Also, as noted earlier, toluene undergoes nitration about 25 times faster than benzene, but chlorination of toluene is over times faster than that of benzene. From this we may conclude that the nitration reagent is more reactive and less selective than the halogenation reagents. Both sulfonation and nitration yield water as a by-product. This does not significantly affect the nitration reaction note the presence of sulfuric acid as a dehydrating agent , but sulfonation is reversible and is driven to completion by addition of sulfur trioxide, which converts the water to sulfuric acid.
The reversibility of the sulfonation reaction is occasionally useful for removing this functional group. The Friedel-Crafts acylation reagent is normally composed of an acyl halide or anhydride mixed with a Lewis acid catalyst such as AlCl 3. Such electrophiles are not exceptionally reactive, so the acylation reaction is generally restricted to aromatic systems that are at least as reactive as chlorobenzene. Carbon disulfide is often used as a solvent, since it is unreactive and is easily removed from the product.
If the substrate is a very reactive benzene derivative, such as anisole, carboxylic esters or acids may be the source of the acylating electrophile. Some examples of Friedel-Crafts acylation reactions are shown in the following diagram. The first demonstrates that unusual acylating agents may be used as reactants. The second makes use of an anhydride acylating reagent, and the third illustrates the ease with which anisole reacts, as noted earlier. The H 4 P 2 O 7 reagent used here is an anhydride of phosphoric acid called pyrophosphoric acid.
Finally, the fourth example illustrates several important points. Since the nitro group is a powerful deactivating substituent, Friedel-Crafts acylation of nitrobenzene does not take place under any conditions. However, the presence of a second strongly-activating substituent group permits acylation; the site of reaction is that favored by both substituents.
A common characteristic of the halogenation, nitration, sulfonation and acylation reactions is that they introduce a deactivating substituent on the benzene ring. As a result, we do not normally have to worry about disubstitution products being formed.
Friedel-Crafts alkylation, on the other hand, introduces an activating substituent an alkyl group , so more than one substitution may take place. If benzene is to be alkylated, as in the following synthesis of tert-butylbenzene, the mono-alkylated product is favored by using a large excess of this reactant.
When the molar ratio of benzene to alkyl halide falls below , para-ditert-butylbenzene becomes the major product. For example, reaction of excess benzene with 1-chloropropane and aluminum chloride gives a good yield of isopropylbenzene cumene. The first and third examples show how alkenes and alcohols may be the source of the electrophilic carbocation reactant. The triphenylmethyl cation generated in the third case is relatively unreactive, due to extensive resonance charge delocalization, and only substitutes highly activated aromatic rings.
The second example shows an interesting case in which a polychlororeactant is used as the alkylating agent. A four fold excess of carbon tetrachloride is used to avoid tri-alkylation of this reagent, a process that is retarded by steric hindrance. The fourth example illustrates the poor orientational selectivity often found in alkylation reactions of activated benzene rings. The bulky tert-butyl group ends up attached to the reactive meta -xylene ring at the least hindered site.
This may not be the site of initial bonding, since polyalkylbenzenes rearrange under Friedel-Crafts conditions para -dipropylbenzene rearranges to meta -dipropylbenzene on heating with AlCl 3.
A practical concern in the use of electrophilic aromatic substitution reactions in synthesis is the separation of isomer mixtures. This is particularly true for cases of ortho-para substitution, which often produce significant amounts of the minor isomer. As a rule, para-isomers predominate except for some reactions of toluene and related alkyl benzenes.
Separation of these mixtures is aided by the fact that para-isomers have significantly higher melting points than their ortho counterparts; consequently, fractional crystallization is often an effective isolation technique. Since meta-substitution favors a single product, separation of trace isomers is normally not a problem. Some substituents enable the ortho-metallation of an aromatic ring. This then permits the introduction of other groups.
For a description of this procedure Click Here. This page is the property of William Reusch. Comments, questions and errors should be sent to whreusch msu. These pages are provided to the IOCD to assist in capacity building in chemical education. The last two steps we covered previously in the generic electrophilic aromatic substitution mechanism , and they are actually very similar between all electrophilic aromatic substitution reactions.
The sulfonyl group, SO 3 H can also be added to an aromatic ring via electrophilic aromatic substitution. In this case the electrophilic reagent is sulfur trioxide, SO 3 a gas which can be introduced by bubbling through the solvent. As with all electrophilic aromatic substitutions, the C-H bond is then deprotonated with a weak base to regenerate the C—C pi bond and restore aromaticity, providing the sulfonic acid product. Aromatic sulfonyl groups have a very interesting property.
If treated with a strong enough acid in the absence of SO 3 , the sulfonic acid group can be removed. Does the product look familiar? Most of the time, this intermediate will just be deprotonated to regenerate the aromatic sulfonic acid.
However, in the case of SO 3 H, there is another pathway to restore aromaticity that is not energetically available in the case of most other substituents. In the presence of a high concentration of SO 3 , benzene would just attack protonated SO 3 again and re-form the sulfonic acid.
But if we just add acid in the absence of SO 3 , then this is less likely to occur. Furthermore, if we vent the reaction say, by bubbling an inert gas like argon through the reaction mixture, which would eventually carry away any gaseous SO 3 along with it , then gaseous SO 3 will be slowly removed from the system.
Answer in the comments. Note 1. This can abstract a hydrogen atom from nitroglycerin, and then — shabang! For more detailed references on these reactions, consult the sections in the reaction guide. The references here are highlights. What would happen if we try to introduce Cl- in p- methyl amino benzene? What possible difference may be there on trying to nitrate or sulfonate the same?
On the other hand any procedure which requires acid will protonate the amine, resulting in an ammonium group. What might be the major product in case of chlorination? Actually I had thought that Cl would go ortho to amino group, but one of our Chemistry faculties at school insists that Cl should go ortho to CH3 group, ie meta to NH2 in order to avoid steric repulsion with amino group… which would, in his opinion, decrease the resonance energy of the benzene ring, by sending NH2 out of the ring, ie.
Please help! With some exceptions, such as the halogens, deactivating substituents direct substitution to the meta location. The following table summarizes this classification. The information summarized in the above table is very useful for rationalizing and predicting the course of aromatic substitution reactions, but in practice most chemists find it desirable to understand the underlying physical principles that contribute to this empirical classification. We have already analyzed the activating or deactivating properties of substituents in terms of inductive and resonance effects , and these same factors may be used to rationalize their influence on substitution orientation.
The first thing to recognize is that the proportions of ortho, meta and para substitution in a given case reflect the relative rates of substitution at each of these sites.
If we use the nitration of benzene as a reference, we can assign the rate of reaction at one of the carbons to be 1. Since there are six equivalent carbons in benzene, the total rate would be 6. If we examine the nitration of toluene, tert-butylbenzene, chlorobenzene and ethyl benzoate in the same manner, we can assign relative rates to the ortho, meta and para sites in each of these compounds.
These relative rates are shown colored red in the following illustration, and the total rate given below each structure reflects the 2 to 1 ratio of ortho and meta sites to the para position. The overall relative rates of reaction, referenced to benzene as 1. Clearly, the alkyl substituents activate the benzene ring in the nitration reaction, and the chlorine and ester substituents deactivate the ring.
From rate data of this kind, it is a simple matter to calculate the proportions of the three substitution isomers. Toluene gives Equivalent rate and product studies for other substitution reactions lead to similar conclusions. The manner in which specific substituents influence the orientation of electrophilic substitution of a benzene ring is shown in the following interactive diagram.
As noted on the opening illustration, the product-determining step in the substitution mechanism is the first step, which is also the slow or rate determining step. It is not surprising, therefore, that there is a rough correlation between the rate-enhancing effect of a substituent and its site directing influence.
The exact influence of a given substituent is best seen by looking at its interactions with the delocalized positive charge on the benzenonium intermediates generated by bonding to the electrophile at each of the three substitution sites. This can be done for seven representative substituents by using the selection buttons underneath the diagram. In the case of alkyl substituents, charge stabilization is greatest when the alkyl group is bonded to one of the positively charged carbons of the benzenonium intermediate.
This happens only for ortho and para electrophilic attack, so such substituents favor formation of those products. Interestingly, primary alkyl substituents, especially methyl, provide greater stabilization of an adjacent charge than do more substituted groups note the greater reactivity of toluene compared with tert-butylbenzene. Structures in which like-charges are close to each other are destabilized by charge repulsion, so these substituents inhibit ortho and para substitution more than meta substitution.
Consequently, meta-products preominate when electrophilic substitution is forced to occur. Halogen X , OR and NR 2 substituents all exert a destabilizing inductive effect on an adjacent positive charge, due to the high electronegativity of the substituent atoms. By itself, this would favor meta-substitution; however, these substituent atoms all have non-bonding valence electron pairs which serve to stabilize an adjacent positive charge by pi-bonding, with resulting delocalization of charge.
Consequently, all these substituents direct substitution to ortho and para sites. The conditions commonly used for the aromatic substitution reactions discussed here are repeated in the table on the right.
The electrophilic reactivity of these different reagents varies. Also, as noted earlier, toluene undergoes nitration about 25 times faster than benzene, but chlorination of toluene is over times faster than that of benzene. From this we may conclude that the nitration reagent is more reactive and less selective than the halogenation reagents. Both sulfonation and nitration yield water as a by-product. This does not significantly affect the nitration reaction note the presence of sulfuric acid as a dehydrating agent , but sulfonation is reversible and is driven to completion by addition of sulfur trioxide, which converts the water to sulfuric acid.
The reversibility of the sulfonation reaction is occasionally useful for removing this functional group. The Friedel-Crafts acylation reagent is normally composed of an acyl halide or anhydride mixed with a Lewis acid catalyst such as AlCl 3. Such electrophiles are not exceptionally reactive, so the acylation reaction is generally restricted to aromatic systems that are at least as reactive as chlorobenzene.
Carbon disulfide is often used as a solvent, since it is unreactive and is easily removed from the product. If the substrate is a very reactive benzene derivative, such as anisole, carboxylic esters or acids may be the source of the acylating electrophile.
Some examples of Friedel-Crafts acylation reactions are shown in the following diagram. The first demonstrates that unusual acylating agents may be used as reactants. The second makes use of an anhydride acylating reagent, and the third illustrates the ease with which anisole reacts, as noted earlier.
The H 4 P 2 O 7 reagent used here is an anhydride of phosphoric acid called pyrophosphoric acid. Finally, the fourth example illustrates several important points. Since the nitro group is a powerful deactivating substituent, Friedel-Crafts acylation of nitrobenzene does not take place under any conditions. However, the presence of a second strongly-activating substituent group permits acylation; the site of reaction is that favored by both substituents.
A common characteristic of the halogenation, nitration, sulfonation and acylation reactions is that they introduce a deactivating substituent on the benzene ring. As a result, we do not normally have to worry about disubstitution products being formed. Friedel-Crafts alkylation, on the other hand, introduces an activating substituent an alkyl group , so more than one substitution may take place.
If benzene is to be alkylated, as in the following synthesis of tert-butylbenzene, the mono-alkylated product is favored by using a large excess of this reactant. When the molar ratio of benzene to alkyl halide falls below , para-ditert-butylbenzene becomes the major product.
For example, reaction of excess benzene with 1-chloropropane and aluminum chloride gives a good yield of isopropylbenzene cumene. The first and third examples show how alkenes and alcohols may be the source of the electrophilic carbocation reactant.
The triphenylmethyl cation generated in the third case is relatively unreactive, due to extensive resonance charge delocalization, and only substitutes highly activated aromatic rings. The second example shows an interesting case in which a polychlororeactant is used as the alkylating agent. A four fold excess of carbon tetrachloride is used to avoid tri-alkylation of this reagent, a process that is retarded by steric hindrance.
The fourth example illustrates the poor orientational selectivity often found in alkylation reactions of activated benzene rings. The bulky tert-butyl group ends up attached to the reactive meta -xylene ring at the least hindered site. This may not be the site of initial bonding, since polyalkylbenzenes rearrange under Friedel-Crafts conditions para -dipropylbenzene rearranges to meta -dipropylbenzene on heating with AlCl 3.
A practical concern in the use of electrophilic aromatic substitution reactions in synthesis is the separation of isomer mixtures. This is particularly true for cases of ortho-para substitution, which often produce significant amounts of the minor isomer. As a rule, para-isomers predominate except for some reactions of toluene and related alkyl benzenes.
Separation of these mixtures is aided by the fact that para-isomers have significantly higher melting points than their ortho counterparts; consequently, fractional crystallization is often an effective isolation technique. Since meta-substitution favors a single product, separation of trace isomers is normally not a problem.
Electrophilic Substitution of Disubstituted Benzene Rings When a benzene ring has two substituent groups, each exerts an influence on subsequent substitution reactions. The activation or deactivation of the ring can be predicted more or less by the sum of the individual effects of these substituents.
The site at which a new substituent is introduced depends on the orientation of the existing groups and their individual directing effects. We can identify two general behavior categories, as shown in the following table. Thus, the groups may be oriented in such a manner that their directing influences act in concert, reinforcing the outcome; or are opposed antagonistic to each other.
Note that the orientations in each category change depending on whether the groups have similar or opposite individual directing effects. The products from substitution reactions of compounds having a reinforcing orientation of substituents are easier to predict than those having antagonistic substituents.
For example, the six equations shown below are all examples of reinforcing or cooperative directing effects operating in the expected manner. Symmetry, as in the first two cases, makes it easy to predict the site at which substitution is likely to occur. Note that if two different sites are favored, substitution will usually occur at the one that is least hindered by ortho groups.
The first three examples have two similar directing groups in a meta-relationship to each other. In examples 4 through 6, oppositely directing groups have an ortho or para-relationship. The major products of electrophilic substitution, as shown, are the sum of the individual group effects. The strongly activating hydroxyl —OH and amino —NH 2 substituents favor dihalogenation in examples 5 and six. Substitution reactions of compounds having an antagonistic orientation of substituents require a more careful analysis.
If the substituents are identical, as in example 1 below, the symmetry of the molecule will again simplify the decision.
Case 3 reflects a combination of steric hindrance and the superior innate stabilizing ability of methyl groups relative to other alkyl substituents. Oxidation of Alkyl Side-Chains The benzylic hydrogens of alkyl substituents on a benzene ring are activated toward free radical attack, as noted earlier. Furthermore, S N 1, S N 2 and E1 reactions of benzylic halides , show enhanced reactivity, due to the adjacent aromatic ring.
The possibility that these observations reflect a general benzylic activation is supported by the susceptability of alkyl side-chains to oxidative degradation, as shown in the following examples the oxidized side chain is colored.
Such oxidations are normally effected by hot acidic pemanganate solutions, but for large scale industrial operations catalysed air-oxidations are preferred. Interstingly, if the benzylic position is completely substituted this oxidative degradation does not occur second equation, the substituted benzylic carbon is colored blue. These equations are not balanced. Two other examples of this reaction are given below, and illustrate its usefulness in preparing substituted benzoic acids.
Reduction of Nitro Groups and Aryl Ketones Electrophilic nitration and Friedel-Crafts acylation reactions introduce deactivating, meta-directing substituents on an aromatic ring. The attached atoms are in a high oxidation state, and their reduction converts these electron withdrawing functions into electron donating amino and alkyl groups. Examples of these reductions are shown here, equation 6 demonstrating the simultaneous reduction of both functions.
Note that the butylbenzene product in equation 4 cannot be generated by direct Friedel-Crafts alkylation due to carbocation rearrangement. The zinc used in ketone reductions, such as 5, is usually activated by alloying with mercury a process known as amalgamation.
Several alternative methods for reducing nitro groups to amines are known.
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