We often think of and draw Grignard reagents like so:

ethylmagnesium bromide

Reactivity-wise and when we draw mechanisms, we sometimes make it even simpler for ourselves and picture Grignard reagents as relatively stable carbo-anions (even though the carbon-magnesium bond is in fact covalent and not ionic).

This works very well in almost all cases. But the true nature of Grignard reagents is much more complex than this. Their actual composition depend strongly on solvent, concentration, method of preparation, presence of additives (lithium chloride is really popular nowadays) and so on. In aprotic non-oxygen containing solvents, such as hexane or toluene, Grignard reagents form clusters of two or several equivalents of organomagnesium species (a little like borane (BH3), which in the blink of an eye dimerizes to diborane, even though it formally lacks enough electrons to form typical 2-electron single bonds). In ethers, such as THF, there is a strong interaction between the Grignard species and the ether oxygen. Moreover, one should pay attention to the often neglected Schlenk equilibrium that at times makes things even more complicated.

But there is yet another thing that we almost never talk about. The halide (chloride, bromide, iodide and, in rare cases, fluoride) so called spectator ion. Unless we just buy them ready-made, we prefer to prepare Grignards from bromides or iodides, because it is easier to get the initial reaction going, without really considering that at the end of the day, in some cases, the counter-ion may have a dramatic effect on the outcome of the reaction we are trying to accomplish.

Table 1

This table, which I have stolen from a fairly recent Breit paper (Angew. Chem. Int. Ed. 2008, 47, 5451-5455. DOI: 10.1002/anie.200800733), is a good illustration of what I am trying to highlight here.

In this specific publication the authors do try to explain the fact that a bromide counter ion gave 11 % yield after full conversion of the starting material (entry 5), while chlorides gave sterespecific (>99% ee) products in quantitative yields under optimized conditions (later in the same paper; Table 4 is pure beauty by the way).

In the given mechanism for this reaction (the story continues here: Org. Lett. 2009, 11, 4668-4670. DOI: 10.1021/ol901944b), the spectator ion is not even included as an integral part in the illustration of the proposed transition state, which tentatively explains why this specific reaction works so well and gives enantiopure products.

After reading these articles, I think I like organomagnesium chlorides more than I did before, even if they are a pain in the ass to prepare sometimes.

In an ideal world, the perfect scientist is an independent observer. The perfect spectator ion should live up to the same standards. I am so disappointed in you, Mr Bromine!


5 Responses to Spectator ions — Not always innocent bystanders

  1. I think this should be related to the popupar Knochel procedure for the generation of well-behaved Grignards (iPrMgCl/LiCl).

    • drfreddy says:

      Yeah, adding a dash of LiCl seems to do wonders for a great deal of reactions; not only Grignard related stuff. Stille couplings and Diels-Alders too, for instance. (Also, lithium salts do wonders against bipolar disorder and certain psychiatric conditions alike.)

  2. milkshake says:

    one aspect that is troubling here is use of THF. As a rule you don’y use aliphatic triflates in THF because they are hard enough electrophiles to alkylate THF oxygen, which leads to unfortunate THF polymerization. I admit that 2-triflyloxy esters might be stable enough and well behaved enough (I isolated a triflate ester like this by accident once, it survived the column) but I would much rather stay away from THF in case of triflates, after I witnessed THF polymerization in action.

    Also a good trick how to get rid of pesky bromides from Grignard is to prepare grignard in ether, then adding dry dioxane and distilling ether out. Doixane forms poorly soluble adduct with MgBr2 which precipitates out, the supernatants are enriched with R2Mg species. You can then add some ZnCl2, LiCl, etc to restore the chlorides. The only drawback is that you can lose some Grignard in the precipitation process so it is better to titrate the dioxane solution afterwards, or use a larger excess of Grignard to compensate for the loss.

  3. bandi says:

    The question seems not so simple to me. In Bartoli reaction (nitrobenzene + vinyl-grignard -> indole) the vinylMgCl practically did nothing while vinylMgBr worked smoothly in our hands. Without any additives or magic words.

    • drfreddy says:

      Interesting. I have done a couple of Bartoli myself back in the days. We used vinyl magnesium bromide just because we had it on the shelf. It worked well for us. A feeble attempt at a rationale then: R-magnesium bromides have more oomph than R-magnesium chlorides. (True??) In the case of Bartoli (interesting mechanism by the way, check it out), perhaps that extra reactivity is needed to get the reaction going, while it in the case of Negishi/Kumada-type of reactions on sp3-triflates, it is too reactive, resulting in loss of sterechemical integrity. How does that sound?

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