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Topic: LAH reduction of Amide mechanism  (Read 12683 times)

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Offline azmanam

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LAH reduction of Amide mechanism
« on: March 09, 2011, 09:11:55 AM »
I don't know how I feel about the mechanism of LAH reduction of an amide generally proposed in undergrad textbooks.  I've always lived by the mantra 'never draw a positive charge in a basic mechanism/negative charge in acidic mechanism' (except for the counter ion... but we don't care about that part).  We don't kick out RO- under acidic conditions, nor have an alcohol directly attack an unactivated carbonyl because we'd draw O- in the intermediate. 

The step I have problems with is the expulsion of the aluminum hydroxide in the first reduction step.  That generates a carbocation/iminium ion intermediate.  I'm real uncomfortable drawing a carbocation in a basic mechanism.  I'm also uncomfortable with -O-Al-H3 as a leaving group with a 2- charge.

Am I being too meticulous or do others share my concerns?  I'm teaching this mechanism in class in a few days and don't want to sound like a doofus.  Please advise!
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Offline azmanam

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Re: LAH reduction of Amide mechanism
« Reply #1 on: March 09, 2011, 09:16:27 AM »
I like this mechanism much better, which completely avoids positive charges... but I've never seen it drawn this way.  Not in my textbook, not in another textbook, not on the MSU e-text[1], not on the UCalgary site[2]...

[1] http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/crbacid2.htm
[2] http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch20/ch20-3-4-2.html
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Offline Doc Oc

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Re: LAH reduction of Amide mechanism
« Reply #2 on: March 09, 2011, 09:55:51 AM »
I like the 2nd one better as well, but I doubt that many of the undergrads will care one way or the other.  Most of them will groan about having to learn another mechanism.

Offline stewie griffin

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Re: LAH reduction of Amide mechanism
« Reply #3 on: March 09, 2011, 11:48:27 AM »
I don't have the correct answer for you but I too was always bothered by the mechanism typically taught here. I like the second mech better.
Perhaps if it were a more advanced class you could actually explain the merits/drawbacks of each mechanism, but for a typical 2nd yr orgo class I assume most won't ever notice the positive charge in basic media problem.

Offline stewie griffin

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Re: LAH reduction of Amide mechanism
« Reply #4 on: March 09, 2011, 06:46:14 PM »
Azmanam, what happens though when you have two alkyl groups on the amide nitrogen? Your second mechanism wouldn't be applicable then.
Is there a reason why can't we just postulate a direct SN2 by hydride on the intermediate aminal.

Offline azmanam

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Re: LAH reduction of Amide mechanism
« Reply #5 on: March 10, 2011, 08:03:02 AM »
Yeah, I thought about that after my op, too.  Secondary amides couldn't be deprotonated.  But I agree, I like an SN2-like attack of hydride displacing the -OAlH2.

Thanks for the thoughts, all. 
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Offline movies

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Re: LAH reduction of Amide mechanism
« Reply #6 on: March 10, 2011, 10:53:02 AM »
Don't forget about the Li in your mechanism.  The amide is almost certainly coordinated to Li before the first hydride addition (not the reactivity difference between LiAlH4 and NaAlH4).  You could then consider that the leaving group might be the aggregate of Li–O–AlH3.

I am skeptical of the direct SN2 displacement.  It's pretty sterically demanding.

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