In organic synthesis, using excess reagents is a common strategy to maximize the conversion and product yield as this increases the probability of collisions between the desired functions. However, by using excess reagents you are guaranteed to have organic impurities from the unreacted reagents in your crude product.

Removing Organic Impurities

Among the different strategies to purify the final reaction mixture from these excess reagents, column chromatography is one of the most common. Unfortunately, it consumes vast amounts of solvent and can be tedious as well as hard to scale-up. Other techniques such as crystallization, activated carbon and solvent extraction each have their drawbacks.

Crystallization exposes the molecules of interest to elevated temperatures for prolonged periods, risking thermal degradation. The final recovery of the product of interest is also lower than with other techniques.

Nobody likes to handle bulk charcoal (although there is a solution for that, but that’s a story for another time). Also, it is not selective towards specific impurities.

Finally, solvent extraction also requires a large quantity of solvents and may be hard to optimize.

Nonetheless, purification of the final product is not only important for compound purity as it can influence the desired product’s properties or the next reactions in a synthesis, but also it is necessary in order to avoid potential genotoxic impurities and environmental hazards. Scavengers are not only good for metallic impurities, but they can also selectively bind to organic impurities which include potential genotoxic impurities.

There are known interactions between some SiliaBond Organic Scavengers and chemical functions, and a screening test is always recommended as every matrix is different. Even the SiliaMetS Metal Scavengers can sometimes be used for organic molecule scavenging as is seen in the Application Note Appn_SM008-0 in which SiliaMetS DMT was the most efficient scavenger to remove benzyl bromide from a crude product.

To simplify the screening process, the table above shows which scavengers act as an ionic, nucleophile, or electrophile scavenger towards selected functions. Ionic scavengers are ideal to scavenge charged species, while nucleophile scavengers are good for electron-poor functions or vice versa, and electrophile scavengers are good for electro-rich functions (true for functions even if not presented in the above table).

Do It Smartly

Once the best organic scavenger is selected, the optimization of the scavenging parameters can be done the same way as with Metal Scavengers. You can find a full list of the parameters in Application Note Appn_SM001-1 (also discussed here and here).

Organic scavengers can be used either for direct scavenging of the undesired compound to isolate the Active Pharmaceutical Ingredients (API) or for the catch and release of the API.

Direct Scavenging

For direct scavenging, the functional group grafted on the silica support will specifically react with a compound (the unreacted excess reagent or other impurities). The scavenger can be mixed with the crude product, directly in the reaction vessel (either in the round-bottom flask, in an Erlenmeyer after a standard work up, in the reactor, or in the continuous flow system), then filtered out to recover the API. Another option is to recirculate the product in an E-PAK cartridge to avoid the filtering step altogether.

It is important to note that no activation step is required, there is no need for anhydrous conditions or extra apparatus (except for filtering). Take a look at how easy it is with the following case study as an example.

Catch and Release

When using the catch and release method, the SiliaBond Scavenger is pre-packed in a Solid Phase Extraction (SPE) cartridge. After conditioning the cartridge, the crude product is loaded and trapped onto the cartridge bed. The washing solvent is selected to wash out and filter excess reagents and / or other impurities. The API is eluted with the elution solvent and recovered. Other impurities could stay trapped on the functionalized silica. Pretty much like the usual steps of SPE.

Check these two different sample mixtures undergoing this type of purification.

Direct Scavenging vs Catch and Release

Choosing a method depends mainly on your application needs and reaction parameters. In some cases, it is a matter of convenience as both may be possible. One example comes from the Application Note SB012 “Working with SiliaBond Carbonate”, where both bulk and SPE cartridges were used to purify an amide coupling reaction by scavenging HOBt.

Bulk (Direct Scavenging) SPE
1. Add 2 - 4 equivalents of SiliaBond Carbonate to the HOBt solution (in DMF). Conditioning - 1 x column volume of DMF
2. Stir for 1 hour at room temperature. Loading - Load the HOBt solution
3. Remove the SiliaBond Carbonate by filtration and rinse with DMF. Rinsing - 1 x column volume of DMF
4. Solvent evaporation gives the HOBt free solution.

Number of Equivalents Method Reaction Time (min) Final HOBt Concentration* (ppm) Scavenging Yield (%)
3 Bulk 5 32 99.4
60 32 99.4
SPE - <5 >99.9
4 Bulk 5 22 99.6
10 22 99.6
60 21 99.6
SPE - <5 >99.9

* Determined by GC-MS. Initial HOBt concentration: 5 000 ppm in DMF.

Why Is It Smart?

Using scavengers is the smart way because it is selective, with almost perfect product recovery.

It uses significantly less solvent than the other methods. In the Application Note Appn_SM009-0, the quantity of sorbent and solvent used for scavenging and chromatography were compared and scavengers proved to be the most economical in quantity of material used.

Elemental impurity removal using different techniques on crude product (1,925 ppm initial rhodium impurity), 22°C
Scavenger Loading
(% w/w)
Solvent used
(mL/g of crude)
Experiment time
Final concentration
Silica gel chromatography (bare silica F60 superior grade, 40 - 63 µm, 60 Å) 3,800 (SiliaFlash) 420 (10 % to 30 % acetone in hexanes) 0.75 365
SiliaCarb C-CA (bulk) 100 (SiliaCarb) 100 (methanol) 4 81
SiliaCarb C-CA +
SiliaMetS Diamine (bulk)
100 (SiliaCarb)
100 (SiliaMetS)
100 (methanol)
210 (ethyl acetate)
4 + 4 49
SiliaCarb C-CA +
SiliaMetS Imidazole (bulk)
100 (SiliaCarb)
100 (SiliaMetS)
100 (methanol)
210 (ethyl acetate)
4 + 4 53
SiliaCarb C-CA +
SiliaMetS Diamine/Imidazole (bulk)
100 (SiliaCarb)
200 (SiliaMetS)
100 (methanol)
210 (ethyl acetate)
4 + 4 40
SiliaCarb C-CA E-PAK cartridge 125 (SiliaCarb) 90 (methanol) 4 44
SiliaCarb C-CA E-PAK +
SiliaMetS Diamine E-PAK +
SiliaMetS Imidazole E-PAK
125 (SiliaCarb)
200 (SiliaMetS)
90 (methanol)
75 (ethyl acetate)
4 + 4 23

Moreover, the products don’t have to be exposed to elevated temperatures like they need with other methods (but they could if required since it may help get faster scavenging).

Most importantly scavengers are straightforward to scale-up. No need for special equipment or re-optimizing the process. Scavenging on a large-scale takes approximately as much time as scavenging in a lab-scale. It is efficient. It is smart.

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