Electrophilic aromatic substitution

Substitution? The characteristic reactions of benzene involve substitution in which the resonance stabilized ring system is maintained:

Reactivity - an electron source, benzene reacts with electron deficient reagents - electrophilic reagents.

Electrophilic aromatic substitution 1. Nitration ArH + HNO3/H2SO4 ArNO2 + H2O 2. Sulfonation ArH + H2SO4/SO3 ArSO3H + H2O 3. Halogenation ArH + X2/FeX3 ArX + HX

Friedel - Crafts reactions 4. Friedel - Crafts alkylation ArH + RCl/AlCl3 ArR + HCl 5. Friedel - Crafts acylation ArH + RCOCl/AlCl3 ArCOR + HCl

Substituent effects 34% 63% 3% Toluene is more reactive than benzene.....

Reactivity How is “reactivity” determined in the lab? Compare the time required for reactions to occur under identical conditions. Compare the severity of reaction conditions. Make a quantitative comparison under identical reaction conditions.

Substituent effects In some way, the methyl group makes the ring more reactive than that of the unsubstituted benzene molecule. It also directs the attacking reagent to the ortho and para positions on the ring.

Substituent effects 2% 7% 91% Nitrobenzene undergoes substitution at a slower rate than does benzene. It yields mainly the meta isomer.

Substituent effects A group which makes the ring more reactive than that of benzene is called an activating group. A group which makes the ring less reactive than benzene is called a deactivating group. A group which leads to the predominant formation of ortho and para isomers is called an “ortho - para directing group.” A group which leads to the predominant formation of the meta isomer is called a “meta directing group.”

Activating, o,p directors All activating groups are o,p directors. strongly activating -OH -NH2 -NHR -NR2 moderately activating -OR -NHCOR weakly activating -aryl -alkyl

Deactivating, m directors All m directors are deactivating. -NO2 -SO3H -CO2H -CO2R -CONH2 -CHO -COR -CN + + -NH3 -NR3

Deactivating, o, p directors -F, -Cl, -Br, -I

Orientation in disubstituted benzenes Here the two directing effects are additive.

Orientation in disubstituted benzenes When two substituants exert opposing directional effects, it is not always easy to predict the products which will form. However, certain generalizations can be made....

Orientation in disubstituted benzenes Strongly activating groups exercise a far greater influence than weakly activating and all deactivating groups.

Orientation in disubstituted benzenes If there is not a great difference between the directive power of the two groups, a mixture results: 58% 42%

Orientation in disubstituted benzenes Usually no substitution occurs between two meta substituents due to steric hindrance: 37% 1% 62% ......nitration

Synthesis of m-bromonitrobenzene In order to plan a synthesis, we must consider the order in which the substituents are introduced....... If, however, we brominate and then nitrate, the o and p isomers will be formed.

Orientation and synthesis If a synthesis involves the conversion of a substituants into another, we must decide exactly when to do the conversion. Let’s look at converting a methyl group into a carboxylic acid: Now let’s see how we can make the three nitrobenzoic acids:

The nitrobenzoic acids m-nitrobenzoic acid bp 225oC bp 238oC

The nitrobenzoic acids o-nitrobenzoic acid p-nitrobenzoic acid

Nitration HONO2 + 2H2SO4 H3O+ + 2HSO4- + NO2+ nitronium ion - a Lewis acid

The structure of the intermediate carbocation The positive charge is not localized on any one carbon atom. It is delocalized over the ring but is particularly strong on the carbons ortho and para to the nitro bearing carbon.

Sulfonation

Halogenation

Friedel - Crafts alkylation

An electrophilic carbocation?

An electrophilic carbocation?

An electrophilic carbocation? ~33% ~67%

An electrophilic carbocation? When RX is primary, a simple carbocation does not form. The electrophile is a complex:

Limitations Aromatic rings less reactive than the halobenzenes do not undergo Friedel - Crafts reactions. A polysubstitution is possible - the reaction introduces an activating group! Aromatic compounds bearing -NH2, -NHR or -NR2 do not undergo Friedel - Crafts substitution. Why?

Friedel - Crafts acylation - the reaction

Friedel - Crafts acylation acylium ion

Limitations

The mechanism slow, rate determining step fast Evidence - there is no significant deuterium isotope effect.

Isotope effects A difference in rate due to a difference in the isotope present in the reaction system is called an isotope effect.

Isotope effects If an atom is less strongly bonded in the transition state than in the starting material, the reaction involving the heavier isotope will proceed more slowly. The isotopes of hydrogen have the greatest mass differences. Deuterium has twice and tritium three times the mass of protium. Therefore deuterium and tritium isotope effects are the largest and easiest to determine.

Primary isotope effects These effects are due to breaking the bond to the isotope. Thus the reaction with protium is 5 to 8 times faster than the reaction with deuterium.

Evidence for the E2 mechanism - a large isotope effect

The mechanism slow, rate determining step fast Evidence - there is no significant deuterium isotope effect.

The reactivity of aromatic rings The transition state for the rate determining step: Factors which stabilize carbocations by dispersal of the positive charge will stabilize the transition state which resembles a carbocation; it is a nascent carbocation.

Carbocation stability electron donation stabilizes the carbocation electron withdrawal destabilizes the carbocation

Orientation An activating group activates all positions on the ring but directs the attacking reagent to the ortho and para positions because it makes these positions more reactive than the meta position. A deactivating group deactivates all positions on the ring but deactivates the ortho and para positions more than the meta position. Why? Examine the transition state for the rate determining step for ortho, meta and para attack.

CH3 - an o/p director ortho attack 3° meta attack para attack 3°

NO2 - a m director ortho meta para

NO2 - a m director para

NH2 - an o/p director??

Halogen - a deactivating group Deactivation results from electron withdrawal:

Halogen - an o/p directing group o/p directors are electron donating. How can a halogen substituent donate electrons?

Halogen - an o/p directing group