[lespaul]

Hi Everyone,

Im trying to figure out why there are such large difference in solubility within the given xanthines.

Solubility / pKa*


Caffeine – 21600mg/L water / 10.4 pKa

Theophylline – 7360 mg/L water – 8.81 pKa

Theobromine – 330mg/L water – 10.4 pKa


* Data provided by http://chem.sis.nlm.nih.gov at same temp.

Observations:

• Caffeine and theobromine are almost identical differing only in a H as opposed to a methyl in caffeine (both in position 1) - they also have identical pKas.
  But in the case of theophylline the H (instead of methyl) is on the 5 carbon purine ring - so this may explain the difference in pKa (10.4 vs 8.81)

Question - can anyone explain how the pKa or presence/lack thereof a methy group effects solubility in water?

- If the difference is based on pKa then it wouldnt explain why caffeine is ~65 more soluble than theobromine (they have the same pKa). For theophylline I can see how the lower pKa can influence solubility since most of it will be in its ionized form, but if this were the case it would also be much more soluble than caffeine (again, all in water at 25C).

Can anyone provide some additional input? Thanks

[fledarmus]

Where did they get those numbers? Especially for caffeine; I don't see how it has a particularly acidic proton. I haven't found a good source yet that has all three numbers or even reasonable measurement data, but I would not expect the backbone proton to be pulled at that low a pH, and certainly not a methyl proton.

I know that doesn't answer the solubility question. Perhaps it has something to do with their ability to stack together to form nice crystals? Did you consider their melting points?

 

[lespaul]

Hi fledarmus,

Thanks for catching that - I just saw that the pKa I stated for caffeine was not at 25C but rather 40C. The correct pKa at 25C is 14.0. See images, references listed in original post.

I have not looked at the melting points yet - but what would be the correlation. Lower melting point = higher solubility? Higher mp = lower solubility?

Thanks

[fledarmus]

what does the melting point imply about the stability of the crystalline form? How would this relate to possible solubility of very closely related structures?

[lespaul]

Fledarmus,

First off Im not a chemist, just an engineer with an interest in chemistry.

I would guess that the lower the mp the higher the solubility and vice versa. But this of course will depend on the solution, so Im not sure if this will help. But again, Im not a chemist.

[lespaul]

Im still a bit stumped as to why caffeine is so  much more soluble in water that the others. It has 3 methyl groups (as opposed to 2 in the others) which makes it less polar - and also less soluble. But for reason reason in spite of this, its still more soluble.....any thoughts?

[Jasim]

Could electronic induction be the cause? maybe those methyl groups are positioned just so to change the electron density on the nitrogens making them more polar? Nitrogen does have a lone pair...What about resonance forms? Nitrogren can donate that lone pair in a resonance structure to push a charge around.
 For aqueous solubility it's all about polarity and charge. Somehow those methyl groups are increasing polarity and charge density somewhere on the molecule.

Those rings are aromatic. How do carbon substituents on aromatic rings affect the electron density of the aromatic system? They donate electron density into the system. The methyl groups are contributing electron density onto the nitrogens by electronic induction. That makes the nitrogens richer in electrons, which makes them more polar and have greater partial charge.

[lespaul]

Hi Jasim,

Thanks for the input - it makes sense!

I didnt take into consideration that fact that these aromatic rings may be playing a significant role. Its been engrained in my mind that methyl groups tend to decrease polarity and the more you have, the less polar it is....though maybe only true for alkanes and other non-aromatic structures.

Thanks

[orgopete]

I think fledarmus was giving the best clue, melting point. All of the compounds should be polar enough to be water soluble. However, everything is relative. What if the homomolecular interactions (crystal) are stronger than heteromolecular ones (water-solute)? Carboxylic acid and amides are well known to hydrogen bond in dimers. If that were true, then we may ask whether the melting points correlate with the solubility (as suggested).

Caffeine, mp 227-228°C
Theophylline, mp 270-274°C
Theobromine, mp 357°C

If we use the melting point as a crude measure of intermolecular forces, then it is strongest for theobromine and weakest for caffeine. You may also find it useful to review the base pairing of DNA and RNA.

The solubility is seemingly not limited by the polarity of the compounds, per se, but rather by the much stronger intermolecular bonds with themselves in their crystalline states. Caffeine, the least able to form hydrogen bonds with itself is now the most soluble in water. 

[lespaul]

Ahh yes!! Thank you orgopete (& fledarmus, Jasim) - melting point does provide some valuable insight into solubility.

I completely forgot about the entire issue of 'enthalpy of solution' which is stated as:

dH(enthalpy of sol) = dH1 (e.solute) + dH2 (e.solvent) + dH3 (mixing)

[where 'd' means delta, 'e.' = enthalpy]

Since its easier to 'break' up caffeine's intermolecular attractions (as dictated by its lower mp) it can quickly become hydrated by water and  dissolve. Water (dH2) on the other hand requires a high amount of energy due to H-bonding, and dH3 (mixing) is quite low. In either case the point is that its more favorable for caffeine to dissolve when compared to theobromine/theophylline in water.

Sorry if Im repeating what everyone said already, just putting all the pieces together.

Thanks again for all your help guys (or gals)!!

lespaul