Common Reaction Types in Heterocyclic Chemistry 11Reaction with fl uoride anion, sometimes provided by TBAF (tetra-n-butylammonium fl uoride, n-Bu 4 NF) can alterna-
tively be utilised to remove silicon blocking substituents, by a different mechanism.
Ring substituents that release electrons favour electrophilic attack and substituents that withdraw electrons slow such
processes down. For example, alkyl groups are moderately electron-releasing by an inductive mechanism; alkoxy,
hydroxy and amino are more strongly electron-releasing via a mesomeric mechanism. Groups that disfavour elec-
trophilic attack are nitro, cyano, ester and ketone, via both inductive and mesomeric effects. Further, substituents
favour (or disfavour) electrophilic attack regioselectively. The electron-releasing groups selectively stabilise Wheland
intermediates (and the transition states that lead to them) in which the electrophile has been added ortho or para to
the substituent. The electron-withdrawing groups destabilise selectively the Wheland intermediates in which the elec-
trophile has been added ortho or para to the substituent and thus lead to substitution at the least-deactivated position,
the meta position. Under most circumstances, electrophilic substitutions are irreversible and the ratio of isomeric
products is determined by kinetic control.
In the context of the electrophilic substitution of heterocycles, one can view the heteroatom(s) as a directing group
within the ring, as opposed to substituents on the ring in benzene chemistry. The way in which the heteroatom
infl uences the facility and regioselectivity of electrophilic attack for the six- and fi ve-membered situations is dis-
cussed in detail on pages 34 and 78, respectively, and is summarised below for pyrrole and pyridine as prototypes.
The fi ve-membered heterocycles undergo electrophilic substitution easily; the six-membered heterocycles are only
readily substituted with electrophiles if there is an activating substituent on the ring, cf. phenol above.