Reagent Friday: Thionyl Chloride (SOCl2)

by James

in Alcohols, Alkyl Halides, Organic Chemistry 2, Organic Reagents

In a blatant plug for the Reagent Guide and the Reagents App for iPhone, each Friday  I profile a different reagent that is commonly encountered in Org 1/ Org 2. 

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).
[NOTE added later: there are significant differences in how this reaction is taught at different schools. Consult your instructor to be 100% sure that this applies to your course]. See post here

 

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!

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{ 26 comments… read them below or add one }

mamid December 3, 2011 at 11:43 am

Make some extra space for the 3rd structure in the 4th reaction scheme (Formation of alkyl chlorides), so that the chlorine on the right is shown properly. But otherwise, great work, as usual. Maybe a few words about alternative reagents for this transformation would be useful, too.

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james December 4, 2011 at 4:12 am

Thanks. I really appreciate your constructive suggestions.

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DrFreddy December 5, 2011 at 12:07 pm

One might add that thionyl chloride is not flat, as it is commonly depicted, but pyramidal, just like amines with one lone pair sticking out. (Sulfoxides substituted with two different groups are therefore chiral. The inversion barrier is often high enough to make the separation of sulfoxide enantiomers possilble.)

If you think thionyl chloride is bad, which it indeed is, you should also know it has an evil twin: Sulfuryl chloride (SO2Cl2). That is one unhappy liquid.

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james December 9, 2011 at 6:12 pm

I have thankfully avoided working with SO2Cl2, but that doesn’t mean I haven’t experienced it from fume hood neighbors. Nasty stuff!

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vivek kumar January 31, 2012 at 6:28 am

really good

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Kevin September 25, 2012 at 4:30 am

There are two mechanisms to this reaction. In general, treatment of a chiral secondary alcohol to thionyl chloride gives predominantly RETENTION of stereochemistry and NOT inversion…..

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james September 25, 2012 at 9:39 am

True. That’s why I put the disclaimer at the bottom.

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babak October 1, 2012 at 1:53 am

HI
I am going to do a acylation reaction of acid with thionyl chloride in persent of methylene chloride (solvent) and DMF(catalyst) at room temperature.i don’t have experience to this reaction.
according to TLC method, Progress of the reaction is low.
The raw material(acid) is a HCl salt in N atom.
Please guide me
thank you and best regards

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james October 1, 2012 at 10:09 am

Your acid halide is probably hydrolyzing to the carboxylic acid on the TLC.

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babak October 13, 2012 at 7:56 am

I dont know. but the secont step is acylation of fridle-crafts and in this step i dont have produt. that is,probably i dont have acyl halide in the first step.

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Mal December 7, 2012 at 4:34 pm

Hi,

I learnt in school that Alcohols, alkyl flourides, ethers and amines do not typically undergo sn2 reactions. But why is this alcohol undergoing a sn2 reaction? the transition state is not a tosylate or mesylate right? I don’t understand this. Can you please explain! thanks a lot! :)

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james December 16, 2012 at 6:01 pm

Well, the coordination of oxygen to the sulfur makes the oxygen a good leaving group (much like a tosylate or mesylate); hence the chloride ion can then displace it in an SN2 reaction!

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Rico May 8, 2013 at 11:19 pm

I am sorry but who taught you that mechanism? Alcohols and SOCl2 always react with retention and it’s an ipso-substitution, not SN2, there is no backside attack and no pentavalent transition-state. If you want an inversion, you need a catalytic nucleophile (e.g. lewis-base or heteroatom-solvent) which basically is cheating the mechanism because the nucleophile inverts the stereocenter, not the chloride, which itself inverts the new stereocenter. The mechanism as drawn above is wrong. It’s not a white lie, it’s just a wrong mechanism. SOCl2 is specifically used for retention!

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aısha May 29, 2013 at 4:04 am

hi
i want to buy of you 2mt thionyl chloride first to check the quality and your ability on shipping it to tehran
then after it i will buy 20mt
yours trully

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james May 29, 2013 at 4:47 pm

Oh sure, I’ll have your 2 metric tons of SOCl2 sent to Tehran by next Tuesday.

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Sumit July 29, 2013 at 11:58 am

You said that SOCl2 is sovent dependent. So please tell me What happens when SOCl2 reacts with (S)-2-butanol in presence of ether and also what happens when solvent is pyridine?
The far I can guess that Both the solvents are polar aprotic and the reaction will go for Sn2 mechanism. So Tell me where will retention and where will inversion will occur. And also the products’ name from the reaction.

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uday October 29, 2013 at 5:20 am

i want to ask you sir .in mechanism of formation of chloroalkane with socl2 why sulphur is attracting electrons of oxygen yet oxygen is more electronegative?
please reply.

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ajay December 24, 2013 at 12:59 pm

sir as a viewer has asked about this rxn in presence of pyridine pls show it also as it may enhance understanding.according to me pyridine would accept h+ from hcl and give cl- and normally the product has retention of configuration and using pyridine may give excess cl- will give inversion product

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John Dominic January 18, 2014 at 6:39 am

I really wonder if SOCl2 could produce a dense fumes or cloud of SO2 or HCl when spilled into water… I mean, you can recreate it once again. Although in my observation, it is possible only if amines (any amines or ammonia) content is present. Then the fumes (white cloudy) is hard to expel, because they settle down and exhausting them will be difficult.

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James January 20, 2014 at 10:36 am

It most certainly does. Although you are correct that the react with amines or ammonia would be more rapid.

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John Dominic January 18, 2014 at 6:46 am

In my observation, I believe that synthesizing compound is one part, and separating the product and purifying and recrystallizing is the major part :)

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Cody March 14, 2014 at 11:23 pm

Nice Job here.
I do have a question. How does the a reaction proceed when there is both an alcohol and an ester present? Esterification of Amino Acids in the presence of thionyl chloride and methanol for example. I assume it is a competing reaction, but the thing that confuses me is ester product is favored, while the alcohol seems to be more reactive.
Any comments would be appreciated, Thanks.

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Michael March 18, 2014 at 10:10 pm

Does anyone have an experimental procedure for actually performing a chlorination of an alcohol with inversion of configuration? I’ve found lots of slides and lectures notes on the theory behind the mechanism, but nothing stepwise showing how it was really performed in a lab and what yields were achieved in the product.

I recently tried this experiment with a trans-4-t-butylcyclohexanol/pyridine and SOCl2 and seemed to fail quite miserably.

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patel viral June 3, 2014 at 3:02 am

is it possible to convert ketone(C=O) into chloride(C-Cl) by by thionyl chloride and DMF?

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James June 26, 2014 at 5:20 pm

No, it isn’t. By itself, the process you describe is a reduction.

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ANUP KUMAR June 11, 2014 at 3:09 pm

Thanks for the blog. I am very thankful to you. :)

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