Benefits of Protecting Groups in Organic Synthesis

In organic synthesis, a molecule may contain two or more functional groups. In order to prevent one of the functional groups from being destroyed by the reaction, a certain reagent is often used to protect it first, and the protective agent will be removed after the reaction is completed. The protection of hydroxyl, amino and amino groups are most commonly seen. There are many types of protective reagents, which are widely used in the synthesis of drug molecules. Each protective reagent has corresponding de-protection conditions.

What is protecting group?
As mentioned above, the protecting group is a group whose main purpose is to protect the functional group (improve its stability) through a specific chemical reaction. Various protecting groups have been developed to stabilize the chemical properties of the original site according to the purpose.

In addition, protecting groups can also bring about many other benefits:

Improve solubility and reduce polarity
Sugars and amino acids are often used as the starting point for synthesis. However, such compounds are highly polar, and most of them are insoluble in organic solvents, and some are soluble in water, resulting in very low yields. In this case, this can be improved by protecting the polar functional group.

Improve crystallinity
When refining synthetic intermediates, especially in the case of expanding the reaction, it is desirable to avoid the column as much as possible. At this time, a suitable protective group can be selected by recrystallization to improve the formation of crystals. The commonly used functional groups here are –Br and −NO2.

Changes in biological activity
In physiologically active substances, biological polymers are very likely to interact with each other due to the action of polar functional groups. By introducing protective groups, the lower polar functional groups can be shielded and the biological activity can be reduced.

Changes in volatility
By introducing protective groups, the molecular weight becomes larger and the boiling point rises. As a result, the solvent can be simply removed by rotary evaporation under reduced pressure, and the drying can be made easier. In addition, if hydroxyl groups are converted to methyl ether or R-O-TMS, etc., the molecular weight increases while the polarity decreases, which results in increased volatility. In this case, it is easier to perform mass analysis or GC.

Make structural analysis easier
Adding a strong UV-absorbing protective group to a chemical that does not originally have a UV absorption band can improve the high-sensitivity detection in HPLC.

In short, a good protecting group should meet the following requirements: first, it must be selectively removed by reaction with easily available harmless reagents in a high yield, and these reagents will not attack the regenerated functional groups. Second, a protecting group will produce a derivative (not involving the generation of a new chiral center), which is easily separated from the by-products that are formed or cleaved with it. Third, the protecting group should hardly produce additional functional group characteristics to prevent other reactions from taking place.

In order to achieve the best reaction effects, a variety of protective groups have been continuously developed. In order to ensure the progress of the reaction, it is necessary to grasp their respective characteristics and choose and use them reasonably according to the actual situation. Reagents that can provide the protecting groups are called protection reagents.