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ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH301:11

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All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
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Stereochemistry is the study of the different spatial arrangements of atoms in a given molecule. The stereochemistry of radical halogenations can be understood from three different situations:
Halogenation to form a new chiral center:
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Radical Anti-Markovnikov Addition to Alkenes: Overview01:25

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The addition of hydrogen bromide to alkenes in the presence of hydroperoxides or peroxides proceeds via an anti-Markovnikov pathway and yields alkyl bromides.
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Radical Formation: Elimination00:51

Radical Formation: Elimination

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Another method of radical formation is the elimination process. It is the opposite of the addition route and is driven by the instability of the radical. For example, as depicted in Figure 1, dibenzoyl peroxide yields a pair of unstable radicals upon homolysis. Given its instability, this radical spontaneously undergoes elimination via a C–C bond cleavage to form a relatively more stable phenyl radical. The mechanism involves cleavage of the bond between the α and β positions with respect...
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Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is...
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Acid Halides to Amides: Aminolysis01:07

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Aminolysis is a nucleophilic acyl substitution reaction, where ammonia or amines act as nucleophiles to give the substitution product. Acid halides react with ammonia, primary amines, and secondary amines to yield primary, secondary, and tertiary amides, respectively.
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
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Testing the limits of radical-anionic CH-amination: a 10-million-fold decrease in basicity opens a new path to

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Summary

This study introduces a new method for intramolecular C-H amidation using amides, achieving "reductant upconversion" and forming hydroxyisoindolines. The reaction uses molecular oxygen and TEMPO to activate less reactive amides.

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Area of Science:

  • Organic Chemistry
  • Catalysis
  • Reaction Mechanisms

Background:

  • Intramolecular C-H amidation is crucial for synthesizing nitrogen-containing heterocycles.
  • Activating less nucleophilic N-anions like amides for C-H functionalization remains a significant challenge.
  • Existing methods often require harsh conditions or pre-functionalized substrates.

Purpose of the Study:

  • To develop a novel method for intramolecular C-H amidation of unprotected amides.
  • To elucidate the reaction mechanism, including the role of radical intermediates and reductant upconversion.
  • To expand the scope of N-anions participating in C-H functionalization reactions.

Main Methods:

  • Utilizing potassium tert-butoxide (t-BuOK) as a base and molecular oxygen as an oxidant.
  • Employing N,N-dimethylformamide (DMF) as a solvent and TEMPO as an additive.
  • Investigating the reaction pathway through experimental studies and computational analysis.

Main Results:

  • Successful intramolecular C-H amidation of amides to form hydroxyisoindolines under mild conditions.
  • Demonstrated "reductant upconversion" where a weak reductant is converted to a stronger one.
  • Identified a novel mechanism involving radical-anion intermediates, C-N bond formation, and subsequent C-H oxidation.
  • TEMPO additive was found to activate less reactive amides, broadening the substrate scope.

Conclusions:

  • A new, efficient method for synthesizing hydroxyisoindolines from unprotected amides has been established.
  • The study provides fundamental insights into radical-mediated C-H functionalization and reductant upconversion.
  • This work offers a versatile platform for accessing complex nitrogen-containing compounds.