BASES 1

basicity

tendency of the neutral amine to accept H+ (or equivalently how stable the conjugate acid is)

What are amines

weak bases

best way to determine basicity of amines

determine the pKa of their conjugate acid

higher pKa = stronger base

what does the ability of a base to accept a H+ depend on

How much electron density is on the nitrogen

How stable the protonated form is in that solvent

short range electron effects

intramolecular effects acting on the nitrogen itself

inductive effect of alkyl groups

alkyl groups push electron density towards N making N more able to accept H+ -> increases basicity

3>2>1 in ORGANIC SOLVENT

non polar organic solvents basicity trend and explanation

3>2>1

Solvation of ions is poor - molecule stabilizes itself

- Electron donating alkyl groups push electrons towards N

On a tertiary amine - 4 R groups

More R groups = more electrons on N = more basic

This is why tertiary amines are strongest bases in organic solvents

aqueous solvents basicity trend and explanation

Water stabilises charged species (RNH3+) using hydrogen bonds - gets protonated

Primary and secondary can form more H bonds - v stable - this is because they have N-H bonds which are H donors

Tertiary - bulky - fewer H bonds - less stable Protonated forms are not well solvated in water - less basic overall

how does resonance affect basicity

more resonance = less basic

how does aromaticity affect basicity

more aromaticity = less basicity

how does hybridisation affect basicity

basicity of N increases with increased p character

-> sp3>sp2>sp

how do substituents effect basicity

electron withdrawing -> decrease basicity

electron donating -> increase basicity

why are many amino drugs formulated as salts

salts dissolve more easily

- amines are very reactive, oxidised easily and not very stable

uncommon salts

some drugs are too insoluble for ordinary hydrochloride salts to work

in this case we may use large polar organic acids

these give greater overall polar surface area for hydration and solubility improves

oral administration of amines and their salts - after oral consumption

salt starts to dissolve we get an equilibrium with water

RNH3+Cl- + H2O -><- RNH2 + H3O+

where the equilibrium lies depends on the pH of the medium and pKa of the amine

oral administration of amines and their salts - stomach

low pH

- increase conc of H3O+ - shifts equilibrium to the left

- the solution pH is below base pKa - expect protonation of the amine

- dissolution maintains the amine salt

oral administration of amines and their salts - small intestine

- pH increases

- low conc of H3O+ -> equilibrium shifts to the right

- pH may rise over pKa

- drug exists in unionized form - RNH2 - this form can be absorbed

- this is why amines are absorbed in the small intestine and acids in the stomach

UNLESS PKA IS V HIGH