Alcohols, Epoxides and Ethers
SOCl2 Mechanism For Alcohols To Alkyl Halides: SN2 versus SNi
Last updated: August 11th, 2022 |
SOCl2 Mechanism With Alcohols, With And Without Pyridine: Nucleophilic Substitution (SN2) Versus Nucleophilic Substitution With Internal Return (SNi)
Most of the time, the reaction of alcohols with thionyl chloride is taught as an SN2 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 SN2 with inversion, or… as a reaction with retention!? via the SNi mechanism. That latter part is what this post is about.
Table of Contents
- “I’m Sorry But Who Taught You That Mechanism” ?
- What Really Happens In The Reaction Of SOCl2 With Secondary Alcohols: The SNi Mechanism
- Nucleophilic Substitution With Internal Return: SNi
- Adding SOCl2 AND Pyridine Leads To Inversion (via SN2)
- Pyridine Shuts Down The SNi Mechanism
- Summary: SOCl2 And Alcohols – SN2 versus SNi
- Notes: How Do Schools In North America Deal With This Dichotomy?
- (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 on Reagent Friday discussing the mechanism of SOCl2 converting secondary alcohols to alkyl chlorides with secondary through an SN2 pathway:
About six months ago this post arrived in the comments:
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:
- What really happens in the reaction of SOCl2 with secondary alcohols (the SNi mechanism) and why it gives retention
- Why adding pyridine to SOCl2 results in inversion (via SN2) and not retention
- How do most textbooks and schools across North America deal with this mechanistic dichotomy (hint: most don’t)
- What’s an instructor to do?
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 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:
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.
If it ended there, life might be simpler. But less interesting! [That is the sound of a can of worms being opened].
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.
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.
The bottom line is this:
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.
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 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:
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.
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.
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.
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 : – )
- Ueber die gegenseitige Umwandlung optischer Antipoden
Chem. Ber. 1896, 29 (1): 133–138
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.
- 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
Prof. C. K. Ingold and Hughes developed the ‘SN/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 SN1 vs. SN2.
- The decomposition of chlorosulphinic esters
Michael P. Balfe and Joseph Kenyon
J. Chem. Soc. 1940, 463-464
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.
- 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
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).
- 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
- 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
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.
- 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
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 SNi 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 SNi process.
- The textbook March’s Advanced Organic Chemistry (7th) 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:
- Counterattack reagents in organic reactions and in syntheses
Jih Ru Hwu, Bryant A. Gilbert
Tetrahedron 1989, 45 (5), 1233-1261
- 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