[uglepik]

I'm a doing an EDC (cabodiimide) coupling in DMF between a carboxylic acid and a primary, unhindered alcohol. By problem is that my acid is a crystal that has some crystal water. I'm adding DMAP (0.1 equiv).

Now to the question. How much can I expect the water to lower my yield? I have about the same molarity of alcohol as I do of water. Which is the more reactive in such a setting - alcohol or water? Which is the best nucleophile towards a carbonyl group?

My own thought is that alcohol is better - since alcoxide/alcohol is less stable than hydroxide/water I'm figuring it's also a poorer leaving group.

Any thoughts?

Andreas

[discodermolide]

You should try and replace the crystal water with ethanol if you can, this by dissolving in ethanol and evaporating several times.
If you can't do this, add mol. sieve to the reaction to remove the water as the compound dissolves. Then you should not have a problem.
There are easier ways to esterify a carboxylic acid with ethanol, why use EDC, very expensive and a pain to get rid of the urea by-product!

[uglepik]

You should try and replace the crystal water with ethanol if you can, this by dissolving in ethanol and evaporating several times.
If you can't do this, add mol. sieve to the reaction to remove the water as the compound dissolves. Then you should not have a problem.
There are easier ways to esterify a carboxylic acid with ethanol, why use EDC, very expensive and a pain to get rid of the urea by-product!

Mol. sieves might be an idea, but that doesn't diminish my interest in which species is the better nucleophile :-) I don't need a super yield, so I'm mainly interested in knowing how much the water is going to influence the reaction. EDC is a great reagent for my purpose, we have the money (and it's very small scale) and the urea is dialyzed off afterwards, so it needs to be water soluble,

[discodermolide]

As the ethanol will be in excess with respect to the water (I assume this) ethanol will be the better reactant.

[orgopete]

While one could establish reaction conditions to determine the nucleophilicity of water versus different alcohols, it would only have fleeting significance. In this reaction, Le Chatelier's principle will apply. If stoichiometric quantities of alcohol, carbodiimide, and water are present, then the rates should remain comparable as the concentrations will be more important in the overall reaction rate. As the alcohol is consumed, the water concentration will increase its rate, etc. If a very large molar excess of alcohol is used and unless water were much more reactive, the alcohol will dominate the reaction rate.

There are other Le Chatelier's principle controlled reactions which would suggest water and alcohols have similar rates of reaction. Fischer esterifications and hydrolysis and acid catalyzed ketal formation and hydrolyses are generally controlled by the concentrations of the reagents and seem little affected by the relative reactivity of an alcohol or water.

Disco beat me to this.

[uglepik]

I appreciate your answers and you are obviously right. However, I do not have the possibility of adding any of the reagents in a large excess. For this reason (and out of general interest), it would be fun to know which is the stronger nucleophile... alcohol or water.

[discodermolide]

Looks like Orgopete's answer tells you this.
It this is the case in your reaction use mol sieve powered to mop up the water.

[AC Prabakar]

Obviously alcohol is stronger nucleophile when compare to water.
I am anticipating the following phenomenon:
As per mechanism of  cabodiimide mediated/activated esterification/amidation the initial step involves the formation of carboxylate ion(O ^-) from free acid (please correct me if I am  wrong as i studied this mech. long back!!). Imagine the presence of water at this point! It will not allow the formation of activated acid effectively(same reason alcohol is stronger nucleophile than water!) because of which the reaction may not go for completion. Hence the availability of excess nucleophile also may not be helpful!!!
Of course i don't have any proof to support my assumption at this point of time.
This may be one of the reason apart from competency between water and nucleophile for activated acid to make the reaction stagnant!!!



 

[fledarmus]

Which alcohol? And under what conditions?

See http://chemrat.com/ChemHog2/Organic%20Chem_files/NUCLEOPH.DOC - water is about 100X better than simple alcohols as a nucleophile, but the deprotonated forms of both water and alcohol are about 10⁵-fold better than the protonated forms and are approximately equal. However, water also has a lower pKa than alcohols, and in neutral or weakly basic conditions, an equimolar mixture of water and alcohol will have a higher concentration of hydroxide ions than alkoxide ions, further increasing the rate of the water reaction.

I've run a lot of esterification and transesterification reactions over the years, and my sense is that water is stronger than methanol, which is stronger than ethanol. To out-compete the water, I need to use at least 100X the amount of methanol.

If you have water present in an EDC reaction, I doubt that you will see any product at all. The water will rapidly quench your activated ester, assuming that it doesn't quench your EDC before it can react. I would suggest either molecular sieves, as Discodermolide suggests, or when you start your reaction, add the carboxylic acid to your solvent and dry over MgSO₄ to remove the waters of hydration. Then filter and add the rest of your reagents.