13
$\begingroup$

I recently answered a question about Breaking Bad's initial methamphetamine production method (i.e. the reduction of (pseudo)ephedrine). The reaction is as follows:

Ephedrine to methamphetamine using HI/P (Source)

It is infamously known as the $\ce{HI/P}$ reduction and was (and still is somewhat) a real plague in the United States until cough medicine containing ephedrine came under tightened control. That for an introduction, now the question: what is actually the reaction mechanism of the $\ce{HI/P}$ reduction?

The first step seems like a simple $\ce{S_{N}2}$ substitution of $\ce{I^{-}}$, catalyzed by the protonation of the alcohol group by hydroiodic acid (making it a far better leaving group). But what is the mechanism after that? How is phosphorus involved? Does the $\ce{HI/P}$ reduction have any legal use?

$\endgroup$
  • 3
    $\begingroup$ I guess finding an actual reaction mechanism for this is on the edge of impossible. The first part is probably protonation/ activation and something between $\ce{S_{N}1/S_{N}2}$. The second step is most likely carried out with red phosphorous as an electron source and removal of $\ce{PI3}$. But as for all redox reactions, there are too many possible pathways to determine the mechanism. As for the legal use, there are possibly more effective and selective (and less dangerous) methods to reduce organic compounds. $\endgroup$ – Martin - マーチン Aug 25 '14 at 8:04
  • 4
    $\begingroup$ Theoretical examinations of these reactions are fine, I think. $\endgroup$ – jonsca Aug 26 '14 at 2:17
  • $\begingroup$ You may find this article illuminating. The authors propose a stepwise SET mechanism with $\ce{HI}$ being catalytic, recycled by $\ce{P_{red}}$. $\endgroup$ – Greg E. Aug 27 '14 at 1:54
14
$\begingroup$

According to the source mentioned in the comments to your question, the first step is indeed nucleophilic substitution of the OH group by $\ce{I-}$, faciliated by protonation of the alcohol. For the second step ($\ce{HI}$ reduction), a radical species was found as an intermediate, and therefore a reduction by single electron transfer (SET) with oxidation of $\ce{I-}$ to $\ce{I2}$ is proposed. Red phosphorus is required for the regeneration of $\ce{HI}$ from $\ce{I2}$. $\ce{P_{red}}$ reacts with $\ce{I2}$ to the phosphorus iodides $\ce{PI3}$ and $\ce{PI5}$, which are subsequently hydrolyzed to $\ce{H3PO3}$/$\ce{H3PO4}$ and $\ce{HI}$, which is reused in further reduction steps. Catalytic amounts of $\ce{HI}$ are therefore sufficient to run the reaction in the presence of phosphorus. However, a too low concentration of $\ce{I-}$ will lead to elimination instead of substitution in the first reaction step.

enter image description here

(Image source)

The SET mechanism of the reduction is not described in detail in the article, so the following is a bit speculative. As a resonance-stabilized radical is involved, homolytic cleavage of the $\ce{C-I}$ bond is one of the first steps, which gives the benzylic radical $\ce{R.}$ and an iodine radical $\ce{I.}$. A single electron is transferred from $\ce{I-}$ to $\ce{R.}$, forming the carbanion $\ce{R-}$ and $\ce{I.}$, which recombines with another iodine radical to $\ce{I2}$. Protonation of $\ce{R-}$ yields the final product.

$\endgroup$
5
$\begingroup$

As for the second part of the question, this reaction is actually used commercially in the fine chemicals and specialty chemicals industry. An example that comes to mind is the reduction of 4-hydroxymandelic acid to 4-hydroxyphenylacetic acid. This intermediate is used in one route to the popular beta blocker "atenolol". Of course, as mentioned in the comments, other reactions are often favored when possible. In addition to the issues mentioned, phosphorus and iodine are both relatively expensive.

$\endgroup$

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.