[Sonic Hedgehog]

Hi all,
Does anyone have a simple procedure for the hydrolysis of an amide?  Is it easier with acid or base?  I wasn't able to find much online...

Or if not hydrolysis, are there any other reactions that amides can undergo at relatively mild conditions?

Thanks
SonicH

[Babcock_Hall]

Did you look under peptide hydrolysis?  The acidic conditions are pretty harsh, and I don't happen to recall much about basic conditions at the moment.

[kriggy]

Basic conditions I used was to reflux with KOH. Probably could work under milder conditions if you tosylate the nitrogen (in case of primary amide)

[Sonic Hedgehog]

I couldn't find much on peptide hydrolysis unfortunately.

I was going to try heating with NaOH without reflux, hopefully that works. 
I don't need to isolate the product of this reaction, I'm just trying to chemically alter the amide in some way.  Are there any other reactions that amides undergo at relatively mild conditions (maybe less than 75deg) using common laboratory reagents?

Thanks for your help

S

[Babcock_Hall]

Peptide acid hydrolysis came up on this forum about a year ago, and I seem to recall discussing how to degas the constant boiling HCl.
http://www.chemicalforums.com/index.php?topic=89829.msg323413#msg323413

[kriggy]

I couldn't find much on peptide hydrolysis unfortunately.

I was going to try heating with NaOH without reflux, hopefully that works. 
I don't need to isolate the product of this reaction, I'm just trying to chemically alter the amide in some way.  Are there any other reactions that amides undergo at relatively mild conditions (maybe less than 75deg) using common laboratory reagents?

Thanks for your help

S

They can be alkylated for example. They can be converted into amine using hoffman rearangement. Its realy hard to tell becuase I am not sure what exactly you want to do neither what is your substrate structure

[Sonic Hedgehog]

They can be alkylated for example. They can be converted into amine using hoffman rearangement. Its realy hard to tell becuase I am not sure what exactly you want to do neither what is your substrate structure

The substrate is a bile acid called tauroursodeoxycholic acid, I'm trying to hydrolyse it, or modify it in some way to change it's mass (I want to change its mass to charge ratio on a mass spec).
Thanks for the Hoffman rearrangement idea, I saw an article using hypochlorite for this reaction but couldn't access the article :/.
The bile acid also has 2 hydroxyl groups which I thought about trying to modify, but I don't want to use dichromate to oxidise, and most other reactions that I know about occur at conditions which are more extreme than I would like...

[Sonic Hedgehog]

Peptide acid hydrolysis came up on this forum about a year ago, and I seem to recall discussing how to degas the constant boiling HCl.
http://www.chemicalforums.com/index.php?topic=89829.msg323413#msg323413

Cheers, I'll give it a read 😊

[wildfyr]

By far the easiest way to functionalize this material for Mass spec in my mind is to TBDMS protect the alcohols. Such silyl ether protection is a very standard procedure for helping to volatilize compounds that don't want to fly. TBDMS protection is also dead easy using TBDMS-chloride and imidazole at room temp.

[Sonic Hedgehog]

By far the easiest way to functionalize this material for Mass spec in my mind is to TBDMS protect the alcohols. Such silyl ether protection is a very standard procedure for helping to volatilize compounds that don't want to fly. TBDMS protection is also dead easy using TBDMS-chloride and imidazole at room temp.

That sounds ideal , I'm using LCMS as opposed to GCMS, so the injection solvent is usually methanol/acetonitrile or water, do you think that reaction would be compatible with acetonitrile for example?  A few of the methods I saw online use DMF...

[wildfyr]

Yes, I usually run it in dcm or acetonitrile

Here is a reddit post where I give out some detail on how I like to run such reactions

https://www.reddit.com/r/chemistry/comments/6g7lqk/what_is_your_favourite_chemical_reaction_and_why/

[Sonic Hedgehog]

Thanks that's really useful

[kriggy]

Be careful because it has two OH groups, you might get mixture of mono/bis silylated compounds. Also the sulfonyl OH might react as well. Silicon has very high affinity for oxygen so you might want to work realy careful to get reproducible synthtetic results

[wildfyr]

You can use a significant overequivalence to make sure there are no mono-substituted ones. For MS, some leftover silyl ether dimer won't matter. Or its easy enough to get off with a silica plug like I mention in the reddit post.

I've never heard of protecting sulfonates with TBDMS, but I feel like it would be very hydrolyzable and fall apart during aqueous workup or in the LC, unlike the protected alcohols. I also had this PM exchange with OP that I would like to post here because it contains important info

Hey mate, I just had a few more questions I was hoping you could help me with regarding the TBDMS reaction.

You mentioned that you need an aprotic solvent- my alcohol is actually in human plasma (which obviously contains water), do you think I would have to remove the water?
Sorry with all the questions, I'm not a chemist haha.
I appreciate your help

All the best,

S

Yeah, you definitely would need to totally dry it out. Freeze drying would probably work best.

So its just your molecule in a solution of various salts right? Few to no other organic molecules in it?

PS This sort of discussion is still well suited for doing on your post. We want information disseminated as widely as possible.
-wildfyr

[wildfyr]

@kriggy I found this (http://onlinelibrary.wiley.com/doi/10.1002/047084289X.rb381.pub2/abstract)

tert-Butyldimethylsilyl Trifluoromethanesulfonate

"(highly reactive silylating agent and Lewis acid capable of converting primary, secondary, and tertiary alcohols1b to the corresponding TBDMS ethers, and converting ketones2 and lactones2a,3 into their enol silyl ethers;...

Handling, Storage, and Precautions: the material should be stored under argon at 0 °C. The compound has an unpleasant odor and reacts rapidly with water and other protic solvents.