Question of regioselectivity in acylation of thiophene

In the above reaction, I understand that $\ce{AlCl3}$ is acting as a Lewis acid to generate an acylium ion, which is a strong electrophile.

Would this electrophile attack at carbon 2 or 3?

I think it would attack at C-3, as the resulting positive charge at C-2 would be stabilized by resonance using the lone pair on sulfur.


1 Answer 1


Friedel-Crafts acylation reactions are well documented on thiophenes, and go with high regioselectivity for the 2-position (or 5-position, which is equivalent in the case of unsubstituted thiophene) rather than the 3-position (or 4-position). Joule and Mills' Heterocyclic Chemistry (5th ed., p 327) gives the following two examples:

Formylation and acetylation of thiophene with Lewis acids

The regioselectivity can be explained through consideration of the intermediates involved when the thiophene attacks the electrophilic carbenium species.

Intermediates in electrophilic substitution of azoles

One is able to see that the intermediate species produced by attack at the 2-position is able to be drawn in three resonance forms, whilst the intermediate produced by attack at the 3-position is only able to be drawn in two resonance forms. As a general rule of thumb, the more resonance forms one can draw, the more 'stable' and intermediate, and hence the energy required to access it is lower, hence in the case of thiophene we get preferential electrophilic substitution at the 2/5-position.

(When looking at the intermediates, we can also consider the type of conjugation involved. Attack at the 2-position yields a linearly conjugated intermediate, which is lower in energy than the cross conjugated intermediate from attack at the 3-position).


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