance structure appears with a positive charge on an electronegative atom (oxygen or nitrogen). All this stabilizes the intermediate and increases the reaction rate (resonance activation).
In the case of toluene, substitution at both the ortho- and d-positions results in a more stable cation than when the electrophile attacks the meta-position.
In the boxed resonance structures, the positive charge is on the tertiary carbon atoms (tertiary carbocations, see Chapter 5). When attacking the meta position, no tertiary carbocation is formed. Here again, ortho- and para-substitution goes through slightly more stable intermediate species than meta-substitution and than substitution in benzene itself. Therefore, substitution in toluene is directed to the ortho and para positions and proceeds somewhat faster than substitution in Lysol (activation due to the inductive effect).
All deactivating groups, including the nitro group, have the property of withdrawing electrons from the aromatic ring. The result of this is destabilization of the intermediate cation. Especially
(click to view scan)
Intermediates arising from attack at the ortho and para positions are strongly destabilized, since the partial positive charge is located immediately next to the nitro group (the corresponding resonance structures are boxed). Therefore, meta substitution is preferred over ortho and para substitution. Nitrobenzene undergoes electrophilic substitution much more difficult than benzene, since the electron density in the ring is reduced and the mutual attraction of the aromatic ring and the electrophile is weakened.
Electrophilic addition reactions occur in two stages through the formation of an intermediate cation. Different substituents on the benzene ring have different effects on substitution rates and orientations. This effect can be explained taking into account the stability of the intermediates formed in each case.
Most characteristic of aromatic hydrocarbons reactions substitution. In this case, the reactions do not result in destruction of the aromatic sextet of electrons. There are also numerous examples of reactions radical halogenation And oxidation side chains of alkylbenzenes. Processes in which a stable aromatic system is destroyed are not very common.
IV.1 Electrophilic aromatic substitution (seAr)
A. MechanismS E Ar (Substitution Electrophilic in Arenes)
Electrophilic substitution in the aromatic ring is one of the most well-studied and widespread organic reactions. Most often, the end result of electrophilic substitution is the replacement of a hydrogen atom in the aromatic ring with another atom or group of atoms:
Electrophilic substitution reactions in the aromatic ring (as well as electrophilic substitution reactions accession to C=C bonds) begin with the formation -complex - the electrophilic agent coordinates with the benzene molecule due to the latter’s electron system:
In the benzene ring, the system, being stable (stabilization energy; see Section II), is not disrupted as easily as in alkenes. Therefore, the corresponding -complex can not only be fixed using physicochemical methods, but also highlighted.(note 24)
As a rule, the stage of formation of the β-complex proceeds quickly and Not limits speed the whole process.
Next, the aromatic system is disrupted, and a covalent bond between the electrophile and the carbon atom of the benzene ring occurs. In this case, the -complex turns into a carbocation (carbenium ion), in which the positive charge is delocalized in the diene system, and the carbon atom attacked by the electrophile is transferred from sp 2 - V sp 3 - hybrid state. This cation is called -complex . As a rule, education stage-complex is speed determining. Delocalization of the positive charge in the -complex is not carried out uniformly between the five carbon atoms, but due to the 2,4,6-positions of the benzene ring (compare with the allylic cation, where the positive charge is distributed between the 1,3-positions):
During electrophilic addition to alkenes, an -complex is also first formed, which then turns into an -complex, but the further fate of the -complex in the case of electrophilic reactions of alkenes and arenes is different. -The complex formed from alkenes is stabilized by trance- addition of a nucleophile; -the complex formed from the aromatic system is stabilized with the regeneration of the aromatic sextet -electrons: (note 25)
Below is the energy profile of such a reaction (note 27) (E a is the activation energy of the corresponding stage):
Let us emphasize once again that the reactions S E Ar, which result in substitution, In fact the mechanism is an addition reaction followed by elimination.
B. Orientation of addition in monosubstituted benzenes
When considering electrophilic substitution reactions in monosubstituted benzenes, two problems arise: 1. A new substituent can enter into ortho-, meta- or pair-position, as well as replace an existing substituent (the latter, the so-called ipso-substitution , less common - see section IV.1.D (nitration). 2. The rate of substitution may be greater or less than the rate of substitution in benzene.
The influence of the substituent present on the benzene ring can be explained based on its electronic effects. Based on this criterion, substituents can be divided into 3 main groups:
1. Substituents that accelerate the reaction compared to unsubstituted benzene ( activating ) and directing substitution in ortho ,- pair - provisions.
2. Substituents that slow down the reaction ( decontaminating ) and directing substitution in ortho, -para- positions .
3. Substituents that slow down the reaction ( decontaminating ) and directing substitution in meta - provisions.
Substituents noted in paragraphs. 1.2 ( ortho-, para-orientators ) are called substituents of the first kind ; noted in paragraph 3 ( meta-orientators ) - substituents of the second kind . Below is an assignment of commonly occurring substituents according to their electronic effects.
It is obvious that electrophilic substitution will occur the faster, the more electron-donating the substituent in the nucleus is, And the slower, the more electron-withdrawing the substituent in the nucleus is.
For explanation orientation substitutions, let us consider the structure of -complexes under attack in ortho-, meta- And pair-position of monosubstituted benzene (as already noted, the formation of -complexes is usually the rate-determining stage of electrophilic substitution; therefore, the ease of their formation should determine the ease of substitution at a given position):
If group Z is an electron donor (it does not matter whether it is inductive or mesomeric), then when ortho- or pair-attack, it can directly participate in the delocalization of the positive charge in the -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 based on the so-called dynamic effect , i.e. distribution of electron density in the reacting molecule. The orientation of electrophilic substitution in monosubstituted benzenes can also be explained from the point of view static electronic effects - distribution of electron density in a non-reacting molecule. When considering the shift in electron density along multiple bonds, it can be noted that in the presence of an electron-donating substituent, most increased electron density in ortho- And pair- positions, and in the presence of an electron-withdrawing substituent, these positions are most impoverished electrons:
A special case is represented by halogens - being substituents on the benzene ring, they deactivate it in electrophilic substitution reactions, but are ortho-, pair-orientators. Deactivation (decrease in the rate of reaction with electrophiles) is due to the fact that, unlike other groups with lone electron pairs (such as -OH, -NH 2, etc.), which have a positive mesomeric (+M) and negative inductive effect ( -I), halogens are characterized by a predominance of the inductive effect over the mesomeric effect (+M< -I).(прим.30)
At the same time, halogen atoms are ortho,para-orientants, since they are able, due to the positive mesomeric effect, to participate in the delocalization of the positive charge in the -complex formed when ortho- or pair- attack (structures IV, VII in the above diagram), and thereby reduce the energy of its formation.
If the benzene ring has not one, but two substituents, then their orienting action may coincide ( consistent orientation ) or not match ( inconsistent orientation ). In the first case, you can count on the preferential formation of some specific isomers, and in the second, complex mixtures will be obtained. (Note 31)
Below are some examples of consistent orientation of two substituents; the place of preferential entry of the third substituent is shown by an arrow.
The demand for benzene is determined by the development of industries consuming it. The main applications of benzene are the production of ethylbenzene, cumene and cyclohexane and aniline.