Choice of Solvent (MeCN vs H<sub>2</sub>O) Decides Rate-Limiting Step in S<sub>N</sub>Ar Aminolysis of 1-Fluoro-2,4-dinitrobenzene with Secondary Amines:  Importance of Brønsted-Type Analysis in Acetonitrile

Um, Ik‐Hwan; Min, Se-Won; Dust, Julian M.

doi:10.1021/jo701549h

Cited by 65 publications

(97 citation statements)

References 57 publications

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“…The decomposition step is a bit more involved compared to the case of anionic nucleophiles, since the system formally loses a proton in addition to F − . A number of competitive decomposition processes have been postulated; expulsion of F − followed by deprotonation, 29 base-catalyzed deprotonation followed by loss of F − , 29,34 and the expulsion of HF in a concerted manner. 35 Which step in the reaction mechanism that is rate-determining is largly dependent upon the solvent.…”

Section: Neutral Nucleophiles and Hf As Leaving Groupmentioning

confidence: 99%

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

et al. 2012

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We have investigated practical and computationally efficient methods for the quantitative prediction of regioisomer distribution in kinetically controlled nucleophilic aromatic substitution reactions. One of the methods is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. We show that predictions from this method can be used quantitatively both for anionic nucleophiles with F(-) as leaving group, as well as for neutral nucleophiles with HF as leaving group. The σ-complex approach failed when the leaving group was Cl/HCl or Br/HBr, both for anionic and neutral nucleophiles, because of difficulties in finding relevant σ-complex structures. An approach where we assumed a concerted substitution step and used such transition state structures gave quantitatively useful results. Our results are consistent with other theoretical works, where a stable σ-complex has been identified in some cases, whereas others have been indicated to proceed via a concerted substitution step.

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Section: Neutral Nucleophiles and Hf As Leaving Groupmentioning

confidence: 99%

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

et al. 2012

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“…In the case of attack of anionic nucleophiles (such as MeO − ) on fluorinated aromatics, the intermediate σ-complex is anionic and the leaving group is F − , whereas in the case of neutral nucleophiles (such as NH 3 ) the intermediate σ-complex is zwitterionic and the leaving group is HF. The departure of H and F can proceed along different mechanisms [7–9]. …”

Section: Introductionmentioning

confidence: 99%

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

Liljenberg¹,

Brinck²,

Rein³

et al. 2013

Beilstein J. Org. Chem.

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SummaryA computational approach using density functional theory to compute the energies of the possible σ-complex reaction intermediates, the “σ-complex approach”, has been shown to be very useful in predicting regioselectivity, in electrophilic as well as nucleophilic aromatic substitution. In this article we give a short overview of the background for these investigations and the general requirements for predictive reactivity models for the pharmaceutical industry. We also present new results regarding the reaction rates and regioselectivities in nucleophilic substitution of fluorinated aromatics. They were rationalized by investigating linear correlations between experimental rate constants (k) from the literature with a theoretical quantity, which we call the sigma stability (SS). The SS is the energy change associated with formation of the intermediate σ-complex by attachment of the nucleophile to the aromatic ring. The correlations, which include both neutral (NH3) and anionic (MeO−) nucleophiles are quite satisfactory (r = 0.93 to r = 0.99), and SS is thus useful for quantifying both global (substrate) and local (positional) reactivity in SNAr reactions of fluorinated aromatic substrates. A mechanistic analysis shows that the geometric structure of the σ-complex resembles the rate-limiting transition state and that this provides a rationale for the observed correlations between the SS and the reaction rate.

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“…Rate constant for these reactions in water was less than the other solvents. It was clearly observed that the rate constants for the reaction in DES was in a good agreement with the acetonitrile and water , …”

Section: Resultsmentioning

confidence: 66%

“Zero VOC” Synthetic Strategy – Aromatic Amination Reactions in Deep Eutectic Solvents

Valvi

Tiwari

2018

Eur J Org Chem

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Rising concern for environment hazards resulting from the use of volatile organic compounds (VOCs) is prompting many chemists to use “green” solvents like water, polyethylene glycol, ionic liquids and deep eutectic solvents (DES). With a few notable exceptions, many of these processes still need to use volatile organic solvents for the workup and isolation of products. In the present report, we demonstrate a “zero VOC” protocol which eliminates the need to use organic solvents for any stage of the reaction. As a proof of concept, nucleophilic aromatic substitution reactions of 1‐halo‐2,4‐dinitrobenzene with secondary amines were carried out in deep eutectic solvents. The reaction workup involved the addition of water for separating the product from the DES. Evaporation of water led to recovery of the DES, which exhibited good recyclability. The reaction in deep eutectic solvents was much faster than that in many other solvents, as confirmed by the kinetic studies. An attempt was made to elucidate the origin of this rate enhancement based on analysis activation parameters and correlation with the polarity parameters. The results show that use of deep eutectic solvents can take chemists a step closer towards the “zero VOC” synthetic strategy.

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Choice of Solvent (MeCN vs H₂O) Decides Rate-Limiting Step in S_NAr Aminolysis of 1-Fluoro-2,4-dinitrobenzene with Secondary Amines: Importance of Brønsted-Type Analysis in Acetonitrile

Cited by 65 publications

References 57 publications

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

“Zero VOC” Synthetic Strategy – Aromatic Amination Reactions in Deep Eutectic Solvents

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Choice of Solvent (MeCN vs H2O) Decides Rate-Limiting Step in SNAr Aminolysis of 1-Fluoro-2,4-dinitrobenzene with Secondary Amines: Importance of Brønsted-Type Analysis in Acetonitrile

Cited by 65 publications

References 57 publications

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

“Zero VOC” Synthetic Strategy – Aromatic Amination Reactions in Deep Eutectic Solvents

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Product

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Choice of Solvent (MeCN vs H₂O) Decides Rate-Limiting Step in S_NAr Aminolysis of 1-Fluoro-2,4-dinitrobenzene with Secondary Amines: Importance of Brønsted-Type Analysis in Acetonitrile