SOCl2 Mechanism For Alcohols To Alkyl Halides: SN2 versus SNi

SOCl₂ Mechanism With Alcohols, With And Without Pyridine: Nucleophilic Substitution (S_N2) Versus Nucleophilic Substitution With Internal Return (S_Ni)

• Most of the time, the reaction of alcohols with thionyl chloride is taught as an S_N2 reaction. And indeed, on primary alcohols this is definitely the case.
• The problem arises with secondary alcohols, where the reaction can be taught either as a classical S_N2 with inversion, or… as a reaction with retention!? via the S_Ni mechanism. That latter part is what this post is about.

Table of Contents

1. “I’m Sorry But Who Taught You That Mechanism” ?
2. What Really Happens In The Reaction Of SOCl₂ With Secondary Alcohols: The S_Ni Mechanism
3. Nucleophilic Substitution With Internal Return: S_Ni
4. Adding SOCl₂ AND Pyridine Leads To Inversion (via S_N2)
5. Pyridine Shuts Down The S_Ni Mechanism
6. Summary: SOCl₂ And Alcohols – S_N2 versus S_Ni
7. Notes: How Do Schools In North America Deal With This Dichotomy?
8. (Advanced) References and Further Reading

1. Conversion Of Alcohols To Chlorides With SOCl₂ Proceeds With Inversion…Right? Well, Maybe Not Always

Some time ago I published this post about SOCl₂ discussing the mechanism of SOCl₂ converting secondary alcohols to alkyl chlorides with secondary  through an S_N2 pathway:

About six months ago this post arrived in the comments:

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 S_Ni mechanism) and why it gives retention
2. Why adding pyridine to SOCl₂ results in inversion (via S_N2) 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?

2. What Really Happens In The Reaction of SOCl₂ With Secondary Alcohols: The S_Ni 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. 

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 S_N2 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 S_N2 reaction is sometimes called Walden inversion in his honor. By the time most students encounter SOCl₂ in their courses, the S_N2 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 S_N2 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) S_N2, and then Cl- coming in for the second?

3. Nucleophilic Substitution With Internal Return: S_Ni

Good idea – but this retention of configuration occurs even in cases where no group can possibly do an intramolecular S_N2. There must be something else going on. And after a lot of experimental work, this is the best proposal we have:

This is called, S_Ni (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].

4.Why Adding SOCl₂ AND Pyridine Leads To Inversion via The S_N2 Mechanism

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.

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 S_Ni mechanism.

5. Adding Pyridine To SOCl₂ Shuts Down The S_Ni Mechanism

Even though the S_Ni 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 S_N2 reaction.

6. Summary: SOCl₂ And Alcohols, With Or Without Pyridine – S_N2 Versus S_Ni

The bottom line is this:

SOCl₂ plus alcohol gives retention of configuration, SOCl₂ plus alcohol plus pyridine gives inversion of configuration (S_N2)

You might be asking, “how common is this S_Ni 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 S_Ni with loss of CO₂ but this isn’t seen very often at all in your typical first year course.

Notes

This might not interest everybody so I’m putting it in a note.

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 S_Ni (with dioxane solvent)
• Solomons (8th ed p. 506-507) Shows conversion of primary alcohol to primary alkyl chloride via S_N2. No mention of S_Ni or stereochemistry.
• McMurry (6th ed p. 608) Shows conversion of primary alcohol to primary alkyl chloride (S_N2) No stereochemistry shown.
• Vollhardt (2nd ed p. 288) Shows mechanism (S_N2) for primary alcohol; no discussion of S_N2.
• Jones (2nd ed p. 830) Shows S_N2 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 S_Ni mechanism at all. In four textbooks where SOCl₂ is mentioned, the reaction is shown as proceeding through an S_N2 mechanism. There’s no warning sign saying, “wait! the S_N2 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:

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 S_N2 mechanism.

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

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 S_Ni reaction of SOCl₂ being taught… once.

So What’s An Instructor To Do?

First of all, a mea culpa. I drew the SOCl₂ as proceeding through inversion and an S_N2 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 S_N2 to S_Ni. 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 S_N2 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 S_N2-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 S_N2 or S_Ni 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 : – )

(Advanced) References and Further Reading

1. Ueber die gegenseitige Umwandlung optischer Antipoden
   Walden
   Chem. Ber. 1896, 29 (1): 133–138
   DOI: 10.1002/cber.18960290127
   Original publication on Walden inversion.It is interesting to trace the development of this reaction mechanism through the literature. Early papers were in disagreement regarding the mechanism reconciling the observations that inversion of configuration was observed with base (e.g. pyridine), and retention of configuration without base.
2. Reaction kinetics and the Walden inversion. Part VI. Relation of steric orientation to mechanism in substitutions involving halogen atoms and simple or substituted hydroxyl groups
   W. A. Cowdrey, E. D. Hughes, C. K. Ingold, S. Masterman and A. D. Scott
   J. Chem. Soc. 1937, 1252-1271
   DOI: 10.1039/JR9370001252
   Prof. C. K. Ingold and Hughes developed the ‘S_N/E’ nomenclature used to describe reaction mechanisms, now known as the Hughes-Ingold nomenclature. In part C of this paper, they do note the observation that SOCl₂ alone reacts with secondary alcohols with retention of configuration, whereas SOCl₂+pyridine goes through inversion. However, no mechanism is proposed as they try to fit these observations into their limiting paradigm of S_N1 vs. S_N2.
3. The decomposition of chlorosulphinic esters
   Michael P. Balfe and Joseph Kenyon
   J. Chem. Soc. 1940, 463-464
   DOI: 10.1039/JR9400000463
   This early paper also features an attempt to rationalize the observed stereochemistries. Retention of configuration is due to “a molecular rearrangement the steric course of which is controlled by the dimensions of the chlorosulphinate molecule”, while inversion is caused by pyridine binding to sulfur. The yield of inverted product can be increased by using an excess of pyridine.
4. A Study of the Reaction of Alcohols with Thionyl Chloride
   William E. Bissinger and Frederick E. Kung
   Journal of the American Chemical Society 1947, 69 (9), 2158-2163
   DOI: 10.1021/ja01201a030
   A nice study on the reaction of alcohols with SOCl2, useful if one is looking for a place to start optimization of this reaction (with regards to stoichiometry).
5. The Kinetics and Stereochemistry of the Decomposition of Secondary Alkyl Chlorosulfites
   Edward S. Lewis and Charles E. Boozer
   Journal of the American Chemical Society 1952, 74 (2), 308-311
   DOI: 10.1021/ja01122a005
6. The Decomposition of Secondary Alkyl Chlorosulfites. II. Solvent Effects and Mechanisms
   E. Boozer and E. S. Lewis
   Journal of the American Chemical Society 1953, 75 (13), 3182-3186
   DOI: 10.1021/ja01109a042
   Ref. 4 describes mechanisms for the decomposition of secondary alkyl chlorosulfites. Apparently different mechanisms are in effect when these are decomposed in dioxane or toluene. In dioxane, retention of configuration is observed, while in toluene inverted chlorides are obtained. This is ascribed to the ability of dioxane to coordinate to the carbon and assist with C-S bond cleavage.
7. Studies in Stereochemistry. XVI. Ionic Intermediates in the Decomposition of Certain Alkyl Chlorosulfites
   Donald J. Cram
   Journal of the American Chemical Society 1953, 75 (2), 332-338
   DOI: 10.1021/ja01098a024
   An early paper by Prof. D. J. Cram (UCLA), who was a contemporary of Prof. Saul Winstein (who came up with the concepts of ‘internal return’ and ‘intimate ion pair’ used to describe this S_Ni mechanism). Prof. Cram would later on receive the Nobel Prize in Chemistry in 1987 for his work on molecular host-guest chemistry. This is the paper rationalizing the differing stereochemistries of the reaction of alcohols with SOCl₂ in the presence/absence of base (e.g. pyridine) and is the first paper in the literature describing the reaction of alcohols + SOCl₂ as an S_Ni process.
8. The textbook March’s Advanced Organic Chemistry (7^th) mentions:
   “[…] the reaction of alcohols with thionyl chloride to give alkyl halides usually proceeds in this way, with the first step in this case being ROH + SOCl₂ à ROSOCl (these alkyl chlorosulfites can be isolated).
   Evidence for this mechanism is as follows: The addition of pyridine to the mixture of alcohol and thionyl chloride results in the formation of alkyl halide with inverted configuration. Inversion results because the pyridine reacts with ROSOCl to give ROSONC₅H₅ before anything further can take place. The Cl^– freed in this process now attacks from the rear. The reaction between alcohols and thionyl chloride is second order, which is predicted by this mechanism, but the decomposition by simple heating of ROSOCl is first order”.
   Unfortunately, no references are provided.Prof. Jih Ru Hwu (now in Taiwan) attempted to popularize reagents that would react via internal return (such as SOCl₂) as ‘ Counterattack Reagents’ early in his career:
9. Counterattack reagents in organic reactions and in syntheses
   Jih Ru Hwu, Bryant A. Gilbert
   Tetrahedron 1989, 45 (5), 1233-1261
   DOI: 10.1016/0040-4020(89)80123-1
10. Silicon reagents in chemical transformations: the concept of ‘counterattack reagent’
    R. Hwu, S.-C. Tsay, K. Y. King and D.-N. Horng
    Pure Appl. Chem. 1999, 71 (3), 445-451
    DOI: 10.1351/pac199971030445