Grignard Reagents & Alkyl Halides

[90210]

This might seem like a silly question, but why wouldn't a Grignard Reagent reaction with an Alkyl Halide?

For example: CH3CH2CH2MgBr and CH3CH2CH2Cl

Is it possible to form: CH3CH2CH2CH2CH2CH3 (hexane) + ClMgBr

My second question is regarding: NaH

I understand it exhibits both extremely basic and nucleophilic properties. For something like a ketone... would it attack the carbonyl carbon or deprotonate the neighboring alpha carbon, or both? I was just curious because for an example in TBR they deprotonated the alpha carbon instead. I was curious if my understanding was wrong.

Thank you.

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[sibitrum]

I know that you cannot use Grignards or organolithium reagents as nucleophiles for Sn2s. I think it has something to do with metal complexing.

Regarding NaH, in general, it is a much better base than nucleophile so it will preferentially form the enolate over attacking the carbonyl. Once the enolate is formed, it will not be attacked, because it does not have a good LUMO at that point.

 

[MT Headed]

This might seem like a silly question, but why wouldn't a Grignard Reagent reaction with an Alkyl Halide?

Well, if they did react with alkyl halides to any great degree, it would be really difficult to create Grignard reagents in the first place:

R-Br + Mg --> R-MgBr
...quickly followed by...
R-MgBr + R-Br --> R-R + MgBr2

This is called coupling, and in the real world it does happen. My ochem book says "In fact, coupling is a side reaction that hurts the yield of many Grignard reactions." My book is mysteriously silent on the reason why it doesn't happen all the time though.

 

[orgohacks]

This might seem like a silly question, but why wouldn't a Grignard Reagent reaction with an Alkyl Halide?

For example: CH3CH2CH2MgBr and CH3CH2CH2Cl

Is it possible to form: CH3CH2CH2CH2CH2CH3 (hexane) + ClMgBr

My second question is regarding: NaH

I understand it exhibits both extremely basic and nucleophilic properties. For something like a ketone... would it attack the carbonyl carbon or deprotonate the neighboring alpha carbon, or both? I was just curious because for an example in TBR they deprotonated the alpha carbon instead. I was curious if my understanding was wrong.

Thank you.

Great question. Remember, we do the experiments first, then backwards-rationalize the reason later. Experiments where this has been attempted (countless times) show that SN2 reactions of Grignards with alkyl halides tend to be very poor reactions. One of the major byproducts is elimination to form an alkene, but other products are formed too.
The reason that has been proposed is usually covered in advanced organic chemistry courses - it's called Hard-Soft-Acid-Base theory (try wikipedia). Grignard reagents are classic examples of "hard" reagents.

SN2 reactions DO work in certain cases w/ organocuprates, especially with allylic and benzylic halides. Organocuprates are not as basic as Grignard reagents and are more likely to undergo such reactions as the SN2.

NaH is a strong base, but is not a good nucleophile. It essentially never attacks the carbonyl carbon - it is always a base. [perhaps you're thinking of NaBH4, which does attack the carbonyl carbon?]. The example you are citing makes sense, although it is usually used to deprotonate alcohols and alkynes.

hope this helps - James

 

[orgohacks]

Well, if they did react with alkyl halides to any great degree, it would be really difficult to create Grignard reagents in the first place:

R-Br + Mg --> R-MgBr
...quickly followed by...
R-MgBr + R-Br --> R-R + MgBr2

This is called coupling, and in the real world it does happen. My ochem book says "In fact, coupling is a side reaction that hurts the yield of many Grignard reactions." My book is mysteriously silent on the reason why it doesn't happen all the time though.

coupling DOES happen in certain cases - especially allylic halides (recall that allylic halides are especially reactive in the SN2). A former colleague of mine was making allyl Grignard once and described it as "a gigantic pain in the ass."

 

[90210]

Great question. Remember, we do the experiments first, then backwards-rationalize the reason later. Experiments where this has been attempted (countless times) show that SN2 reactions of Grignards with alkyl halides tend to be very poor reactions. One of the major byproducts is elimination to form an alkene, but other products are formed too.
The reason that has been proposed is usually covered in advanced organic chemistry courses - it's called Hard-Soft-Acid-Base theory (try wikipedia). Grignard reagents are classic examples of "hard" reagents.

SN2 reactions DO work in certain cases w/ organocuprates, especially with allylic and benzylic halides. Organocuprates are not as basic as Grignard reagents and are more likely to undergo such reactions as the SN2.

NaH is a strong base, but is not a good nucleophile. It essentially never attacks the carbonyl carbon - it is always a base. [perhaps you're thinking of NaBH4, which does attack the carbonyl carbon?]. The example you are citing makes sense, although it is usually used to deprotonate alcohols and alkynes.

hope this helps - James

Thank you James for clearing this up. I had that written in my notes but didn't understand why (the whole Grignard's reacting with Benzylic or Allyic alkyl halides only). This was very helpful.

 

[movax]

Thank you James for clearing this up. I had that written in my notes but didn't understand why (the whole Grignard's reacting with Benzylic or Allyic alkyl halides only). This was very helpful.

It's a really common pitfall in a lot of orgo courses/texts I've found. You learn this great reaction in class that's in your textbook with a given mechanism, but you never realize that the actual real-world implementation of that reaction is a gigantic pain with single-digit percentage yields. A lot of students just end up keeping in their heads that "yeah, if I want X, all I do is react A + B and I get X", not factoring in competing products or thermo vs. kinetic stability.

I think generally if the test question really wants to you start thinking in detail about a given mechanism / reaction, the passage will have the extra tidbits of info you need (such as mentioning multiple products, a table given yields at different temps, etc.). Don't think it expects you to know the intricacies of industrial synthesis of reagents off the top of your head.