[mycotheologist]

Heres the question:

I have no idea how to answer either of these questions. I know that the methyl group attached to the carboxyl groups alpha carbon will decrease the acidity due to electron donating properties. It doesn't look like the carbonyl group is conjugated with the aromatic rings so I don't think they will increase the acidity too much. Thats all I can say about it though, I have no idea how to estimate the pKa.

I'm also confused about question b. I suppose one advantage is that the salt is not acidic.

[sjb]

For a) it does say roughly, so perhaps just consider the pKa of acetic acid itself? For b) what makes an effective drug?

[mycotheologist]

What makes an effective drug is high potency, high selectivity and low toxicity. I don't know the mechanism behind NSAIDs activity but I think this is a generalised question, not one relating specifically to this class of drug. Potency I know is determined by bioavailability (distribution) and ability to interact with the target once its reached it. I don't know how much converting the acid to the potassium salt will alter its lipophilicity, I'm assuming that if its a weak acid, the potassium salt will also have a similar dissociation constant but I may be wrong there. I know that ibuprofen isn't very soluble in water and is thus relatively lipophilic, enabling it to cross lipid membranes easily and I know that you need to strike a balance because if its too lipophilic then the blood can't carry it (because it won't dissolve in it) very well and will get stuck in lipid membranes etc. I've read a fair bit about distribution and a bit about SARs but I'm having trouble applying the knowledge to this scenario.

[sjb]

Are ions generally more or less soluble than neutral molecules in water? in lipids?

[mycotheologist]

More soluble but the acid is also an ion. Like I said, I'm guessing the potassium ion will have a dissociation constant, similar to how to the proton does.

[Babcock_Hall]

The free acid is a neutral molecule, not an ion.

[mycotheologist]

Well that depends on its pKa. Some of the free acid is dissociated into ions. If you replace the H⁺ ion with a K⁺ ion, there will still be a dissociation constant won't there. Then again, I may have that wrong. Lets use acetic acid as an example. When you convert it into sodium acetate, does the NaCOO completely dissociate into Na⁺ and COO^- ions or does it have a dissociation constant similar to the way partially soluble salts like AgCl do?

[zoork34]

Getting back to the original question,

The best way to predict the pKa of molecules is to memorize a list of some basic ones, like acetic acid, the mineral acids, protonated amines, alcohols, etc.  Then, when you see a complex molecule like this, you can say "oh, this is about the same as acetic acid, so the pKa is around 5." 

You are correct in saying that the potassium form is less acidic.  It should also be more water soluble, due to the dissociation of the cation and anion.  The acid form would not dissociate much in pure water because it needs a base to deprotonate it.  In pure water, the equilibrium would look like:

R-COOH + H₂O    R-COO^-  +   H₃O⁺

In this case, the hydronium ion is a much stronger acid than the carboxylic acid, so the equilibrium will be shifted to the left. 

Also, sometimes big carboxylic acids like this can dimerize and be completely insoluble in water, as in the case of benzoic acid.