[zs3889]

Hi guys, I am working on a total synthesis project, which requires us to figure out the mechanisms for each step/reaction.

Anyway, I am kinda stuck in few reactions though, here are the 3 reactions that I am not able to solve the mechanism, and 3 of them are protection of alcohol.

The picture that I attach in this post is the reaction scheme and the reagents, hope you guys can help me out!

For the TBS and TIPS protecting groups, what I have in mind is that LDA deprotonates the OH group, and the O- attacks the TBSOTf and TIPSOTf? But I dont know what are the sturctures of TBSOTf and TIPSOTf, but I am guessing that TIPSOTf is triisopropylsilyl trifluoromethanesulfonate? I am not sure.

For the trityl protecting group, there are triethylamine and DMAP, both are bases and I dont know which one of them is supposed to deprotonate the OH group, so O- can be formed and attack the TrCl (similar to above).

[discodermolide]

The bases are there to mop up the acid formed i.e. HCl and triflic acid.
DMAP is a catalyst.

[zs3889]

So are you saying that OH groups are not deprotonated and O- is not formed. Instead, the lone pairs of OH groups launch the attack directly on the silicon on TBSOTf/TIPSOTf, and OTf leaves as anion, then takes away the H on OH so it would go form positive charged to neutral? Sorry for the bad english :/

[zs3889]

I just drew it out on a piece of paper, does it look right?

What about the trityl? similar kind of mechanism?

thank you so much!


p/s: I mistakenly wrote S instead of Si 

[orgopete]

I just drew it out on a piece of paper, does it look right?

What about the trityl? similar kind of mechanism?

thank you so much!


p/s: I mistakenly wrote S instead of Si 

Which is a stronger base, NEt₂iPr or CF₃SO₃(-)?

Is DMAP used in forming trityl ether? (Just asking)

[zs3889]

I just drew it out on a piece of paper, does it look right?

What about the trityl? similar kind of mechanism?

thank you so much!


p/s: I mistakenly wrote S instead of Si 

Which is a stronger base, NEt₂iPr or CF₃SO₃(-)?

Is DMAP used in forming trityl ether? (Just asking)

I suppose CF3SO3(-) is stronger due to its oxyanion? but it can form resonance with the other 2 oxygen atoms which are adjacent to it...hmmm..i am confused lol.

But I would still think the OH is deprotonated by CF3SO3(-) because the R group is bulky, as well as the triisopropylsilyl, LDA would have trouble reaching the OH group..

[orgopete]

I like to use pKa values to understand mechanisms, so it is good data to have an idea about or look them up.

Remember, the stronger the acid, the weaker the conjugate base.

Triflic acid, pKa -14
Et3NH(+), pKa 10.75

Do you want to modify the mechanism? [BTW, LDA is lithium diisopropylamide, iPr2N(-) Li(+)]

[zs3889]

I like to use pKa values to understand mechanisms, so it is good data to have an idea about or look them up.

Remember, the stronger the acid, the weaker the conjugate base.

Triflic acid, pKa -14
Et3NH(+), pKa 10.75

Do you want to modify the mechanism? [BTW, LDA is lithium diisopropylamide, iPr2N(-) Li(+)]

Hmm ok so the deprotonation of OH group is done by the diisopropylethylamine then? because its a stronger base than CF3SO3(-)? (sorry for messing up the LDA and diisopropylethylamine haha)

Yea pKa is very useful in figuring out the mechanism but im bad at it   gotta spend more time on it.

The bases are there to mop up the acid formed i.e. HCl and triflic acid.
DMAP is a catalyst.

but as discodermolide replied earlier, he said that the bases are to mop up the acid formed such as triflic acid, so I assumed that CF3SO3(-) depronates the OH and becomes triflic acid then gets neutralized by the bases like diisopropylethylamine?  



And also for the trityl protecting group, I am guessing that it has the same mechanism too? lone pairs on OH attack the partially positive carbon on TrCl, and triethylamine deprotonates the OH, as it is a stronger base than Cl(-)

(HCl is a stronger acid pKa -8, whereas Et3NH+ pKa ~10)

[orgopete]

… the bases are to mop up the acid formed such as triflic acid, so I assumed that CF3SO3(-) depronates the OH and becomes triflic acid then gets neutralized by the bases like diisopropylethylamine?  

If you a had proton to be abstracted, why would you think triflate ion would be more basic than diisopropylethylamine?

I agree with having to figure out what acids and bases are actually present in reaction mechanisms. I too have to think carefully about what acids and bases are present in reactions. Sometimes, you may find that only small amounts of material may be protonated or deprotonated. This was the dilemma I encountered with trying to find a good example of an acid catalyzed aldol condensation. Carbonyl groups are not very basic and once protonated, only a fraction of them lose a proton to form an enol. An enol probably cannot react with an aldehyde or ketone without protonation. The concentrations reduce the reaction rates. It would be much easier to catalyze an aldol condensation under basic conditions.

In that context, I would expect an aliphatic amine to deprotonate an alcohol and thus increase the reaction rate in an acylation or alkylation reaction (even though it would be working against an unfavorable equilibrium). If the base only picked up protons from oxonium ions that may form in a reaction, then very weak bases would be sufficient in this reaction. I surmise diisopropylethylamine will have a higher reaction rate than N,N-dimethylaniline even though both are sufficiently basic to "mop up the acid formed".

[al77]

What about the deprotection of protecting groups like this? I suppose the most common way is to use p-TsOH to generate the H+ which protonates and the O, and the TBS/TIPS group leaves as cation, which gets attacked by methanol. I am not confident with the mechanism though.