You don't need ultrasonic for this type of reaction. Also the amount of catalyst is excessive. Otherwise - yep. 97% conversion rate, and if the timings are right (you stop early enough) you can even get a dominant d9 60%
You don't need ultrasonic for this type of reaction. Also the amount of catalyst is excessive. Otherwise - yep. 97% conversion rate, and if the timings are right (you stop early enough) you can even get a dominant d9 60%
Please review the following procedure to ensure it is correct and if there are any errors:
Preparation of the Reaction Mixture:Weighing CBD Isolate: Accurately weigh 50 g of CBD isolate with 98% purity. Dissolving CBD: Slowly add a solvent (e.g., ethanol or isopropanol) to the flask containing CBD. It is recommended to use about 100-200 ml of solvent for complete dissolution of CBD. Use a magnetic stirrer to ensure uniform dissolution of CBD in the solvent.
Addition of Acid Catalyst:Choosing a Catalyst: For example, hydrochloric acid (HCl), which is commonly used for the isomerization of CBD into Δ⁹-THC. Adding the Catalyst: For 50 g of CBD isolate with 98% purity, add 0.5-2.5 g of HCl (1-5% of the CBD weight). For 1% HCl = 0.49g HCl, and for 5% HCl = 2.45g HCl.
Carefully add the acid to the CBD solution and mix thoroughly using a magnetic stirrer. It is important to achieve even distribution of the catalyst in the solution.
Heating and Isomerization:Temperature Control: Heat the mixture to a temperature of 100-150°C, preferably 125°C, but no higher than 150°C to prevent degradation. This is critical for activating the reaction. Use a thermometer for accurate control. Using a Water Bath: To more stably control the temperature, it is recommended to use a water bath, maintaining the desired temperature. If using a water bath, heat the mixture for 1-2 hours. If the temperature is too high, molecule degradation may occur; if too low, the reaction will not proceed. Note: It is important to regularly monitor the temperature and avoid overheating. Stopping the reaction earlier will help preserve some of the original CBD if you need less Δ⁹-THC.
Monitoring the Reaction:Reaction Time: The isomerization of CBD to Δ⁹-THC at this temperature takes 1-2 hours. It is important to monitor the process and track the time: if you want to obtain less Δ⁹-THC, the reaction can be stopped after 1 hour.
Cooling the Mixture:Stopping the Reaction: Once the desired conversion is achieved, cool the mixture to room temperature. If using a water bath, simply turn off the heat source. Control: After cooling, it is important to ensure that the reaction has been stopped.
Neutralizing the Acid:Adding a Base: To neutralize the excess acid, add a sodium hydroxide (NaOH) solution or another alkaline substance. Add NaOH drop by drop, carefully checking the pH of the mixture with a pH meter. The goal is to achieve a neutral pH (around 7). Caution: NaOH should be added carefully to avoid vigorous reactions and heat release.
Removal of the Solvent:Evaporating the Solvent: If the solvent has not fully evaporated, use a vacuum evaporator or a standard evaporator at a temperature not higher than 50-60°C to remove any remaining solvent. This will leave a concentrated extract containing Δ⁹-THC.
Purification and Filtration:Removing Impurities: After the reaction is complete and the acid catalyst has been neutralized, filter the mixture through filter paper or use more advanced purification methods such as column chromatography. Goal: To obtain pure Δ⁹-THC free from residual catalysts and other undesirable impurities. Chromatography significantly improves the purity of the final product.
Obtaining Δ⁹-THC:Product: After purification, you will have a mixture containing Δ⁹-THC, ready for use. If necessary, further chromatography or other purification methods can be performed to achieve higher purity Δ⁹-THC.
### **Why Does Δ8-THC Predominate Over Δ9-THC?**
The primary reason is the **thermodynamic stability of Δ8-THC**. Under acid-catalyzed conditions (pTSA + heating), the following occurs:
1. **Formation of a carbocation** upon opening of CBD's epoxide ring.
2. **Rearrangement** into the more stable Δ8-THC (less steric strain in the cyclohexene ring).
3. **Δ9-THC** is a kinetically controlled product, but under heating, it partially isomerizes into Δ8.
**Factors favoring Δ8 formation:**
- Elevated temperature (>40°C).
- Prolonged reaction time.
- Strong acid (pTSA is more aggressive than, e.g., Lewis acids).
---
### **How to Increase Δ9-THC Yield?**
To shift the ratio toward Δ9-THC:
#### **1. Modify Reaction Conditions**
- **Temperature:**
- Optimal range: **0–25°C** (cold slows Δ9→Δ8 isomerization).
- Use an **ice bath** instead of heating.
- **Catalyst:**
- **Milder acids** (e.g., **boron triflate (BF₃·Et₂O)** or **CSA (camphorsulfonic acid)**).
- pTSA is too strong and promotes unwanted rearrangements.
- **Reaction time:**
- **5–10 min** (ultrasound helps shorten the duration).
- Longer time = more Δ8.
#### **2. Optimize the Protocol**
- **Solvent:**
- **Hexane/toluene** instead of DCM (less polar solvents may improve selectivity).
- **Oxygen protection:**
- Work under **nitrogen/argon** to prevent oxidation and side reactions.
- **Reaction quenching:**
- Immediate neutralization (ice-cold water + NaHCO₃) after ultrasound treatment.
#### **3. Chromatographic Purification (if needed)**
- **Column chromatography** (SiO₂, hexane:EtOAc) can separate Δ9 from Δ8.
- **Δ9-THC yield will decrease**, but purity will improve.
**Expected ratio:** Up to **70:30 (Δ9:Δ8)** under ideal conditions.
---
### **Why Does the Original Protocol Favor Δ8?**
- Heating to **38°C** + **pTSA** accelerates the thermodynamically favorable Δ9→Δ8 isomerization.
- Lack of reaction time control (isomerization may continue post-sonication).
**Conclusion:** To prioritize **Δ9-THC**, you must:
1. Lower the temperature.
2. Use a less aggressive catalyst.
3. Precisely control reaction time.
