TPR Inductive effect + pKa

[663697]

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Water bound to which of the four hemes was most likely shown to have the lowest pKa?

A. Native H-NOX correct answer
B. Mutant 1
C. Mutant 2
D. Mutant 3

The explanation is: "Since all of the iron atoms are in the same formal oxidation state (+3), the changes in redox potential speak to the relative electron deficiency of each iron. A large positive redox potential indicates an easily reducible, electron deficient, iron center. The rules regarding inductive effects apply in this case. An electron deficient heme will be particularly electron withdrawing, which will cause the protons on bound water to become increasingly acidic. This means that the protein with the largest reduction potential will have the lowest pKa"

I don't understand their reasoning in the bolded statement. I think I'm still shaky on what constitutes an EDG vs EWG, but I was under the impression that the EWG would have to be somewhat electronegative in order to pull electron density toward itself, similar to fluorine, but this isn't the case for Fe(3+).. can somebody tell me what I'm missing?

 

[Lawpy]

Well there are several concepts involved so it helps to simplify things by focusing on each concept separately and seeing how they relate to one another. This is one of the harder questions (probably among the hardest) seen on the MCAT due to multilevel reasoning.

Electron donating groups (EDGs) and electron withdrawing groups (EWGs) may seem complicated but the key hint is in their names. EDGs donate electron density to a pi bond in a conjugated system and thus makes it more nucleophilic (because having more electron density makes the pi bond more negative and thus more attracted to positively charged nucleus). EWGs do the opposite: they withdraw electron density from a pi bond in a conjugated system, making it less nucleophilic and more electrophilic (because having less electron density makes the pi bond less negative/more electron deficient).

Don't confuse electronegativity with EDGs/EWGs: oxygen and nitrogen in ethers and amines are more electronegative than carbon but donate electron density; whereas carbonyl groups withdraw electron density. The reason has to do with the overall charge of the functional groups: ethers, amines and alcohols have a negative charge on the nitrogen and oxygen atoms so they donate electron density. Whereas carbon and nitrogen atoms in carbonyl and nitro groups have a positive charge and thus withdraw electron density. ( http://www.mhhe.com/physsci/chemist...ics/carey04oc/ref/ch12substituenteffects.html and Electrophilic aromatic directing groups - Wikipedia )

To keep things simple, think EWGs make compounds electron deficient = electrophilic and EDGs make compounds electron rich = nucleophilic. To relate electrophilicity/nucleophlicity with acidity, the Lewis acid-base theory becomes very useful. A Lewis acid is an electron pair acceptor and a Lewis base is an electron pair donor. Immediately we see electrophile = electron deficient = needs more electrons = will accept electrons = Lewis acid, and likewise nucleophile = electron rich = can donate electrons = Lewis base (Lewis Concept of Acids and Bases)

So combining the concepts, EDGs make a compound less acidic and thus a higher pKa, while EWGs make a compound more acidic and thus a lower pKa.

Now redox potential is short for reduction potential, which measures the tendency for a chemical entity to accept electrons and become reduced. Remember OIL RIG: oxidation is loss of electrons, reduction is gain of electrons. Redox potential thus measures the relative electron deficiency of a chemical entity. A negative redox potential means the entity is electron rich, so it can't reduce (but it can oxidize and lose electrons). A positive redox potential signals electron deficiency.

So this means positive redox potential = electron deficiency = needs more electrons = will accept electrons = Lewis acid. From the chart, the native state H-NOX heme has the most positive redox potential (it's furthest to the right in horizontal axis) and thus is the most electron deficient, most acidic and has lowest pKa.

In retrospect, EDGs/EWGs don't seem to be relevant here since the question links between redox potentials and acidity, but it's good to see how the concepts connect.

 

[aldol16]

So heme groups have a special place in chemistry because those R positions above can be substituted and that will either increase or decrease the electron-withdrawing nature of the heme. There are synthetic heme models called porphyrins that take advantage of this precise fact - you can make really electron-deficient porphyrins by putting electron-withdrawing groups like a lot of fluorines at the R positions. This will cause the heme ligand to withdraw electron-density from the metal center, raising the iron's affinity for electrons and therefore also raising its redox potential. Conversely, you can put electron-donating groups there to reduce the electron affinity of the iron. If the iron doesn't want electrons, it doesn't want to be reduced and therefore this lowers the redox potential of the iron. It's a huge field actually, and iron chemistry is usually separated into heme and non-heme.

 

[aldol16]

Electron donating groups (EDGs) and electron withdrawing groups (EWGs) may seem complicated but the key hint is in their names. EDGs donate electron density to a pi bond in a conjugated system and thus makes it more nucleophilic (because having more electron density makes the pi bond more negative and thus more attracted to positively charged nucleus). EWGs do the opposite: they withdraw electron density from a pi bond in a conjugated system, making it less nucleophilic and more electrophilic (because having less electron density makes the pi bond less negative/more electron deficient).

Excellent explanation above. I would add here that EDGs and EWGs are not limited to pi frameworks - they also operate via sigma frameworks. In terms of concrete examples, hyperconjugation is a sigma-framework effect that alkyl groups can participate in. That's why we call alkyl groups mildly donating groups. Similarly, the inductive effect is an overall effect that electronegative elements can have on a saturated molecule.

 

[Lawpy]

Excellent explanation above. I would add here that EDGs and EWGs are not limited to pi frameworks - they also operate via sigma frameworks. In terms of concrete examples, hyperconjugation is a sigma-framework effect that alkyl groups can participate in. That's why we call alkyl groups mildly donating groups. Similarly, the inductive effect is an overall effect that electronegative elements can have on a saturated molecule.

Right that's true. I was thinking in terms of aromatic compounds like benzene.

So heme groups have a special place in chemistry because those R positions above can be substituted and that will either increase or decrease the electron-withdrawing nature of the heme. There are synthetic heme models called porphyrins that take advantage of this precise fact - you can make really electron-deficient porphyrins by putting electron-withdrawing groups like a lot of fluorines at the R positions. This will cause the heme ligand to withdraw electron-density from the metal center, raising the iron's affinity for electrons and therefore also raising its redox potential. Conversely, you can put electron-donating groups there to reduce the electron affinity of the iron. If the iron doesn't want electrons, it doesn't want to be reduced and therefore this lowers the redox potential of the iron. It's a huge field actually, and iron chemistry is usually separated into heme and non-heme.

I was thinking porphyrins played a role in biochemistry (like in heme synthesis).

And yeah it definitely makes sense why EWGs increase the iron affinity: they simply further withdraw electron density from the already positive iron center, making the heme even more electrophilic = more electron deficient = increased acidity = lower pKa.

 

[aldol16]

I was thinking porphyrins played a role in biochemistry (like in heme synthesis).

Hemes are porphyrins - they're basically the same thing. Hemes belong to the porphyrin class of compounds. Specifically, it's protoporphyrin IX.

 

[Lawpy]

Hemes are porphyrins - they're basically the same thing. Hemes belong to the porphyrin class of compounds. Specifically, it's protoporphyrin IX.

Yeah the wording was a bit confusing since it read porphyrins = synthetic heme models. Although I'm curious, do you consider vitamin B12 to be a porphyrin?

 

[aldol16]

Yeah the wording was a bit confusing since it read porphyrins = synthetic heme models. Although I'm curious, do you consider vitamin B12 to be a porphyrin?

Where did you read that? That's not accurate. Porphyrins are a general class. They include synthetic heme models but also protoporphyrin IX. The metal center in B12 is a corrole, not a porphyrin. Jack Halpern actually did some good work investigating why nature doesn't use porphyrins in B12: http://pubs.acs.org/doi/abs/10.1021/ja00238a039

 

[Lawpy]

Where did you read that? That's not accurate. Porphyrins are a general class. They include synthetic heme models but also protoporphyrin IX. The metal center in B12 is a corrole, not a porphyrin. Jack Halpern actually did some good work investigating why nature doesn't use porphyrins in B12: http://pubs.acs.org/doi/abs/10.1021/ja00238a039

Interesting paper. Apparently the flexibility of the ligand backbone is necessary for proper function of vitamin B12-dependent enzymes, and the porphyrins are too rigid.

 

[aldol16]

Interesting paper. Apparently the flexibility of the ligand backbone is necessary for proper function of vitamin B12-dependent enzymes, and the porphyrins are too rigid.

Yes, the flexibility of the equatorial ligand often has effects on reactivity correlates such as regioselectivity and even stereoselectivity. The porphyrin ligand, however, is much more important than the others because of its prevalence - without it, your liver cannot function, as the cytochrome P450s use metalloporphyrins to oxidize C-H bonds on toxins and drugs so that your body can excrete it.