If there’s one thing you learn how to do well in Org 1, it’s make alcohols. Let’s count the ways: hydroboration, acid-catalyzed hydration, oxymercuration for starters, and then substitution of alkyl halides with water or HO(–). If you want to extend it even further, there’s dihydroxylation (to make diols) using OsO4 or cold KMnO4, and even opening of epoxides under acidic or basic conditions to give alcohols.
There’s just one issue here and it comes up once you try to use alcohols in synthesis. Let’s say you want to use that alcohol in a subsequent substitution step, getting rid of the HO(–) and replacing it with something else. See any problems with that? Remember that good leaving groups are weak bases – and the hydroxide ion, being a strong base, tends to be a pretty bad leaving group.
So what can we do?
What you want to do is convert the alcohol into a better leaving group. One way is to convert the alcohol into a sulfonate ester – we talked about that with TsCl and MsCl. Today I’m going to talk about a second approach: converting alcohols into alkyl chlorides with thionyl chloride (SOCl2). This is a useful reaction, because the resulting alkyl halides are versatile compounds that can be converted into many compounds that are not directly accessible from the alcohol itself.
If you take an alcohol and add thionyl chloride, it will be converted into an alkyl chloride. The byproducts here are hydrochloric acid (HCl) and sulfur dioxide (SO2).
There’s one important thing to note here: see the stereochemistry? It’s been inverted.*(white lie alert – see below) That’s an important difference between SOCl2 and TsCl, which leaves the stereochemistry alone. We’ll get to the root cause of that in a moment, but in the meantime, can you think of a mechanism which results in inversion of configuration at carbon?
As an extra bonus, thionyl chloride will also convert carboxylic acids into acid chlorides (“acyl chlorides”). Like alcohols, carboxylic acids have their limitations as reactants: the hydroxyl group interferes with many of the reactions we learn for nucleophilic acyl substitution (among others). Conversion of the OH into Cl solves this problem.
So how does it work?
As you might have guessed, conversion of alcohols to alkyl halides proceeds through a substitution reaction – specifically, an SN2 mechanism. The first step is attack of the oxygen upon the sulfur of SOCl2, which results in displacement of chloride ion. This has the side benefit of converting the alcohol into a good leaving group: in the next step, chloride ion attacks the carbon in SN2 fashion, resulting in cleavage of the C–O bond with inversion of configuration. The HOSCl breaks down into HCl and sulfur dioxide gas, which bubbles away.
The mechanism for formation of acid chlorides from carboxylic acids is similar.
Real life tips
Like many sulfur-containing compounds, thionyl chloride is noseworthy for its pungent smell. Thionyl chloride has a nauseating sickly-sweet odor to it that imprints itself forever upon your memory . One accident that occurred during my time as a TA involved a student dropping a flask with 5 mL of thionyl chloride into a rotovap bath outside the fume hood. The cloud of SO2 and HCl that formed cleared the teaching lab for half an hour, so you can imagine what thionyl chloride would do if exposed to the moisture in your lungs. Treat with caution, just as you would if you were working with phosgene.
*Here’s the white lie. Although it’s generally taught in Org 1/ Org 2 that SOCl2 leads to 100% inversion of configuration, in reality it’s not always that simple. Inversion of configuration with SOCl2 is very solvent dependent. Depending on the choice of solvent, one can get either straight inversion, or a mixture of retention and inversion. For the purposes of Org 1 and Org 2, most students can ignore this message. For more details see March’s Advanced Organic Chemistry
P.S. You can read about the chemistry of SOCl2 and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF. The Reagents App is also available for iPhone, click on the icon below!