Mixed claisen condensation: diethyl carbonate w/ NaOCH2CH3

[Genecks]

I'm reading my organic chem. book as a supplement to lectures, and I came across an oddball aspect of mixed claisen condensations. Supposedly, there is the trend that an alpha-carbon attached to the other carbonyl carbon of the other ester.

 

Ok, but how is that working for diethyl carbonate?

It doesn't seem to have an alpha-carbon or alpha-protons.

 

How does this work out? I'm guessing if I could see the mechanism, I could make sense of it; but there is no mechanism for that particular compound.

 

I'm guessing that the oxygen acts like carbon for the mechanism? As such, the oxygen, similar to the alpha-carbon's position, attaches to the carbonyl carbon of the other ester?

 

This is just an abstraction with a leap of faith.

Edited March 7, 2011 by Genecks

[Horza2002]

I'm not exactly sure what your asking here...it's not quiet making sense. A mixed Claisen condensation is a reaction between two different reagents (i.e. two different esters or an ester and another carbonyl compound). The example you have given above with diethylcarbonate and ethoxide can't undergo a Claisen condensation. As you have said, there is no alpha-proton and the two sets that are present in diethyl carbonate are not acidic enough to be deprotonated. The only thing that can happen here is the ethoxide anion attacking the carbonyl of the carbonate which will then eliminate an ethoxide to get you back to the start.

 

However, if your were to do a mixed Claisen condensation using diethylcarbonate as your electrophile, then it would work (see attached file). This would be an efficient way to add an ester group in the beta position to your original carbonyl.

claisen.pdf

[Dan_Ny]

However, if your were to do a mixed Claisen condensation using diethylcarbonate as your electrophile, then it would work (see attached file). This would be an efficient way to add an ester group in the beta position to your original carbonyl.

 

Yeah, that makes sense. How electrophilic are these Dialkylcarbonates compared to esters?

[mississippichem]

Yeah, that makes sense. How electrophilic are these Dialkylcarbonates compared to esters?

 

They should be more electrophilic. The carbonyl in a dialkyl carbonate has oxygens "pulling" electron density on both sides as opposed to just one in the ester. I imagine the carbonyl carbon of dialkyl-carbonate is barely shielded at all relatively speaking.

[Dan_Ny]

They should be more electrophilic. The carbonyl in a dialkyl carbonate has oxygens "pulling" electron density on both sides as opposed to just one in the ester. I imagine the carbonyl carbon of dialkyl-carbonate is barely shielded at all relatively speaking.

 

Yupp, that's what I think, too.

[Horza2002]

I would have said that it was less reactive actually. Yes you do have two oxygen atoms pulling electron denisty away from the central carbonyl, but you also have an extra pair of electrons in conjugation with the system. An ester is less reactive than a ketone because the second oxygen's lone pair is in conjugation shielding the carbon. In carbonate, you have another pair of electrons shielding the carbon.

[Dan_Ny]

I would have said that it was less reactive actually. Yes you do have two oxygen atoms pulling electron denisty away from the central carbonyl, but you also have an extra pair of electrons in conjugation with the system. An ester is less reactive than a ketone because the second oxygen's lone pair is in conjugation shielding the carbon. In carbonate, you have another pair of electrons shielding the carbon.

 

Ah, right, of course. I wouldn't call it shielding though, it should be rather a transfer of electron density (well, you said it - conjugation). Just wondered about the reactivity in the first place because I have never come over a nucleophilic attack to a carbonate like this. There may be something in the literature, though. But if they are less electrophilic than, lets say, amides, it is clear why I've never seen it before.

Edited March 9, 2011 by Dan_iel

[Horza2002]

No, its not shielding, but people had been using that terminology so far so I kept with it to prevent confusion.

 

I havn't seen a reaction like this before...but I think that might due to non-specific reactions. If you look in the file I added previously, the inital product after the reaction is a diester. If I am right about the electrophilicity, then this will be more reactive than diethylcarbonate and so react again to give a mixture. In this case, the major product will be determined by which reaction is fastes; deprotonation of the dicarbonyl or attack of another enolate.

 

I think I might have to have a look on SciFinder tomorrow when I get to the office to see if people have used this method before.

 

I've just been having a look around actually, and I'm not so sure now. In protecting group chemisrty, carbamates (R-NH-C(O)-O-R) are more suseptiable to amides (R-NH-C(O)-R).

 

Apparently Fmoc, Boc and Cbz (all carbamates) are more reactive to Grignards and organolithiums than an the corrosponding amides. I wonder if the additional lone pair of electrons actually destailises the structure more than the "shielding" of the carbon; we are adding another two electrons to the same pi-system. Im definately going to have to go do some research on this now...

[Dan_Ny]

No need, I've already looked up scifinder.

Bioorganic & Medicinal Chemistry

Volume 16, Issue 18, 15 September 2008, Pages 8737-8744

(See attachment)

 

So we have here a secondary amine as the nucleophlie which has the choice between the carbonate and the ester functionality and it goes for the ester carbon. In this case the reactivity of the ester really is higher.

 

Well it is fun to talk about, though. Because it could to a certain extent actually be the type of nucleophile that chooses between its electrophilc target. The electron-poorer carbonate functionality might be the harder electrophile and therefore more prone to attack by something hard, lets say grignards or organolithiums, while the "electron-richer" ester is softer, making the amine, a soft base attack itself.

 

(((This is a rather heretical remark: It is quite fun that in Chemistry we will always find explanations for everything - might it be the HSAB concept or inductive effects oder hyperconjugation or whatever effect overriding the other... In the end one can "explain" everything and therefore - nothing. Well, of course I'm exaggerating a lot... But sometimes I get that feeling...)))

 

I definitely have to find an example where BuLi has to attack that kind of structure. I would guess, though, that it might attack the carbonate, rather.

Edited March 10, 2011 by Dan_iel

[Horza2002]

Weel this structure is a corss between an acid anhydride and a carbonate and it attacking the carbonyl of the anhydride is consisten with my idea about the carboante being mroe stable.

 

It is well known that the identity of the nucleophile has a pronounced impact on the regioselectivity of reactions. It might also be that Grignards and organolithium species are simply to reactive, even for these stabilised functional groups. It would appear that my initial guess of the additional lone pair is more important.

[Dan_Ny]

Indeed, it is more stable - but it is not consistent with your observation that carbamides are more stable than carbamates, is it? And still, the question remains, if "carbonates" are also more stable towards harder nucleophiles. I will look that up tomorrow, I think.

Edited March 10, 2011 by Dan_iel

[mississippichem]

I would have said that it was less reactive actually. Yes you do have two oxygen atoms pulling electron denisty away from the central carbonyl, but you also have an extra pair of electrons in conjugation with the system. An ester is less reactive than a ketone because the second oxygen's lone pair is in conjugation shielding the carbon. In carbonate, you have another pair of electrons shielding the carbon.

 

Interesting. It's a question of which effect wins out, less electron density, or one two more electrons total. Hm.

 

I'll Scifinder it as well.

 

No, its not shielding, but people had been using that terminology so far so I kept with it to prevent confusion.

 

I used the term shielding to refer to the notion that the electrophilicity is ultimately from the oxygen nucleus. Less electron density leading to less "shielding" of the nucleus' coulombic charge. Sorry if that caused confusion.

[Dan_Ny]

Well, enolates also seem to attack the ester rather than the "carbonate" group. The nature of the nucleophile on the regioselectivity seems to be less important than the nature of the electrophile in this case.

Edited March 10, 2011 by Dan_Ny