TBR Acidity factors

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TBR breaks acidity factors into 2 categories: primary that are based on the characteristics of the atom connected to the proton in question (size, el-neg and hybridization) and secondary (rest of molecule effects: donation/withdrawal via reasonance, donation/withdrawal induction).

I assumed primary ones are called that because we are to consider them first before looking for "tie-breakers" in the secondaries.

I don't understand this problem on page 39 of TBR organic 1:


What is observed when histidine is protonated on its side chain?
It is basically between imine and amine nitrogen and they pick some answer based on reasonance (2ndary factor).

Why are we looking into reasonance (secondary factor) when these 2 nitrogens are differently hybridized (primary factor)! Or does this hybridization only get used for protic acidity analysis?
Imine is sp2, so it should be more acidic, hence less basic.

Can someone list acidity factors in a proper order if one exists in this hocus pocus of a "science"? 😡

Edit:
So they mention something about aromatic stability, so does it go:

proton atom size > proton atom el-neg > aromatic stability > proton atom hybridization > all secondaries in the order they list?

 

[BerkReviewTeach]

You have the correct idea in considering primary effects first, then secondary effects. This just happens to be a case where one of the secondary effects has an influence on a primary effect.

Because of resonance (and in this case aromatic resonance), both of those nitrogens are sp2-hbridized. That's why the histidine sidechain is planar. So they are equal by primary effects and we next consider the availability of the lone pair to be donated. Ony one of the electron pairs can be shared, because one of the nitrogens has its lone pair tied up in the aromatic ring.

BTW, hocus-pocus is the perfect description.

 

[Tbrquestions]

I still don't understand this one , driving me nuts lol. Will you please explain using baby steps. Thank you!

 

[aldol16]

Why are we looking into reasonance (secondary factor) when these 2 nitrogens are differently hybridized (primary factor)! Or does this hybridization only get used for protic acidity analysis?
Imine is sp2, so it should be more acidic, hence less basic.

The reason for the confusion is because you remembered an algorithm that doesn't always work instead of basic principles of acidity. You have to understand where acidity comes from (i.e. where the electrons are) in a molecule. If you understand this, you don't need to memorize anything about "primary" or "secondary" factors. I have never used those terms or heard them used in my entire experience as a PhD chemist.

Now, it's not an imine vs. an amine because those nitrogens on the histidine are (for your purposes here; there are differences due to the attachment of the rest of the peptide but those effects are minimal here) chemically identical. In other words, there is an important resonance structure that contributes equally to the "real" structure. That resonance structure swaps the places of what you characterize as "imine" and "amine." Draw it to make sense of it - deprotonate the "amine" and push those electrons up to the "imine" to see this.

The issue with characterizing resonance as a "secondary" factor is that resonance is actually always super important because resonance is just a way of representing the complexity of the real molecule. In other words, the molecule does not actually oscillate between both resonance forms in real life but it's actually a mix of the two resonance forms together. That's how it actually exists. So neither amine nor imine exist but both exist. It's complicated but you have to think about resonance forms as a way to represent a single molecule in a single state that truly exists in nature.

 

[JustinM88]

The reason for the confusion is because you remembered an algorithm that doesn't always work instead of basic principles of acidity. You have to understand where acidity comes from (i.e. where the electrons are) in a molecule. If you understand this, you don't need to memorize anything about "primary" or "secondary" factors.

Could you elaborate on this? Whenever I think of 'acidity' I think about that H+ (which doesn't have electrons) that's either loosely hanging onto the molecule or has dissociated into solution...

 

[aldol16]

Could you elaborate on this? Whenever I think of 'acidity' I think about that H+ (which doesn't have electrons) that's either loosely hanging onto the molecule or has dissociated into solution...

Think about where the electrons are at in the rest of the molecule. For example, compare trifluoroacetic acid with acetic acid. Why is acetic acid less acidic?

 

[JustinM88]

Think about where the electrons are at in the rest of the molecule. For example, compare trifluoroacetic acid with acetic acid. Why is acetic acid less acidic?

Ah this is that concept about how atoms like F are electron withdrawing groups and alkyl groups are electron donating groups.

If the electrons are closer to where that particular "H--" is on the molecule then the molecule is less acidic (because it won't likely lose that H b/c the electrons are keeping it tightly bound to the molecule)

-but-

if the electrons are pulled farther away from that "H--", then this molecule will more likely lose this H (and so it's more acidic) b/c once it loses this H the molecule is still quite stable ...