HCl gas, commonly known as hydrochloric acid gas in the laboratory, is a frequently used gas in the organic synthesis process. Hydrogen chloride gas is water-free and is mostly useful for reactions sensitive to water, like the Pinner reaction, removing Boc protecting groups, removing silyl protecting groups, and removing MOM protecting groups. Of course, you can directly buy HCl methanol solution and HCl dioxane solution, but these commercially available solutions have a limited shelf life and will absorb water after being used several times. Reagents that have been opened for a period of time will significantly affect the reaction effect.
If there is an HCl gas cylinder in the laboratory, it is of course the most convenient, but because HCl gas cylinders are very dangerous, accidents are likely to occur if they are not handled properly, so there are rarely HCl gas cylinders in synthesis laboratories. Is there a way to quickly prepare HCl gas directly in the laboratory? Of course there is, and here are a few methods.
Concentrated Sulfuric Acid(H2SO4)+ Solid Sodium Chloride
This method can quickly obtain a relatively large amount of continuous HCl gas, which is suitable for reactions that require continuous introduction of HCl gas, such as the Pinner reaction. Usually, dry hydrogen chloride gas is introduced at 0°C in an anhydrous solvent (such as benzene, chloroform, nitrobenzene, dioxane, etc.). The operation is also very convenient. To get dry hydrochloric acid gas, slowly drip concentrated sulfuric acid onto solid sodium chloride. Then, pass the gas through concentrated sulfuric acid to dry it. The gas output can be adjusted by the drop rate. The prepared HCl gas can be used directly for the reaction, or it can be passed into various cooled solutions to prepare the required HCl solution.
Some people also say that HCl gas can be obtained by dropping concentrated sulfuric acid into concentrated hydrochloric acid, but this method contains too much water and the drying effect is not good.
Methanol(MeOH）+ Acetyl Chloride(Accl)
A very important application of hydrochloric acid gas is the removal of Boc protecting groups. The hydrochloride generated after deprotection generally obtains solids after concentration, and the product state is usually better than that of trifluoroacetic acid deprotection. HCl methanol solution is the most commonly used deprotection reagent. In the experiment, acetyl chloride can be slowly added to methanol under cooling to quickly obtain HCl methanol solution. The conversion of acetyl chloride to methyl acetate has little effect on the reaction. One disadvantage of this method is that if methanol contains water, acetic acid may be generated. If BocNHR is deprotected and the next step is directly amidated, the residual acetic acid may cause a side reaction to generate acetamide.
Methanol + Thionyl Chloride
This method is actually similar to method 2. Slowly add thionyl chloride to methanol under cooling, but it is better than method 2 in that it avoids the side reaction that may be caused by acetic acid. In addition, thionyl chloride consumes water, which can strictly limit the water content in the solution system.
Other Methods
- Add concentrated hydrochloric acid to anhydrous calcium chloride. Since anhydrous calcium chloride can form CaCl2-2H2O, it has a strong water-fixing ability.
- Mix sodium chloride and sodium bisulfate and heat (250℃).
