Glycerol as a green solvent for amination of aryl halides glycerol OR copper "copper catalyzed"

Question

Accepted Answer

Glycerol is a moderately effective green solvent for copper-catalyzed Goldberg-type aminations, demonstrating significantly higher efficiency when utilized as a component of a choline chloride-based Deep Eutectic Solvent (DES) rather than as a pure solvent (Direct, High; PMID: 33543179) «✓ PMID:33543179».

## Effectiveness in C-N Coupling
*   **Yield Comparison:** In a model CuI-catalyzed amination of 4-iodotoluene with 2-methylbenzamide, pure glycerol (Gly) achieved a 51% yield. In contrast, the DES mixture 1ChCl/2Gly (Choline Chloride/Glycerol) increased the yield to 66% under identical conditions (80 °C, 12 h, under air) (Direct, High; PMID: 33543179) «✓ PMID:33543179».
*   **Temperature Optimization:** Increasing the reaction temperature to 100 °C in the 1ChCl/2Gly solvent further improved the yield of the secondary amide to 72% (Direct, High; PMID: 33543179) «✓ PMID:33543179».
*   **Relative Performance:** While glycerol-based solvents are effective, they are generally less active than aqueous media for aromatic amides; for example, pure water and the DES 1ChCl/2H2O achieved yields of 85% and 80%, respectively, in the same model reaction (Direct, High; PMID: 33543179) «✓ PMID:33543179».

## Mechanistic and Sustainable Advantages
*   **Synergistic Stabilization:** The improved performance of glycerol-based DES compared to pure glycerol is attributed to a positive synergistic effect between the quaternary ammonium salt (Choline Chloride) and the natural polyol. This interaction enhances the catalytic rate of the copper species within the tridimensional hydrogen-bond network of the DES (Direct, High; PMID: 33543179) «✓ PMID:33543179».
*   **Ligand and Solvent Roles:** In Goldberg-type aminations, glycerol-based solvents still require bidentate ligands (such as ethylene diamine) for high activity; suppression of the ligand in 1ChCl/2Gly resulted in a dramatic decrease in yield to 10% (Direct, High; PMID: 33543179) «✓ PMID:33543179». Evidence from related C-O coupling reactions suggests these alcohol-based DES components may further stabilize copper salts, potentially acting as non-innocent media (Indirect, Medium; PMID: 34762333).
*   **Green Synthesis Profile:** Glycerol is a biorenewable, earth-abundant, and non-volatile solvent, fulfilling key Green Chemistry principles by replacing volatile organic compounds (VOCs) (Direct, High; PMID: 33543179) «✓ PMID:33543179». 
*   **Bench-Type Conditions:** A significant advantage of using these sustainable media is the ability to perform reactions under "bench-type" settings, specifically in the absence of a protecting atmosphere (under air) and at lower temperatures than typical Ullmann/Goldberg couplings (Direct, High; PMID: 33543179) «✓ PMID:33543179».
*   **Recyclability:** The catalytic system and the eutectic solvent can be successfully recycled for at least four consecutive runs without significant loss of yield, reducing the overall E-factor (environmental factor) of the synthesis (Direct, High; PMID: 33543179) «✓ PMID:33543179».

[How does the performance of 1ChCl/2Gly compare to water-based Deep Eutectic Solvents in Goldberg-type aminations?](#cta)

[What are the specific ligand requirements for copper-catalyzed C-N coupling when using glycerol-based green solvents?](#cta)

[Does the use of glycerol-based solvents allow for the amination of aliphatic amides in addition to aromatic ones?](#cta)