Sciencemadness Discussion Board

Troubles with Lithium-Halogen exchange reaction.

duning - 18-5-2019 at 17:33

Hi,

I am trying to make Tris(4-cynophenyl)phosphine by the reaction of benzobormonitrile and PCl3.

The procedure I am following says that the reaction was carried out below -100C but it does not say why.

On my first try I slowly added 1eq of benzobromonitrile in THF to the cooled(-110C ethanol/LN2) n-buthyllithium solution 1eq 1.6M in hexanes. Then PCl3 in THF at -90C. I extracted it with diethyl ether. The yield was less than 10%

On my second attempt I used 2eq of n-buthyllithium and temp. -80C( methanol/LN2), I assumed that temperature does not matter that much. I extracted it wtih CH2Cl2. Yield 0%. Benzobromonitrile didn't even fully react. WTF???

The procedure claims 50% yield. My questions are:

Is temperatures below -100C required for substituting bromine in bromobenzene derivatives? Some authors carries out Lithium-bromine exchange reaction with dibromobenzene in -66C and -78C others in -95C or -90C. Honestly I don't know what to do.

Do I have to use 1eq or 2eq of n-Buthyllithium? Second eq is theoretically used in reaction with buthylbromide, but most papers says 1eq or 1.1eq. I think 2eq is required when using aryl iodides, but I am not sure.

Should I add buthyllithium to the cooled solution of benzobromonitrile or solution of benzobromonitrile to the cooled solution of buthyllithium(this is what I did)?

Sigmatropic - 19-5-2019 at 01:53

Gather some in process control samples. Specifically quench a sample with some protic solvent and take an nmr to ensure your starting material has been lithiated. Then go from there. BuLi should very very rapidly do halogen lithium exchange. There should be no reason but you could try other organolithiums such as phenyl lithium but these are less active than BuLi.

Dr.Bob - 19-5-2019 at 18:40

It might be that the anion can react with the nitrile in the molecule above -100 C, but that would not leave SM behind. But that does not sound like the problem. For n-butyl lithium, the first eq exchanges with the bromine, creating the anion and bromobutane. That can eliminate to create HBr and butene, so that kills another equivalent of nBuLi. So you likely need at least 2 eq, and once the anion reacts with the PCl3, that will create more acid, so you may need to buffer the reaction with more base yet.

AvBaeyer - 19-5-2019 at 18:58

The butyl lithium should be added to your bromo-nitrile substrate at -100. You do not want your nitrile group to be in the presence of a large excess of BuLi. You want to minimize reaction of the BuLi with the nitrile which will be competitive with metal-halogen exchange at higher temperatures and/or in the presence of excess BuLi. The reaction should only require 1 eq of BuLi if the temperature is low enough. Metal-halogen exchange reactions are extremely fast even at very low temperatures. Once metal-halogen exchange has occured, the resulting p-cyanophenyl lithium will be of much reduced reactivity regarding self-reaction.

How good is your BuLi? Was your THF really dry? I assume that you were using an argon or nitrogen atmosphere.

duning - 20-5-2019 at 15:32

Quote: Originally posted by AvBaeyer  
The butyl lithium should be added to your bromo-nitrile substrate at -100. You do not want your nitrile group to be in the presence of a large excess of BuLi. You want to minimize reaction of the BuLi with the nitrile which will be competitive with metal-halogen exchange at higher temperatures and/or in the presence of excess BuLi. The reaction should only require 1 eq of BuLi if the temperature is low enough. Metal-halogen exchange reactions are extremely fast even at very low temperatures. Once metal-halogen exchange has occured, the resulting p-cyanophenyl lithium will be of much reduced reactivity regarding self-reaction.

How good is your BuLi? Was your THF really dry? I assume that you were using an argon or nitrogen atmosphere.



I used fresh BuLi. My THF is as dry as it can be, freshly distilled from sodium/benzophenone under argon atmosphere and then dried using freshly activated 4A molecular sieves for 24h.

The prep I am following says to add bromobenzonitrile to the cooled BuLi solution at the temperatures below -100. I think the major issue was my reaction mixture not maintaining the temperature strictly below -100. I purified my product on a column and I recovered 5 fractions. F1 was bromobenzonitrile, F2 is something I cannot identify, H NMR showed two multiplets in the aromatic protons region, two dublets that integrates perfectly and one damned singlet that integrates as 1.5H at 7.66, no idea what is this. F3 was my prodcut, F4 was 4,4'-dicyanobiphenyl and F5 with no aromatic protons no idea what is this. I also didn't find any butyl insertion products.

I searched through literature and asked my fellow chemists and this is what I am came up with:

I will strictly keep the temperature at -116 using ethanol/LN2 bath at all time. I will add bromobenzonitrile(just like the prep suggests) to the BuLi in THF and hexanes(some kind of Trapp mixture) as fast as possible to avoid side reactions but still at -116. Then I will immediately and slowly add PCl3 in THF, and allow them to react for 1h.

You are right about the 1eq of BuLi, "Preparative Polar Organometallic Chemistry volume 1" on page 190, it says that at these temperatures 1.1eq of BuLi is used, it seems that the butyl insertion reaction is not fast enough and BuBr doesn't react with the bromoarene.

As far as I understand 2eq of BuLi are used when using t-BuLi or alkyl iodide/aryl iodide.



[Edited on 20-5-2019 by duning]

duning - 23-5-2019 at 09:47

Update:

Success!

I did everything just like I've described in my previous post and it worked!

The yield was 50% just as the prep claims and the product was quite pure. The temperature HAS TO BE below -100C at all times.