Chem101 - literally

[Phloston]

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So you've got a tertiary amine --> uncharged --> permissive of membrane transcytosis.

Now let's say you've got a quarternary amine, but all of the R groups are undeniably hydrophobic; is the mere fact that it's quaternary, and now technically positively charged, sufficient to prevent membrane transcytosis?

 

[smartparts]

So you've got a tertiary amine --> uncharged --> permissive of membrane transcytosis.

Now let's say you've got a quarternary amine, but all of the R groups are undeniably hydrophobic; is the mere fact that it's quaternary, and now technically positively charged, sufficient to prevent membrane transcytosis?

Honestly don't know the answer but I'd say it depends on the substitutions. Four, small, non-polar substitutions might allow it to pass maybe? Is there a compound you have in mind?

 

[Phloston]

Quite frankly, I actually recall a question from my MCAT, on the biological sciences section, where they showed a cell, and then they had an extracellular molecule that was a tertiary amine. Anyway, the question then showed that a methyl group was added orthogonally to the amine (making it quaternary), but then it also had a positive charge at that point (which makes sense because N is stable with 3 bonds).

The question asked what effect adding the methyl group would have. At first I saw the positive charge and selected that it would decrease penetration into the cell, but then I re-thought it, and my final answer was that it would actually increase penetration because it was a methyl.

To this day I have never questioned that answer of mine, until I was just re-reading part of my annotated FA, and I have written that physostigmine can cross the BBB because it's a tertiary amine, but that some of the other AChE inhibitors can't cross because they're quaternary.

By all means, I haven't researched the R-groups of the quaternary amines for those latter compounds, but for a moment I was like, "wait, the tertiary amine passes but the quaternaries don't?"

Perhaps on that MCAT question, the tertiary would have passed anyway, but the methyl that was added further assisted that.

 

[loveoforganic2]

They have lipophilic salts that are used as phase-transfer catalysts (e.g. tetraphenylphosphonium chloride), so I could see it being a possibility that a cation could transfer across a cell membrane. The way your MCAT question was phrased though, I would absolutely have answered that it would decrease cell membrane permeability, both from a test-taking "what the question maker is looking for" point of view and an "actually the case" point of view. I really doubt the addition of any lipophilic R group is going to increase the lipophilicity of a compound when it becomes a cation by doing so.

 

[Akarat]

I don't know if this is correct or not, but what if the hydrophobic R groups shielded the charged nitrogen from exerting its polar effects? It would be somewhat analogous to a micelle, you have polar on the outside and nonpolar on the inside. In this situation, you would have nonpolar on the outside and polar on the inside.

In regards to the MCAT question, would we have to consider if a methyl group is large enough to shield the charged nitrogen?

 

[loveoforganic2]

I don't know if this is correct or not, but what if the hydrophobic R groups shielded the charged nitrogen from exerting its polar effects? It would be somewhat analogous to a micelle, you have polar on the outside and nonpolar on the inside. In this situation, you would have nonpolar on the outside and polar on the inside.

In regards to the MCAT question, would we have to consider if a methyl group is large enough to shield the charged nitrogen?

A methyl group almost certainly wouldn't be, it occupies relatively little space. More classical "bulky" groups are things like trimethylsilyl- and tertbutyl-. Regardless, I doubt this would be what they'd want you to look at. My assumption would be "hey, adding a 4th thing here makes it positive, and charged things don't passively diffuse across membranes"

 

[smartparts]

A methyl group almost certainly wouldn't be, it occupies relatively little space. More classical "bulky" groups are things like trimethylsilyl- and tertbutyl-. Regardless, I doubt this would be what they'd want you to look at. My assumption would be "hey, adding a 4th thing here makes it positive, and charged things don't passively diffuse across membranes"

I think you are right. Tiotropium has 2 methyl substitutions on the amine and ipratropium has a methyl group+isopropyl group and neither can cross membranes or the BBB.

Source: Goodman & Gilman Pharmacological Basis of Therapeutics

 

[Phloston]

Yeah, I did some additional research and tetraethylammonium requires a counter anion, which means the methyl couldn't have made the moiety more hydrophobic.