Basicity Unlike most
amines, indole is not
basic: just like
pyrrole, the aromatic character of the ring means that the
lone pair of electrons on the nitrogen atom is not available for protonation. Strong acids such as
hydrochloric acid can, however,
protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the
enamine-like reactivity of the portion of the molecule located outside of the
benzene ring. The protonated form has a
pKa of −3.6. The sensitivity of many indolic compounds (e.g.,
tryptamines) under acidic conditions is caused by this protonation.
Electrophilic substitution The most reactive position on indole for
electrophilic aromatic substitution is C3, which is 1013 times more reactive than
benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan.
Vilsmeier–Haack formylation of indole will take place at room temperature exclusively at C3. : Since the pyrrolic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring generally takes place only after N1, C2, and C3 are substituted. A noteworthy exception occurs when electrophilic substitution is carried out in conditions sufficiently acidic to exhaustively protonate C3. In this case, C5 is the most common site of electrophilic attack.
Gramine, a useful synthetic intermediate, is produced via a
Mannich reaction of indole with
dimethylamine and
formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan. :
N–H acidity and organometallic indole anion complexes The N–H center has a p
Ka of 21 in
DMSO, so that very
strong bases such as
sodium hydride or
n-butyl lithium and water-free conditions are required for complete
deprotonation. The resulting
organometalic derivatives can react in two ways. The more
ionic salts such as the
sodium or
potassium compounds tend to react with
electrophiles at nitrogen-1, whereas the more
covalent magnesium compounds (
indole Grignard reagents) and (especially)
zinc complexes tend to react at carbon 3 (see figure below). In analogous fashion,
polar aprotic
solvents such as
DMF and
DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as
toluene favour C3 attack. :
Carbon acidity and C2 lithiation After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction of
N-protected indoles with
butyl lithium or
lithium diisopropylamide results in lithiation exclusively at the C2 position. This strong nucleophile can then be used as such with other electrophiles. : Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole, as did Katritzky.
Oxidation of indole Due to the electron-rich nature of indole, it is easily
oxidized. Simple oxidants such as
N-bromosuccinimide will selectively oxidize indole
1 to
oxindole (
4 and
5). :
Cycloadditions of indole Only the C2–C3
pi bond of indole is capable of
cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa
et al. have developed this
Diels-Alder reaction to form advanced
strychnine intermediates. In this case, the 2-aminofuran is the
diene, whereas the indole is the
dienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions. : Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented. One example is the
Pictet-Spengler reaction between
tryptophan derivatives and
aldehydes, which produces a mixture of
diastereomers, leading to reduced
yield of the desired product.
Hydrogenation Indoles are susceptible to hydrogenation of the imine subunit to give
indolines. ==See also==