SN2 versus SNi | Chemistry Optional Notes for UPSC PDF Download

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:

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

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?

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:
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.

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.
Observation: When base is added, SOCl₂ now gives 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.

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.

Why inversion this time? Because pyridine displaces chlorine from sulfur, and "internal return" from the leaving group cannot occur
The result is an S_N2 reaction!

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)