Case Studies - Scavenger Study #1

Comparing Silica and Polymer Supported Scavengers

The use of solid supported scavengers has become a common method for post synthesis purification. Polystyrene or PS based scavengers are the most widely available form of solid supported scavengers due to low cost of manufacturing. However the PS backbone greatly influences the behavior of the scavenger in terms of solvent compatibility and reaction rate. Silica bound scavengers have the advantage of a rigid non-swelling backbone that eliminates solvent compatibility and kinetic issues. Additionally, silica bound scavengers are easier to handle due to the absence of static.

Bound amine and isocyanate are two very popular functionalities as scavengers due to their ability to scavenge a wide range of electophiles and nucleophiles respectively and therefore are the basis of our study. Below is a collection of internal data and an external study by researchers at Hoffman La-Roche.

Kinetic Comparison

Since the Silica is surface functionalized it reacts much faster than conventional polymer bound reagents where the reaction is slowed by the rate of diffusion through the polymer and can be slowed further by the polymer’s ability or inability to swell.

Products % Scavenged Si-Amine >99.9% PS-Amine 71.8% PS-Amine 72.3% PS-Trisamine 82.8% PS-Triamine 64.9% Condition 3 eq relative to the phenyl chloroformate, 1hr at room temperature in DCM, % scavenged by GC-MS

Solvent Comparison

To work effectively PS-based scavenger must be allowed to swell. In highly compatible solvents such as DCM and THF this can result in a 10-fold volume increase making product recovery difficult. Silica neither swells nor shrinks and our end-capping procedure provides a rigid insoluble support even in pure methanol. The rate of scavenging is unaffected by its environment making it suitable for use in solvents more suited for combichem such as acetonitrile (ACN)¹

Scavenging of Acid Chlorides

When selecting a scavenger to use in library synthesis robustness is the key selection factor. Researchers at Hoffman La–Roche compared PS-trisamine to Si – Amine for the removal of acid chlorides in the synthesis of 2,9-disubstituted guanines.² They had hypothesized that since PS-trisamine has two primary amines per molecule versus Si –amine that has one primary amine per molecule that PS-trisamine should be the more effective scavenger since they were working in THF, which is highly compatible with polymer. However, using Si-amine to remove excess acid chloride gave higher yields and better purity in 15 of the 16 reactions. The results are shown below.

R1 Scavenging Methyl n-Propyl Benzyl Cyclohexylmethyl R2 method Yield Purity Yield Purity Yield Purity Yield Purity Trisamine 34 99 51 86 28 99 39 99 Si - Amine 68 99 75 88 37 88 55 99 Trisamine 68 78 69 95 63 98 49 96 Si - Amine 79 91 75 99 77 98 69 93 Trisamine 34 99 60 91 32 99 42 99 Si - Amine 75 99 82 99 42 99 60 99 Trisamine 57 79 70 86 53 74 76 53 Si - Amine 78 75 99 97 99 99 64 99

Summary

Silica supported scavengers provide numerous advantages over their polystyrene counterparts. They scavenged faster, generate higher purities and yields and are solvent independent. They are also easier to work with due to the absence of static and do not require extensive washing. All resulting in time and cost savings for you.

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