[vaduvur]

Hi all,

I'm looking at ways to selectively allylate a secondary amine (with allyl bromide), in the presence of a primary alcohol 2 carbons away. Literature search suggests that 1.5 eq of a base like K2CO3 and 2.0 eq of allyl bromide should do it. How come the OH doesn't get allylated, under these conditions?

Thanks for your time.

vaduvur

[James Newby]

Hi, i did an allylation a couple of weeks ago.

The nitrogen is a better nucleophile than the alcohol on oxygen.  ie the N can tolerate a positive charge better than the O.

I was lucky that my oxygen had a protecting group on it.  The allylation didnt work at room temp so i refluxed over the weekend

[vaduvur]

The nitrogen is a better nucleophile than the alcohol on oxygen.

Great Jim. Thanks.

How then would one explain the selective O-allylation of a primary alcohol, in the presence of a secondary amine, in the following papers?

JACS/2003/15796
Synthesis/2006/4087

They use NaH, and premix the starting material with the base and a Phase Transfer Catalyst (optional), before adding the allyl bromide.

vaduvur

[James Newby]

under basic conditions the more acidic OH proton is removed.  This now makes the oxygen a better nucleophile so allylation occurs here instead.

Allylation with nitrogen doenst need the basic conditions, just some K2CO3 to mop up the HBr formed.

Please dont call me Jim, its my uncles name not mine!

[cundi]

The key question is the base that you need to use and its role in the reaction.
The amine does not need base to attack the allylbromide. The alcohol does not attack by itself; it is the alcoholate which reacts with the Br-allyl
In the case that you had mentioned, I think that the base is use as scavenger of the HBr generated.
So if you use K2CO3, probably you are not able to generate the alcoholate, but it is enough to neutralized the acid formed.

I hope it can help you.

[vaduvur]

under basic conditions the more acidic OH proton is removed.

Quantitatively, what would be a good way to understand this concept? Considering that the pKa of a secondary amine is lower than that of a primary alcohol (http://www.chem.wisc.edu/areas/reich/pkatable/index.htm and http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf), am I wrong in assuming that any base that's good enough to deprotonate a primary -OH will most certainly deprotonate a secondary -NH, perhaps preferentially?

The amine does not need base to attack the allylbromide.

If a base is added to the substrate, though, wouldn't it preferentially abstract the NH-proton, over that of the -OH?

The following paper -- Tetrahedron Letters / 1999 / 7581 -- where reacting a secondary-amino-tetra-primary-alcohol in pyridine and excess acetic anhydride gave the non-N-Acylated tetra-acetate in 60% yield beats me.

Thanks.

[Squirmy]

I can understand your confusion...the second link lists pKa's for amines (similar to ammonia, NH3), but in actuality the values are for ammonium ions (similar to NH4+).

A neutral amine (pKa ~ 35-40) is generally much less acidic than an alcohol (pKa ~ 16-20), but an ammonium ion (pKa ~ 9-11) is more acidic than an alcohol.

[vaduvur]

I can understand your confusion...the second link lists pKa's for amines (similar to ammonia, NH3), but in actuality the values are for ammonium ions (similar to NH4+).

 

Ah, that helps. Thanks. So I suppose the pKa of neutral pyridine is around 20?

[sjb]

Obviously it depends what pyridine proton (alpha, beta or gamma) you're removing, but I'd think that the Ka for the C₅H₅N  C₅H₄N^- + H⁺ equilibria would be considerably lower, and so a much higher pKa ?

[macman104]

Vaduvur, you could also reason that alcohols should in general be more acidic.  The bond between O-H is more polarized than N-H, oxygen is more electronegative and can stabilize a negative charge better than nitrogen can.  These factors all lead to an increase in acidity.

[vaduvur]

Vaduvur, you could also reason that alcohols should in general be more acidic.  The bond between O-H is more polarized than N-H, oxygen is more electronegative and can stabilize a negative charge better than nitrogen can.  These factors all lead to an increase in acidity.