Todd:Chem3x11 ToddL5

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Chem3x11 Lecture 5

Still under construction Sat May 5.

This lecture is about Neighbouring Group Participation (sometimes also called Anchimeric Assistance).

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Key concepts

• Groups/atoms with available electrons positioned near the carbon involved in a substitution reaction can influence the reaction
• 2
• 3

Simple Examples of NGP

A sulfur atom in the 2-position of an alkyl halide greatly increases the reactivity of that alkyl halide.

Scheme 1: Effect of a Sulfur Atom in the 2-Position of an Alkyl Chloride

This is not terribly surprising when you realise that S is a good nucleophile. Though we give these kinds of influences the fancy name of neighbouring group participation (NGP) or anchimeric assistance, keep in mind it's just intramolecular nucleophilic attack. The reaction goes through a high energy intermmediate (a sulfonium ion), and you might want to pause and think what that will mean in terms of its rate behaviour and whether this is an S_N1 or S_N2 reaction.

Scheme 2: Role of the Sulfur Atom in NGP

These kinds of structures (2-chlorothioethers) are sometimes called mustard gases, and were used with terrible effect as chemical weapons in World War I. The sulfonium ion can react with many biomolecules, yet if it reacts with water it produces HCl which can burn and blister the skin. This is an unusual example - chemistry is typically a Force for Good.

Besides effects on rates of reactions, NGP has very considerable influence on reaction stereochemistry, which we'll now look at.

Stereochemical Effect of NGP

What Happens in a Simple Case

If we imagine a molecule that could display NGP, but for some reason did not, then a regular S_N2 nucleophilic displacement would go with inversion of configuration. Obviously the diastereomer of the starting material behaves the same way.

Scheme 3: Direct S_N2 Nucleophilic Displacements without NGP

In fact what happens is this:

Scheme 4: Nucleophilic Displacements with NGP

Whatever you do, don't memorize this. We need to look at the mechanism, when everything will become clear and obvious.

Why That Happens

Let's take the top example first, and redraw the molecule so that the internal nucleophile (SMe) is antiperiplanar to the tosylate, since this is the geometry required if there is going to be NGP.

Scheme 5: Redrawn Versions of the Starting Material (R,S)-Isomer

Now let's do the internal displacement, and draw the sulfonium ion in each case. Like any regular SN2 reaction (which this is not, because there's only one molecule involved, but the idea is the same) there is inversion at the centre where the attack happens.

Scheme 6: Formation of the Reactive Intermediate Sulfonium Ion

Notice how the intermediate has a kind of symmetry - it's chiral, but has an axis of rotational symmetry. The molecule is C₂ symmetric, which is an important kind of symmetry in organic chemistry. The upshot is that it doesn't matter where the acetate attacks, the end result will be the same molecule. But let's make sure:

Scheme 7: Attack of Acetate on C₂-Symmetric Sulfonium Ion

Now let's look at the other diastereomer of the starting material and see why the outcome is so different.

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