silicycle inc. ultrapure silica gels and chemistry - application … · 2011. 4. 7. · 2008...
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2008 c a talo g�
Si
[email protected], www.SiliCycle.comTel.: 1 418.874.0054, Toll-free: 1 877.SILICYCLE (North America only)
SiliaBond
®
Application Note B4.0 Comparing Silica and Polymer Supported Products
The use of solid supported scavengers has become a common method for post-synthesis purification. Poly-styrene 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-swell-ing 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 scavenger due to their ability to remove a wide range of electrophiles and nucleophiles and therefore are the basis of our study. Below is a collection of internal data and an external study completed by the chemists 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 to swell.
Scavenging of Phenylchloroformate
Scavenger % Scavenged
Si-Amine
> 99.9%
PS-Amine
71.8%
PS-Amine
72.3%
PS-Trisamine
82.8%
2008 c a talo g�
Si
[email protected], www.SiliCycle.comTel.: 1 418.874.0054, Toll-free: 1 877.SILICYCLE (North America only)
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PS-Triamine
64.9%
conditions: 3 eq. relative to phenylchloroformate, 1 h at room temperature in Dcm, % scavenged by Gc-mS.
Scavenging Amines with Bound �socyanate
Scavenger Benzylamine Aniline
Si–isocyanate >97% 74%
PS-isocyanate (1st source) >97% 60%
PS-isocyanate (2nd source) 81% 60%
conditions: 3 eq. relative to amine, 1 h at room temperature in Dce, % scavenged by Gc-mS.
SoLvenT comPARiSon
To work effectively, PS-based scavengers 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 yields a rigid insoluble support even in pure methanol. The rate of scavenging is unaffected by its environment making it adequate for use in solvents more suited for combichem such as acetonitrile (Acn).1
Scavenging of Benzylamine in Different Solvents
Scavenger THF DCM ACN
Si–isocyanate >98% >98% 95%
PS-isocyanate (1st source) >98% >98% 79%
PS-isocyanate (2nd source) >98% >98% 88%
conditions: 3 eq. relative to amine, 1 h at room temperature, % scavenged by Gc-mS.
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 one for Si–amine that PS-trisamine should be the most effective scavenger since they were working in THF, which is highly compatible with polystyrene. However, using Si–amine to remove excess acid chloride gave higher yields and better purity in 15 of the 16 reactions.
1 nicewonger, R; Ditto, L.; varady, L. Tetrahedron Lett. 2000, 41, 2323-23262 mccomas, W; chen, L; Kyungjin, K. Tetrahedron Lett. 2000, 41, 3573-3576
2008 c a talo g��
Si
[email protected], www.SiliCycle.comTel.: 1 418.874.0054, Toll-free: 1 877.SILICYCLE (North America only)
SiliaBond
®
Hoffman La-Roche Scavenger Comparison
R1R2
Scavenging method
Methyl n-Propyl Benzyl Cyclohexylmethyl
Yield Purit Yield Purit Yield Purit Yield Purity y
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
conditions: 1.5 eq. relative to acyl chloride, stirred overnight at room temperature in THF. isolated yield reported, purity determined by Lc-mS.
SummARy
Silica-supported scavengers have numerous advantages over their polystyrene counterparts. They scavenge 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.
N
N
O
H2NR1
Ph
BEMP
R2COCl (2.0 eq)
THF B:
N
NH2
S i NH2
(1.5 eq. excess over acyl chloride)
(1.5 eq. excess over acyl chloride)
N
N
O
NH
R1
Ph
NH2R2
O
A: