[cyion]

Hi I was just wondering how I'm supposed to remember pKas if functional groups in drug molecules. I'm guessing I just have to learn ball park ranges, but what should I do when a pKa is in the ball park of multiple groups in the molecule. For instance in the drug Loperamide there are 2 tertiary amides but there is only 1 answer when it came down to assigning the group that had a pKa of 8.6.

[Babcock_Hall]

You must be referring to the pK_a values of their respective conjugate acids.  Loperamide has one 3° amine and one 3° amide.  Perhaps you can explain how this structural difference in the two functional groups affects pK_a.

[cyion]

in the exam question it just gives you a pKa which is 8.6, is there any way you can differentiate between the 2? as it just asked me to know which it was and then say if it was acting as an acid or base which is obviously a base.

[Babcock_Hall]

Let me rephrase my previous question.  These two nitrogen atoms are very different.  Which nitrogen do you think would be more basic, and why?

[cyion]

Let me rephrase my previous question.  These two nitrogen atoms are very different.  Which nitrogen do you think would be more basic, and why?

I think the N subbed into the cyclic ring would be more basic so would have a higher pKa. So could I say that the cyclic amine has a weaker conjugate acid than the other

[Babcock_Hall]

http://www.qorganica.es/qot/T11/acido_base_amidas_e_exported/
I agree with your conclusion, but I don't think that it has much to do with the nitrogen atom's being in a ring or not in a ring.  The lone pair on nitrogen in an amide is delocalized and the oxygen atom has some of this electron density; it is easy to show this by drawing resonance structures.  I found one pK_a for a primary amide listed as -0.4.  The lone pair on the amine is not delocalized in this way.

[Vidya]

Hi I was just wondering how I'm supposed to remember pKas if functional groups in drug molecules. I'm guessing I just have to learn ball park ranges, but what should I do when a pKa is in the ball park of multiple groups in the molecule. For instance in the drug Loperamide there are 2 tertiary amides but there is only 1 answer when it came down to assigning the group that had a pKa of 8.6.

Amide nitrogen lone pairs are delocalized due to resonance with carbonyl pi bond.So amide nitrogen is less basic means its conjugate acid is stronger and hence low pKa value for  conjugate acids of amides.
Amines N lone pairs are not delocalized (No Resonance)so it is stronger base than amide and its conjugate acid will be weaker and hence high pKa value.