PrimoPyro (Hive Prodigy)
09-15-02 17:09
No 356555
      Solvents and Stabilization in Grignard Reactions  Bookmark   

Hi. smile

I was thinking about something last night that I want to share with you here, because I happen to like all of you so much. tongue

I just deleted about two pages worth of this post, because it quickly became a basic educational tutorial on solvents for Grignard Reactions, and at the last minute I decided that is not this post's purpose, and it is likely not needed anyway. I'll get straight to the point instead.

As you know, ether is crucial to the Grignard Reaction. Many catalysts are known for increasing the yields of Grignard reactions through various concepts, ranging from increasing the reactivity of magnesium, to providing inert reaction conditions, thus inhibiting side reactions that lower yield. (this is about where it tangently became a tutorial last time, and is being avoided now).

I was thinking about something else that I think is as important as all these other things, when regarding yield: Stabilization of the Grignard Reagent RMgX itself. In short, the solvent: ether.

Ethers are needed to stabilize RMgX species. In a tutorial I once read regarding Grignard Reactions, it was stated that 2 moles of ether are required to stabilize every one mole of grignard adduct, because two ether oxygens bond to each magnesium atom to stabilize it. Makes sense.

It's obvious that the greater the ability to stabilize a grignard adduct that an ether has, the better your yields should be, up to a certain cap, which is what we are trying to maintain of course. How do we quantify this property though? Easy.

I have been comparing the general properties of several ethers commonly used as solvents: Diethyl ether, tetrahydrofuran, glyme, diglyme, and tetraglyme. I had originally included dioxane, but I nixed it entirely early on because of it's high toxicity, and have boycotted that compound at the advice of slappy. Dioxane is not an option, at least for me.

Here is a short list of properties I have compiled earlier this morning:

M.W. = molecular weight
r.d. = relative density
m.p. = melting point
b.p. = boiling point
sol. = water solubility in g/100mL

Diethyl Ether: Et-O-Et: M.W.: 74.1224g/mol m.p.: -116.3*C b.p.: 34.6*C r.d.: 0.7134 sol.: 6.9g/100mL H2O Odor Threshold: 0.33ppm

Tetrahydrofuran/THF: C4H8O: M.W.: 72.1066g/mol m.p.: -109.4*C b.p.: 66*C r.d.: 0.886 sol.: 30g/100mL H2O Odor Threshold: 2-50ppm

Glyme/1,2-dimethoxyethane: C2H4(OMe)2: M.W.: 90.1218g/mol m.p.: -58*C b.p.: 85*C r.d.: 0.9683 sol.: 10g+/100mL H2O

Diglyme/bis-(2-methoxyethyl)-ether: O(EtOMe)2: M.W.: 134.1748g/mol m.p.: -64*C b.p.: 162*C r.d.: 0.94 sol.: miscible w/H2O

Tetraglyme/Tetraethyleneglycol dimethyl ether: Me(OEt)4OMe: M.W. 222.28g/mol m.p.: -30*C b.p.: 275*C r.d.: 1.01

I had the thought that since stability is related to oxygen content in an ether, then likewise the greater the oxygen content per volume of solvent, the greater the stabilization strength of that volume. Since liquids are measured in volume, especially solvents are, I decided to use volume as my unit to give the best end comparison so the "best ether" would stand out more.

At first, I had only decided to compare oxygen content per molecule (not accounting for density) and had not hunted down densities for each compound. It's a good thing I took the research a little bit further because this portion gave an inaccurate result!

Diethyl ether, according to the data I have supplied, which has all been gleaned from and two chemical supplier catalogs, has an oxygen content of 21.5% by weight. Since diethyl ether is by far the most commonly used ether solvent on the planet, I decided to use it as the standard to compare all other ethers to. As it turns out, the most common ether is actually the worst choice in the group....

THF has an oxygen content of 22.2%. Pretty much the same as Et2O, but then again, look at their structures, THF is diethyl ether minus two protons. No real big difference. The first big jump we see is in glyme, which has an oxygen content of 35.5%. Diglyme is slightly higher, at 35.77%, and tetraglyme comes in at 36% oxygen by weight.

Now like I said, at this point I had not thought about varyinf densities, but I did take into account pricing. It is obvious that the glymes offer much better characteristics than Et2O or THF, and since all three are so close together (at this point) it is natural that the lowest priced glyme would offer the best choice. This compound would be diglyme.

One large supplier that I looked at offers glyme at $32.00 per 500g. Diglyme is $21.00 per 500g. Tetraglyme is not offered in 500g of course, that would make it easy. It is priced at $20.00/250g and $52.50/1kg. Diglyme is the best offer in smaller amounts.

But when you consider that each compound has a different density, and you measure a solvent by volume, yet these ranking values are computed relative to mass, you realize that these values alone don't yield accurate comparisons. So we look to the densities.

Using diethyl ether as the standard, we easily see the comparison of stabilizing strength between ethers, shown as a percentage relative to the standard, diethyl ether = 100%. This is easily computed from the necessary minimum moles of Et2O to stabilize 1M of Grignard Reagent. This is related to the oxygen content.

2M Et2O is needed per 1M RMgX

Et2O: 2M = 144.25g
 rd: 0.7134
  = 202.2mL 100%

THF has the same oxygen content (one atom per molecule) as Et2O, and likewise requires 2M THF / 1M RMgX

THF: 2M = 144.21g
 rd: 0.886
  = 162.8mL 124%

This means that for stabilization (not counting solvation of the actual compound RMgX, which may require more than the minimum amount to stabilize the Mg atom.) 162.8mL THF = 202.2mL Et2O, which corresponds to a stabilization value of 124% the strength of Et2O. Now you know what the values mean.

Glyme: 1M = 90.1218g
 rd: 0.9683
  = 93.1mL 217%

Glyme has two oxygen atoms per molecule, meaning that 1M glyme / 1M RMgX is the minimum oxygen content to satisfy complete stabilization. Keep in mind that I am not saying that it is ok to substitute a mere 93mL of glyme for 202mL Et2O in a grignard reaction. There are other factors that apply as well, and also one should not bank on complete stabilization occurring.

Now we're seeing the men seperated from the boys, so to speak. 217% the stabilization ability as Et2O, and Et2O is far more common......

Diglyme: 0.67M = 89.8971g
 rd: 0.94
  = 95.6mL 211.5%

Ooh! What happened!? Diglyme looked so good before, it appeared to be the best option of the entire group. With a mere 0.27% greater oxygen content than glyme, but with a whole 3% less density value, made diglyme fall a little short in this ranking. They are still close, though.

Tetraglyme: 0.4M = 88.912g
 rd: 1.01
  = 88mL 229.7%

And tetraglyme appears to be best afterall. Almost 230% the stabilization strength of diethyl ether, mL for mL. I'm thinking ether choice might be something one might want to seriously consider when considering these reactions. I would think using the same quantity of an ether with 211% the stabilization ability the stated ether, would give you better chances at a successful reaction, considering the purpose of the ether as solvent is not just to solvate the reactants, but more importantly to stabilize the grignard reagent, and allow for it's formation in the first place.

So something you might want to consider next time is: Glyme and diglyme might be about 1.5 times as expensive as THF or Et2O depending on where you shop, but they have better properties, are nowhere near as watched as Et2O might be, don't have that characteristic smell of Et2O, and I have been told they smell "nowhere near as nasty as THF" by a friend, heh. All good points.

What I would like to know is, are glymes especially toxic, or are they like most common solvents: don't drink it, rub it on your skin, get it in your eyes, or inhale large amounts of it, and you'll be okie dokie. Or.........was it a potential candidate for a weapon of wartime, lol.



Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.
(Hive Prodigy)
09-15-02 17:36
No 356561
      Oh That Figures  Bookmark   

Now that I check the stats on dioxane, I realize what a shame it is that it is so toxic:

(CH2CH2O)2 (cyclic) Ethylene glycol ethylene ether.

1M = 88.106g
 rd: 1.033
  = 85.3mL
   = 237%

Heh, damnit, that figures, the toxic one has to be the best one.

I am wondering, paraformaldehyde is a cyclic ether. Unstable in aqueous environments I know, but what about in ether solution. It's comparison is 53% oxygen content and solid versus the highest oxygen content of 36% by weight of tetraglyme. I'm wondering if paraformaldehyde dissolves in ethers, I think it would but I do not know for certain.

If it didn't depolymerize, I wonder if one could add some of it to a diethyl ether solution to increase the ether oxygen content (this is hypothetical, not practical) or would it depolymerize to formaldehyde and fuck up the reaction?


Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.
(Stoni's sexual toy)
09-17-02 15:09
No 357283
      Yes, paraformaldehyde will react with grignards, ...  Bookmark   

Yes, paraformaldehyde will react with grignards, and no, it isn't readily soluble in ethers as far as I know.

I'm not convinced that your reasoning of O content and stabilisation works as presented. As far as I know the more common ethers THF and Et2O work best for grignards, and the price difference is big enough to usually rule out the higher homologues, even if they are able to produce somewhat higher yields (which I'm not sure of at all). If that was the case then using PEGs would be the best choice!
You also have to consider other factors like reaction workup. Et2O and THF can be rotovapped/distilled easily.

I'm not fat just horizontally disproportionate.
(Hive Prodigy)
09-17-02 16:22
No 357294
      PEGs  Bookmark   

If that was the case then using PEGs would be the best choice!

Aren't PEGs of the structure [-CH2CH(OH)-] and thus are alcohols?


Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.
(Stoni's sexual toy)
09-17-02 16:32
No 357298
      > Aren't PEGs of the structure and thus are ...  Bookmark   

> Aren't PEGs of the structure [-CH2CH(OH)-] and thus are alcohols?
That's polyvinylalcohol, not PEG. PEGs have the following structure:

One or two alcohol ends won't affect your yield much when the PEG has a molecular weight of e.g. 4000 or more. cool

I'm not fat just horizontally disproportionate.
(Hive Prodigy)
09-17-02 16:49
No 357303
      Density?  Bookmark   

And what of their density?

Couldn't one just methylate the end alcohols with diazomethane or methyl iodide or something to make a polyglyme? tongue

Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.
(Stoni's sexual toy)
09-17-02 17:12
No 357307
      > And what of their density? Close to 1.  Bookmark   

> And what of their density?

Close to 1.0 if I remember correctly, at least as solids.

> Couldn't one just methylate the end alcohols with diazomethane
> or methyl iodide or something to make a polyglyme?

I'd rather use a PEG which has one end already etherified. PEGs are produced by anionic, ring opening polymerisation of ethylene oxide. This reaction can for example be started with a base like KOH, which produces terminal OHs on both ends. When you use KOMe instead there will only be one OH on one end of the molecule and a MeO on the other. Another possibility is using alcohols like glycerine, pentaerythritol or carbohydrates as starters, this will produce star shaped PEGs which are also commercially available, and when you know where to look you can get them for pretty cheap by the barrel or even truckload. They are even available with the remaining alcohol ends 'capped' by all kind of functional groups, like alkenes (allylethers, methacrylates etc), amines (trade name Jeffamines), esters, isocyanates and what not.
Oooopps! Pretty off-topic by now! Sorry!
But as I said, that wouldn't be necessary when using high molecular weight PEGs (i.e. if that worked at all), since the concentration of OH would be very low, probably too low to interfere with grignard formation. Your yields might be diminished only by a percent or two (if that worked at all).
Good luck drying PEG though, they are pretty hygroscopic!

I'm not fat just horizontally disproportionate.