Ch 15 Reactions of Aromatic Compounds

Intro Aromatic hydrocarbons are known generally as arenes. An Aryl group is formed by the removal of a hydrogen, and is symbolized with Ar- We have already talked about how stable the double bonds are in arenes due to conjugation. They resist typical addition reactions

Intro We have also said that the pi electrons form clouds above and below the ring This makes nucleophilic attack very unlikely as well The most characteristic reactions of arenes are a new type of reaction called Electrophilic Aromatic Substitution, (EAS)

EAS Generic reaction: The electrophiles in these reactions are either a positive ion (E+) or some other electron deficient species with a large partial positive charge

EAS Mechanism: Aromaticity- Broken in 1st step- reactions usually require high temps Regained in 2nd step- reason for substitution instead of addition Arenium Ion- somewhat stabilized by resonance; delocalized positive charge

Arenium ion Substituents already on the ring can effect the stability of the arenium ion, and therefore effect the reaction. Substituents on the ring are divided into 2 classification The first deals with how the substituents effect the reactivity of the ring The second deals with how the substituents effect the orientation of the incoming electrophile

Reactivity of the Ring Those substituents whose presence make the ring more reactive than benzene are called activating groups, or Activators Those that make the ring less reactive than benzene are called De-activating groups, or Deactivators

Reactivity of the Ring If we look at the energy diagram we see that the 1st step is the RDS and that the Arenium ion is a true intermediate, not a transition state. By increasing the stability of the arenium ion, we would be lowering it energy, therefore, lowering the activation energy for the RDS, making the reaction occur faster.

Reactivity of the Ring This is how Activating groups work They help to stabilize the Arenium Ion How can the Arenium Ion be stabilized?

Reactivity of the Ring Activating groups stabilize the arenium ion by donating electrons into the cation. Strong Activators Moderate Activators Weak Activators

Reactivity of the Ring Deactivating groups have the opposite effect They decrease the stability of the arenium ion, thereby increasing it energy, which increases the activation energy for the reaction, making the reaction occur slower. Note: Notice I said slower! The reaction will still occur, just at a slower relative rate compared to benzene.

Reactivity of the Ring Don’t think that just because a ring has a deactivating group, that it won’t undergo a reaction. For most reactions, it will still react just with a slower relative rate. How would a group deactivate a ring?

Reactivity of the Ring Deactivators destabilize the arenium ion by withdrawing electrons from the cation ion. Strong Deactivators Moderate Deactivators Weak Deactivators

Orientation The second classifications groups can be divided into deals with the way they influence the orientation of the incoming electrophile Some substituents tend to direct the electrophiles to the ortho and para positions relative to themselves; while others tend to direct the electrophile to the meta positions.

Orientation To understand how these groups “direct” the incoming electrophile, we again look at the arenium ion. More specifically, we look at the resonance structures of the arenium ion once the electrophile adds to the ring.

Orientation Notice with both the ortho and para positioning of the electrophile, the carbocation can be shown on the carbon directly bonded to the substituent With the meta positioning of the electrophile, the carbocation never reaches the carbon attached to the substituent.

Orientation Activators are electron donors, so their stabilizing effects would be greater with the carbocation directly bonded to them. Thus, all activators are ortho/para directors By contrast, deactivator are electron withdrawing groups, so they want to avoid being directly bonded to the carbocation Thus, strong and moderate deactivators are meta directors

Exception Of course there is an exception! Halogens are weakly deactivating due to their electronegativity, but ortho/para directors due to an additional resonance structure.

Types of EAS Reactions All EAS reactions occur through the same, basic mechanism. The only difference is the way the electrophile is created/introduced Examples:

Halogenation of Benzene Benzene does not react with chlorine or bromine unless a lewis acid catalyst is present Examples: Mechanism:

Nitration of Benzene Examples: Mechanism:

Sulfonation of Benzene General reaction: This reaction is an equilibrium We can influence the equilibrium by the methods we use By using conc. H2SO4 or fuming H2SO4 (contains added SO3), the equilibrium is pushed to the right, increasing the amount of sulfonated benzene.

Sulfonation of Benzene By using dilute acid and steam, we can push the equilibrium to the left, removing the sulfonyl group. The steam helps remove the volatile aromatic compound as it forms Mechanism:

Sulfonation of Benzene The control of this equilibrium is fairly simple and is therefore very useful! Often, we may introduce a sulfonic acid group to influence other reactions, then remove it later. Example:

Friedal-Crafts Alkylation Discovered in 1877 as a new method of making alkyl benzenes, (Ar—R) General Reaction: Mechanism:

Friedal-Crafts Alkylation Friedel-Craft alkylations are not restricted to alkyl halides and aluminum chloride Many other pairs of reagents that form a carbocation or species like carbocations, can be used. Examples: There are several important limitations of FC reactions. We will discuss these after the FC acylations

Friedal-Crafts Acylation The acyl group is basically half a ketone, it’s an alkyl bonded to a carbonyl A reaction which introduces an acyl group is an acylation There are two common acyl groups: The F.C. Acylation reaction is an effective means of introducing an acyl group onto an aromatic ring

Friedal-Crafts Acylation FC Acylations are often carried out using an aromatic ring and an acyl chloride in the presence of a lewis acid Examples The acyl chloride, aka acid chlorides, can be prepared by adding thionyl chloride, SOCl2 or phosphorus pentachloride, PCl5, to carboxylic acids Examples:

Friedal-Crafts Acylation FC acylations can also be carried out using carboxylic acid anhydrides as the electrophile Example In most FC acylations, the electrophile is the acylium ion Mechanism:

Limitations to FC Reactions As we said, there are several restrictions that limit the usefulness of FC alkylations and acylations 1) When the carbocation formed from the alkyl halide, alkene, or alcohol can rearrange to a more stable carbocation, it usually does so and the major product obtained from the reaction is usually the one from the more stable carbocation. Example:

Limitations to FC Reactions 2) Friedel-Crafts reactions usually give poor yields when powerful electron withdrawing groups are present on the aromatic ring or when the ring bears an –NH2, -NHR, or –NR2 group. This includes all meta directing groups plus the amine groups The deactivated rings are too electron deficient to undergo a FC reaction

Limitations to FC Reactions As for the amines, they become deactivating groups due to their reaction with the lewis acid. Example

Limitations to FC Reactions 3) Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations Examples 4) Polyalkylations often occur When putting activating groups on, in general, such as alkyl groups, the product after the first addition is more reactive than the starting material Example Polyacylations do not occur since the acyl group is a deactivating group

Synthetic Applications Applications of the Friedel-Crafts Acylation reaction followed by the Clemmensen Reduction Acylations have the advantage of not rearranging due to the resonance stabilized acylium ion. Since they do not rearrange, FC Acylations followed by reductions provide a better way for producing unbranched alkyl benzenes. Examples

Clemmenson Reduction A Clemmenson reduction is used to reduce the ketone adjacent to the aromatic ring down to the methylene group. Example The clemmenson reduction only reduces the carbonyl adjacent to the aromatic ring!

Reactions of the Side Chain of Alkyl Benzenes Compounds that have both aromatic and aliphatic groups are also called arenes Toluene, ethyl benzene, and isopropylbenzene are alkylbenzenes Phenylethene, commonly known as styrene, is an example of an alkenylbenzene The aliphatic portion of these compounds is commonly called the side chain

Benzylic Radicals and Cations The carbon directly attached to the aromatic ring in a alkyl benzene is the benzylic carbon Hydrogen abstraction from this carbon creates the benzyl radical Example Departure of a leaving group from the benzylic position produces a benzylic carbocation example

Benzylic Radicals and Cations Both radicals and cations are conjugated unsaturated systems and both are unusually stable They have approximately the same stability as the allylic radical and cation This can be show with resonance example

Halogenation of the Side Chain Reaction via benzylic Radicals Earlier we saw we could add bromine and chlorine to the actual ring with a lewis acid present This is done by creating an electrophile out of the bromine and/or chlorine We can add a bromine and/or chlorine to a benzylic carbon by promoting radical conditions and not using a lewis acid catalyst Examples: Mechanism:

Halogenation of the Side Chain Because of the stability of the benzylic radical, it forms faster than other radicals, therefore, halogenation at the benzylic site is always the major product Example:

Alkenyl Benzenes Alkenyl benzenes that have their double bonds conjugated with the benzene ring are more stable than those that do not: This is proven by the acid catalyzed dehydration reaction which is known to give the most stable alkene:

Alkenyl Benzenes Although the conjugated double bond is more stable, the same reactions are still seen: HBr addition in presence of peroxides: HBr addition with no peroxides:

Oxidation of the Side Chain Strong oxidizing agents oxidize the alkyl groups of alkyl benzenes to benzoic acid using potassium permanganate: Example The first step in this process is the abstraction of a benzylic hydrogen! (meaning there has to be one there!!)

Oxidation of the Side Chain In order for the oxidation to take place, there must be a benzylic hydrogen or the benzylic carbon must be unsaturated Examples:

Oxidation of the Benzene Ring Conversely, the benzene ring of alkylbenzenes can be oxidized to the carboxylic acid by using ozone followed by peroxide General reaction: Example: Note: Must watch for other functional groups

Synthetic Applications The substitution reaction of aromatic rings and the reactions of side chains of alkyl and alkenyl benzenes, when taken together, offer us a powerful set of reactions for organic synthesis with great regio-control Part of the skill is using these reactions is deciding the order in which reactions should be carried out

Examples Synthesize o-bromonitrobenzene from benzene. Synthesize p-nitrobenzoic acid from benzene

Use of Protecting/Blocking Groups Very powerful activating groups such as amino groups and hydroxyl groups cause the benzene ring to be so reactive, that multiple and/or undesirable reactions may take place These groups may also react with some of the reagents, such as HNO3 and H2SO4

Use of Protecting/Blocking Groups Amino groups must be protected by either adding acetyl chloride or acetic anhydride to convert the amino group to an acetamido group The acetamido group is only mildly activating and can easily be removed with dilute acid examples

Use of Protecting/Blocking Groups Groups such as the –SO3H, which are easy to put on and take off, are also used as blocking groups For example, say we wanted to make o-nitroaniline: Because of the size of the acetamido group, the ortho sites are sterically hindered, so if we add the nitro at this point, the major product would be para.

Use of Protecting/Blocking Groups Instead, we add a sulfuric acid group, which goes para, then the nitro which can only go ortho to the acetamido group The sulfuric acid group can the be removed along with the acetyl chloride group at the same time.

Orientation in Disubstituted Benzenes When two different groups are present on a benzene ring, the more powerful activating group generally determines the outcome of the reaction Example Because all ortho/para directors are more activating than meta directors, the ortho/para director determines the orientation of the incoming group Example:

Orientation in Disubstituted Benzenes Sterics also play an important role Substitution does not occur between meta substituents if another position is open and directed example

Allylic and Benzylic Halides in Nucleophilic Substitution Reactions Allylic and benzylc halides are classified in the same way as other halides, just add the allylic or benzylic Tertiary allylic and benzylic halides still only undergo Sn1 reactions due to the steric hinderance. The difference is with the primary allylic and benzylic halides. Because they would form a very stabilized carboncation, primary allylic and benzylic halides may undergo Sn1 reactions

The Birch Reduction Benzene can be reduced to 1,4-cyclohexadiene by using an alkali metal (Na, Li, or K) in a mixture of liquid ammonia and an alcohol Example: This reaction is the only example we will see that combines ionic and radical steps in the mechanism! Mechanism:

The Birch Reduction Substituent groups on the ring can affect the reaction as well One very important example of the Birch reduction includes: