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Organometallics

By James Ashenhurst

Reactions of Grignard Reagents

Last updated: September 11th, 2019 |

All About The Reactions of Grignard Reagents

Here’s the summary for today’s post:

Summ_slide

So far in this series we’ve introduced organometallic compounds and said that their carbons tend to be nucleophilic. We’ve learned how to make them from alkyl, alkenyl or aryl halides (along with some ways not to make them!) and saw that they are very strong bases.

So what now? Well, we want to know what we can actually DO with these things, right?

So let’s get started!

Table of Contents

  1. Reminder: Grignard Reagents Are Nucleophiles
  2. Addition of Grignard Reagents To Epoxides
  3. Reaction of Grignard Reagents With Aldehydes And Ketones
  4. Reaction of Grignard Reagents With Esters
  5. Why Do Grignards Add Twice To Esters? The Mechanism
  6. Summary: Reactions of Grignard Reagents
  7. Notes

1. Reminder: Grignard Reagents Are Nucleophiles

I know we’ve said this many times in this series already, but it bears repeating: Grignard reagents are nucleophiles, meaning that they (specifically the carbon bound to Mg) will readily donate a pair of electrons to an appropriate electrophile.

We’ve already seen them react with weak acids, where the electrophile is electrophilic hydrogen (H+).

More interesting and useful for us is a variety of carbon based electrophiles, because we can thus combine Grignard reagents with those species to form new carbon-carbon bonds. And since carbon-carbon bonds constitute the “backbone” of molecules in organic chemistry, it turns out that this class of reactions is very useful. As a matter of fact, it won its discoverer, Victor Grignard, the Nobel Prize for Chemistry back in 1912.

For our purposes, the key carbon-based electrophiles that Grignard reagents react with are epoxides, aldehydes, ketones, and esters. Let’s go through them in turn.

2. Addition of Grignard Reagents To Epoxides

Epoxides (“oxiranes” if you are an IUPAC stickler) are 3-membered cyclic ethers which possess considerable ring strain.  As we’ve seen, this ring strain makes them somewhat “spring loaded” toward attack by nucleophiles, which will result in formation of a new bond to carbon and opening of the ring.

Negatively charged nucleophiles (such as Grignards) tend to react with epoxides in a manner similar to the SN2 reaction: attack occurs at the least substituted carbon of the epoxide. Here’s an example:

0-epoxides

Note the bonds that formed and broke here: we formed a new C-C bond (between carbons A and B), and broke a C-O bond (between carbon A and the oxygen). This resulted in a negatively charged oxygen (alkoxide): to produce final alcohol product, we typically quench the reaction with a source of acid, forming O–H.

Here’s how the reaction works. The hard thing is to recognize that the nucleophile is the pair of electrons in the C-Mg bond: remember from previous posts that carbon is strongly δ- (nucleophilic) because of its greater electronegativity as compared to magnesium. It might be helpful to imagine the Grignard reagent below as CH3CH2– . Other than that the reaction is fairly straightforward if you’ve seen an SN2 reaction before: we simultaneously form C-C and break C-O.

1-grignard-epox

Note that this reaction also forms an “alkoxide”. In order to obtain our neutral alcohol product at the end, we must perform second step:  a “workup” (“quench”) with a source of acid. This is written a variety of ways – H+, H3O+, H2O, or just “acid workup”. This step occurs after our key Grignard reaction, for what should be obvious reasons – Grignard reagents are destroyed by acid.

Another thing to keep in mind is stereochemistry of the epoxide.Consistent with an SN2 reaction, if the reaction occurs at a secondary carbon, we will observe inversion of configuration: 

3. Reaction of Grignards With Aldehydes and Ketones

A second class of important electrophiles that react with Grignards (and arguably THE most important class of electrophiles) is aldehydes and ketones. If you haven’t covered the reactions of these functional groups yet, a short summary would be this: the carbonyl carbon is an electrophile, and when nucleophiles react at this carbon, it’s accompanied by cleavage of the C-O pi bond (π bond). More on that mechanism (“addition”) in a second.

2-grig-aldket-1

Here are some examples of reactions of Grignards with aldehydes and ketones. Note that in each case we are forming a new bond between the carbonyl carbon (labelled A) and the carbon bound to magnesium (labelled B), and we are breaking the C-O pi bond in the process.
2-aldehydes_ketones

So how does this reaction work?

Let’s get familiar with a VERY important mechanism called “addition” (sometimes called, “1,2-addition”). This is by far the most important reaction of the carbonyl group, and if you give yourself a dollar for every time you will see variations of it in Org 2, you can buy yourself a vacation to Hawaii by the end of the semester. Not really, but almost.

3-ketone-mech

Note that this reaction also forms an “alkoxide”. In order to obtain our neutral alcohol product at the end, we must perform a “workup” (“quench”) with a source of acid, forming O-H.

4. Reaction of Grignard Reagents With Esters

Esters are close relatives of aldehydes and ketones: they consist of a carbonyl group directly attached to an OR group. As you might expect, they react with Grignards in a similar fashion to aldehydes and ketones: with formation of a new C-C bond and breakage of a C-O (pi bond).

However, there’s a twist with the reaction of esters that isn’t present with aldehydes and ketones. Look carefully: what’s different?

4-esters

Note that in both cases we added two equivalents of our Grignard reagent to the ester, forming a tertiary alcohol.

Wait a minute – how did this happen?!

5. Why Is There “Double Addition”With Esters? The Mechanism

This reaction incorporates the second most important mechanism of carbonyls (next to “addition”), namely, “elimination“. In fact “elimination” is the exact reverse of “addition” ! Let’s walk through it. There are 4 steps.

  • In the first step,  the Grignard performs an addition reaction on the ester, forming C-C and breaking C-O (pi), giving us an intermediate with a negatively charged oxygen. We’ve seen this type of reaction before in the addition of Grignards to aldehydes and ketones.
  • Now comes the new step: elimination (sometimes, “1,2 elimination”). This intermediate has a reasonably good leaving group (OCH2CH3 in the case below). What happens next is reformation of the C-O pi bond with expulsion of the leaving group (CH3CH2O in the case below). In other words, we form C–O π and break a C–O single bond.  The new product is a ketone.

[Why might “elimination” happen for esters but not for aldehydes or ketones? Because we are expelling only a moderately strong base (RO) as compared with the extremely strong bases H or R (which would be the leaving groups were this to happen with aldehydes or ketones)]. You can think of “basicity” as a proxy for “stability”. Alkoxides, which are expelled in this elimination reaction, are reasonably stable by themselves. Hydrides and most carbanions are more than 1025 more unstable. Plus, the elimination reaction begins with an alkoxide intermediate. We are essentially just swapping one alkoxide for another.   [Note 1] ]

  • But wait! There’s more! After Step 2, we have a new ketone. As we’ve seen before, Grignards will react quickly with ketones in yet another addition reaction [Step 3]. Here, as in Step 1, we form C–C and break C–O (pi). The result is a tertiary alkoxide (the conjugate base of a tertiary alcohol).

[Wait, you might ask. If we just use one equivalent of Grignard reagent, is it possible to get the reaction to stop at the ketone stage? The short answer is “no”. [See note 3 for the long answer]]

  • Finally, protonation of this tertiary alkoxide yields the tertiary alcohol (Step 4). 

Here’s the graphical walkthrough:

5-ester mech

6. Summary: Reactions of Grignard Reagents

That does it for the key reactions of Grignard reagents you’ll see in most Org 1 and Org 2 courses.

In the next post we’ll talk about yet another way to screw up formation of Grignard reagents, and it involves the reactions in this post.

Next Post: Protecting Groups In Grignard Reactions


Notes

Note 1: Although alkoxides (RO, the conjugate base of alcohols, pKa 16-18) are not on anyone’s list of Great Leaving Groups, they are some 25 orders of magnitude better leaving groups than hydrides (H–, the conjugate base of hydrogen, pKa 40) and more than 30 orders of magnitude better than alkyl groups (R- , the conjugate base of alkanes, pKa 50). Thus, when the alkoxide intermediate is formed in Step 1, there is not any deep energetic penalty for the C-O pi bond to reform and for RO- to be expelled: after all, we are simply replacing a strong base (the O- ) with one of comparable basicity.

[Note 2] Why are ketones more reactive towards Grignard reagents than esters? This requires understanding the phenomenon of pi donation. The lone pair on oxygen donates electron density into the carbonyl carbon. This is worthy of a separate post, but here’s the bottom line:

pi donation

[Note 3] Alas, no. Using 1 equivalent of Grignard will result in 0.5 equivalents of a tertiary alcohol and 0.5 equivalents of the starting ester. The reason why is that Step 2 [elimination] is quite fast! Once elimination occurs, we will have ketone in the presence of an ester. For interesting reasons [see Note 2] ketones are more reactive than esters toward Grignard reagents, which means they will be consumed more quickly.

Comments

Comment section

53 thoughts on “Reactions of Grignard Reagents

  1. A question:If one equivalent of grignard reagent is made to reacts with a compound that contains a double bond and a carbonyl group(C=O),grignard will attack which one?

    1. Esters are certainly less reactive than ketones. I don’t know of a good competition experiment between a carbonyl halide and a ketone or aldehyde. All I would say is that in these three cases the first addition is very fast.

  2. I was wondering about the reactivity of different grignards reagents, with the same R group. Meaning I, Cl, Br. If I where to have two methyl halogens in the solution, which one would be more readily to form the grignard?

    1. Certainly not for primary or secondary amides. For intro organic chemistry puposes, generally amides considered to be unreactive…. but google “weinreb amide” for a more advanced treatment.

    1. The reagent can get protonated in cases where the Grignard or the ketone are sterically hindered. One complication of acidity of the alpha position of aldehydes or ketones is that the alpha C-H bond must be aligned with the C=O bond in order for it to be acidic; otherwise the resulting carbanion would not be resonance stabilized. There is no such barrier to addition to the carbonyl.

  3. Forgive me if I’m wrong, but for the illustration that appears just above the header “2. Reaction of Grignards With Aldehydes and Ketones,” did the ethyl group (going out of the plane) in the cycloheptane ring change to a methyl group by mistake?

  4. Hi, why can’t Grignards react with the alpha carbon on ketones and aldehydes since the pKa of that alpha carbon is around ~20 while the pKa of an alkane hydrogen is ~50?

    1. Great question Jon. One of the tricky bits we don’t mention too much is that in order for the C-H bond to actually be acidic, it has to be aligned at 90 degrees to the carbonyl. So when the Grignard is in the vicinity of the carbonyl, two things can happen; it can add, or it can remove the C-H bond. However like I said the C-H bond has to be aligned perfectly for that to happen, whereas the carbonyl is under no such restraint.
      The upshot is that addition tends to be faster than deprotonation in this case, so long as the carbonyl isn’t too sterically hindered.

    1. Methylcyclopropane, no, because there’s no electron sink for the carbanion that would result. They can certainly react with acidic hydrocarbons like terminal alkynes and cyclopentadiene.

    1. Sounds about right. I wouldn’t want to try to run a competition experiment between an acid chloride and an aldehyde, but aldehydes are certainly more reactive than ketones.

    1. That’s a great question. I put in both because you might see either. It’s very instructor dependent.

      For introductory organic purposes, however, you can think of them as the same.

      In practice NH4Cl is a little milder, especially with acid-sensitive molecules that might react with H3O+ . NH4Cl is a “safe choice” when you need a mild acid for workup.

    1. Hi Adam, it would depend on several factors. If you’re talking about epoxide opening, then if you start with a chiral, non-racemic epoxide, you’ll end up with a chiral, non racemic product because the stereocenter is unaffected. If you’re talking about addition to an achiral aldehyde or ketone, then in the absence of any chiral influence you’ll obtain a racemic product. If you’re talking about addition to a chiral, but racemic aldehyde or ketone then in the absence of any chiral influence you’ll end up with a mixture of diastereomers. This is a good question and deserves its own blog post.

  5. Is it possible to form a ‘Grignard’ reagent with other Gp2 metals? Are the larger Gp2 metal ions not sufficiently polarising due to their lower charge density? I just ran an exam revision course and found this thread very useful for an unusual A level chem topic.

  6. Reactivity order of all oxygen contain compounds towards grignard reagent(aldehyde,ketone,ester,acid chloride,carboxylic acid,acid anhydrides,acid amide)?

  7. Hey, what will be the product for a three degree alcohols reacting with ‘traces of GR and H+’. Thankyou!

  8. Ok… I get what grignard reagent would do with all the above-mentioned compounds… But I am stuck on this question…
    Acetyl bromide reacting with excess of CH3MgI followed by treatment with a saturated solution of NH4Cl gives???

    1. You’ve got an an acid chloride reacting with an excess of Grignard reagent. Acid chlorides react similarly to esters. The Grignard adds twice.
      In many cases the workup step says, “H+”. However this can cause confusion because H+ in the presence of a tertiary alcohol can lead to formation of a carbocation (remember sn1 with alcohols). So instead of H+, NH4+ Cl- is sometimes used in the workup step. This is a strong enough acid (pKa 10) to protonate the negatively charged oxygen, but not a strong enough acid to protonate the neutral OH and thus go down the SN1/E1 pathway.
      Does that help?

    1. On an absolute scale, it will correlate pretty well with basicity, but that’s not taking steric factors into account. The problem with Grignards is usually not that they aren’t “reactive enough”, but that the substrate is sterically hindered and side reactions result.

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