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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: columbo123 on March 15, 2021, 10:44:06 AM

Title: Ortho-Lithiation vs. alpha-Lithiation
Post by: columbo123 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?
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: rolnor 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.
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: Guitarmaniac86 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.
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: rolnor 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.
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: wildfyr on March 17, 2021, 10:03:57 PM
21°C? how do you maintain that temp? haha
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: columbo123 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.
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: wildfyr on March 18, 2021, 06:55:29 PM
please do!
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: columbo123 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., HA gets deprotonated selectively. A second, very small TLC spot probably indicates partwise attack on HB, but in a neglectable ratio.

Greetings.
Title: Re: Ortho-Lithiation vs. alpha-Lithiation
Post by: rolnor on June 09, 2021, 02:44:49 AM
Interesting, thanx!