[Nescafe]

Hi,

Why is it that in most peptide coupling mechanisms such as that with cyanuric chloride to generate the acid chloride from the acid they always show the acid attacking first then deprotonation via base. Are not bases such as DIPEA or TEA (Pka 10 and 9 respectively) strong enough to deprotonate the acid first (giving it a negative charge) and then the anion makes the attack and not the neutral form?

Thanks,

Nescafe.

[NotExactly]

reactants such as cyanuric chloride and thionyl chloride are extremely reactive so even though you'd think that an acid-base reaction would happen first, the rates may be comparable (depending on your acid of course).  Another good thing to remember about these types of reactions is that you generally don't use stoichiometric amounts of your tertiary amine base.  It's only purpose here is to transfer protons so it is only needed in a catalytic amount. 

[Nescafe]

Well what I'm curious about is the correct way of drawing out the mechanism for when you have an acid, you add triethyl amine and a reagent like cyanuric chloride into a reaction vessel. Does the acid in its neutral form attack the reagent? Or does the base deprotonate it first and then the anion make the attack? The pka of dipea is 10, pka of a carboxylic acid is around 4 I'd expect the acid to be deprotonated first then attack reagent ( cyanuric chloride for example) but mostly I see the acid in its neutral form ( RCOOH) making the attack first then the base mops up the proton. I'm wondering which is the proper way.

Nescafé

[orgopete]

These mechanisms can be difficult to describe. I agree that triethylamine will form the carboxylate salt of the carboxylic acid at the start of the reaction. What sometimes happens is a generation of large amounts of acid may change the equilibrium. I think the cyanuric acid mechanism is probably entirely as the carboxylate salt.

[Nescafe]

These mechanisms can be difficult to describe. I agree that triethylamine will form the carboxylate salt of the carboxylic acid at the start of the reaction. What sometimes happens is a generation of large amounts of acid may change the equilibrium. I think the cyanuric acid mechanism is probably entirely as the carboxylate salt.

Thank you, it makes sense.

Nescafe.

[Doc Oc]

Hi,

Why is it that in most peptide coupling mechanisms such as that with cyanuric chloride to generate the acid chloride from the acid they always show the acid attacking first then deprotonation via base. Are not bases such as DIPEA or TEA (Pka 10 and 9 respectively) strong enough to deprotonate the acid first (giving it a negative charge) and then the anion makes the attack and not the neutral form?

Thanks,

Nescafe.

One thing of note, the pKa of TEA/DIPEA are not 9/10, those are the pKas of the protonated ammonium species.  Typical amine pKas are more in the 30-35 range, depending on the base.

Taking that into consideration, your peptide coupling reaction almost certainly proceeds through the carboxylate/ammonium intermediate due to the differences in pKa.  Alcohol protections often proceed first by attack of the alcohol and deprotonation afterwards.  Perhaps whoever showed you that mechanism confused the two.