Sciencemadness Discussion Board

Substitute sodium hydride for potassium hydride?

Douchermann - 28-8-2009 at 23:38

Hey guys, I've asked this question a few places. In the formation of Indole-4-boronic acid, can sodium hydride be substituted for potassium hydride? I understand potassium hydride is a much stronger reducing agent, however it is also around 5-6 times the price. Here is the particular procedure in question:

To a suspension of KH (4.57 g of a 30% suspension in mineral oil, 32.9 mmol) was added a solution of 4-bromo-indole (5.88g, 30.0 mmol) in anhydrous ether (25 ml). The reaction was stirred at r.t. for 30 min under N2 and the reaction was cooled in an acetone-dry ice bath (-78°C) with stirring. Precooled t-BuLi solution in hexane (33.0 ml, 66.0 mmol) was cannulated into the reaction and the reaction was kept stirring for another 20 min. Neat B(n-BuO)3 (24.1 ml, 90.0 mmol) was added into the reaction by syringe under vigorous stirring. The reaction mixture became thick when it was allowed to warm to r.t., and more anhydrous ether (30 ml) was added under N2. The reaction was allowed to stand overnight at r.t. with vigorous stirring. The thick reaction mixture was diluted with more anhydrous ether and then transferred slowly into 1 M aqueous H3PO4 (300 ml) at 0°C. The mixture was stirred at r.t. for 40 min, and extracted with ether (100 ml x 30). The combined organic layer was extracted with 1 N NaOH (50 ml x 3). Ether (100 ml) was added to this aqueous solution and the mixture was acidified to pH = 2 using 1M H3PO4. The organic layer was separated and the aqueous layer was extracted with ether (100 ml x 2). The combined ether layer was dried over Na2SO4 and evaporation of solvent in vacuo left a beige solid (4.24g, 88.0%).

Nicodem - 29-8-2009 at 00:37

KH was used there just to protect indole by deprotonation. NaH can do the same, but maybe the sodium salt of 4-bromoindole is less soluble in diethyl ether.
Neither KH or NaH are considered reducing agents, because the number of literature cases where a reduction of anything else but a proton are limited to a few anomalies. They are bases, that's why KH is used in the above examples to protect t-BuLi from the indole's NH group.
I must add that for someone that plans to use something as hazardous as t-BuLi and something as expensive as 4-bromoindole, you sound quite irrational by being stingy about KH. If this is the first time you are doing a lithiation, particularly with something as pyrophoric as t-ButLi, you really should know learn all the basics of organic chemistry first, read all there is to known about lithiation, read about all the practical aspects of it, and have someone experienced to guide you during the first experiment. t-BuLi near flammable solvents is not something to take lightly!

panziandi - 29-8-2009 at 05:00

I have to agree with Nicodem. If you are asking about substituting KH for NaH based on cost, yet you are using t-BuLi and 4-bromoindole and Schlenk techniques, you should reconsider what you propose to do! There is a reason the author opted to use KH, it likely wasn't because they had an extra few £'s kicking around so they thought they'd opt for a more expensive base, it's likely that they tried NaH and found the yields were substantially lower.

entropy51 - 29-8-2009 at 06:46

Just to emphasize Nicodem's cautionary note:

Researcher Dies After Lab Fire
January 22, 2009
Lab Safety Researcher Dies After Lab Fire
UCLA research assistant burned in incident with tert-butyl lithium

A research assistant in the department of chemistry and biochemistry died on Jan. 16 from injuries sustained in a laboratory fire that occurred in December, the university has confirmed. The chemical, which ignites spontaneously in air, splashed onto Sangji's clothes and set them on fire.

Chemical & Engineering News, 87(4), January 26, 2009

len1 - 29-8-2009 at 08:15

Their reactivity goes as

LiH < NaH < KH

They are good metalation agents in org chem

The latter has smaller lattice energy so is more reactive. I assume they do not work so well as reducing agents (though the thermodynamic suggests they are strongly reducing) due to their lack of solubility and perhaps some kinetic factors.

Many things in the chemistry lab more dangerous than copper sulphate can be placed in the same category is tBuLi, never thought of it as a particular hazard. As for the accident, i guess its the burning hexane/pentane that killed here - there wasnt enough BuLi

Six feet from the fume hood was an emergency shower. When the employee’s gloves and clothing caught fire, she ran from the area away from the shower. One of the post-docs used his lab coat to smother the flames. 911 was called. UCLA Fire Dept. and emergency medical, Los Angeles City Fire, and Los Angeles County Haz Mat. The EMTs put the employee in the safety shower for gross decon and then transported her to the ER. She’s currently in the Grossman burn unit in Sherman Oaks with second degree burns on her arms and third degree burns on her hands, a total of about 40% of her body. There was very little damage to the lab. Bill has not interviewed the employee.

DJF90 - 29-8-2009 at 08:35

I have always been taught that sodium and potassium hydrides are non-nucleophilic/non-reducing - I believe this is due to the kinetic factor; The hydride ion is so small it can easily abstract a proton from even very hindered positions, and it is the acid-base reaction that is fastest - many orders of magnitude higher than any nucleophilic process. Hence the nucleophilic property of the hydrides is non-existant - adding excess hydride still does not invoke nucleophilic attack, only double deprotonation.

Douchermann - 29-8-2009 at 11:23

@Nicodem - Thank you, I was misguided, I was just doing common association with hydrides.

The reason why it might seem that I'm being stingy is because I don't look at reagents at a dollar/gram base. From my supplier, the minimum quantity of potassium hydride I could get is 100 grams, which is well over $400. Where as with sodium hydride, the same amount is under $100. I could put that extra $300 towards the bromoindole.

@panziandi - That's what I'm worried about : if there was an actual reason they chose the potassium salt as opposed to the sodium variant.

I will be reading up on this of course, but this sole issue makes the difference between something I'm actively working on, or something sitting on the back burner.

zed - 31-8-2009 at 19:50

I've read papers on the subject. As I recall, just off the top of my head. You should not try to substitute NaH for KH.

Yields are much higher with KH.

Still, I may be confused. For $300.00 Bucks, a quick survey of available references may be in order.