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A pragmatic procedure for predicting regioselectivity in nucleophilic substitution of aromatic fluorides |
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| Authors: | Magnus LiljenbergTore Brinck,Bjö rn HerschendTobias Rein,Glen RockwellMats Svensson |
| Affiliation: | a AstraZeneca, Sweden Operations, S-151 85 Södertälje, Sweden b Physical Chemistry, School of Chemical Science and Engineering, KTH—Royal Institute of Technology, S-100 44 Stockholm, Sweden c AstraZeneca R&D, Pharmaceutical Development, S-151 85 Södertälje, Sweden d AstraZeneca R&D, Medicinal Chemistry, S-151 85 Södertälje, Sweden |
| Abstract: | The scope and limitations of a method for predicting the regioisomer distribution in kinetically controlled nucleophilic substitution reactions of aromatic fluorides have been investigated. This method is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. A wide set of substrates and anionic nucleophiles have been investigated. Predictions from this method can be used quantitatively—these agree to an average accuracy of ±0.5 kcal/mol with experimental observations in eleven of the twelve investigated reactions. |
| Keywords: | Nucleophilic substitution Regioselectivity Computational σ-Complex DFT |
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