80 Pyrroles
N-Deprotonation and N-metallated pyrroles
TheN-hydrogen of pyrrole can be quantitatively removed with strong bases giving a pyrryl anion. The pKa for this
process is 17.5, which, contrasted with the value for pyrrolidine of ~44, shows pyrrole to be appreciably more acidic
than an amine. Pyrryl anions are still aromatic species, with two lone pairs associated with the nitrogen, one orthogo-
nal to the ring and participating in the aromatic sextet, and the second in the plane of the ring and available for reaction
with electrophiles without disrupting the aromaticity, thus allowing N-substitution.
N-Substitution can also be achieved via small concentrations of the pyrryl anion generated by weaker bases, such
as 4-dimethylaminopyridine (DMAP). Syntheses of N-Boc-pyrrole and N-TIPS-pyrrole illustrate the synthetically
important electrophilic trapping of pyrryl anions. N-Alkylation similarly employs alkyl halides with a pyrryl anion.
N-Arylation of pyrroles can be achieved with the assistance of a catalyst – copper has been used most frequently.
C-Metallated pyrroles
N-Substituted pyrroles can be deprotonated with strong bases, selectively at an -position, producing organometallic
intermediates that react even with weak electrophiles, for example aldehydes and ketones, giving -substituted prod-
ucts. If appropriately chosen, the N-(blocking) substituent can then be removed to give N-hydrogen products. Some
N-substituents also facilitate the -metallation by induction and/or coordination to the lithium.