Electrophilic aromatic substitution E V Blackburn 2008 Substitution

Electrophilic aromatic substitution © E. V. Blackburn, 2008

Substitution? The characteristic reactions of benzene involve substitution in which the resonance stabilized ring system is maintained: © E. V. Blackburn, 2008

Reactivity - an electron source, benzene reacts with electron deficient reagents - electrophilic reagents. © E. V. Blackburn, 2008

Electrophilic aromatic substitution 1. Nitration Ar. H + HNO 3/H 2 SO 4 Ar. NO 2 + H 2 O 2. Sulfonation Ar. H + H 2 SO 4/SO 3 Ar. SO 3 H + H 2 O 3. Halogenation Ar. H + X 2/Fe. X 3 Ar. X + HX © E. V. Blackburn, 2008

Friedel - Crafts reactions 4. Friedel - Crafts alkylation Ar. H + RCl/Al. Cl 3 Ar. R + HCl 5. Friedel - Crafts acylation Ar. H + RCOCl/Al. Cl 3 Ar. COR + HCl © E. V. Blackburn, 2008

Substituent effects 34% 63% 3% Toluene is more reactive than benzene. . . © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

Substituent effects 2% 7% 91% Nitrobenzene undergoes substitution at a slower rate than does benzene. It yields mainly the meta isomer. © E. V. Blackburn, 2008

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. ” © E. V. Blackburn, 2008

Activating, o, p directors All activating groups are o, p directors. strongly activating -OH -NH 2 -NHR -NR 2 moderately activating -OR -NHCOR weakly activating -aryl -alkyl © E. V. Blackburn, 2008

Deactivating, m directors All m directors are deactivating. -NO 2 -SO 3 H -CO 2 R -CONH 2 -CHO -COR -CN + -NH 3 + -NR 3 © E. V. Blackburn, 2008

Deactivating, o, p directors -F, -Cl, -Br, -I © E. V. Blackburn, 2008

Orientation in disubstituted benzenes Here the two directing effects are additive. © E. V. Blackburn, 2008

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. . © E. V. Blackburn, 2008

Orientation in disubstituted benzenes • Strongly activating groups exercise a far greater influence than weakly activating and all deactivating groups. © E. V. Blackburn, 2008

Orientation in disubstituted benzenes • If there is not a great difference between the directive power of the two groups, a mixture results: 58% 42% © E. V. Blackburn, 2008

Orientation in disubstituted benzenes • Usually no substitution occurs between two meta substituents due to steric hindrance: 37% 1% 62%. . . nitration © E. V. Blackburn, 2008

Synthesis of mbromonitrobenzene 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. © E. V. Blackburn, 2008

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 three nitrobenzoic acids: © E. V. Blackburn, 2008

The nitrobenzoic acids m-nitrobenzoic acid © E. V. Blackburn, 2008

The nitrobenzoic acids o-nitrobenzoic acid p-nitrobenzoic acid © E. V. Blackburn, 2008

Nitration HONO 2 + 2 H 2 SO 4 H 3 O+ + 2 HSO 4 - + NO 2+ nitronium ion - a Lewis acid © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

Sulfonation © E. V. Blackburn, 2008

Halogenation © E. V. Blackburn, 2008

Friedel - Crafts alkylation © E. V. Blackburn, 2008

An electrophilic carbocation? © E. V. Blackburn, 2008

An electrophilic carbocation? ~33% ~67% © E. V. Blackburn, 2008

An electrophilic carbocation? When RX is primary, a simple carbocation does not form. The electrophile is a complex: © E. V. Blackburn, 2008

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 -NH 2, -NHR or -NR 2 do not undergo Friedel - Crafts substitution. Why? © E. V. Blackburn, 2008

Friedel - Crafts acylation - the reaction © E. V. Blackburn, 2008

Friedel - Crafts acylation acylium ion © E. V. Blackburn, 2008

Limitations © E. V. Blackburn, 2008

The mechanism slow, rate determining step fast Evidence - there is no significant deuterium isotope effect. © E. V. Blackburn, 2008

Isotope effects A difference in rate due to a difference in the isotope present in the reaction system is called an isotope effect. © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

Evidence for the E 2 mechanism - a large isotope effect © E. V.

The mechanism slow, rate determining step fast Evidence - there is no significant deuterium isotope effect. © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

Carbocation stability electron donation stabilizes the carbocation electron withdrawal destabilizes the carbocation © E. V. Blackburn, 2008

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. © E. V. Blackburn, 2008

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

NO 2 - a m director ortho meta para © E. V. Blackburn, 2008

NO 2 - a m director para © E. V. Blackburn, 2008

NH 2 - an o/p director? ? © E. V. Blackburn, 2008

Halogen - a deactivating group Deactivation results from electron withdrawal: © E. V. Blackburn,

Halogen - an o/p directing group o/p directors are electron donating. How can a halogen substituent donate electrons? © E. V. Blackburn, 2008