a heterocycle… heterocycles - cpb-us-e1.wpmucdn.com · basicity of the nitrogen atoms. 2.1...

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 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.


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


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


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


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


L13-3

Imidazole

Pyridine

Pyrimidine Purine


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


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


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


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.

a heterocycle… heterocycles - cpb-us-e1.wpmucdn.com · basicity of the nitrogen atoms. 2.1...

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