Polarizability and Inductive Effect (TPR FL)

[663697]

P is supposed to represent lipophilicity in the graph. The passage states that there is "1) an increase in polarity with the inclusion of polar C—F bonds, decreasing P, and 2) a decrease in the overall polarizability of the molecular surface with the inclusion of nonpolarizable fluorine atoms, increasing P".

My thought was that increasing the # of F atoms would contribute to the inductive effect and cause the compounds to be more acidic, thus less lipophilic, but the graph shows otherwise.
Also, what does it mean by "nonpolarizable F atoms"? Is it due to them having the largest electronegativity so their electron cloud cannot be polarized?

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[aldol16]

My thought was that increasing the # of F atoms would contribute to the inductive effect and cause the compounds to be more acidic, thus less lipophilic, but the graph shows otherwise.

Their argument here is that there are two competing effects to take into account. The first is what you mention - the polarity of the C-F bond. This would cause local polarity to increase, leading to a decrease in log(P). This is beyond the scope of the MCAT, but log(P) is a value commonly used in the drug industry to predict lipophilicity. It's a simple determination - in short, you take octanol and water, which are immiscible, and shake up your compound in it. Then you measure how much is in each phase and divide the amount in octanol by the amount in water. Octanol is supposed to mimic lipids by virtue of its long hydrocarbon tail and slightly polar head. But the point is that here, you not only have to take into account the new C-F bonds but also the overall polarizability of the molecule. This leads into your second question.

Also, what does it mean by "nonpolarizable F atoms"? Is it due to them having the largest electronegativity so their electron cloud cannot be polarized?

F atoms are not polarizable because of their small size. Smaller atoms or ions are generally less polarizable because their electron cloud isn't dispersed. Since fluorine atoms are not very polarizable, their argument is that this decreases the overall polarizability and this would lead to an increase in log(P), or lipophilicity. This effect competes with the increased polarity of C-F bonds as compared to C-H bonds.