pKa and ionisation

• what does ionisation refer to?

  to development of charge on molecules (or functional groups) as a result of an imbalance in number of protons and electrons (exchange in protons)
• in drugs what does ionisation generally result from?

  the reversible loss or gain of protons (H+)
• what does the ionisation of a molecule have a direct impact on?

  • solubility
  • permeability
  • excretion
  • distribution
  • on and off target protein binding
  • lipophilicity
• what is Ka and pKa

  Ka is the equilibrium constant for the dissociation of an acid and pKa is the dissociation constant of an acid.

  • p function is identical to pH

  
• why is H+ often termed as H3O+?

  when an acid dissociates in water (losing proton), the free proton won't be completely free but will be involved in the hydrogen bonding network of the water + start to associate with the lone pairs in the water and interact with the oxygen atoms

  
• under standard conditions the H+ concentration in pure water is 10^-7 M and so OH- concentration is also 10^-7 M

  
• what is the Ka of water?

  10^-14 and so pKa is 14 which mean water is a weak acid
• [H2O] in water is not variable... It’s concentration therefore has no impact on rate and it has zero-order like behaviour and so water can be removed from the question and you get this equation:

  
• as solution becomes more acidic, the concentration of H+ increases. If the concentration of H+ increases ten fold, the concentration of OH- decreases ten fold to maintain the equilibrium constant
• pH +pOH = 14 - this means that the sum of [H+] and [OH-] will always be equal to 14 on the p scale
• what is pKb?

  Not the pKa of a base but the equilibrium constant of a base de-protonating water in order to lose its ionisation.
• pKa - a molecule losing a proton to protonate water

  pKb - a molecule deprotonating/extracting a proton from water
• for basic compounds - treat the protonated form (the conjugated acid) as the acidic species and think about it in the way where it will protonate water

  
• Assuming the parent compound is neutral:

  For an acid dissociation (lose proton) = ionisation - negativity charged

  For a base association (gain a proton) = ionisation - positively charged

  
• what does a higher pKa mean?

  weaker acid + equilibrium lies to the left
• a lower pKa means equilibrium lies to the right - as lower pKa = higher Ka
• Compound is 50% ionised when pH=pKa - because when Ka=[H+] then [A-]=[HA]
• if you lower the pH by one unit = makes it more acidic, increasing the [H+] tenfold. This means the [H+] is now 10 times greater than the Ka.

  A) 90.9%

  B) 9.1%

  
• what if the pH decreases by 2?

  A) 99%

  B) 0.99%

  C) 100

  
• what happens if solution becomes less acidic?

  A) unionised

  B) ionised

  C) smaller

  
• the % of ionisation can be calculated for any pH using this process... 

  A) HA

  B) A-

  
• what is the equation for % compound ionised (charged)?

  where charge = -1 for acids and 1 for bases

  A) 100

  B) pH-pKa

  C) 1

  
• for an acidic compound...?

  Acids become ionised by losing a proton.

  Low pH: solution is rich in H+ and Equilibrium lies to the left - LESS IONISATION

  High pH: solution is deficient in H+ and Equilibrium lies to the right - MORE IONISATION

  
• when an ionisable species with a given pKa is in a solution where the pH is the same as the pKa - the compound is 50% ionised
• when pH (for acids) is lower than the pKa by 1 unit - acid is still mostly in its protonated form (not ionised) = ~10% has dissociated and become ionised

  • if lower by 2 units only less than 1% has become ionised

  when pH is higher than the pKa by 1 unit - acid will mostly be in its ionised form = ~90% will have dissociated and be ionised (10:1 ratio)

  • if higher by 2 units - more than 99% will be ionised

  
• what does it mean when it asks you for what the predominant state of this acid or base?

  The predominant state refers to whether the acid or base exists primarily in its protonated or deprotonated form in a given solution. (ionised form or unionised form)
• for a basic compound...?

  Bases become ionised by gaining a proton.

  Low pH: solution is rich in H+ and Equilibrium lies to the left - MORE IONISATION

  High pH: solution is deficient in H+ and Equilibrium lies to the right - LESS IONISATION

  A) HB+

  B) B

  
• the more H+ ion concentration the more protonation will occur for bases and so bases become ionised at lower pHs
• when pH (for bases) is lower than the pKa by 1 unit - base will be mostly protonated and be ionised (~10% dissociation) = ~90% ionised

  • when lower by 2 units - greater than 99% ionised

  when pH is higher than the pKa by 1 unit - base will mostly be unionised and stay in dissociated form - ~10% ionised

  • when higher by 2 units - less than 1% ionised, 99% neutral

  
• low pKa for a acid = strong acid but a low pKa for a base = weak base
• what's the main trend in pKa of acids?

  • the more stable the anion is the stronger the acid will be and so the lower pKa - as it will be more capable of donating that proton to water
• why are some anions more stable than others?

  sharing of charge - the more charge is located on the single atom that's becoming ionised the less happy the ionisation event will be
• how does electronegativity affect the stability and acidity of an anion/acid?

  More electronegative atoms (that carry the charge) will be happier with the negative charge and will always be more acidic than less electronegative atoms in similar environments.

  e.g. methanol (pKa 16) is more acidic than methyl amine (pKa ~ 35) because of the difference in putting the negative charge on an oxygen vs nitrogen

  
• how does electron withdrawing groups affect the stabilisation of anions of acids?

  Nearby electron withdrawing groups increase the stability of the anion. The electronegative groups (e.g. fluorines) withdraw electrons through sigma bonds which increases the acidity of the nearby atom that will carry the charge.
• what are some examples of electron withdrawing groups?

  • halogen - fluorine, chlorine etc
  • carbonyl group (C=O)
  • nitro group (-NO2)
  • -CN
  • sulfone group (-SO2R)
• what is resonance?

  sharing of charge across atoms
• how does resonance stabilise the anion of acids to make them more acidic?

  delocalising the charges around atoms. e.g. phenol

  There is resonance in phenol(pKa 10) itself; there's a non bonded pair of electrons next to a double bond. The charge in the anion form of phenol can be moved around the molecule = and is so able to put some of the negative charge on the oxygen to the carbons. The sharing of that anion around the π system causes a million fold increase in acidity compared to cylohexanol (pKa 16)

  
• anytime where a negative charge can resonate into a ring system or into another double bond that will cause an increase in acidity (lower pKa)
• when you combine the electronegativity of atoms with electron withdrawing groups, with the ability to have resonance = a larger effect so more acidic i.e. like carboxylic acids

  resonance of negative charge onto more electronegative atoms has a larger effect

  
• why is Trifluroacetic acid very strong?

  because in COOH - there is resonance stabilisation between the two oxygens + there's electronegative atoms sharing the charge. And the Fluorine atoms are nearby electron withdrawing groups pulling charge further away