SOCl2 and the SNi Mechanism

by James

in Alcohols

Some time ago I published this post on Reagent Friday discussing the mechanism of SOCl2 converting secondary alcohols to alkyl chlorides with secondary  through an SN2 pathway: 
SOCl2 mechAbout six months ago this post arrived in the comments: 

2-Blog_Comment

Slapdown! First of all, Rico is correct that the mechanism showing inversion with SOCl2 is not what happens experimentally. When a secondary alcohol is treated with SOCl2 (and nothing else) the usual pathway is retention

The record should be set straight about this, so this post will cover: 

  1. What really happens in the reaction of SOCl2 with secondary alcohols (the SNi mechanism) and why it gives retention
  2. Why adding pyridine to SOCl2 results in inversion (via SN2) and not retention
  3. How do most textbooks and schools across North America deal with this mechanistic dichotomy (hint: most don’t)
  4. What’s an instructor to do? 

1. What Really Happens In The Reaction Of SOCl2 With Secondary Alcohols: The SNi Mechanism

In the late 19th century, Paul Walden performed a series of fundamental experiments on the stereochemistry of various reactions of sugars (and sugar derivatives). Walden noted that when (+)-malic acid  treated with PCl5, the product was (–) chlorosuccinic acid – a process that proceeded with inversion of stereochemistry. When (+) malic acid was treated with thionyl chloride (SOCl2), however the product was (+)-chlorosuccinic acid. This proceeds with retention of stereochemistry. 

3-walden

How can we understand this? 
The reaction of malic acid with PCl5 leading to inversion of stereochemistry is an example of what we now call the SN2 reaction, and Walden was the first to make the observation that the stereochemistry is inverted. In fact the process of stereochemical inversion observed during the SN2 reaction is sometimes called Walden inversion in his honor. By the time most students encounter SOCl2 in their courses, the SN2 is a familiar reaction. 

What is much more curious is the  observation that malic acid treated with SOCl2 leads to substitution with retention.  Sharp readers may recall that “retention” of stereochemistry can be obtained if two successive SN2 reactions occur [double inversion = retention]. Perhaps that is what is going on here? Maybe the carboxylic acid of malice acid can act as a nucleophile in a first (intramolecular) SN2, and then Cl- coming in for the second? 

 Good idea – but this retention of configuration occurs even in cases where no group can possibly perform an intramolecular SN2. There must be something else going on. And after a lot of experimental work, this is the best proposal we have: 

4-sni

This is called, SNi (nucleophilic substitution with internal return): what happens here is that SOCl2 corrdinates to the alcohol, with loss of HCl and formation of a good leaving group (“chlorosulfite”). The chlorosulfite leaving group can spontaneously depart, forming a carbocation, and when it does so,  an “intimate ion pair” is formed, where the carbocation and negatively charged leaving group are held tightly together in space. From here, the chlorine can act as a nucleophile – attacking the carbocation on the same face from which it was expelled – and after expulsion of SO2, we have formation of an alkyl chloride with retention of configuration. 

So the chlorosulfite leaving group (SO2Cl) is quite special in that it can deliver a nucleophile (chlorine) to the same face it departs from, with simultaneous loss of SO2

If it ended there, life might be simpler. But less interesting! [That is the sound of a can of worms being opened]

2. Why Adding SOCl2 And Pyridine Leads To Inversion (via SN2)

Here’s the twist.  As it turns out, the stereochemistry of this reaction can change to inversion if we add a mild base – such as pyridine.  

5-base-inversion

Retention of stereochemistry with SOCl2 alone, inversion with SOCl2 and pyridine. What’s happening here? How does pyridine affect the course of this reaction? 

Both reactions form the “chlorosulfite” intermediate. But when pyridine (a decent nucleophile) is present, it can attack the chlorosulfite, displacing chloride ion and forming a charged intermediate. Now, if the leaving group departs, forming a carbocation, there’s no lone pair nearby on the same face that can attack.

In other words, by displacing chloride ion, pyridine shuts down the SNi mechanism

Even though the SNi can’t occur here, we still have a very good leaving group, and a decent nucleophile – chloride ion – and so chloride attacks the carbon from the backside, leading to inversion of configuration and formation of a C-Cl bond. This, of course, the SN2 reaction. 

6-base-inversion-mech

The bottom line is this: 

SOCl2 plus alcohol gives retention of configuration, SOCl2 plus alcohol plus pyridine gives inversion of configuration (SN2) 

7-bottom line

You might be asking, “how common is this SNi mechanism? Is it something which occurs in a large number of other reactions we commonly encounter in introductory organic chemistry?”

To be frank, not really. There are some cases where species called chloroformates can also undergo the SNi with loss of CO2 but this isn’t seen very often at all in your typical first year course. 

So here comes the dilemma. 

3. How do most textbooks and schools across North America deal with this mechanistic dichotomy?

Conversion of alcohols to alkyl halides is a useful transformation because alcohols are poor leaving groups by themselves, whereas alkyl chlorides will readily participate in substitution and elimination reactions. In many introductory organic chemistry courses, SOCl2 has traditionally been used as an example of a reagent that will convert alcohols to alkyl chlorides. 

When I consulted my textbook collection for how the mechanism is covered, here’s what I found: 

  • Wade (5th ed. p 463) Shows conversion of secondary alcohol to secondary alkyl chloride via SNi (with dioxane solvent)
  • Solomons (8th ed p. 506-507) Shows conversion of primary alcohol to primary alkyl chloride via SN2. No mention of SNi or stereochemistry.
  • McMurry (6th ed p. 608) Shows conversion of primary alcohol to primary alkyl chloride (SN2) No stereochemistry shown. 
  • Vollhardt (2nd ed p. 288) Shows mechanism (SN2) for primary alcohol; no discussion of SN2. 
  • Jones (2nd ed p. 830) Shows SN2 of Cl on “R” ; no mention of stereochem
  • Clayden, Klein – no mention of SOCl2 as a reagent for converting alcohols to alkyl chlorides

Only one textbook (in this admittedly incomplete sample) mentions the SNi mechanism at all. In four textbooks where SOCl2 is mentioned, the reaction is shown as proceeding through an SN2 mechanism. There’s no warning sign saying, “wait! the SN2 doesn’t happen for secondary alcohols”. If it’s not in the textbook, chances are it won’t be in the course.  So it’s not surprising that the most common interpretation of this is that inversion will occur for secondary alcohols: 
This leads to situations like the following. Here is a part of an exam key from a very non-obscure R1 university: 

Inversion

This is a question that tests stereochemistry, and students are expected to write that the SOCl2 proceeds with inversion at a secondary carbon, proceeding through an SN2 mechanism. 

There are exceptions. Another school *of similar reputation) tests this reaction as an SNi. 

Retention

In summary, across North America at least, the discussion of the stereochemistry of SOCl2 reactions with secondary alcohols is a huge mess. I don’t have any data to back this up, but in all my hours of tutoring I have encountered the SNi reaction of SOCl2 being taught… once. 

4. So What’s An Instructor To Do?

First of all, a mea culpa. I drew the SOCl2 as proceeding through inversion and an SN2 process because I’ve aimed the Reagent Guide at the broadest sub-section of students, and it’s most often taught as giving inversion. I should have been more clear that it was more complicated and there was so much confusion on the topic – so I’m grateful to commenters like Rico and others who have brought this to my attention.  

Organic chemistry is so wonderfully rich and deep. With the luxury of having already learned all this stuff, I can look back and find it fascinating that just by switching from a primary to a secondary carbon, or from switching to a SO2Cl leaving group, one can change the mechanism from SN2 to SNi. The leaving group can provide its own nucleophile! How cool! 

If I was in an introductory class with a full course load and a lot of other lab courses however, my attitude might be different: more like, “Jeezus, YHGTBFKM, is this ever obscure.” 

I’ve asked other instructors what they do when they encounter this topic. Here’s what one has to say:

At the second yr / intro level, we keep it very simple. We only talk about it being an SN2 and going with inversion and thus complementary to the HX reactions. We ignore solvent effects for the thionyl chloride reactions.

Here’s another: 

I teach it as inversion. Oxygen attacks sulfur, kicks out chloride. Pyridine deprotonates oxygen. Chloride attacks carbon, C-O bond breaks to form 2nd pi bond of SO2, kicks out chloride. Inversion of stereochemistry as chloride attack is SN2-like.

 It’s an instructors’ prerogative to pick their battles. I can completely understand how time and attention are limiting factors, and instructors inevitably have to make compromises about what gets included, what gets skipped, and how much detail they choose to include.  The fundamental lesson here – to pay attention to stereochemistry of chiral alcohols when converting to alkyl chlorides – is ultimately more important than whether the reaction goes SN2 or SNi in certain situations. However,  it would be really nice to see more consistency on this reaction from the textbook writers so that everyone is singing from the same hymnal. 

This instructor said it best: 

Some of my colleagues just use PCl5 and move on with their lives : – )

 

 

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{ 26 comments… read them below or add one }

mevans

Thanks for this, James. I’d say you threw the book on his slapdown! This is clearly a complicated issue.

Now, hindsight is 20/20, but I suppose it makes pretty good sense that chloride, a weak nucleophile, doesn’t displace chlorosulfite in an SN2 fashion.

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azmanam

Could you invoke the thermodynamic stability and entropic favorability of forming SO2 gas as a factor in why chloride might displace chlorosulfite in SN2?

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James

I probably shouldn’t have written “slap down”, I am glad he brought this subject up.

PCl5 is sufficient to result in inversion of alcohols via an SN2 process with chloride as nucleophile so even with hindsight I think it’s hard to see.

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RxnRunner

I was taught that in this context retention of configuration is due to the fact that two net inversions occur. The first inversion takes place when the amine (or pyridine in this case) performs an Sn2 displacement on the chlorosulfite. This would generate SO2, the chloride ion, and the activated pyridinium moiety. The second inversion occurs when the chloride ion displaces the pyridine group, resulting in an overall retention of stereochemistry. Would there be an easy way to test the mechanism you propose?

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James

If there are two SN2 reactions then we would expect complete retention of stereochemistry. In the SNi process we are going through an intimate ion pair – there is a carbocation, so we should see some leakage of the optical purity through a pure SN1 type pathway. If we started with an optically pure chlorosulfite I would expect that the optical purity would decrease with increasing reaction temperature or increasing solvent polarity as both of these factors should disrupt the intimate ion pair.

Also I don’t believe that pyridine would be selective for an aliphatic secondary carbon over the electrophilic sulfur, but one could alternatively measure the reaction rate with respect to pyridine concentration. If it’s straight SN2, you’d expect a linear increase in rate with increasing pyridine conc, whereas if it’s the proposed SNi, you’d see a plateau in reaction rate with increased pyridine conc since the slow step will likely be ionization, not attack at sulfur.

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Abhijit

With reference to the reaction of SOCl2 with secondary alcohol in presence of pyridine, pyridine acts as a base and it removes the proton from HCl, resulting in formation of free Cl- ion, and Cl-, being an effective nucleophile, attacks Chlorosulphite from the back in normal SN2 fashion.

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Arkya

Is this mechanism of SNi applicable only for secondary alcohols or for all alcohols in general?

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Jeremy

I don’t think you’d need to worry about this with primary alcohols since the active site wouldn’t be a stereocenter (hence no stereochemistry to invert or retain).

With tertiary alcohols, the carbocation formed is much more stable so you’re more likely to get a racemic mixture.

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James

Yes, exactly right about point 1.

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Jane

With tertiary alcohols, the carbocation formed is much more stable. But there are many alkyl groups around carbocation, anion can not attack it because of steric effect i think. So the anion will attack β H, product would be alkene i think.

In SNi mechanism, when carbocation is formed, does carbocation rearrangement occur like common SN1 mechanism?

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Arush

@Arkya, I suppose that the secondary alcohol is just to prevent the migration of an alkyl group (as the case may be) to form a more stable carbocation. Frankly speaking, I do not see why this shouldn’t take place in a primary alcohol as well.
Could someone please verify?

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Spud

Why is it necessary for pyridine to act as a nucleophile? Being the stronger base, wouldn’t it just deprotonate the protonated chlorosulfite leaving the chloride free for an SN2 reaction. There seem to be many reasonable variations here. For me with respect to inversion, the simpler the better. Where is the literature on this that will clean up the inversion mechanism?

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James

I’d refer you to March’s Advanced Organic Chemistry (I used 5th ed but any ed. will do) for a full discussion. James

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Patrick

First, I have to say that Rico was wrong by saying that Alcohols and SOCl2 ALWAYS react with retention of configuration.

Sometimes, you can get retention of configuration and sometimes inversion of configuration. The key thing to remember is the solvent use in the reaction.

If you want a better understanding of what is going on you must consult the primary litterature on the topic. I suggest for all of you reading these books and articles :

Carey and Sundberg Part A Advanced organic chemistry
J. Org. Chem., 2013, 78 (5), pp 2118–2127
J. Org. Chem., 1993, 58, pp 2822
and references therein

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Vaibhav

Can R-OH +PCL5 show SNi

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James

To the best of my knowledge SNi is mainly observed with SOCl2.

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Look@s

There is another thing here: you (and many others, me too in the past) formulate the initial SN reaction at sulfur (not carbon!) as proceeding via addition/elimination. That is of course an analogy to the reaction of carbonyl compounds. It is probably more realistic to formulate it as a concerted substitution at sulfur. That is because the S=O “double bond” is not really a double bond, but a polarized single bond, thus it may not actually like to react by addition/elimination mechanisms.
See for the similar case of the first step in acid chloride formation from SOCl2, which Henry Rzepa calculated: http://www.ch.imperial.ac.uk/rzepa/blog/?p=6816

As concerns the main question of SN2 vs SNi (with retention) in SOCl2 initiated alcohol chlorinations:
• my experience tells me that generalizations made in textbooks often rely on very few actual examples in the literature, which are introduced at some point and then copied by other authors. Many of the examples are from the older (pre-NMR, HPLC) literature and might not always survive a more accurate reinvestigation with modern analytical techniques.
• the example you give for SNi (malic acid) is maybe not good, because they might show neighboring group effects with double SN2; better examples for SNi are chiral alcohols with no neighboring groups in the molecule.
• The malic acid examples are (with other reaction conditions: PCl5) classical examples for Waldens inversion, but again such old chemistry is often less well understood than textbooks might imply. See for a recent discussion of the Walden examples: http://pubs.rsc.org/en/Content/ArticleLanding/2006/CC/b517461a
• Personally, I have started checking the original literature to most of the reaction examples I teach in my lecture. Also, I hardly use any hypothetical problems any longer in tests, but I search actually performed examples via Reaxys.

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Alan

One of my o chem students brought me to this post today. Nice exposition. I’m one of those guilty instructors, both in terms of what I teach and how it shows up on exams.

Here’s a pet peeve: the Lewis structures in this post. The structures never show the lone pair on S so it often appears that S should be charged. Of course, getting all the S chemistry and structural info right is just an added hassle when teaching this material (and I don’t think PCl5 solves this problem either) so maybe we are obliged to simplify? Or as you put it so nicely, we have to pick our battles. Still, there should be some way to inform students that the story we are telling is incomplete, no?

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Yash

Is this only in case of secondary alcohols?
And is this SNi only for SOCl2 and not others from its family(PBr3, PCl5 etc)
Why????

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James

Only for SOCl2 and not PBr3, PCl5. The mechanism is largely for secondary alcohols. It’s not impossible for it to operate with primary alcohols, but you would be unlikely to be able to tell given that there is no stereocenter possible.

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Ramnath Mallah

carboxylic acid won’t interfere with SOCl2 in case of malic acid..? how carboxylic acid remain unaffected..?
plz check example 2 in given link
https://www.masterorganicchemistry.com/2011/12/03/reagent-friday-thionyl-chloride-socl2/

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Tobias

Hi there,
Great explanations! In your mecanism “Why does SOCl2 give retention” you noted that chlorosulfite can be isolated. How is this possible? Do you have any supporting litterature on the subject?

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James

Hi, I would suggest looking it up here, http://pubs.acs.org/doi/abs/10.1021/ja01098a024 . You can also go to March’s Advanced Organic Chemistry and look up “chlorosulfite”.

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Joanna

In the problem with malic acid why does the alcohol group react and not the carboxylic acid? It’s more reactive I thought.

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Naveen Reddii

@Hi everyone..
1. I think The SNi only goes well for primary, secondary alcohols with SOCl2, tertiary alcohols will undergo elimination, along with substitution. Any comments on this…
2. I suppose the kinetics of reaction to be first order, the formation of intimate pair from chlorosulphite is RDS. Any comments…

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Rupinder Singh

Hi James.
I’m a Chemistry teacher and we recently had a question in a paper in our institute.
The question used an epoxide and reacted with PCl5 to give a dichloro product. Now the doubt that arose amongst us is whether the 2nd Cl atom will add via SNi or SN2.
I have not been able to find any source online which has an example of an epoxide reacting with PCl5.

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