[Urbanium]

Greetings,

during the recent medchem exam there was one question in which a series of bioactive compounds were drawn, and among all, there were two compounds in which the only two differences were that: a) alkylic chain length was different and b) ester (-COO-) was replaced with the peptide (-CONH-). The adjacent substituents were identical.

One of the questions in the text were "why does the replacement of ester with peptide bond increase the stability of this compound? Ignore the enzymatic stability, but consider this from purely chemical point of view"?

And I had no idea. What makes peptide group chemically more stable than an ester group (if all the other parts of molecule are identical)?

[Babcock_Hall]

Have you learned anything else about peptide bonds, their geometry perhaps?

[Urbanium]

Nope. Only about the primary-secondary etc. structure of polypeptides, but that was very general stuff during the biochem course. Can you enlighten me, what would be connection to the chemical stability?

[Babcock_Hall]

It is a forum rule that you must show an attempt before we can help you.  My last post was my effort to prompt you for some of your thoughts.  Did your biochemistry class mention the planarity of the peptide bond?  That might be a place to start.

[Urbanium]

Did your biochemistry class mention the planarity of the peptide bond?  That might be a place to start.

Hmm, not quite to be honest. Isn't the ester group itself also planar? I don't see how could I link that to chemical stability, the "bulkiness" does not seem to be the case in here. The starting difference between these two groups is in the part of group which has either an O or NH, and the only thing that got into my mind is some inductive influence of carbonyl oxygen on charge (δ±) on the adjacent ester O or peptide N (which also has a H). But that's all, and I couldn't conclude anything. 

[kriggy]

Look into mesomeric structures of ester and amide bond. See the difference?

[Urbanium]

Look into mesomeric structures of ester and amide bond. See the difference?

Mesomery? Are you talking about the fact amide bond can have a tautomer and ester can't or about the resonance? To me both mesomers look unstable, I don't see the point? (attachment)

I still don't see how is that linked to the chemical stability (when it comes to interaction of ester/amide with other chemicals or e.g. pH change)?

[Babcock_Hall]

It would be nice if the question defined stability in more detail, although I have been assuming that the question referred to nonenzymatic hydrolysis.  The C-N bond has partial double bond character in an amide (I recall one estimate .  Planarity is one manifestation of that, although I have heard the ester bond referred to as essentially planar.  One might look into the rates of rotation around the C-N versus the C-O bond.  This link discusses deviations from planarity of the peptide bond.
http://www.nature.com/nsmb/journal/v8/n3/full/nsb0301_201.html

[Irlanur]

I would just argue with the electrophility/reactivity of the carbonyl carbon. In addition you could talk about the different pKa of the leaving groups in an ester/amide.

[PL]

HI,

Amide bond is more stronger than ester bond. The ester bond is at 120 degree angle which makes the estre bond less rigid and more volatile than the corresponding amide. Thus peptide is chemically more stable.