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View Poll Results: What position is kinetically favored for substitution?
3-Cl 0 0%
5-Cl 1 100.00%
6-F 0 0%
Voters: 1. You may not vote on this poll

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Old Sep 16th 2019, 04:39 PM   #1
Daijo
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Question Hardest SNAr Regioselectivity Prediction

During one of my internship in a big pharma in San Francisco, I had to prepare a new core by SNAr on a tetrahalopyrimidine. Link to Reddit post

Predicting the regioselectivity of the second SNAr may seem obvious to an experienced eye, but take your time and explain. Will the substitution occur at the 3rd, 5th or 6th position?


I have the experimental result in my head and will reveal it after some posting.
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Last edited by Daijo; Sep 16th 2019 at 04:44 PM.
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Old Sep 18th 2019, 11:23 PM   #2
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Best leaving group

We need to check best leaving group and carbon which is most electron deficient here.
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Old Sep 19th 2019, 10:42 PM   #3
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It doesn't matter which is best leaving group. The first step is irreversible in basic conditions (formation of the anionic sigma-complex). We just need to know the lowest energy barrier that should be correlated to the intermediate's stability (Hammond's postulate for a endergonic step with a late transition state). We have to look at the most stabilized sigma-complex and look at steric hindrance for its formation.
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Old Oct 2nd 2019, 08:01 AM   #4
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We basically have to find out which of these two intermediates is more stable.
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