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Topic: Is this the right sequence of reactions/reagents?  (Read 7815 times)

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Offline G O D I V A

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Is this the right sequence of reactions/reagents?
« on: November 20, 2009, 02:16:47 AM »
The question I have is:

Indicate the reagents and conditions required (no mechanisms) to convert benzene, , into the trisubstituted benzene, , and then into the benzoic acid derivative, . Several steps requiring isolation of intermediate products may be required for each conversion.

Below is what I've done:
(1) Are the reagents/conditions I stated the right ones, I'm not 100% sure
(2) I've drawn out what I think are the right mechanisms to get those products (I know the question says no mechanisms, I did it just for my revision), but I'm not 100% sure again.  I remember some substituents are ortho, para, or meta directing but I'm not sure which is to come first.  I.e. should step (2) come before (1) or (5) before (4)?
(3) What does the "Several steps requiring isolation of intermediate products may be required for each conversion" mean.


Offline Scatter

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Re: Is this the right sequence of reactions/reagents?
« Reply #1 on: November 20, 2009, 02:44:11 AM »
Awesome.  I can't wait till I'm able to do problems like this.

Offline nj_bartel

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Re: Is this the right sequence of reactions/reagents?
« Reply #2 on: November 20, 2009, 02:48:02 AM »
I don't think the product in 3 would be your major product.

Offline kryptoniitti

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Re: Is this the right sequence of reactions/reagents?
« Reply #3 on: November 20, 2009, 05:36:14 AM »
Commenting on the first step:
You might encounter problems getting just toluene because toluene is more reactive than your starting reactant(because of activating alkyl substituents), leading to further alkylation and producing di-, tri-methyl benzene. But if selectivity/yield isn't the main issue here then it probably doesn't matter too much.

Offline tmartin

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Re: Is this the right sequence of reactions/reagents?
« Reply #4 on: November 20, 2009, 07:37:27 AM »
To address your second question: I think that the order you have 4 and 5 in is OK.  However, you may want to remember that making a grignard reagent in the presence of an acidic proton can lead to self quenching of the grignard reagent.  In this case, it's OK, it still gives you the desired product (the quenching step with acid/water would be protonating the carboxylate), but if you wanted to add that grignard reagent into an electrophile other than H+, you would not get the desired product.


Offline G O D I V A

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Re: Is this the right sequence of reactions/reagents?
« Reply #5 on: November 20, 2009, 08:43:09 AM »
I don't think the product in 3 would be your major product.

How come?

Commenting on the first step:
You might encounter problems getting just toluene because toluene is more reactive than your starting reactant(because of activating alkyl substituents), leading to further alkylation and producing di-, tri-methyl benzene. But if selectivity/yield isn't the main issue here then it probably doesn't matter too much.

I realised this, but I wasnt sure how to isolate it.  The question said "Several steps requiring isolation of intermediate products may be required for each conversion", so I figured (if my reagents/conditions stated were correct and toluene was produced) then it would need to be isolated, but I don't know how to do that


To address your second question: I think that the order you have 4 and 5 in is OK.  However, you may want to remember that making a grignard reagent in the presence of an acidic proton can lead to self quenching of the grignard reagent.  In this case, it's OK, it still gives you the desired product (the quenching step with acid/water would be protonating the carboxylate), but if you wanted to add that grignard reagent into an electrophile other than H+, you would not get the desired product.

Why is that?

Offline orgopete

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Re: Is this the right sequence of reactions/reagents?
« Reply #6 on: November 20, 2009, 10:01:51 AM »
I don't think the product in 3 would be your major product.
I agree. The usual rule is the most activating group controls regioselectivity. If the methyl directed the bromination, why shouldn't it direct the alkylation as well?

Q, is this a post diazonium chemistry problem? (If yes, then it is a hint.)
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Offline tmartin

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Re: Is this the right sequence of reactions/reagents?
« Reply #7 on: November 20, 2009, 10:12:34 AM »
If you look at the pKa's of the two protons in question, the carboxylic acid proton (pKa's around 4 give or take) is far more acid than the resulting arene proton (pKa's around 35-40).  This would push the equilibrium to formation of the carboxylate (it's really not in equilibrium, as the carboxylate will not deprotonate the aromatic proton).  If you wanted instead of H on the aromatic ring, a methyl group, your proposed method would probably not give the desired product.

Offline stewie griffin

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Re: Is this the right sequence of reactions/reagents?
« Reply #8 on: November 20, 2009, 10:18:37 AM »
orgopete and nj_bartel:
I think that in step three the reaction would be at the site para to the bromine. Yes the methyl directs the bromine ortho/para during the bromine installation. But once you have a bromine and a methyl you have to decide which is now more activating. Halogens are interesting in these reactions b/c although they are deactivating via inductive effect, they are activating (and ortho/para directing) due to resonance with the lone pairs. The methyl however is only ortho/para directing due to inductive effects. I think resonance with the bromine wins out here.

Offline azmanam

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Re: Is this the right sequence of reactions/reagents?
« Reply #9 on: November 20, 2009, 10:43:48 AM »
Hey Stewie, I'm real proud of you and I'mma let you finish, but...

I think a different order of addition may be more appropriate.  I postulate the t-butyl group goes on first (with the same mono vs di vs trisubstitution problems, but that's going to happen no matter which you do first).

The t-butyl group will block the ortho positions and direct the bromine to the para position quite nicely as the sole product.

At that point, the methyl group won't go ortho to the t-butyl for steric reasons, and as stewie mentioned, the bromine will probably preferentially drive the reactivity anyway to give the methyl ortho to the bromine.

Last steps are fine, imho.
« Last Edit: November 20, 2009, 11:01:18 AM by azmanam »
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Offline orgopete

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Re: Is this the right sequence of reactions/reagents?
« Reply #10 on: November 20, 2009, 10:57:17 AM »
While not my favorite reference, http://www.freechinapatent.com/view-tid-217606-cid-76.html

A process for preparing 2-fluoro-4-bromotoluene and 2-fluoro-4-bromobenzyl bromide with para-aminotoluene as initial raw material includes such steps as forming salt, nitration, diazotization, bromo-substituted synthesis to obtain 2-nitro-4-bromotoluene, reduction, diazotization and fluorination to synthesize 2-fluoro-4-bromotoluene, and optical bromination to synthesize 2-fluoro-4-bromobenzyl bromide, and features simple operation, low cost and high output rate.

So, 4-bromotoluene nitrated, reduced and diazotized to fluoro went ortho to CH3, not ortho to Br.

This is how I thought this might have been done, nitrate benzene, reduce to aniline, acetylate, add t-butyl, add methyl, hydrolyze, diazotize to bromo, oxidize to acid. If the o-t-butylbenzoic acid is wanted, reduce the diazonium salt directly and oxidize. I think the regiochemistry will be fine. I don't think rearrangements will be a problem.
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Offline irciniastatin J

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Re: Is this the right sequence of reactions/reagents?
« Reply #11 on: November 20, 2009, 03:15:52 PM »
Check MSU's etextbook. They have a good section on EAS

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