[e.d.kim]

Hello!

I need to present an article about a drug synthesis. I cannot rationalise one step in the synthesis.

The step is shown below:



My questions are:

1) Why does acetic anhydride not touch the hydroxyl group on the carbon number 1?

2) Similarly, why does phosphorus tribromide formed by the reaction of the red phosphorus with bromine only react with the hydroxyl group on the first carbon?

Thanks in advance

[Dan]

My questions are:

1) Why does acetic anhydride not touch the hydroxyl group on the carbon number 1?

2) Similarly, why does phosphorus tribromide formed by the reaction of the red phosphorus with bromine only react with the hydroxyl group on the first carbon?

1. How do you know Ac₂O doesn't react at O1?

2. What is the functional group at C1?

[e.d.kim]

1. You mean the carbon 1?

2. The functional group at C1 is a hemiacetal. But phosphorus tribromide can also react with hydroxyl groups on other carbons, can't it?

[Dan]

1. You mean the carbon 1?

No, oxygen 1. Ac₂O is reacting at O, not C.

2. The functional group at C1 is a hemiacetal. But phosphorus tribromide can also react with hydroxyl groups on other carbons, can't it?

Potentially. Usually this reaction is done in two stages - the Ac₂O is added first, then PBr₃ (or P/Br₂) is introduced after the acetylation is complete.

What is the mechanism of bromination at C1? Why might it occur more easily at C1 than the other positions?

[e.d.kim]

Oh, I'm getting something.

1) What if the acetic anhydride does react with oxygen 1? This happens in the first step.

2) Then in the second step the bromide substitutes the acetoxy group.

3) The second step happens only on the carbon 1 because it is more electrophilic than other carbons.

How does it sound.

[Dan]

3) The second step happens only on the carbon 1 because it is more electrophilic than other carbons.

Why is it more electrophilic? What is the mechanism?

[e.d.kim]

3) The second step happens only on the carbon 1 because it is more electrophilic than other carbons.

Why is it more electrophilic? What is the mechanism?

The mechanism is following:

1) The oxygen of the hydroxyl group 1 reacts with the phosphorus electrophile, and the bromide leaves. This is an SN2 reaction. The step creates a phosphorus ester which is a good leaving group.

2) The bromide formed in 1) reacts with the C1. This is also an SN2 reaction.

3) The 2) happens on the carbon 1 because other carbons have poorer leaving groups (acetoxy- groups). Plus, the C1 is more electrophilic as it is connected to two oxygens.