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CHEM 109, Lecture 13 UCSC, Binder
L13-1
OUTLINE Nucleic Acids & Nucleotide Structure
- Heterocycles – Aromaticity & Basicity - H-Bonding
HW Online: nucleoside and nucleotide town! Heterocycles
Rules for Aromaticity
1. There must be a ring! 2. All atoms in ring are sp2 (conjugated/resonance) 3. Huckel Rule (4n+2)
Hybridization Review # of electron groups around atom
Hybridization
sp3
sp2
sp
Heterocycles Daniel Palleros 3
Heterocycles A heterocycle…
is an anchor, is a window, is a door,
is an ion, a cation and some more,
gets reduced, gets oxidized
is biology’s wild card.
Heterocycles are cyclic compounds in which one or more atoms of the ring are
heteroatoms: O, N, S, P, etc. They are present in many biologically important molecules
such as amino acids, nucleic acids and hormones. They are also indispensable
components of pharmaceuticals and therapeutic drugs. Caffeine, sildenafil (the active
ingredient in Viagra), acyclovir (an antiviral agent), clopidogrel (an antiplatelet agent)
and nicotine, they all have heterocyclic systems.
N
NN
N
CH3
CH3
H3C
O
O
HN
N
N
N
CH3O
O
S OO
N
N
CH3
HN
NN
N
O
H2NO
OH
caffeine sildenafil acyclovir
N
SCl
(S)-clopidogrel
H COOCH3
N
N
CH3
nicotine
Here we will discuss the chemistry of this important group of compounds beginning with
the simplest rings and continuing to more complex systems such as those present in
nucleic acids.
Heterocycles Daniel Palleros 3
Heterocycles A heterocycle…
is an anchor, is a window, is a door,
is an ion, a cation and some more,
gets reduced, gets oxidized
is biology’s wild card.
Heterocycles are cyclic compounds in which one or more atoms of the ring are
heteroatoms: O, N, S, P, etc. They are present in many biologically important molecules
such as amino acids, nucleic acids and hormones. They are also indispensable
components of pharmaceuticals and therapeutic drugs. Caffeine, sildenafil (the active
ingredient in Viagra), acyclovir (an antiviral agent), clopidogrel (an antiplatelet agent)
and nicotine, they all have heterocyclic systems.
N
NN
N
CH3
CH3
H3C
O
O
HN
N
N
N
CH3O
O
S OO
N
N
CH3
HN
NN
N
O
H2NO
OH
caffeine sildenafil acyclovir
N
SCl
(S)-clopidogrel
H COOCH3
N
N
CH3
nicotine
Here we will discuss the chemistry of this important group of compounds beginning with
the simplest rings and continuing to more complex systems such as those present in
nucleic acids.
CHEM 109, Lecture 13 UCSC, Binder
L13-2
Aromaticity & Basicity You do not need to memorize these pKa’s or heterocyclic ring structures-names,
but you should develop a general understanding of relative basicity, as determined by conjugate acid stability.
Pyrrole like this… not like this…
…vs. pyrrolidine
Heterocycles Daniel Palleros 11
N
NN
N
H
7
9N
NN
N
7
9
H
H9 H7 In solution, both tautomers exist in equilibrium in equal amounts. However, from a
biological standpoint, the tautomer with hydrogen on N9, called H9, is more important
than the one with the hydrogen on N7 (H7), because in biological systems N9 is usually
the most reactive nitrogen and gets attached to other molecules by losing its hydrogen. As
we will see in one of the HW problems, there are more tautomers of purine (a total of
four), but only H9 and H7 exist in significant amounts.
A summary of pKa values for all the heterocycles discussed so far is presented in the
table below.
Table of pKa values for selected heterocycles
N
HH
N
HH
N
H
N
H
N
N
H
N
H
N
N
H
N
NN
N
H
N
N
H
H
+
N
NN
N
H
H
+
Pyrrole Pyrrolidine
Imidazole
Pyridine Pyrimidine
Purine
17.5 0.4 11.3! 35
14.2 6.95
5.25 1.3
8.9 2.4
N
NN
N
H
8.9
N
H H
11.2
Piperidine
3. π−Excessive and π-Deficient Heterocycles
The presence of a nitrogen atom in an aromatic ring affects the electron density of the rest
of the atoms. The N atom can act as an electron donor or an electron withdrawing group.
If the nitrogen atom acts as an electron-donor, there is a net gain in electron density in the
ring and the ring is called π-excessive. If, on the other hand, the nitrogen atom acts as an
electron-withdrawing group, the aromatic ring loses electron density and is called π-
deficient.
NH
Heterocycles Daniel Palleros 5
nucleic acids and pharmaceuticals. We will pay special attention to the hybridization and
basicity of the nitrogen atoms.
2.1 Pyrrole
The nitrogen atom is sp2 hybridized. The N electron pair is in a p orbital, perpendicular to
the plane of the ring and overlapping with the other p orbitals. There are a total of 6 π
electrons, which is a Hückel number (remember Hückel numbers are 2; 6; 10, etc.) and,
therefore, the molecule is aromatic.
N H
sp2
N H
HH
H
H
6 pi electrons
nonbasic
You may wonder why the hybridization of the nitrogen atom is sp2 and not sp
3 as
expected for a nitrogen attached to three other atoms. The answer to this question can be
found in the fact that the sp2 hybridization makes the nitrogen coplanar with the rest of
the molecule and places the lone electron pair in a p orbital parallel to the other p orbitals.
This leads to orbital overlap, aromaticity, and further stability. If the nitrogen were sp3
hybridized, it wouldn’t be coplanar and the molecule couldn’t be aromatic.
N
HHH
H
H
sp3
nonaromatic
Heterocycles Daniel Palleros 5
nucleic acids and pharmaceuticals. We will pay special attention to the hybridization and
basicity of the nitrogen atoms.
2.1 Pyrrole
The nitrogen atom is sp2 hybridized. The N electron pair is in a p orbital, perpendicular to
the plane of the ring and overlapping with the other p orbitals. There are a total of 6 π
electrons, which is a Hückel number (remember Hückel numbers are 2; 6; 10, etc.) and,
therefore, the molecule is aromatic.
N H
sp2
N H
HH
H
H
6 pi electrons
nonbasic
You may wonder why the hybridization of the nitrogen atom is sp2 and not sp
3 as
expected for a nitrogen attached to three other atoms. The answer to this question can be
found in the fact that the sp2 hybridization makes the nitrogen coplanar with the rest of
the molecule and places the lone electron pair in a p orbital parallel to the other p orbitals.
This leads to orbital overlap, aromaticity, and further stability. If the nitrogen were sp3
hybridized, it wouldn’t be coplanar and the molecule couldn’t be aromatic.
N
HHH
H
H
sp3
nonaromatic
NH
CHEM 109, Lecture 13 UCSC, Binder
L13-3
Imidazole
Pyridine
Pyrimidine Purine
Heterocycles Daniel Palleros 7
The pKa of pyrrole (the dissociation of the H on the nitrogen) is 17.5. Compared to the
pKa of pyrrolidine (≈ 35), it is about 20 orders of magnitude lower.
Pyrrolidine
N
H
pKa ! 35
sp3
+ H2O
N+ H3O+
sp3
The higher acidity of pyrrole is due to the sp
2 hybridization of its N; sp
2 hybridized atoms
have more s-character, their electrons are in lower energy levels than in sp3 hybridized
atoms and, thus, yield more stable anions.
2.2 Imidazole The imidazole ring is aromatic. Both N atoms are sp
2 hybridized. The N attached to H
(N1) has the electron pair in a p orbital, perpendicular to the plane of the ring. This
electron pair forms part of the six-electron aromatic cloud and, like in the case of pyrrole,
is not available for protonation. The double-bonded nitrogen (N3), on the other hand, has
the electron pair in an sp2 hybrid orbital which lies outside the ring and, thus, does not
form part of the aromatic system. This electron pair is available for protonation.
NN H
HH
H
NN H
6 pi electrons
sp2
inside the ring; aromaticnot available for protonation(nonbasic N)
outside the ringavailable for protonation(basic N)
1
2
3
45
not available for protonation
available for protonation
It is worth mentioning that once the basic N gets protonated, both N atoms become
indistinguishable because of resonance:
+H3N CO2-
Histidine
NHN NH3+N
NHHistamine
OPh
PhNMe2
BenadrylDiphenylhydramine-HCl
(an anti-histamine)
CO2
H
Cl
N
Heterocycles Daniel Palleros 9
ring in an sp2 hybrid orbital and is available for protonation, making pyridine a basic
heterocycle. The pKa of the conjugate acid of pyridine is 5.25.
N
pyridine
N
outside the ringavailable for protonation(basic N)
N
H
pKa = 5.25
pyridinium ion
Pyridine, like most aromatic amines, is less basic than aliphatic amines of the same size.
Of particular interest is the comparison with the aliphatic amine piperidine because they
both are six-membered heterocycles. The pKa of the ammonium salt of piperidine
(piperidinium ion) is 11.2, some six orders of magnitude less acidic than the ammonium
salt of pyridine (pKa = 5.25), making piperidine about six order of magnitude more basic
than pyridine.
N
H H
pKa = 11.2
piperidinium ion
N
H
piperidine
The decreased basicity of pyridine in relation to piperidine is a result of the difference in
the hybridization of the N atoms. The N atom in pyridine is sp2 hybridized while in
piperidine it is sp3 hybridized. The sp
2-hybridized N atom of pyridine has more s-
character and stabilizes the electron pair better. The stabilization of the electron pair
decreases its basicity.
2.4 Pyrimidine Pyrimidine is also an aromatic amine. It has a total of 6 π electrons. Both N atoms are
equivalent and sp2 hybridized. Both electron pairs lie outside the aromatic ring in sp
2
hybrid orbitals. Both N are slightly basic. Pyrimidine is less basic than pyridine because
of the inductive, electron-withdrawing effect of the second N atom. The pKa of the
conjugate acid of pyrimidine is 1.3 (compare to the pKa of the conjugate acid of pyridine,
5.25).
N
N
H
N
N
pKa = 1.3
Note also that pyrimidine is about six orders of magnitude less basic than imidazole (pKa
of conj. acid 6.95).
N
NN
NN
NH
CHEM 109, Lecture 13 UCSC, Binder
L13-4
Nucleobases
Nucleoside = (Nucleobase + Ribose) - H2O
Nucleotide = (Nucleobase + Ribose + Phosphate) – 2 H2O Hydrogen Bonding – many options for pairing; only one is naturally occurring per pair H-bond donor (has the H) = d; H-bond acceptor (has the lone pair) = a
G-C Base Pair A-T Base Pair
N
NNH
NNH2
NH
NNH
NO
NH2
N
NH
NH2
O
NH
NH
O
O
R
Adenine
Guanine
Cytosine
Thymine, R = CH3Uracil, R = H
Heterocycles Daniel Palleros 20
only the nitrogen atoms whose electron pairs are outside the ring can act as H-bond
acceptors. If the electron pair is inside the ring, forming part of the aromatic π system, is
not available to accept H-bonds. In the structures below the nucleobases are shown as
they appear in nucleic acids, bound to the rest of the nucleic acid through one of the N
atoms (shown as a squiggly bond). Their H-bond donor (d) and acceptor (a) capabilities
are indicated.
N
NN
N
NH2
N
NN
N
O
NH2
N
N
NH2
O
d
a
a
a a
a
a
d
d
d
a
a
Adenine Guanine Cytosine
H
N
N
O
O
H3C
N
N
O
O
Thymine Uracil
a
a
a
d
a
H H
d
You may wonder why the NH2 group in adenine, guanine and cytosine, with a free
electron pair on the nitrogen atom, acts exclusively as an H-bond donor and not as an H-
bond acceptor. The answer can be found in the resonance forms of these nucleobases
(shown below for cytosine). In one of the resonance forms, there is positive charge on the
N atom of the NH2 group making it an unlikely acceptor of H-bonds.
N
NH
NH2
O
N
NH
NH2
O
etc.
unable to accept H-bonds
Once the nucleobase is forming part of a nucleic acid molecule, not all of the atoms that
can form H-bonds actually do. Only those indicated by stars () and moons () form
important H-bonds in DNA and RNA. In the figure below, stars indicate H-bond donors
and moons, acceptors.