14
$\begingroup$

C-F bond is the strongest single bond in organic chemistry with a bond energy of $\ce{453 kJ\,mol^{-1}}$. And it is very difficult to break this bond and F does not act as a leaving group.

However, in organophosphates, F acts as a leaving group. For example, take an organophospate such as sarin(below). When this binds with acetylcholinesterase (enzyme), F is leaving as a fluoride ion. How can this be explained w.r.t. the P-F bond energy of $\ce{490 kJ\,mol^{-1}}$, which is even higher than that of C-F. Is this possible because of the catalytic activity of the enzyme?

Sarin

According to David O'Hagana, Chem. Soc. Rev. 2008, *37 , 308-319, C-F bond is very strong due to the difference of electronegativities of C(2.55) and F(4.0), and the resultant ionic character of the bond. However, the electronegativity of P is 2.19 and according to this, P-F bond must be much difficult to be broken. But, this is not the reality. Sarin can be hydrolyzed (Andrew F. Kingery and Herbert E. Allen, Toxicological \& Environmental Chemistry 1995, 47, 155-184.) at pH 6 ($\ce{25\,^{\circ}C}$) with a half life of 312 hours in aqueous solution.

$\endgroup$
  • 1
    $\begingroup$ Well, did you at least check proper values? Bond energies vary... Not that this approach is terribly useful, as you can see. $\endgroup$ – Mithoron Mar 30 '16 at 21:36
  • $\begingroup$ So what approach should I use then? I tried looking for the actual bond energies, but couldn't find. $\endgroup$ – chemkatku Mar 31 '16 at 15:15
  • 1
    $\begingroup$ Enzymes can make miracles. $\endgroup$ – Marko Apr 12 '16 at 21:13
9
+50
$\begingroup$

I am reluctant to post this as an answer because it is not really backed up by much research, but since nobody has said anything yet, here's my theory:

It is probably to do with the fact that the covalently bound sarin (which necessarily involves kicking out either $\ce{RO-}$ or $\ce{F-}$) mimics the transition state for acetylcholine hydrolysis too well, such that the expulsion of one of those two leaving groups is much more favoured than in aqueous solution.

Acetylcholinesterase (AChE) is very similar to a typical serine protease, and serine proteases are very well-studied. I am going to postulate that the mechanism of acetylcholine (ACh) hydrolysis in AChE is exactly the same as it is in a typical serine protease. So first, let's look at what the enzyme does normally. It's nothing special, just a nucleophilic acyl substitution:

ACh hydrolysis

(There's an additional glutamate residue, analogous to the aspartate in a serine protease, that fixes the conformation of His440, but it's not directly relevant to the mechanism. Also, there's an anionic site which binds to the positively charged quaternary nitrogen, but that's also irrelevant.)

ACh hydrolysis Part 2

The acyl-enzyme intermediate then goes on to be hydrolysed by water (not relevant here).

The reason why the enzyme can catalyse the reaction is because it stabilises the transition state for the ester hydrolysis, which means that the activation energy for hydrolysis is decreased and the rate is increased. (Strictly, it provides an alternative hydrolysis pathway in which the activation energy is lower - but the point is that since the catalysed hydrolysis is mechanistically similar to the uncatalysed hydrolysis, the enzyme must play a role in stabilising a tetrahedral intermediate or transition state.)

The transition state looks something like this (partial charges omitted):

Hydrolysis TS

Sarin is a potent AChE inhibitor because it covalently binds to the active serine residue as in the left-hand side of this diagram:

Sarin covalent modification

You can see that structurally, this is very similar to the transition state shown above. If the enzyme stabilises the TS above, this covalent binding of sarin to the enzyme must also be extremely stable. I do not pretend to know exactly how it is stabilised, but it must be related to the specific 3-D conformation of the enzyme. If you do not kick out the fluoride ion (right-hand side), then it does not quite resemble the transition state so well.

What this means is that there is a strong driving force for the fluoride ion to be expelled, in order for it to reach that stable, 4-coordinate phosphorus form.

That leaves one question that I feel is worth addressing, which is why fluoride is expelled instead of isopropoxide. Honestly, I do not know. As pointed out by jerepierre, fluoride is certainly a better leaving group than isopropoxide ($\mathrm{p}K_\mathrm{a}(\ce{HF}) = 3.17$, $\mathrm{p}K_\mathrm{a}(\ce{^{i}PrOH}) = 16.5$ - quite a large difference), and it might very well just be that. On the other hand, as with most biological systems, it is difficult to give a full explanation of why things happen the way they do, and applying (relatively) simple chemistry heuristics might not be the full picture. As to what other factors might influence this, I can only guess that is that there might be some hydrogen bonding arrangement that requires the specific size of the oxygen in the $\ce{-OR}$ group over the size of the fluorine (in the catalysis TS, there is an oxygen there as well). Essentially, I am saying that the LH diagram resembles the TS more than the RH diagram (don't quote me on it though...):

Fluoride vs isopropoxide

$\endgroup$
  • 1
    $\begingroup$ Note that, in case of tabun, the reaction also works with $\ce{CN-}$ instead of $\ce{F-}$. $\endgroup$ – Loong Apr 12 '16 at 22:39
  • $\begingroup$ "... why fluoride is expelled instead of isopropoxide." Fluoride is a better leaving group than an alkoxide. $\endgroup$ – jerepierre Apr 13 '16 at 0:34
  • 1
    $\begingroup$ @jerepierre Yes, I think it's not unlikely that isopropoxide picks up a proton from somewhere else when it's leaving though. $\endgroup$ – orthocresol Apr 13 '16 at 0:37
  • $\begingroup$ Wow It's so cool that this came up. I've been wondering the exact same thing for the last week! I asked a couple of my professors about it and this is the first time I've seen a reasonably satisfying answer. $\endgroup$ – gannex Apr 13 '16 at 3:26
5
$\begingroup$

I would point out (as did the author of the question) that sarin hydrolyzes in water in days to weeks without the need of an enzyme, and also that carboxylic acid fluorides (e.g. acetyl fluoride) also rapidly hydrolyze, despite the strength of the C-F bond. The ability of these acyl fluorides to hydrolyze is due to the relative ease of addition of water or hydroxide with formation of a tetrahedral intermediate (or pentacovalent intermediate in the case of phosphorus) - likely helped by the electron withdrawing characteristic of the fluorine atom - followed by expulsion of fluoride, which is a relatively stable anion and is a pretty good leaving group. Keep in mind that the term "bond strength" typically refers to the energy required to cleave a bond homolytically to form radical species. That is quite unfavorable in the case of P-F and C-F bonds.

$\endgroup$

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service, privacy policy and cookie policy

Not the answer you're looking for? Browse other questions tagged or ask your own question.