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Ortho-Lithiation vs. alpha-Lithiation
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Topic: Ortho-Lithiation vs. alpha-Lithiation (Read 2587 times)
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columbo123
New Member
Posts: 8
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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 H
A
is favoured over H
B
in the similar molecule without a OMe group on the phenyl ring. Does anybody have more knowledge on wheter alpha-lithiation at the H
A
site or ortho-lithiation at H
C
, promoted by the direct-metallating group OMe, is favoured?
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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.
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Guitarmaniac86
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Posts: 240
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Medicinal Chemist
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.
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Don't believe atoms, they make up everything!
rolnor
Chemist
Sr. Member
Posts: 2292
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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.
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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
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columbo123
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Posts: 8
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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.
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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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columbo123
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Posts: 8
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Re: Ortho-Lithiation vs. alpha-Lithiation
«
Reply #7 on:
June 09, 2021, 02:38:50 AM »
Better late than never,
for those of you who were curious: With LDA at -78 °C in THF anh., H
A
gets deprotonated selectively. A second, very small TLC spot probably indicates partwise attack on H
B
, but in a neglectable ratio.
Greetings.
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rolnor
Chemist
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Posts: 2292
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Re: Ortho-Lithiation vs. alpha-Lithiation
«
Reply #8 on:
June 09, 2021, 02:44:49 AM »
Interesting, thanx!
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Ortho-Lithiation vs. alpha-Lithiation