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electrons does each molecule have? Where are the most accessible
electrons in each? Display the electrostatic potential map for pyridine
and compare it to the corresponding map for benzene. Would you expect
electrophilic attack on pyridine to occur analogously to that in benzene?
If so, should pyridine be more or less susceptible to aromatic
substitution than benzene? If not, where would you expect electrophilic
attack to occur? Explain.
214 Chapter 15 Heterocycles
Thiophene undergoes electrophilic substitution resulting in two possible
isomers, e.g., for nitration.
According to Frontier Molecular Orbital (FMO) theory, thiophene's most
reactive site can be identified by examining the shape of its highest-
occupied molecular orbital (HOMO). Which atoms contribute to thiophene's
HOMO? Which atom(s) contributes the most? Which nitration product should
Another way to assess thiophene's reactivity is to compare the
intermediate ions formed by addition of N02+. Examine the structures,
charge distributions and electrostatic potential maps of
thiophene+nitronium at C2 and thiophene+nitronium at C3. Draw all of the
resonance contributors needed to describe these structures. Which, if
either, better delocalizes the positive charge? Compare the energies of
the two intermediates. Which product should form preferentially if the
reaction is under kinetic control? Are these results consistent with FMO
Does the fact that thiophene reacts similarly to benzene mean that it is
aromatic? One way to tell is to calculate first and second hydrogenation
energies of thiophene, leading to dihydrothiophene and
tetrahydrothiophene, respectively. (The energy of hydrogen is provided at
Whereas the initial hydrogenation both breaks a % bond, as well as
destroys any aromatic stabilization, the second hydrogenation only breaks
the % bond. Is this difference large as in benzene (see discussion at
right), or is it much smaller or neglible? Is thiophene aromatic?
HOMO of thiophene reveals the
most likely site for electrophilic attack.
Electrostatic potential map for thiophene+nitronium at C2 shows most
positively-charged regions (in blue) and less positively-charged regions
E(H2) =-1.1230 au
Hydrogenation of benzene to 1,3-cyclohexadiene is endothermic by .011 au
(6 kcal/mol), while hydrogenation of 1,3-cyclohexadiene to cyclohexene is
exothermic by .041 au (26 kcal/mol). The difference, .051 au (32 kcal/
mol), is one measure of the aromaticity of benzene.
Chapter 15 Heterocycles 215
HOMO of indole reveals the ost likely sites of lectrophilic attack.
Electrophilic Substitution of Indoles
The indole ring system appears in many naturally-occuring substances
including the amino acid tryptophan and the drug reserpine.
In addition to electrophilic attack on the pyrrole ring in indole, there
is the possibility for additions to the fused benzene ring. First examine
the highest-occupied molecular orbital (HOMO) of indole. Which atoms
contribute the most? What should be the favored position for
electrophilic attack? Next, compare the energies of the various
protonated forms of indole (C protonated only). These serve as models for
adducts formed upon electrophilic addition. Which carbon on the pyrrole
ring (C2 or C3) is favored for protonation? Is this the same as the
preference in pyrrole itself (see Chapter 15, Problem 2)? If not, try to
explain why not. Which of the carbons on the benzene ring is most
susceptible to protonation? Rationalize your result based on what you
know about the reactivity of substituted benzenes toward electrophiles.
Are any of the benzene carbons as reactive as the most reactive pyrrole
216 Chapter 15 Heterocycles
Tautomers of Hydroxypyridine and Hydroxypyrimidine
Many heterocyclic compounds exist as mixtures of tautomers. For example,
2-hydroxypyridine exists in equilibrium with 2-pyridone.
The equilibrium abundances of the tautomers is influenced by substituents
and solvent among other factors.
Examine the geometry and atomic charges of 2-pyridone to see if it is
localized as indicated in the drawing above, or delocalized (as in 2-
hydroxypyridine). If you need to, write alternative Lewis structures to
that provided above. How many n electrons does 2-pyridone possess? Is 2-
Compare energies of 2-hydroxypyridine and 2-pyridone to see which
tautomer is preferred. Use equation (1) to calculate the equilibrium
concentrations of the two at room temperature.
Repeat your analysis for tautomeric equilibria between 4-hydroxypyridine