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Topic: Why do halogen substituents make molecules more lipophilic?  (Read 12845 times)

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Offline CrimpJiggler

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Why do halogen substituents make molecules more lipophilic?
« on: October 27, 2011, 02:15:04 PM »
I was reading about the effects of adding substituents in designing drugs and read that halogens, like methyl groups, make the molecule more lipophilic. Don't halogens would make molecules more polar since they are so electronegative? I thought halogens would make a molecule more hydrophilic and less lipophilic, how is it the other way around?

Offline fledarmus

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Re: Why do halogen substituents make molecules more lipophilic?
« Reply #1 on: October 27, 2011, 03:18:08 PM »
That depends on the halogen. The electronegativity difference between carbon and hydrogen isn't that much different from that between carbon and bromine, and is more than the difference between carbon and iodine. It is just oriented in the other direction. In addition, halogens are far, far larger than hydrogens, and the large, soft electron shell is nicely lipophilic, unlike the tiny, hard, single-electron shell of hydrogen.

Carbon-fluorine bonds are much more polarized, and depending on the other groups in the molecule, actually seem to participate in hydrogen-bonding-type interactions with some enzymes.

Offline CrimpJiggler

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Re: Why do halogen substituents make molecules more lipophilic?
« Reply #2 on: October 27, 2011, 05:27:58 PM »
Hydrogens electronegativity is 2.2, iodine is 2.6. You sure you're not thinking of astatine (2.2) when you said the C-I bond has the same polarity as the C-H bond? Why are soft electron shells lipophilic? Is it because theres a large atomic radius for the electrons to move around and conform to the electronic environment of the non-polar solvent? If that was the case then it would be amphiphilic (soluble in both polar and non polar solvents) wouldn't it? Sorry to throw more questions at you, you're reply explained a lot but more questions popped up.

Offline fledarmus

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Re: Why do halogen substituents make molecules more lipophilic?
« Reply #3 on: October 27, 2011, 05:57:19 PM »
I didn't say the polarity was the same, I said the electronegativity difference was about the same. Carbon at 2.5 is about midway between hydrogen and bromine.

Offline orgopete

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Re: Why do halogen substituents make molecules more lipophilic?
« Reply #4 on: January 28, 2012, 12:10:59 AM »
Sorry to *Ignore me, I am impatient* this topic. Intuitively, I also agreed with the original poster, though for different reasons. I thought adding a halogen or rather replacing a CH3-group with a halogen should make the compound less lipophilic and more water soluble.

Rather than repeat what I have already written, you may see my quick comparisons here.
Author of a multi-tiered example based workbook for learning organic chemistry mechanisms.

Offline zaphraud

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Re: Why do halogen substituents make molecules more lipophilic?
« Reply #5 on: January 28, 2012, 12:27:33 AM »
I was reading about the effects of adding substituents in designing drugs and read that halogens, like methyl groups, make the molecule more lipophilic. Don't halogens would make molecules more polar since they are so electronegative? I thought halogens would make a molecule more hydrophilic and less lipophilic, how is it the other way around?

With regard to designing drugs, it likely depends on WHERE you add the halogen. Chances are, if it makes the molecule less polar, its because something polar is on the other end of the molecule already. Also, aren't halogens also often compared with methoxy groups in terms of their ability to bind a receptor? Maybe there was just a typo.

You are correct in your reasoning, and in fact, just plain correct in general. Compare the "new freon" (1,1,1,2-tetrafluoroethane) with ethane to see a popular example of why you are right, although neither are called drugs (and its propane+isobutane that is a non-polar coolant, not ethane (too cold), but whatever)

...Then again, I guess if you choose to compare hexachloroethane with carbide anions, why by golly, I guess adding those halogens do make it less polar!  ::)

p.s. how is it that the firefox spell checker has the right spelling for the IUPAC name of new-freon, but lacks the ability to realize that "colour" is actually a correct spelling??
« Last Edit: January 28, 2012, 12:39:23 AM by zaphraud »

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