[darkdevil]

Hi all!

Suppose I have a compound like this. I only want to reduce one of the two aldehydes into an alcohol. I tried to react it with 1:1 Sodium borohydride but it seems that all of the two aldehydes were reduced. Does NaBH4 reacts in 1:1 ratio or one NaBH4 can actually reduce several aldehydes? What other reagents can I use? Any advice will be greatly appreciated!!

[sjb]

Especially with something like this, where the two aldehydes are the same and reasonably separated you are likely to get a mixture of x:1-2x:x of dial:aldehyde-alcohol:diol.

Controlling x is diifficult. Is there some way you can differentiate before the reduction?

[wildfyr]

Each borohydride delivers 4 hydrides, so you can't just go 1:1 reagent to NaBH4 eq. You could go 1:0.25 But even reducing equivalents is still gonna result in a mess because its a pretty strong reducing agent.  For this pathway, the trick is to add the NaBH4 very slowly so the concentration of hydride at any moment is very low, and double reduction is reduced. You could also try doing the reduction in a small alcohol, it will be less reactive.

What about adding 1 eq of sodium bisulfite to make that insoluble bisulfite adduct, then doing the reduction heterogenously?

Or protect one of them as an acetal with ethyleneglycol? Acetals are supposed to be able to handle NaBH4.


No matter what way you cut it this is a really tough reaction to get selectivity. Its probably easier to protect or convert one of them before you do the thiophene coupling.

[Enthalpy]

Would it be conceivable to remove the mono-alcohol from the reaction as soon as it forms? Maybe it's more soluble in a solvent with hydrogen bonds for instance, or it has a higher boiling point.
(Apologies in advance if I put nonsense)

[wildfyr]

Enthalpy, I had the same thought about doing a biphasic reaction, but to deprotonate the alcohol you need a very basic system. The best way there is to use excess borohydride, but then there is too much of it around, and both sides will probably be reduced before it can transfer phases.

[Borek]

disclaimer: I remember almost nothing from my orgo course.

Somehow - taking into account symmetry of the molecule - I wonder if it is possible to do the conversion "cleanly". It feels like you will always get the mixture, and you can only try to minimize production of diol, but it is inevitably going to show.

So, statistically, the best approach would be to add small amounts of a reducing agent (then diol is present only in minute amounts), and to remove the alcohol out of the mixture. No idea how, aldehydes have in general lower bp than alcohols.

[wildfyr]

Lower BP is because they don't hydrogen bond to one another. Only have H-bond accepter, not H-bond donater.

[Borek]

Lower BP is because they don't hydrogen bond to one another. Only have H-bond accepter, not H-bond donater.

Sure - but the reason doesn't matter here, what matters is that in effect it is not possible to distill the alcohol out.

[rolnor]

I would try to make a molecule from start that does have one alcohol and one aldehydegroup, if I would try to reduce one aldehyde i would try diisobutyl aluminium hydride (DIBAL) at -78°C.  Thats a bulky reagent and maby is a little selective giving more mono-reduction.

[wildfyr]

Lower BP is because they don't hydrogen bond to one another. Only have H-bond accepter, not H-bond donater.

Sure - but the reason doesn't matter here, what matters is that in effect it is not possible to distill the alcohol out.

Yeah, I just thought I'd teach a little tidbit of chemistry .

[clarkstill]

Do a mono-acetal protection? E.g. dehydrate in the presence of 1 eq. ethylene glycol - I think thermodynamics will work in your favour, since the doubly-protected compound looks like it would be sterically strained so the equilibrium should lie towards the mono-protected.

[clarkstill]

Or protect one of them as an acetal with ethyleneglycol? Acetals are supposed to be able to handle NaBH4.

Just realised I'd skimmed this thread and missed wildfyr's suggestion of the same strategy - give him/her the credit if it works!

[wildfyr]

I'm bummed this OP gave us something relatively juicy to sink our teeth into, then hasn't come back to discuss it.

This really is a classical problem in all of organic chemistry: How to do a reaction on just one side of a molecule with bilateral symmetry.

[kriggy]

I would say tryting this is bad idea. If one is stubborn about this then monoprotection might work, but its pretty much the same problem as with the reduction, could be more easy to solve but still I would expect low yields.
I wonder how the dimer is made, is it some kind of homo coupling reaction? I suppose it could be possible to couple the protected and unprotected thiophene together?

[OrganicDan96]

how about diisobutylaluminium hydride (DIBAL). add DIBAL  drop wise to an excess of starting material in a solvent like DCM or THF at room temperature. DIBAL can only do 1 reduction per molecule so it might work. dropwise keeps the starting material in excess so increasing the chance that a different molecule gets reduced each time.