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Topic: Basic Nitrile Hydrolysis  (Read 12947 times)

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Offline UnderGrad

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Basic Nitrile Hydrolysis
« on: August 11, 2010, 11:27:05 PM »
I’m doing an experiment and FAILING HORRIBLY. Not sure what to do. I need to hydrolyze a nitrile (diphenylacetonitrile) to the corresponding carboxylic acid, diphenylacetic acid (I actually plan to reduce to the alcohol later with LiAlH4) but it’s not working and I can’t find any documentation that helps. So basically… diphenylacetonitrile is not water soluble and I want to do the reaction in basic conditions (NaOH) b/c the salt should be easier to isolate and then purify. Also the ammonia will just bubble off instead of forming a salt as it would in acidic conditions. At first I tried to do the reaction in THF/H20 at room temp with 2 equiv. of base. My reactant is readily soluble in THF and toluene and moderately soluble in ether. So anyway I need aqueous conditions for the hydrolysis and I figured I’ll dissolve my nitrile in a large amount of THF and add stochiometric H20 and 2 eq. base and it’ll all be fine. All’s well until I add the base and the phases separate. So I figure I’ll just stir it like crazy and hope for the best. After a few days the THF layer turns yellow so I figure, sweet!, success. According to IR that’s not the case. I really didn’t think it’d work at room temp anyway so I’m not too concerned.
Anyway I decided to do the reaction with toluene and H20 (the phases will separate anyway with THF) so I can reflux it over 100C with toluene. I also decided to use 1 eq. of base since the alpha hydrogen is activated by the two phenyl groups and I don’t want it to dimerize. Oh, I tried it with a dibenso crown ether as a phase transfer catalyst and no luck. And this is like 1g of reactant with 10ml of toluene and 30ml H20. So, any suggestions on how I can get this to work? I don’t think excess base is going to be an option here. I’m kind of reluctant to try acidic conditions but may have to. I don't want to have to go to DMF or DMSO if I can help it.

Offline orgopete

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Re: Basic Nitrile Hydrolysis
« Reply #1 on: August 12, 2010, 07:57:43 AM »
Sometimes insolubility can be useful. If under basic conditions, you could reflux the reaction until the nitrile dissolves completely. However, as noted, the alpha hydrogen is also quite acidic and will compete with addition.

However, I would probably prefer acidic conditions due to the difficulty of eliminating the anion of ammonia under basic conditions.
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Offline Cancer Boy

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Re: Basic Nitrile Hydrolysis
« Reply #2 on: August 12, 2010, 08:45:05 AM »
That's a common problem when using NaOH. Generally, I've found using dioxane/water instead of THF/water can go some way to stopping the phases from separating.

Even better, I just found an experimental detail on Beilstein which uses H2O/ethylene glycol as the solvent. They actually make the NaOH themselves since it's a radiolabelled version, but other than that I would try replicating this exactly as it says.

Sodium metal (25 mg, 1.09 mmol) was added to H218O (0.5 mL, 25 mmol) in ethylene glycol (2 mL, twice distilled under vacuum from sodium). Diphenylacetonitrile (193 mg, 1.00 mmol) was added, and the resulting mixture was heated at 150 °C for 17 h. To the cooled mixture was added aqueous HCl (0.2 M, 30 mL) and the solution was extracted with ether. The combined organic layers were dried with MgSO4 and the solvent was removed, leaving the acid as white solid (205.7 mg, 0.96 mmol, 95%).

Grotjahn et al, J. Am. Chem. Soc, 2001, 123, 8260-8270

Offline stewie griffin

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Re: Basic Nitrile Hydrolysis
« Reply #3 on: August 13, 2010, 08:05:09 AM »
I too would suggest dioxane/water as a better solvent that THF/water since it mixes well and you can get the temperature higher.
If you're looking at a two step synthesis here to get to the alcohol anyway, why not just reduce the nitrile to the aldehyde with diisobutylaluminum hydride and then reduce the aldehyde with whatever you want (NaBH4 for example)?? I know lab mates that have reduced nitriles to aldehydes with DIBAL and it's a short reaction time and easier than the heat and beat method that you're doing.
Note: the DIBAL reduction actually gives a imine first, which upon workup/hydrolysis gives you the aldehyde

Offline AC Prabakar

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Re: Basic Nitrile Hydrolysis
« Reply #4 on: August 28, 2010, 09:11:30 AM »
You can use ethanolic KOH in water.The advantage in this method is only stochiometric amount of water can be used.
This method works well for water insoluble compounds.But the reaction completing at very harsh condition.

In our lab we too experienced the same situation as your case.That time the reaction was progressed(we could see the absence of starting material) but we couldn't see the product!Analysis shows that after amide formation form cyano,the reaction was almost stagnant for 2-3Hrs. upon marinating the reaction at the same reflux condition we got the product.

I hope this will work!!Good luck!

Offline discodermolide

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Re: Basic Nitrile Hydrolysis
« Reply #5 on: August 28, 2010, 09:29:09 AM »
Sometimes insolubility can be useful. If under basic conditions, you could reflux the reaction until the nitrile dissolves completely. However, as noted, the alpha hydrogen is also quite acidic and will compete with addition.

However, I would probably prefer acidic conditions due to the difficulty of eliminating the anion of ammonia under basic conditions.
You don't get the "anion of ammonia" you get the sodium salt of the carboxylic acid and ammonia as a leaving group. The alpha hydrogen will not compete under these conditions, not acidic enough.
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Offline movies

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Re: Basic Nitrile Hydrolysis
« Reply #6 on: August 28, 2010, 10:44:35 AM »
I have done some nitrile hydrolyses recently and these conditions worked great for me (slow, but effective):

LiOH•H2O (3 equiv), 3:1 MeOH/H2O (0.4 M substrate concentration), 50 °C


I think LiOH is generally more effective than other hydroxides because of Lewis acidity and solubility.

For ester hydrolysis I have always favored the THF/H2O mix as opposed to MeOH, but otherwise identical conditions.  The THF & aqueous phases are separate at room temp, but usually coalesce when heated, in my experience.

Offline orgopete

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Re: Basic Nitrile Hydrolysis
« Reply #7 on: September 01, 2010, 11:13:59 AM »
… the alpha hydrogen is also quite acidic and will compete with addition.

However, I would probably prefer acidic conditions due to the difficulty of eliminating the anion of ammonia under basic conditions.
You don't get the "anion of ammonia" you get the sodium salt of the carboxylic acid and ammonia as a leaving group. The alpha hydrogen will not compete under these conditions, not acidic enough.
The pKa of diphenylacetonitrile is 17.5. Deprotonation seems likely to me. Not knowing what chemistry the poster might be thinking about, I thought it useful to note this.

Just so we are discussing the same mechanism, I have written four possible mechanisms for this reaction. The first is what I think is the currently correct mechanism. You may find this in your textbook, but some do not. I think this was published by Albert Padwa in the 70's or maybe later. You may find the second (B) in some textbooks. The difference is that these tetrahedral intermediates generally eject the weakest base. The Padwa mechanism enables this to occur from a dianion intermediate while the mechanism in B would suggest loss of hydroxide.

I have included two additional mechanisms that could plausibly eject ammonia. Mechanism C seems implausible that a protonation of the intermediate of the mechanism A should occur. Mechanism D should suffer similarly, though it could occur is the reaction mechanism were closer to neutrality so that a protonated amide were present a priori and attack of hydroxide upon it. However, this does not yield the carboxylate anion as claimed.
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Offline discodermolide

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Re: Basic Nitrile Hydrolysis
« Reply #8 on: September 01, 2010, 12:21:59 PM »
I have done this many times using LiOH, THF/H2O at reflux.
You get ammonia and the lithium salt of the carboxylic acid. The OH- attacks the carbonyl and eliminates NH2- (sodamide or in this case lithium amide) which deprotonates water to regenerate the base and give ammonia. Furthermore the basic conditions form the metal salt of the carboxylic acid. In principal this reaction is catalytic in base.
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Offline orgopete

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Re: Basic Nitrile Hydrolysis
« Reply #9 on: September 04, 2010, 01:56:22 PM »
… and eliminates NH2- (sodamide or in this case lithium amide) …

I don't see how this is different from my suggesting that the "anion of ammonia" is formed during the hydrolysis.

I was not and am not arguing the reaction cannot succeed. I am simply stating that it is not unusual to isolate varying amount of amide as this is generally more difficult than the addition to a nitrile. One might anticipate this to be true because a tetrahedral intermediate generally eliminates the weakest base and the anion of ammonia would not be an expected elimination product in that case.
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Offline discodermolide

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Re: Basic Nitrile Hydrolysis
« Reply #10 on: September 05, 2010, 12:03:10 PM »
As I said I have done this many times and never isolated any amides, you get ammonia and the metal salt of the carboxylic acid. Yields >98.5%. remainder are slight losses of product.
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