Formation of Grignard and Organolithium Reagents

Formation or Grignard Reagents and Organolithium Reagents From Alkyl and Alkenyl Halides

In the last post we introduced the concept of organometallic compounds – molecules where carbon is bound to a less electronegative atom such as Li, Mg, Cu, and many other metals. We said that carbon in these molecules tends to be electron-rich and thus have nucleophilic character, in contrast to functional groups such as alkyl halides, aldehydes, ketones, and epoxides where carbon has electrophilic character. If you need a refresher on what I meant by nucleophilic and electrophilic, read that post first.

In this post we’ll talk about how certain types of organometallic compounds are made – specifically organolithium and Grignard reagents.

Quick summary:

Let’s start with organolithium reagents because they’re the simplest.

Table of Contents

1. Organolithium Reagents As Carbanions (The Conjugate Bases Of R-H)
2. Making Carbanions Through Reduction, Not Deprotonation
3. Formation of Organolithium Reagents From Alkyl Halides
4. Formation of Grignard Reagents
5. Formation of Grignard Reagents:  The Mechanism
6. Notes
7. (Advanced) References and Further Reading

1. Organolithium Reagents As Carbanions

If you look closely, you can approximate the structure of an organolithium reagent (R-Li) as “R(–)” , with lithium as the positive counter-ion: in other words, a carbon bearing a negative charge (we call these species “carbanions”). If you think back to earlier lessons on acids and bases, this structure might look familiar – it’s the conjugate base of a species R-H.

Using butane to stand in for “R-H” here, we get:

Since conjugate bases are made through deprotonation, we might naively think that we could make organolithium species by taking an organic molecule and just adding a super-strong base to rip off the proton.

If you’ve covered alkynes, you’ve seen that that process actually works pretty well in the case of terminal alkynes. They are quite acidic species, having a pK_a of 25 or so. Their unusually high acidity is due to the considerable s-character on the carbon (meaning that the lone pair is held closely to the nucleus).

Trouble is, as we move towards alkenes and alkanes, the direct deprotonation approach doesn’t work so well. That’s because… well, it’s hard to find any species more basic than a deprotonated alkane! Just as the only thing sharp enough to cut a diamond is another diamond, about the only thing basic enough to deprotonate an alkane is… another deprotonated alkane.

This isn’t a practical approach to make organolithiums for several reasons – primarily, the fact that there are often many C-H bonds and it’s hard to selectively remove just one. [For instance, if you tried to make 1-pentyllithium by deprotonating pentane, you could potentially end up with multiple different isomers].

Thankfully, another approach has been devised.

2. Making Anions Through Reduction, Not Deprotonation

If you look at the reaction below, and count the electrons carefully, you might note that the product has two more electrons than the starting material. In other words, particularly if you remember the OIL RIG mnemonic, reduction has occurred.

This means that if we were to add some species which was particularly likely to give up its electrons, we might thus be able to effect this transformation.

Can you think of any members of the periodic table which hold onto their electrons particularly loosely? If you said “the far left part of the periodic table” (particularly the alkali and alkaline earths), ding ding ding! you would be correct.

Lithium, in short, would be a great choice as a reductant for this reaction. [We’ll get to the other metals in a minute].

What might be a good choice for X? One factor which would make this reaction easier is if X(–) was a fairly stable species – a good leaving group, in other words. Good candidates for X are halides such as Cl, Br, and I. A bad candidate would be H(–)  or some other strongly basic version of R(–) , since we’d be generating another unstable anionic species.

Now let’s get to specifics.

3. Making Organolithium Reagents From Alkyl Halides

Lithium, having a very low ionization energy (i.e. it loses its electron easily) is a powerful reducing agent.  Since lithium only has a single valence electron, however, we must add two equivalents if we are to complete the reduction reaction.

To make organolithium reagents, we start with alkyl halides, and add powdered lithium metal (Li or sometimes written as Li⁰ to distinguish it from the ion Li(+) ).

Occasionally the solvent for this reaction is written below the arrow. A common solvent is pentane. Some instructors like to include it. Some don’t. Regardless of whether it’s written there or not, it doesn’t participate in the reaction.

This reaction works for alkyl chlorides, bromides, and iodides, as well as alkenyl halides (fluorides excepted).

If you recall that alkyl halides can be made from halogenation of alkanes, this method thus gives us a 2-step method for formation of highly basic alkyl lithium species from alkanes.

For a pop-up view of the mechanism hover here  or click on the link.

We’ll cover the many useful applications of organolithium reagents in a future blog post.

I’m going to skip organoberyllium reagents here (beryllium is highly toxic, and rarely sees use)  and move straight across from sodium over to magnesium, which comprises a second very important family of organometallic reagents.

The process for making Grignard reagents is very similar to making organolithium reagents: start with an appropriate alkyl halide and add magnesium. Since magnesium has two valence electrons, only one equivalent of Mg is required to balance the reaction. Here’s two examples, showing formation of alkyl and alkenyl Grignard reagents.

Note that Grignards can be made from alkyl or alkenyl chlorides, bromides, and iodides – but not fluorides.

What, you might ask, are Et₂O and THF? These are solvents, which are often written in the reaction scheme, but don’t actually participate in the reaction itself.  Et₂O (diethyl ether, or, sometimes, “ether”) and THF (tetrahydrofuran) are popular choices.  If you’re an introductory student, you probably don’t want to know the deeper reasons why, nor do you need to, so don’t click this link to find out.

In contrast with most of the reagents and reactions we talk about at MOC, you’ll likely have personal experience doing this reaction!

Sitting around for a few minutes staring at your flask containing Mg, ether, and organohalide do absolutely nothing is a rite of passage for every student of organic chemistry.

One key contributor to the “finicky” nature of forming Grignard reagents is that the reaction occurs on the surface of the magnesium metal. For this reason the reaction is highly surface area dependent. Breaking the Mg up into very small chunks will accelerate the reaction. Furthermore, Mg that has been sitting out in the open for awhile often has a surface coating of magnesium oxide (MgO) which is unreactive with alkyl halides. Breaking up the surface helps to expose fresh, unoxidized Mg to the reactants. A pinch of iodine (I₂) or 1,2-dibromoethane can also help to kick-start things.

5. Formation of Grignard  Reagents: The Mechanism

What’s the mechanism of Grignard formation? Usually not covered – it involves free radicals – but if you’re curious, hover here for a pop-up view or click on this link.

From a practical perspective, one key thing to make sure of when preparing organolithium or Grignard reagents is that the solvent and glassware are completely dry. Water (pK_a 14) is death to Grignard and organolithium reagents, which as we said above, act as the equivalent of highly basic alkyl and alkenyl anions.

In the next post, we’ll talk about this and also some other complications of making Grignard reagents.

Next post: Organometallics Are Strong Bases

Notes

What about Organosodium Reagents?

So if lithium works, why not go further down the column of the periodic table? Why not use sodium?

This is an excellent idea – sodium is a great reducing agent, after all. The trouble is, when we try to make organosodium reagents from alkyl halides, what tends to happen is that the carbanions that form then go on to react with our starting alkyl halide (in an SN2 process). The result is a pretty useless reaction you likely don’t need to care about that we call Wurtz coupling.

That’s OK, however. Organolithium reagents are plenty reactive enough for almost every purpose that we’d otherwise want organosodium reagents to do. I mean, who needs Chuck Norris when you’ve got Jackie Chan?

Likewise for organopotassium reagents.  The one application of organopotassium reagents that sees common use is a reagent called Schlösser’s Base , which is strong enough to deprotonate allylic C-H bonds, something not easily done by organolithium reagents.

(Advanced) References and Further Reading:

1. Secondary and Tertiary Alkyllithium Compounds and Some Interconversion Reactions with Them
   Henry Gilman, Fred W. Moore, and Ogden Baine
   Journal of the American Chemical Society 1941, 63 (9), 2479-2482
   DOI: 1021/ja01854a046
   Prof. Henry Gilman (Iowa State) was a pioneer in organometallic chemistry in the first half of the 20^th century. In this paper he describes the synthesis and reactivity of various alkyllithiums (n-butyllithium, s-butyllithium, isopropyllithium, and t-butyllithium). The synthesis is from the alkyl halide and lithium metal, as can be seen in the experimental section.
2. t-Butyllithium
   Paul D. Bartlett, C. Gardner Swain, and Robert B. Woodward
   Journal of the American Chemical Society 1941, 63 (11), 3229-3230
   DOI: 1021/ja01856a501
   This communication is from some legendary figures in organic chemistry and describes the preparation of t-butyllithium.
3. 2-PHENYLPYRIDINE
   C. W. Evans and C. F. H. Allen
   Org. Synth. 1938, 18, 70
   DOI: 10.15227/orgsyn.018.0070
   The first step in this procedure is a preparation of phenyllithium from bromobenzene and lithium metal. Organic Syntheses is a reputable source of reproducible and independently tested synthetic organic procedures.
4. The mechanism of the lithium – halogen Interchange reaction : a review of the literature
   Bailey, W. F.; Patricia, J. J.
   Organomet. Chem. 1988, 352 (1-2), 1-46
   DOI: 10.1016/0022-328X(88)83017-1
   In modern organic chemistry, organolithium reagents are rarely prepared from scratch (i.e. using Li metal), due to the ready availability of alkyllithium reagents from vendors (e.g. MeLi, the BuLi reagents, PhLi, etc.). Instead, these reagents can be used to form other organolithium species through a process known as lithium-halogen exchange.
5. What’s Going on with These Lithium Reagents?
   Hans J. Reich
   The Journal of Organic Chemistry 2012, 77 (13), 5471-5491
   DOI: 1021/jo3005155
   Prof. Hans Reich (U. Wisconsin-Madison) has spent his career studying the behavior of organolithium species, and this is an account of his research and the surprising findings he made. This is classic Physical Organic chemistry.
6. Grignard, V. C. Acad. Sci. 1900, 130, 1322-1324
   The original paper by Victor Grignard describing a new method for alcohol synthesis from hydrocarbons.
7. Victor Grignard and Paul Sabatier: Two Showcase Laureates of the Nobel Prize for Chemistry
   Henri B. Kagan
   Angew. Chem. Int. Ed. 2012, 51, 2-9
   DOI: 10.1002/anie.201201849
   For those interested in the history of science, this is a historical perspective on the lives of Victor Grignard and Paul Sabatier, and gives insight into their lives, how they made their seminal discoveries, and the impact of their work, among other things.
8. Mechanical activation of magnesium turnings for the preparation of reactive Grignard reagents
   Karen V. Baker, John M. Brown, Nigel Hughes, A. Jerome Skarnulis, and Ann Sexton
   The Journal of Organic Chemistry 1991 56 (2), 698-703
   DOI: 10.1021/jo00002a039
   Sometimes the formation of a Grignard reagent using Mg metal can be challenging, and various methods for activating the metal surface have been developed, including mechanical activation by dry-stirring Mg turnings under an inert atmosphere for several hours.
   
   The following 3 papers are mechanistic studies on the formation of Grignard reagents:
9. The Mechanism of Formation of Grignard Reagents: Trapping of Free Alkyl Radical Intermediates by Reaction with Tetramethylpiperidine-N-oxyl
   Karen S. Root, Craig L. Hill, Lynette M. Lawrence, and George M. Whitesides
   Journal of the American Chemical Society 1989 111 (14), 5405-5412
   DOI: 10.1021/ja00196a053
10. Mechanism of Grignard Reagent Formation. The Surface Nature of the Reaction
    M. Walborsky and Janusz Rachon
    Journal of the American Chemical Society 1989 111 (5), 1896-1897
    DOI: 10.1021/ja00187a063
11. Mechanism of Grignard Reagent Formation. Comparisons of D-Model Calculations with Experimental Product Yields
    John F. Garst and Brian L. Swift
    Journal of the American Chemical Society 1989 111 (1), 241-250
    DOI: 10.1021/ja00183a037
12. 4-METHOXY-4′-NITROBIPHENYL
    K. Stille, Antonio M. Echavarren, Robert M. Williams, and James A. Hendrix
    Org. Synth. 1993, 71, 97
    DOI: 10.15227/orgsyn.071.0097
    The second step in this procedure includes the synthesis of p­-anisylmagnesium bromide, which can be a tricky Grignard reagent to prepare and requires special activation of Mg with methyl iodide.
13. The Grignard Reaction – Unraveling a Chemical Puzzle
    Raphael Mathias Peltzer, Jürgen Gauss, Odile Eisenstein, and Michele Cascella
    Journal of the American Chemical Society 2020 142 (6), 2984-2994
    DOI: 10.1021/jacs.9b11829
    Recent (and open-access) article that suggests that the reaction “does not occur via a single process but by an ensemble of parallel reactions.”