A metal scavenging study was performed following the synthesis of a key synthetic intermediate obtained by the Suzuki-Miyaura coupling presented below. Various parameters were investigated like the efficiency of SiliaMetS in different formats, scavenging kinetic, intermediate recevory and purity.
Small-Scale Scavenging (Synthesis Scale ~ 5 g)
Table below shows the most efficient SiliaMetS Metal Scavenger products for the treatment of the reaction mixture after work-up in both bulk and fixed mode bed (pre-packed SPE cartridges).
| SiliaMetS Scavenging Efficiency & Intermediate Results | ||||
| SiliaMetS | Batch Reactor Mode (Bulk) | Fixed Mode (SPE) | Intermediate Recovery | |
| 5 eq., 4 h, 22°C | 5 eq., 4 h, 40°C | 6 mL / 1 g | ||
| SiliaMetS Thiol | 95 % | > 99 % | 98 % | > 99 % |
| SiliaMetS Thiourea | 83 % | 93 % | 99 % | 98 % |
| SiliaMetS Cysteine | 84 % | 91 % | 97 % | > 99 % |
|
SiliaMetS DMT |
97 % | > 99 % | > 99% | 98 % |
| Initial Pd Concentration: | 179 ppm in MTBE | 76 ppm in Toluene | ||
Scavenging Conclusion
Addition of only 5 equivalents of SiliaBond products for 4 hours at the end of the reaction reduces the residual metal concentration to single digit ppm.
Recovery & Purity Conclusion
Palladium was completely removed, while the organic compound was not sequestrated by SiliaMetS products without adding any impurities.
1Org. Proc. Res. & Dev., 2008, 12, p. 896
Larger Scale Scavenging (Synthesis Scale ~ 55 g)
SiliaMetS Metal Scavenger in pre-packed SiliaSep Flash Cartridge is a great alternative for metal removal for process development scale. These cartridges offer excellent scavenging efficiency as shown by results in the following table and time-saving for the chemist. After the first run, almost all the palladium is capted. After three times, less than 1 ppm remained in solution.
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Metal Scavenging in Flow Chemistry (Preliminary Results)
Flow chemistry is a relatively new technique that is gaining in popularity for large scale manufacturing because of the small investment needed to be able to produce large quantities in a short time. SiliaMetS Metal Scavenger can also be used in flow chemistry to scavenge metal. Crude reaction mixture was purified using a Syrris ASIA® Flow Chemistry System.
| SiliaMetS Thiol Scavenging Results in Flow Chemistry | ||||
| Flow Rate | Solution Volume | Contact Time with SiliaMetS Thiol | Time Needed to Treat the Solution |
Scavenging Results |
| 1.50 mL/min | 100 mL | 16 min | 1h10 | 94.0 % |
| 1.00 mL/min | 100 mL | 24 min | 1h40 | 94.3 % |
| 0.75 mL/min | 50 mL | 32 min | 1h10 | 94.5 % |
| 0.50 mLmin | 50 mL | 48 min | 1h40 | 95.0 % |
| Initial Pd Concentration: 547 ppm in EtOAc | Experimental Conditions: | Scavenger Used: SiliaMetS Thiol SiliaMetS Nb. Equivalent: 13.5 eq. Reactors: 2 x 12 mL Reactors in Series |
Total Solution Volume: 100 mL Purification Scale: 12.5g Temperature: 22°C |
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Variation of Phosphorous Ligand Nature & Scavenging
Even for the same metal, a variation in the scavenging efficiency can be observed depending on the nature of the products present inside the solution to be treated. For example, the steric hindrance of the catalyst and the electronic effects of the phosphorous ligands, are factors influencing the removal of the metal. The same suzuki coupling shown on page xx was performed using different phosporous ligands; three monodentate and three bidentate ligands. For comparison purposes, scavenging screening was done by using the same two sets of conditions. No optimization was done to increase SiliaMetS performance. By experience, using longer reaction time or higher temperature will allow for better results.
| SiliaMetS Scavenging Results with Monodentate Ligands | ||||||
| SiliaMetS | Triphenylphosphine [PPh3]![Triphenylphosphine [PPh3]](http://www.silicycle.com/media/images/pph3.gif) |
Tri(o-tolyl)phosphine [P(otol)3]![Tri(o-tolyl)phosphine [P(otol)3]](http://www.silicycle.com/media/images/tri-o-tolyl-phosphine.gif) |
Tri-n-butylphosphine [PnBu3]![Tri-n-butylphosphine [PnBu3]](http://www.silicycle.com/media/images/pnbu3.gif) |
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| 4 eq., 4 h, 22°C | 4 eq., 4 h, 60°C | 4 eq., 4 h, 22°C | 4 eq., 4 h, 60°C | 4 eq., 4 h, 22°C | 4 eq., 4 h, 60°C | |
| SiliaMetS Thiol | 70 % | 97 % | 87 % | 96 % | 26 % | 85 % |
| SiliaMetS Thiourea | 55 % | 86 % | 54 % | 82 % | 18 % | 41 % |
| SiliaMetS Cysteine | 69 % | 76 % | 77 % | 90 % | 17 % | 44 % |
|
SiliaMetS DMT |
95 % | 97 % | 95 % | > 99 % | 36 % | 87 % |
| Initial Pd Concentration: | 27 ppm in EtOAc | 84 ppm in EtOAc | 90 ppm in EtOAc | |||
| SiliaMetS Scavenging Results with Bidentate Ligands | ||||||
| SiliaMetS | 1,1’-bis (diphenylphosphino) ferrocene [dppf] |
1,3-bis (diphenylphosphino) propane [dppp] |
(+/-) BINAP |
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| 4 eq., 4 h, 22°C | 4 eq., 4 h, 60°C | 4 eq., 4 h, 22°C | 4 eq., 4 h, 60°C | 4 eq., 4 h, 22°C | 4 eq., 4 h, 60°C | |
| SiliaMetS Thiol | 50 % | 69 % | 75 % | 90 % | 31 % | 56 % |
| SiliaMetS Thiourea | 3 % | 23 % | 40 % | 60 % | 33 % | 21 % |
| SiliaMetS Cysteine | 29 % | 36 % | 47 % | 55 % | 19 % | 29 % |
|
SiliaMetS DMT |
14 % | 22 % | 95 % | 98 % | 41 % | 64 % |
| Initial Pd Concentration: | 63 ppm in EtOAc | 93 ppm in EtOAc | 16 ppm in EtOAc | |||
Scavenging Conclusion
In all cases, SiliaMetS DMT and Thiol remain the better scavengers throughout the study, even though there is a variation in the nature of the ligand.
Ruthenium-based catalysts are commonly used in organic synthesis, mainly in olefin metathesis reaction [ROM(P) and RCM]. Grubbs and Hoveyda-Grubbs catalysts are certainly the most popular ruthenium-based complexes in that field of applications. Complete ruthenium removal can be tedious using conventional methods.
SiliaMetS allow to reach the maximal tolerated concentration of the residual ruthenium. A ruthenium scavenging study was conducted and various parameters were investigated in order to learn more on their influence on the scavengers’ robustness as well as to establish the best experimental conditions.
| Ruthenium Scavenging Results using SiliaMetS | ||||||||
| SiliaMetS | Grubbs 1st Gen. | Grubbs 2nd Gen. | Hoveyda-Grubbs 1st Gen. | Hoveyda-Grubbs 2nd Gen. | ||||
| Toluene1 | DMF2 | Toluene1 | DMF2 | Toluene1 | DMF2 | Toluene1 | DMF2 | |
| SiliaMetS Thiol | 90 % | 96 % | - | 99 % | 97 % | 93 % | - | - |
| SiliaMetS Thiourea | - | 98 % | - | 96 % | 97 % | 98 % | - | - |
| SiliaMetS DMT | 95 % | 99 %2 | > 99 % | 99 %2 | > 99 %2 | 98 %2 | 98 %2 | 99 %2 |
| SiliaMetS Amine | 95 % | 97 % | 92 % | - | - | - | - | - |
| SiliaMetS Diamine | 99 % | 99 % | 91 % | 94 % | > 99 % | 98 % | - | 90% |
| SiliaMetS Triamine | - | 95 % | - | - | 93 % | 95 % | - | 95 % |
| SiliaMetS TAAcOH | 93 % | - | - | - | - | - | - | - |
| SiliaMetS TAAcONa | 96 % | - | 96 % | - | 98 % | - | - | - |
| Exp. Conditions: | 1 8 eq. of SiliaMetS, 16 h, 80°C; 2 Only 4 eq. of SiliaMetS. Initial concentration: 500 ppm for all ruthenium-based catalysts. | |||||||
| Note: | SiliaMetS Cysteine and Imidazole were not screen in this study (not launch at this moment). Only SiliaMetS results higher than 90% are presented in this table. | |||||||
SiliaMetS vs Other Purification Methods
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The use of SiliaMetS to remove ruthenium catalyst after ring-closing metathesis (RCM) reaction is the most effective purification method (over conventional ones). As demonstrated below, the main advantage is no product lost during the purification step. |
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| Scavenging Results for Various Purification Methods* | ||||||
| Scavenging | Scavenger | Filtration over packed bed of ...2 | Flash Purification | |||
| SiliaMetS DMT1 | Act. Carbon | Celite | Silica | Manual | SiliaSep Cart. | |
| Ruthenium captation | 93 % | 73 % | 24 % | 58 % | 70 % | 73 % |
| 1 Using 4 eq., 16h, 22°C. 2 Solution passed directly on a packed bed of various adsorbents, then washed with the same quantity of solvent. *Quantitative yield obtained for each purification method (adjusted in function of the residual concentration of catalyst). No impurity generated in all cases using the different methods (determined by NMR). |
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Organotin compounds are versatile reagents commonly used in organic synthesis. The two main applications are in Stille couplings or in radical reactions. The removal of tin residues can often be an issue due to the well known high toxicity of this metal.
Traditional removal methods for this particular type of impurity are treatment with an aqueous solution of KF, NH4OH or NaOH, or with bases such as DBU. However, the efficiency of these methods can vary and may be inapplicable for particular compounds.
SiliaMetS Cysteine & TAAcONa can be used as an efficient method to remove tin residues from organic mixtures as demonstrated by the exemples below.
| Tin Scavenging using SiliaMetS Cysteine (TAAcONa) | ||||||
| Reactions | Inital Concentration |
SiliaMetS Cysteine | SiliaMetS TAAcONa | |||
| 4 eq., 4 h, 22°C [2 treatments] | 8 eq., 4 h, 22°C | 4 eq., 4 h, 22°C [2 treatments] | 8 eq., 4 h, 22°C | 4 eq., 16 h, 22°C | ||
| Stille coupling #11 | 3 385 ppm | 99 % | 64 % | 96 % | 62 % | - |
| Stille coupling #21 | 981 ppm | 90 % | 66 % | 66 % | 50 % | - |
| Radical Reduction | 4 090 ppm | 92 % | 88 % | 90 % | 90 % | 90 % |
| 1Pd residues were completely removed after only one treatment with SiliaMetS Cysteine. | ||||||
Osmium products are very useful in organic synthesis. One of the most common product is osmium tetroxide (OsO4), which is a very reliable and powerful reagent for the cis-dihydroxylation of alkenes. However, osmium compounds, in particular OsO4, are highly poisonous, even at low exposure levels, and must be handled with appropriate precautions. Therefore, it is desirable to efficiently remove residual osmium from products of interest.
A scavenging study on three organic reactions involving osmium reactants were performed. The metal scavenging efficiency of SiliaMetS is highlighted in the table on the following page.
| Osmium Scavenging using SiliaMetS | |||||
| SiliaMetS | Dihydroxylation | Sharpless Dihydroxylation | Lemieux-Johnson Oxidation | ||
| 4 eq., 4 h, 22°C | 8 eq., 4 h, 22°C | 8 eq., 16 h, 22°C | 8 eq., 4 h, 22°C | 8 eq., 16 h, 22°C | |
| SiliaMetS Thiol | 87 % | > 98 % | > 98 % | 87 % | 92 % |
| SiliaMetS Cysteine | 89 % | > 98 % | > 98 % | 87 % | 91 % |
| SiliaMetS DMT | 92 % | 97 % | > 98 % | 87 % | 91 % |
| SiliaMetS Imidazole | 87 % | > 98 % | > 98 % | 89 % | 91 % |
| Initial Os Concentration: | 132 ppm in EtOAc | 25 ppm in EtOAc | 21 ppm in EtOAc | ||
| Note: > 98 % of scavenging means < 0.5 ppm of osmium. | |||||
SiliaMetS can be used to remove multiple metals in the same reaction with excellent efficiency. The Negishi coupling presented below was performed and SiliaMetS was used to remove simultaneously residual zinc, palladium and iron present after the reaction.
| Multiple Removal Scavenging Results | |||
| SiliaMetS | Palladium | Iron | Zinc |
| SiliaMetS Cysteine | 95 % | > 99 % | 98 % |
| SiliaMetS DMT | 83 % | 93 % | 99 % |
| SiliaMetS Imidazole | 84 % | 91 % | 97 % |
| SiliaMetS TAAcONa | 97 % | > 99 % | > 99 % |
| Initial Concentration: | 188 ppm in THF | 110 ppm in THF | 6 ppm in THF |
| Conditions: 4 eq. of SiliaMetS (according to palladium), 4 h, 22°C. | |||
SiliaMetS® Thiol (Si-Thiol) is a robust metal scavenger for a variety of metals including Pd, Pt, Cu, Ag and Pb under a wide range of conditions. It has been used in pharmaceutical processes up to the pilot plant scale. It is our most versatile metal scavenger and is the preferred metal scavenger for Pd(II), Cu, Ag, and Hg.
SiliaMetS® Thiourea (Si-THU) is a versatile metal scavenger for all forms of palladium and is widely used in the pharmaceutical industry. It works particularly well in organic solvents. It can also be used to scavenge Ag, Pt, Ru, Rh and Hg. Once complexed with a transition metal, it has been reported as being an effective catalyst.
SiliaMetS® Cysteine (Si-Cys) is the silica bound equivalent of the amino acid Cysteine. By attaching the molecule to the backbone via the amino group, the thiol group remains free and accessible for higher metal scavenging efficiency. It is a versatile metal scavenger for a variety of metals including Pd, Sn, Ru, Pt, Cu, Rh, Cd and Sc under a wide range of conditions and the preferred metal scavenger for tin residues.
SiliaMetS® DMT (Si-DMT) is the silica bound equivalent of 2,4,6-trimercaptotriazine (trithiocyanuric acid). It is a versatile metal scavenger for a variety of metals including Cd, Co, Ni, Pd, Pt, Rh, and Ru under a wide range of conditions and the preferred metal scavenger for ruthenium catalysts.
TMT has been reported to efficiently remove palladium and heavy metals by precipitation. Unfortunately, its solubility in organic solvents causes problem. SiliaMetS DMT solves this issue and almost all solvents can now be used.
SiliaBond® Amine (Si-NH2) is an effective scavenger of acid chlorides, sulfonyl chlorides, isocyanates and other electrophiles. Si-NH2 has been shown to be effective metal scavenger and catalyst for Knoevenagel reactions. SiliaBond Amine is also used in chromatography as normal phase sorbent.
SiliaBond® Amine (Si-NH2) is an effective scavenger of acid chlorides, sulfonyl chlorides, isocyanates and other electrophiles. Si-NH2 has been shown to be effective metal scavenger and catalyst for Knoevenagel reactions. SiliaBond Amine is also used in chromatography as normal phase sorbent.
SiliaMetS® Diamine (Si-DIA) is a proven scavenger for metals and electrophiles. It scavenges acids, acid chlorides, anhydrides, aldehydes, isocyanates, and chloroformates as well as Pb, Ni, and Cd.
SiliaMetS® Triamine (SiliaMetS WAX-3, Si-TRI) is effective for scavenging metals such as Pb, Co, Ru and Pd. Our screening studies have shown it to be the preferred scavenger for Pb. It can also be used as a scavenger for acid chlorides, isocyanates and other electrophiles.
SiliaMetS® Imidazole (Si-IMI) is a versatile metal scavenger for a variety of metals including Cd, Co, Cu, Fe, Ni, Pd, and Rh under a wide range of conditions and the preferred metal scavenger for iron catalysts.
SiliaMetS Imidazole can also be used as an amine base in systems that are generally sensitive to basic conditions compared to other SiliaMetS supported bases.
SiliaMetS® TAAcOH (SiliaMetS Triaminetetraacetic Acid) is a silica bound metal scavenger for Pd(0), Ni(0) and Cu. It is the supported version of EDTA in its free form. It is an effective scavenger for metals in low or zero oxidation states, which includes many of the most synthetically useful catalysts such as tetrakis-(triphenylphosphine)palladium(0).
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