Gilman Reagents (Organocuprates): What They’re Used For

So What Are Gilman Reagents Used For, Anyway?

Last time we talked about how to make Gilman reagents (organocuprates). In this post, we’ll talk about what they’re actually used for.

Gilman reagents have some useful contrasts to Grignard reagents.

• First of all, they can be used to perform conjugate addition reactions (“1,4-addition”) on alpha,-beta unsaturated ketones. In contrast, Grignard reagents tend to only add to the carbonyl carbon.
• Secondly, Gilman reagents are useful nucleophiles for SN2 reactions, forming C-C bonds with primary alkyl halides and sulfonates (e.g. tosylates, mesylates)
• Third, Gilman reagents will convert acid halides to ketones through nucleophilic acyl substitution. Grignard reagents will add twice to acid halides to give tertiary alcohols.

Table of Contents

1. Gilman Reagents vs Grignard Reagents
2. Conjugate Addition: A Key Reaction of Gilman Reagents
3. How do you know whether “normal” or “conjugate” addition will occur?
4. Conjugate Addition Mechanism
5. Gilman Reagents Are Great Nucleophiles For S_N2 Reactions
6. Conclusion: Gilman Reagents
7. Notes
8. (Advanced) References and Further Reading

1. Gilman Reagents vs. Grignard Reagents

As I hinted at last time, Gilman reagents provide an interesting contrast with Grignard and organolithium reagents.

Remember all those examples of Grignard reagents adding to aldehydes, ketones, and esters? Well, Gilman reagents don’t generally do that (they will add to acid chlorides, but I digress)

You might find yourself wondering, “So what?”.  Why do we have to bother learning about these things if they’re not even very reactive?

Well, dear reader, let me fill you in on a second example. We’ll change one small thing, and everything changes.

Let’s put a double bond next to the ketone and run the reaction again.

Whoa. What just happened there?

2. Conjugate Addition: A Key Reaction of Gilman Reagents

The Grignard reagent reacted the same way (to the carbonyl) but for the organocuprate, see that we’ve broken the C-C  π bond (double bond) and formed a new C-C bond ?

If that seems strange to you, it should! Isolated alkenes, such as cyclohexene, for instance, don’t do this reaction.

So there must be something important about the fact that the alkene is next to a carbonyl. Why might that be important?

Look at the resonance forms and you will see a clue.

There is an important resonance form where the carbon two carbons away from the carbonyl carbon (we call this the “beta” (β) position) bears a positive charge. In the resonance hybrid, therefore, that carbon bears some partial positive charge.

In other words, that carbon is electrophilic. It can react with nucleophiles! (Such as organocuprates).

Contrast that with ordinary alkenes, where the resonance form with a carbon bearing a negative charge is not an important resonance form. The fact that the charge is placed on oxygen in the resonance form of an α,β unsaturated system is the key to the relative importance of that resonance form. [Compare the basicity of alkoxides (RO-) and alkyllithiums (R-) and that will give you an idea of their relative stabilities].

[For more, see article – The Michael Addition and Conjugate Addition]

3. Wait: How Do You Know Whether “Normal” Addition or “Conjugate” Addition Will Occur?

This brings up an important question: How do you know whether a nucleophile will attack at the carbonyl carbon (sometimes called “1,2 addition” in our jargon) or at the beta position (“1,4 addition” or “conjugate addition”).

Simple question. Very difficult to answer succinctly, and too big a topic for this post.

Short answer: memorize that Grignards add to carbonyls, while organocuprates do conjugate addition.

(ducks while people throw things at the screen)

I only say “memorize” because in order to adequately understand this phenomenon, we’d have to go into some molecular orbital theory to get at the key concept of “Hard Soft Acid Base (HSAB) Theory“, and at this point, we’re not going to cover it.

What about the mechanism of the reaction? Now that’s something we can cover.

4. Conjugate Addition Mechanism

In the first step, the nucleophile (which is the pair of electrons in the Cu-CH₃ bond, NOT the negative charge on copper!) forms a bond with the beta position of the ketone.  The C-C π bond breaks, forming a negative charge on the alpha carbon.  We can actually go further and draw a resonance form where we form a new C-C π bond and place the negative charge on oxygen. You’ll see this chemical species a lot in subsequent chapters – it’s called an enolate, and it’s very important. (See article: Enolates)

For now, the key takeaway is that the negative charge is on the oxygen, which is considerably more stable (less basic) than having a negative charge on carbon.

Adding acid will protonate the enolate (which is a base, after all) and result in our final product.

5. Gilman Reagents Are Excellent Nucleophiles For S_N2 Reactions

But wait! Conjugate additions aren’t all organocuprates can do.

If you have a keen eye for the other posts in this series, you might have noticed that S_N2 reactions were conspicuously absent on the list of reactions that Grignards are useful for. [Why’s that? Great question. The short answer is, we observe that a lot of side reactions tend to occur, like deprotonation and reduction. Using a Grignard reagent to do an S_N2 reaction to form a C-C bond is generally not a great process]. 

However, once we switch to a Gilman reagent, the S_N2 works well. This is a handy reaction to have in the toolbox for forming C-C bonds.

That about sums it up for Gilman reagents right now. We could add that they can be used to make ketones from acid halides , I hesitate to put that in at the moment, given that this post is long enough as it is. [The general mechanism is covered in this article on Nucleophilic Acyl Substitution. ]

6. Conclusion: Gilman Reagents

Gilman reagents (organocuprates) perform two reactions that Grignard reagents (and organolithiums) do not:

• They perform conjugate additions to α,β unsaturated ketones.
• They are effective nucleophiles for S_N2 reactions.

In the next post, we’ll change to a more controversial topic – transition metal catalyzed reactions.

Next Post: Heck, Suzuki, and Olefin Metathesis Reactions

Notes

Note 1. Yet More Information, Because This Hasn’t Been A Long Enough Blog Post Already

Here’s a quiz for you.  What would be the better nucleophile? An organocopper reagent or an organocuprate reagent?

When thinking about this, analyze the leaving group. Therein lies the clue.

When organocopper reagents act as nucleophiles, they go from neutral, relatively stable compounds to ionic Cu+. Although this is a sweeping generalization, charge minimization is generally associated with greater stability in organic chemistry. We’re going from a neutral compound (organocopper) to a charged ion (Cu+). [I could also add that Cu+, being a soft ion, is not very effective in binding to O-, but that’s a pretty advanced point].

Compare that to organocuprates. There, we’re starting as a relatively unstable charged species, and our final copper product is the neutral organocopper reagent. This is definitely downhill in terms of stability. It’s reasonable to expect that the organocuprate will be more reactive, and hence be a better nucleophile.

The same principle can be used to explain why NaBH₄ is a better reducing agent than BH₃, and LiAlH₄ is a better reducing agent than AlH₃.

(Advanced) References and Further Reading

Gilman reagents, or Lithium organocuprates (R₂CuLi), are useful nucleophiles in organic synthesis. These have a different reactivity from Grignard reagents and organolithiums, since Gilman reagents are softer.

Gilman reagent formation:

1. The Preparation of Methylcopper and some Observations on the Decomposition of Organocopper Compounds
   Henry Gilman, Reuben G. Jones, and L. A. Woods
   The Journal of Organic Chemistry 1952 17 (12), 1630-1634
   DOI:1021/jo50012a009
   One of the first papers by Prof. Henry Gilman (U. of Iowa) on ‘Gilman Reagents’ – diorganocopper compounds. In this case he describes the preparation of dimethylcopper.
   
   Conjugate addition of Gilman reagents:
2. Chemistry of carbanions. XVII. Addition of methyl organometallic reagents to cyclohexenone derivatives
   Herbert O. House and William F. Fischer Jr.
   The Journal of Organic Chemistry 1968 33 (3), 949-956
   DOI: 1021/jo01267a004
3. Conjugate Addition Reactions of Organocopper Reagents
   Gary H. Posner
   React. 1972, 19, 1-114
   DOI: 10.1002/0471264180.or019.01
   Organic Reactions is a series of reviews maintained by the ACS Division of Organic Chemistry, and this review by Prof. Posner, a specialist in cuprate chemistry, covers everything you’d want to know about conjugate additions with copper, as of 1972. Detailed experimental procedures are given towards the end.Ketones can be synthesized by the addition of Gilman reagents to acyl halides:
4. Methyl and -alkyl ketones from carboxylic acid chlorides and organocopper reagents
   G. H. Posner, C. E. Whitten
   Tetrahedron. Lett. 1970, 11 (53), 4647-4650
   DOI: 10.1016/S0040-4039(00)89398-3
   One of the original papers on this reaction. Prof. Posner has done a lot of work studying organocopper chemistry in his career.
5. Organocopper chemistry. Halo-, cyano-, and carbonyl-substituted ketones from the corresponding acyl chlorides and organocopper reagents
   Gary H. Posner, Charles E. Whitten, and Paul McFarland
   Journal of the American Chemical Society 1972, 94 (14), 5106-5108
   DOI: 1021/ja00769a066
   An extension of the previous paper, expanding the substrate scope of the reaction.The S_N2 reaction of Gilman reagents with alkyl halides is also known as the Corey-Posner-Whitesides-House reaction:
6. Selective formation of carbon-carbon bonds between unlike groups using organocopper reagents
   Elias J. Corey and Gary H. Posner
   Journal of the American Chemical Society 1967, 89 (15), 3911-3912
   DOI: 1021/ja00991a049
   Nobel Laureate Prof. E. J. Corey first describes the reaction of Gilman reagents from CH₃Li ((CH₃)₂CuLi) with alkyl and aryl halides to form new C-C bonds.
7. Carbon-carbon bond formation by selective coupling of n-alkylcopper reagents with organic halides
   Elias J. Corey and Gary H. Posner
   Journal of the American Chemical Society 1968, 90 (20), 5615-5616
   DOI: 1021/ja01022a058
   Prof. Corey extends this method to n-butyl and ethyl (from n-BuLi and EtLi) as well.
8. Reaction of lithium dialkyl- and diarylcuprates with organic halides
   George M. Whitesides, William F. Fischer Jr., Joseph San Filippo Jr., Robert W. Bashe, and Herbert O. House
   Journal of the American Chemical Society 1969, 91 (17), 4871-4882
   DOI: 1021/ja01045a049
   Classic paper by Prof. G. M. Whitesides (MIT, now Harvard) on the coupling of Gilman reagents (R₂CuLi) with aryl iodides. This reaction is exhaustively studied, and features a thorough mechanistic investigation, which is why his name is included in the reaction.