May 11, 2021, 07:12:10 PM
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Topic: Ortho-Lithiation vs. alpha-Lithiation  (Read 338 times)

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Offline columbo123

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Ortho-Lithiation vs. alpha-Lithiation
« on: March 15, 2021, 10:44:06 AM »
Hello everybody,
I am currently planning a synthetic route and the fourth step is planned as shown below.
I am now suspicious of where the lithiation with LDA (or optionally BuLi) is likely to happen. Literature states that HA is favoured over HB in the similar molecule without a OMe group on the phenyl ring. Does anybody have more knowledge on wheter alpha-lithiation at the HA site or ortho-lithiation at HC, promoted by the direct-metallating group OMe, is favoured?

Offline rolnor

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Re: Ortho-Lithiation vs. alpha-Lithiation
« Reply #1 on: March 15, 2021, 02:04:46 PM »
Ha and Hb is much more acidic then Hc. Its more difficult to know if Ha is more acidic then Hb, I think you have to just try.

Offline Guitarmaniac86

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Re: Ortho-Lithiation vs. alpha-Lithiation
« Reply #2 on: March 15, 2021, 03:46:30 PM »
In my group where we synthesise polyaromatic and polyheteroaromatic compounds we have deprotonated at Hc but definitely not with LDA, we use nBuLi.

Though Hb and Ha have similar PKa, I would expect LDA would favour Ha because there is less steric hindrance there.

Sorry I can't be of more help than that.
Don't believe atoms, they make up everything!

Offline rolnor

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Re: Ortho-Lithiation vs. alpha-Lithiation
« Reply #3 on: March 15, 2021, 04:00:47 PM »
If you want to lithiate methoxybenzene you do it at 21°C and with BuLi. Its much easier to lithiate thiophene. I guess Hb is on a carbon that is more conjugated, less "thiophene-like" and therefore less acidic than Ha.

Offline wildfyr

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Re: Ortho-Lithiation vs. alpha-Lithiation
« Reply #4 on: March 17, 2021, 10:03:57 PM »
21°C? how do you maintain that temp? haha

Offline columbo123

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Re: Ortho-Lithiation vs. alpha-Lithiation
« Reply #5 on: March 18, 2021, 03:07:10 AM »
Thank you for all the suggestions.
I will conduct the experiment somewhen next week and post the result, if any of you are curious too.

Offline wildfyr

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Re: Ortho-Lithiation vs. alpha-Lithiation
« Reply #6 on: March 18, 2021, 06:55:29 PM »
please do!

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