Mesomeric & Inductive Effects and Hyperconjugation

Properties and Analysis of Materials used in Medicines

Mesomeric Effect

resonance driven electron delocalisation strictly through pi systems

• requires a lone pair or pi bond directly adjacent to the aromatic ring system

Mesomeric Donors

push full negative charges into ortho and para positions

• usually a lone pair of electrons is pushed into the ring

Mesomeric Donor Examples

-NH2, -OH, -X

Mesomeric Withdrawers

delocalise electron density out of the ring selectively at ortho and para positions

Mesomeric Withdrawer Examples

-NO2, -C=O, -C☰N

Tetracaine

boasts a significantly longer duration of action compared to unshielded esters

• mesomeric donor effect of amino group reduces positivity on the ester carbonyl cation

• resistant to hydrolysis

Inductive Effect

driven purely by differences in electro negativity across sigma bonds

• operates across the whole ring structure, but fades rapidly with distance from the substitution site

Inductive Withdrawers

highly electronegative atoms that drop overall electron density

Inductive Withdrawer Examples

-F, -Cl, -O, -N

Halogens

have strong inductive withdrawer effects but weak mesomeric donor effects

• e.g. in fluorobenzene, fluorine takes electrons into itself because it is highly electronegative, but still partitions electrons through the mesomeric effect at ortho and para positions

Unsubstituted Benzene Rings

high density targets for CYP450 enzyme parahydroxylation oxidation

Haloperidol

integrates a parafluorobenzene ring structure

• CYP450 cannot oxidise the deactivated cloud

• fluorine gives it a much longer half life by inhibiting parahydroxylation

Hyperconjugation

applies exclusively to attached alkyl substituents

• spilling of electrons from filled C-H sigma binds directly into an empty or partially filled electron cloud

Key Hyperconjugation Principles

1. orbital geometry requirement - sp3 overlaps with pi orbital and donates electrons into the ring

2. no bond resistance - weak pi donation without lone pairs through delocalisation of electron density

3. stabilising effect - increases ring pi electron density and stabilises cationic intermediates and transition states

4. pharmacy relevance - present in lidocaine

Alkyl Groups

increase electron density on rings, though they have no active lone pairs and 0 electronegativity difference to the ring

• methyl group is the strongest enrichment