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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Rutherford on February 15, 2014, 10:25:43 AM

Title: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 10:25:43 AM
How to solve the attached problem? How does CDI activate the carbonyl group?

Also: Explain why the C=O stretching frequency in 1,1’-carbonyldiimidazole is 100 cm–1 higher than that of 1,1’-carbonyldipyrrolidine.

I thought that the participation in conjugation would reduce the second bond character of the C=O bond, and move it lower, not higher. Where am I wrong at?
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 10:30:10 AM
The a acid OH attacks the CDI carbonyl and eliminates imidazole to produce a sort of mixed anhydride.
See if you can draw the structure and find out what happens next.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 10:34:09 AM
That should be C right? What are A and B? A protonated CDI (only one nitrogen), B deprotonated amino acid?
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 10:47:02 AM
This is C I think.
O=C(OC(N1C=CN=C1)=O)C(N)C
plus imidazole.
God knows what A is.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 10:52:48 AM
I got this. But can't figure out F :(.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 10:59:46 AM
Well the mixed anhydride is attacked by imidazole at the carbonyl to eliminate CO and another imidazole. This gives G!
The other intermediates are ??
So F is probably the ionic intermediate?.
Never seen something like this before, strange scheme.

Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:07:37 AM
How does the imidazole attack D? The lone pair on 1-nitrogen is contributing to the aromaticity.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 11:13:40 AM
A nitrogen of imidazole is nucleophillic.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:20:41 AM
Okay, I see. There would be also more logic if the other N atom in CDI was protonated.

At the end activated Ala is produced, and the amino group of Gly can attack it and form Ala-Gly dipeptide right?
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 11:23:20 AM
Yes that is the whole idea, peptide coupling.
Logic, who applies logic? You can ask where do the protons come from. What starts the whole process off? Protonation of a carbonyl by an amino acid? You could go on for years with this and similar mechanisms.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:27:31 AM
Good. Two more questions: How does the imidazole ring activate the carbonyl group? Why the C=O stretching frequency in 1,1’-carbonyldiimidazole is 100 cm–1 higher than that of 1,1’-carbonyldipyrrolidine.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 11:30:34 AM
Well the imidazole is a good leaving group, and presumably it is electron withdrawing giving the C=O a partial positive charge, the partial negative charge on the imidazole is resonance stabilised into the ring. Draw the resonance structures out.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:34:58 AM
I get a positive charge on imidazole  ???.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 11:41:59 AM
Move the lone pair into the ring.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:45:33 AM
Okay, thanks. But why is the C=O stretching frequency in 1,1’-carbonyldiimidazole is 100 cm–1 higher than that of 1,1’-carbonyldipyrrolidine? Higher position in IR means stronger bond, but the C=O bond has a single bond character in 1,1’-carbonyldiimidazole, so it should be lower in IR.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 11:48:03 AM
this is what I mean
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:49:20 AM
Oh, so the resonance I wrote isn't possible here, but it is in 1,1’-carbonyldipyrrolidine, correct?
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: discodermolide on February 15, 2014, 11:50:23 AM
what is wrong with that?
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: Rutherford on February 15, 2014, 11:51:36 AM
I saw the first time I looked at your post the scheme you uploaded before, but now it's okay.
Title: Re: CDI (carbonyldiimidazole) usage in peptide synthesis
Post by: orgopete on February 16, 2014, 09:15:55 AM
Quote from: discodermolide on February 15, 2014, 11:48:03 AM
this is what I mean

While that could be the mechanism, I don't think it is. An imidazolium anion is fairly basic. I think the key is elimination of a neutral imidazole. The mechanism posted by Raderford was virtually correct, except the wrong nitrogen was protonated. If an amino acid protonated the imidazole, it would free the amino group and make neutral imidazole the leaving group. The other option is to write a concerted proton abstraction, but that will put an entropy load on the reaction.