Leaving group question, pertaining specifically to amide hydrolysis

[HopefulMDclass2020]

I was under the impression that OH was a better leaving group than NH2. Why is it then, in amide hydrolysis that the NH3(after being protonated) leaves instead of the H2O (after it is protonated)?

Thanks in advance

---

Members don't see this ad.

 

[lifetothefullest]

Because NH3 is an excellent leaving group - even better than H20. Another way to think about it is that good leaving groups are weak Lewis bases. Why? Because you want something to stabilize the negative charge and something that wants to donate those electrons away is definitely not stable. NH3 is definitely a weaker base than water.

 

[Cawolf]

Because NH3 is an excellent leaving group - even better than H20.

NH3 is definitely a weaker base than water.

I disagree with these statements. The pkb of ammonia is 4.74 and the pkb of water is 7.00 - so clearly ammonia is a stronger base and likely a poorer leaving group than water.

@HopefulMDclass2020 Consider the conditions that amide hydrolysis occurs in. Even though it may be more favorable for water to leave, there is much more water (likely the solvent) than ammonia present for this reaction. All of the steps are reversible in this chemistry, so it all can happen, and will. The end products will be determined by thermodynamics and Le Chatelier's principle, which ultimately drive the reaction to the carboxylic acid product (or carboxylate under basic hydrolysis).

 

[lifetothefullest]

I disagree with these statements. The pkb of ammonia is 4.74 and the pkb of water is 7.00 - so clearly ammonia is a stronger base and likely a poorer leaving group than water.

Sorry, I misspoke. In general, leaving group strength is negatively correlated with Lewis base strength.

Consider the conditions that amide hydrolysis occurs in. Even though it may be more favorable for water to leave, there is much more water (likely the solvent) than ammonia present for this reaction. All of the steps are reversible in this chemistry, so it all can happen, and will. The end products will be determined by thermodynamics and Le Chatelier's principle, which ultimately drive the reaction to the carboxylic acid product (or carboxylate under basic hydrolysis).

Remember that thermodynamics tell you nothing about the kinetics of the reaction. OP's intuition is correct. I believe there is an equilibrium where your water does leave but all you would do then is essentially generate your initial reactant. So essentially your rate determining step will be governed by a partition of the R-C(OH)2(NH3) species back to reactant or over the transition state to the carboxylic acid.

 

[Cawolf]

Remember that thermodynamics tell you nothing about the kinetics of the reaction

Obviously, but this isn't a kinetically determined product. Amide hydrolysis is carried out under heat for extended duration. Your discussion about this reaction is inaccurate and misleading.

 

[lifetothefullest]

Obviously, but this isn't a kinetically determined product. Amide hydrolysis is carried out under heat for extended duration. Your discussion about this reaction is inaccurate and misleading.

Frankly, your thermodynamic argument does not answer the key question the OP is asking, which is why NH3 leaves and H20 does not. The product is the same - the carboxylic acid. The relative energies of products and reactants are the same. What you're missing is that you do get the partition in the intermediate where some goes back to reactant and some goes on to form product. Le Chatelier only applies to perturbed systems - systems that have been perturbed from equilibrium. You will find that even at equilibrium, the hydrolysis will occur. Why? Because of the partitioning of the intermediate. That's how the system works at equilibrium. Professors often complain about teaching students a concept and then the student goes and applies it to everything erroneously.

You want to just use the organic chemistry approach to it, fine. I don't care. If you want to understand any of the chemistry, you'll need to figure out for yourself how the kinetics works and work out the rate law. That's how chemistry is done.

 

[RH8448]

I will make a guess - someone correct me if I'm wrong. I will go through the thought process. H3O+ is a stronger acid than NH4+. This means that the conjugate base of H3O+ is weaker than NH4+. A weaker conjugate base is a better LG. So H2O is a better LG than NH3+. Think: HCl a strong acid - the Cl- is a great LG.

Does anyone know if the hydrolysis of an amide involves adding a series of acids and bases to the reaction at different steps? Because this would make sense to me, however, I also read that the hydrolysis of amides occurs in basic and acidic conditions.

 

[lifetothefullest]

I will make a guess - someone correct me if I'm wrong. I will go through the thought process. H3O+ is a stronger acid than NH4+. This means that the conjugate base of H3O+ is weaker than NH4+. A weaker conjugate base is a better LG. So H2O is a better LG than NH3+. Think: HCl a strong acid - the Cl- is a great LG.

Yes, that is the OP's point. But we know that the hydrolysis still occurs even though water is a better leaving group. In other words, water does not leave to give you your reactants back but ammonia leaves to give your product even though it's not as good of a leaving group.

Does anyone know if the hydrolysis of an amide involves adding a series of acids and bases to the reaction at different steps? Because this would make sense to me, however, I also read that the hydrolysis of amides occurs in basic and acidic conditions.

That would be quite the hassle! I believe it's either acid catalyzed or base catalyzed - you just need one or the other.

 

[Cawolf]

@lifetothefullest

If it makes you happy to keep saying nonsense, then go ahead. I am unfollowing this thread.

 

[lifetothefullest]

@Cawolf Sorry that you're so narrow-minded you can't accept that you're wrong. #notsorry I really hope you can educate yourself on this sort of chemistry. Or not. Whatever floats your boat.

Unless you can tell everybody why you're applying Le Chatelier to understand an equilibrium process that has not been perturbed from equilibrium or how "thermodynamics" tells you that the ammonia and only the ammonia must leave when there is a lower energy barrier for the water to leave, this is nothing more than a "he says I'm wrong so he must be spewing nonsense."

 

[HopefulMDclass2020]

I would like to thank everyone for their input. The concept is still a little counter intuitive, but I did gain a little bit of clarity through some of the explanations.

 

[amy_k]

The reason the reaction is driven towards the amine/ammonia leaving group rather than H2O has been covered in the above posts, but i just wanted to clarify: the reaction is driven forwards to form the acid-base equilibrium between the acid and the ammonia/amine. This last step neutralizes the acid and forms an ammonium salt and is very exergonic (favorable due to net release of free energy). This is what drives the reaction to completion. I hope that helps OP!

 

[amy_k]

This link http://research.cm.utexas.edu/nbauld/teach/ch610bnotes/ch18.htm explains it brilliantly. (Scroll down to acid catalyzed hydrolysis of amides).