Lecture 8. Friedel-Crafts reaction: Mechanism: Carbocation is the reactive electrophile. AlCl4- picks up a proton.

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1 New Section 3 Page 1 2:37 PM Friedel-Crafts reaction: Mechanism: Carbocation is the reactive electrophile. AlCl4- picks up a proton. Limitations come from the mechanism: Carbocationic intermediates prone to rearrangement to more stable carbocations. In general, primary carbocations do not form. Before they form coordination of the Lewis Acid induces rearrangement, or this complex with a Lewis acid acts as a electrophile in a reaction with the aromatic ring. Secondary and tertiary carbocations are formed as intermediates.

2 New Section 3 Page 2 2:42 PM Other methods for formation of carbocations can also be used: Friedel-Crafts acylation: Mechanism: Acyl cation stabilized by resonance. Does not rearrange. Reduction of the products of acylation: Reduction gives alkyl arenes. We can use the combination of acylation and reduction to acomplishe alkylations that would be impossible using Friedel-Crafts alkylation Friedel-Crafts acylation + reduction = friedel-crafts alkylation

3 New Section 3 Page 3 2:47 PM Wolf-Kishner reduction Acyl cation precursors: Acyl cholride synthesis: Sulfonyl chloride Acid anhydrides can also be used in these reactions as precursors to acyl cations

4 New Section 3 Page 4 2:50 PM Reactivity and selectivity of substituted arenes. The slow step of the reaction is the formation of the arenium cation. This step is slow because it has high activation barrier. The barrier is high because TS is high in energy. We also know from Hammond postulate that this transition state looks like the arenium cation (TS is closer in energy to the arenium cation than it is to the starting materials. So, any substituent that makes the cation intermediate more stable, will make the transition state more stable, and will make the activation barrier lower and would make the reaction faster. Opposite is also true. If substituent makes the arenium cation less stable it will make the reaction go slower. Substituents can affect the stability of the arenium cation through an inductive and/or a resonance effect. Inductive effect. Redistribution of electron density in a molecule according to the electronegativities of the atoms involved by polarization of sigma bonds. Fluorine is more electronegative than carbon and bonds are polarized so that F is partially negatively charged and carbon is partially positively charged. When CF3 group is part of a bigger molecule this polarization of CF bonds is propagated through sigma bonds because now the C-C bond is polarized in a way that moves electrons toward more electronegative fluorine atoms. In this case we say that CF3 group is inductively electronwithdrawing. It takes electrons away from the rest of the molecule through an inductive effect. Inductive effects depend on how electron withdrawing the atoms are. More electron withdrawing they are stronger the effect. Depends on how many of electronwithdrawing atome there are (CF3 is bettor electron withdrawing group than CF2H.) finally it depends on the distance. How many bonds away the group is.

5 New Section 3 Page 5 3:00 PM Resonance effect is when electron distribution in a molecule is effected by the existence of additional resonance structures. Notice that in this case we are moving pi electrons and nonbonding electrons around the molecule. In this case, methoxy group through resonance gives two electrons to the cation. We say methoxy group is a donating group because of it's resonance effect. Notice that methoxy group also exerts an inductive effect. Oxygen is more electronegative than the carbon and It will take electrons away from neighboring carbons through an inductive effect. This effect is smaller than the resonance effect so: However: In the second case there is no resonance effect but there is an electron-withdrawing inductive effect. Overall, in general for N, O, S, and P resonance effect is stronger than inductive effect and for F, Cl, Br, and I it is weaker than the resonance effect. Groups can also be electron-withdrawing through the resonance. Examples: Electrons are relocated from a carbon atom to a more electronegative heteroatom through resonance.

6 New Section 3 Page 6 3:18 PM If group that can be electron-withdrawing through resonance is next to the carbocation that is really bad. There is an inductive electron withdrawing effect and a resonance effect. Resonance effect in this case is harder to see as there are no electrons that we can move away from the cation. The way to think this about this effect it is that the p orbital of the cation goes up in energy because it overlaps (is in conjugation) with the pi orbitals of the electron withdrawing group (in this case pi orbitals of the C=O bond) Cation destabilized through both the inductive and resonance effect. This cation is also destabilized through resonance. There is an overlap of the p orbital of the cation with the conjugated pi system that goes over atoms 2-5. In the first one there is no direct communication between the pi orbitals of the carbonyl and p orbital of the cation. There is only an inductive effect, which is small because of the distance. In the second case, there is a direct interaction between the p orbital of the cation and the pi conjugated system of the rest of the molecule. If you want to check if you are ok with inductive and resonance effects try the problem set I provided. Effect of an electron donating groups on the electrophilic aromatic substitution: Nitration of toluene gives this mixture of products. Effect on substitution in ortho position: Methyl group stabilizes the intermediate by hyperconjugation (shown below). Another way to describe the same thing is that the methyl group gives tertiary carbocation that is more stable than the usual secondary we get in substitution of benzene.

7 New Section 3 Page 7 9:42 PM Effect of substitution in meta position: In this case there is no resonance structure in which cation is right next to the substituent. Substituent and the cation are never in conjugation. So there is no potential for resonance effects (that includes hyperconjugation in which sigma electrons are shared with the pi system). However, methyl group is still donating by induction. It is not a strong effect, but it is an effect.

Electrophilic Aromatic Substitution Reactions

Electrophilic Aromatic Substitution Reactions, Course Notes Archive, 1 Electrophilic Aromatic Substitution Reactions An organic reaction in which an electrophile substitutes a hydrogen atom in an aromatic