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What exactly does fluorination of some compound do in a biological sense?

I read the following things about what fluorine does for drugs:

  • Fluorine withdraws electron density and can make an acid stronger.
  • Fluorine substitution can increase lipophilicity - I don't understand this. Lipids are non-polar; I can't see why adding fluorine would generally decrease the polarity of some molecule ...
  • Carbon-fluorine bonds are exceptionally stable and resist change.

However, can anyone provide some concrete examples of fluorine influencing the behavior of some drug? I could only find very general points on the internet.

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A definitive reference is: "The Many Roles for Fluorine in Medicinal Chemistry" J. Med. Chem., 2008, 51 (15), 4359–4369. In reference to the bullet points:

  1. Fluorine obviously affects $\ce{p}{K_{a}}$ and can make an acid stronger but also a base weaker which could be advantageous when optimising a drug candidate (lead) molecule.
  2. I guess here they refer to $\ce{-CF_3}$ which can increase lipophilicity
  3. That's one of the most useful roles of fluorine. A lot of times you may have a very potent and selective molecule, but when you test it in vivo let's say in rats, it has no effect because it gets metabolised i.e. chemically modified to an inactive molecule by the rats liver (and other mechanisms). This can maybe prevented by changing to an $\ce{C-F}$ bond. For example electron rich aromatic sites are prone to metabolic oxidation. You can block this by fluorination of this site, exchanging the proton for a fluorine.

Have a look at the paper on top, you will find a new world of information.

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  • $\begingroup$ how does the CF3 group increase lipophilicity? $\endgroup$ – Dissenter Nov 22 '14 at 20:10
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    $\begingroup$ @Dissenter The explanation is not as simple and there are different factors that will weigh in depending on the environment of $\ce{-CF_3}$. For example in $\ce{-XCF_3}$ you can claim that the EWG effect decreases the ability of X to form hydrogen bonds with water molecules. To make things more complicated $\ce{-F}$ substitution (as opposed to $\ce{CF_3}$) is less capable of increasing lipophilicity and in fact sometimes it lowers clogP. If you are interested, I suggest you can have a look in relevant literature or submit a new question $\endgroup$ – K_P Nov 22 '14 at 20:50

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