CHEM 191 Module 4 Lecture 9: Aromatic Compounds, Nucleosides, Nucleotides

Aromatic compounds are cyclic and planar molecules with exceptional stability and properties differing from typical alkenes.
They contain rings with either 6 or 10 delocalized $π$ electrons.
These compounds have $sp^2$ hybridized orbitals.
Example: Benzene ( $C<em>6H</em>6$ ), a planar, cyclic compound.
The six $π$ electrons in benzene are delocalized and shared equally around the ring.
Benzene does not react like an alkene, and all carbon-carbon bonds are of the same length.
The cyclic six $π$ electron system in benzene is very stable.

Heterocyclic aromatic compounds contain heteroatoms (e.g., nitrogen) in the ring.
Many nitrogen-containing aromatic compounds play significant roles in living systems.
The reactivity and hydrogen bonding ability of these compounds are largely centered on the basic/nucleophilic nature of the nitrogens.

For a single ring system to be aromatic, it needs 6 $π$ electrons delocalized around the ring for extra stability.
If a compound can achieve this, it will due to the stability this provides.
In some heterocycles, the nitrogen lone pair of electrons is not required to achieve 6 $π$ delocalized electrons in the aromatic system.
When the nitrogen lone pair is not required for aromaticity, it is available for hydrogen bonding and has a $pK_b$ of 8.77. It can act as a hydrogen bond acceptor.
In other heterocycles, the nitrogen lone pair of electrons is required to achieve 6 $π$ delocalized electrons and is not available.
When the nitrogen lone pair is required for aromaticity, it is less available, and the $pK_b$ is 13.6. It can serve as a hydrogen bond donor.

The reactivity and hydrogen bonding ability of heterocycles are crucial for the structure and function of DNA and RNA.
DNA and RNA contain nucleobases, which are heterocycles derived from pyrimidine and purine.
Pyrimidine has 6 $π$ electrons, and both nitrogen's lone pairs sit outside the ring.
Purine has two fused rings, 10 $π$ electrons and three nitrogen's lone pairs sit outside the ring, with one nitrogen's lone pair in resonance in the aromatic ring.
DNA bases: adenine, guanine, cytosine, and thymine.
RNA: uracil replaces thymine.
All are planar and aromatic, and all have both hydrogen bond donors and acceptors.

Nucleosides are formed by combining a sugar unit (D-ribose or 2-deoxy-D-ribose) with a nucleobase (purine or pyrimidine derivative).
RNA contains D-ribose as the sugar, with β linkage stereochemistry.
DNA nucleosides contain D-deoxyribose as the sugar.
The linkage stereochemistry is again β (the sugar at C-1’ in the β-orientation, same side of ring as C-5’).
The aromatic nucleobase is planar, while the sugar is not planar.

Nucleic acids are polynucleotides formed by condensation reactions between the OH group of the phosphoric acid unit at the 5’ position on one nucleotide with the OH group at the 3’ position of another nucleotide.
This condensation reaction forms a phosphate diester.
RNA and DNA are identified/named according to the sequence/order of nucleobases.
The nucleic acid chain has a phosphate at C-5’ at one end and an OH group at C-3’ of the other end.
Like peptides, this gives directionality; writing ‘forwards’ or ‘backwards’ is a different sequence.
By convention, nucleic acids are written with the 5’ phosphate end on the left and the 3’ hydroxyl end on the right (e.g., 5’-AUACCUUGUCAG-3’).

In humans, DNA must be stable enough to remain intact throughout a cell’s lifetime.
RNA is synthesized from the DNA code as required for protein synthesis and is degraded once it has served its purpose (not as stable).
The 2’ OH group in RNA acts as an internal nucleophile, helping to break the phosphate linkage.
RNA hydrolyzes much faster than DNA (by a factor of ~ $3 x 10^9$ ).
This cannot take place in DNA as there is no OH at C-2 in the ribose.

The nitrogen lone pairs not ‘used up’ in aromatic resonance can react.
The N7 of guanine and adenine are nucleophilic and can react with the drug class ‘nitrogen mustards’; double alkylation reactions can occur.