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US20020017487A1 - Surface modification of a porous polymer monolith and products therefrom - Google Patents

Surface modification of a porous polymer monolith and products therefrom Download PDF

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US20020017487A1
US20020017487A1 US09/878,495 US87849501A US2002017487A1 US 20020017487 A1 US20020017487 A1 US 20020017487A1 US 87849501 A US87849501 A US 87849501A US 2002017487 A1 US2002017487 A1 US 2002017487A1
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monolith
product
porous
tube
pore surfaces
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Xian Huang
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Advion Biosciences Inc
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Assigned to ADVION BIOSCIENCES, INC. reassignment ADVION BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HUANG, XIAN
Publication of US20020017487A1 publication Critical patent/US20020017487A1/en
Priority to US10/354,256 priority patent/US6821418B2/en
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    • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
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    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
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Definitions

  • the invention relates to a process for the surface modification of a porous polymer monolith and products produced therefrom.
  • the process relates to the surface modification of a polystyrenic monolith by alkylating its through-pore surfaces and to products so modified.
  • Liquid chromatography as a technique for the separation of soluble, non-volatile compounds, has become over the past 30 years an indispensable tool for chemical and biochemical analyses in numerous disciplines of chemistry and life sciences.
  • separation in liquid chromatography is achieved in a column by selective distribution of the sample molecules between a stationary phase and a mobile phase.
  • the stationary phase is usually highly hydrophobic or non-polar.
  • Conventional reversed-phase liquid chromatography uses 5-10 ⁇ m spherical silica beads that have been modified by covalent attachment of hydrocarbon chains including 4, 8, or 18 carbon atoms to provide a non-polar surface.
  • PS-DVB particles are also widely used as a stationary phase support.
  • the PS-DVB surface can be directly used as the reversed-phase chromatography stationary phase since it is highly hydrophobic.
  • the unfunctionalized PS-DVB particles may present unacceptable poor resolution.
  • the column miniaturization has also been achieved by a porous polymer monolith prepared by free radical polymerization in situ in a fused silica capillary.
  • a porous polymer monolith prepared by free radical polymerization in situ in a fused silica capillary.
  • the development of fritless columns with a polymer-based porous monolith rather than conventional spherical beads has become more and more important since it meets the requirement of today's micro-scale liquid chromatography and capillary electrochromatography as described by Liao and Hjertén (1997 U.S. Pat. No. 5,647,979); Peters et al., Analytical Chemistry, 70 (1998), 2288-2295; Gusev et al., J. Chromatography A, 855 (1999), 273-290; and Zhang et al., J. Chromatography A, 887 (2000), 465-477.
  • alkyl functional groups are directly imparted from a co-monomer, e.g., alkylene dimethacrylate, rather than divinylbenzene used for the initial polymerization as claimed in U.S. Pat. No. 5,453,185 (Svec and Fréchet).
  • a co-monomer e.g., alkylene dimethacrylate
  • divinylbenzene used for the initial polymerization as claimed in U.S. Pat. No. 5,453,185
  • the introduction of a new monomer to the initial polymerization mixture may require redesign of the formulation and conditions including the selection of a new porogen.
  • only those alkyl chains in the polymer surfaces are needed for the separation, while the alkyl chains involved inside the bulk solid support are not necessary. It has been found that alkyl chains imparted by this process do not appreciably improve the resolution of peptides.
  • this method for alkylating the monolith surfaces forms an ineffective stationary phase for separation of relatively smaller biomolecules like
  • That process is not suitable for alkylating the through-pore surfaces of a porous PS-DVB monolith.
  • the solid state catalyst is difficult to introduce into the internal pores of a monolith since the solid catalyst is not very soluble in the alkylating solution.
  • the internal pores of the monolith may become clogged with precipitated solid that remains inside the monolith during the Friedel-Crafts reaction.
  • tin(IV) chloride is a liquid and is easily filled into the monolith porous structure, but it may precipitate insoluble substances during the Friedel-Crafts reaction and it is a very weak catalyst as well.
  • a polymer-based benzene ring is much more difficult to alkylate since the Friedel-Crafts reaction is controlled by diffusion. Heating is preferred for speeding the Friedel-Crafts reaction on a PS-DVB surface.
  • One aspect of the present invention relates to a process for the surface modification of a porous polystyrenic monolith.
  • the process includes wetting the monolith internal pore (through-pore) surfaces with an organic solvent used in the uniform liquid solution.
  • the pore surfaces of the monolith are treated by contacting the monolith pores with a uniform liquid solution containing a Friedel-Crafts catalyst, an alkyl halide, and an organic solvent so as to alkylate the internal pore surfaces.
  • the post-reaction solution is removed from the alkylated pore surfaces by rinsing the organic solvent through the monolith.
  • the alkylated pore surfaces are further washed by sequentially rinsing a series of solvents through the monolith, respectively.
  • Another aspect of the present invention relates to a porous polystyrenic monolith having alkylated internal pore surfaces.
  • the present invention results in a number of advantages over the prior art. It is an advantage of the present invention to provide a simple and reliable process for alkylating internal pore surfaces of a porous polystyrenic monolith.
  • the monolith to be alkylated may be already molded in a fused-silica capillary, a plastic tubing, a micro-channel or hole of a silicon/polymer chip, or a similar opening in a separation device.
  • the monolith is preferably a cross-linked polystyrene copolymer having internal through-pores that a liquid can pass through.
  • FIG. 1 is the total ion current (TIC) profile from the reversed-phase LC-ESI/MS of a tryptic digest cytochrome c described in Example 2. The peaks representing different peptide fragments (T1-12) are labeled.
  • the capillary column having an alkylated porous PS-DVB monolith was produced in Example 1.
  • FIG. 2 is the TIC profile of the tryptic digest cytochrome c from FIG. 1 and the extracted ion current profiles for the selected peptide fragments.
  • FIG. 3 is the reversed-phase LC-ESI/MS of the tryptic digest cytochrome c using the same conditions as for FIG. 1 with the unmodified monolithic PS-DVB column described in Example 2.
  • FIG. 4 is the reconstructed full-scan LC-ESI/MS total ion current (TIC) profile and extracted ion current profiles from the analysis of the synthetic peptide mixture described in Example 4.
  • the capillary column having the alkylated porous PS-DVB monolith was produced in Example 3.
  • FIG. 5 is the mass spectra related to the chromatograms of FIG. 4 and described in Example 4.
  • FIG. 6 is a cross-section view of the monolith showing liquid forced through the monolith molded in a chip with a liquid delivery probe in Example 5.
  • the present invention provides a process for alkylating outer and internal (through-pore) surfaces of a porous polystyrene monolith using the Friedel-Crafts alkylation reaction.
  • the process is preferably effective on a highly cross-linked porous polystyrene monolith.
  • the process includes the step of treating internal pore surfaces of the monolith, preferably, by filling them and then rinsing a uniform liquid solution containing a Friedel-Crafts catalyst, an alkyl halide, and an organic solvent through the monolith.
  • a suitable uniform liquid alkylating reagent solution Preferably, a specific organic solvent is used.
  • both the selected highly strong Friedel-Crafts catalyst and an alkyl halide e.g., linear and primary octadecyl chloride
  • an alkyl halide e.g., linear and primary octadecyl chloride
  • the alkylation reaction can be completed inside the monolith through-pores which eliminates clogging problems while the pore surfaces can be grafted with the desired alkyl groups.
  • the process also includes a subsequent washing step in which the post-alkylation mixture is removed and the functionalized polystyrenic through-pore surfaces are cleaned without precipitation or clogging.
  • a uniform liquid alkylating reagent solution is formulated for treating a porous polymer monolith.
  • the monolith is a polystyrene-based copolymer, preferably, poly(styrene-co-divinylbenzene) (PS-DVB) with a molecular ratio of about 10% to about 50% divinylbenzene.
  • PS-DVB poly(styrene-co-divinylbenzene)
  • the internal pore size distribution and the porosity can be varied with the processes by which the monolith is prepared. Examples of such polystyrenic monoliths include those covered by U.S. Pat. No. 5,334,310 and No. 5,334,310 (Fréchet and Svec) and introduced by J.
  • the porous polystyrenic monolith can be prepared in situ in a tube or open ended structure.
  • Suitable tubes include metal tubes, plastic tubes, capillary tubes, and the like.
  • microchips made from silicon, plastic, glass, and the like.
  • the diameter of the tube is about several millimeters or less.
  • a PS-DVB monolith covalently bonded in a fused silica capillary can be prepared by first silanizing the internal wall of the capillary with the method introduced by Huang and Horváth, Journal of Chromatography A, 788 (1997) 155-164.
  • the PS-DVB monolith is prepared in situ inside a pretreated and silanized fused silica capillary having an inner diameter, preferably the commercially available sizes of about 50 ⁇ m or about 75 ⁇ m.
  • the monomer ratio is 40% (v/v) and the porogen is the co-solvents 1-propanol and formamide.
  • the initiator used is 2′2-azobisisobutyronitrile (AIBN).
  • the PS-DVB monolith is also prepared in situ in commercially available PEEK tubing or stainless steel tubing.
  • the monolith is not covalently bonded onto the inner wall of the PEEK or stainless steel capillary. It is remarkable that a 10 cm long PEEK or stainless steel column (125 ⁇ m I.D., ⁇ fraction (1/16) ⁇ ′′ O.D.) containing such polymer monolith is mechanically stable under a back pressure as high as 200 bar delivered by acetonitrile flow.
  • the through-pore surfaces of the porous polystyrenic monolith are wetted or swelled by the solvent that is used to make the uniform liquid catalyst solution.
  • the monolith is washed sequentially with several organic solvents, such as, methylene chloride, N,N-dimethylformamide, and nitrobenzene or nitromethane.
  • the final pre-wash not only improves surface wetting characteristics but is also preferably compatible with the subsequent alkylating solution. Washing with the initial solvents enables the relatively quick loading of the desired solvent prior to loading the alkylating solution.
  • the solvent for the final pre-wash, nitrobenzene or nitromethane is also the solvent for preparing alkylating solution.
  • the flow is driven through the monolith, usually by pressure. This step is preferably completed at room temperature.
  • a mixture of a Friedel-Crafts catalyst and an alkyl halide is formulated for use with the alkylating process.
  • Suitable Friedel-Crafts catalysts include those that can be dissolved in the solvent and are strong enough to achieve suitable alkylation.
  • the mixture is preferably prepared as a uniform liquid from the Friedel-Crafts catalyst and alkyl halide selected.
  • the Friedel-Crafts catalysts are preferred to be as strong as possible.
  • Preferred are those commercially available strongest Friedel-Crafts catalysts such as aluminum chloride (AlCl 3 ), aluminum bromide (AlBr 3 ) and antimony pentachloride (SbCl 5 ).
  • Suitable solvents include those solvents that can dissolve the Friedel-Crafts catalyst and the alkyl halide and form a uniform liquid reactant.
  • Nitromethane and nitrobenzene can dissolve most alkyl halides, the commercially available strongest Friedel-Crafts catalysts, and are most preferred.
  • nitrobenzene can dissolve an 18-carbon halide such as octadecyl chloride.
  • a uniform liquid solution containing the catalyst and the alkyl halide can be formed from a wide variety of catalyst and alkyl halide combinations.
  • Suitable high concentrations of the catalyst and alkyl halide can be preferably chosen to avoid precipitation during the treatment.
  • Preferred alkyl halides include primary, secondary, or tertiary chloride or bromide.
  • the alkyl groups include linear, branched, cyclic chains, or combinations thereof.
  • hydrophobic groups preferably having 4, 8, or 18 carbon atoms are chosen for the stationary phase.
  • preferred alkyl halides for preparing the uniform liquid alkylating solution include linear primary chloride or bromide having 4, 8, or 18 carbon atoms.
  • the internal pore surfaces of the porous polystyrenic monolith are filled with the uniform liquid alkylating solution described above and then the solution is rinsed through the monolith.
  • the benzene ring can be alkylated under room temperature, gentle heating is preferred to speed and enhance the diffusion-dominated reaction with the polymer surfaces.
  • the preferred reaction temperature for the alkylating solution contacting the pore surfaces is from about 45° C. to about 70° C. Typically, the heating step can take several hours or longer.
  • reaction solution is then removed from the monolith.
  • a post-alkylation wash is preferred for making highly cleaned alkylated monoliths. The risk for pore-clogging is high if the wrong solvent is used, since the residual alkylating mixture can produce solid precipitates or a highly viscous liquid.
  • a preferred solvent for the post reaction wash is the same solvent as that used for preparing the alkylation solution, e.g., nitrobenzene or nitromethane, which removes the post-alkylation solution from the monolith and rinses the alkylated pores by being passed through the monolith. Typically, this wash may not completely remove the residual mixture in the pores.
  • An additional wash is preferably sequentially applied, for example, with N,N-dimethylformamide, 1 M HCl aqueous solution, water, and acetonitrile, respectively.
  • This example illustrates a process for octadecylating a porous PS-DVB monolith formed in situ in a PEEK capillary.
  • a PEEK capillary (internal diameter 0.005-in or 125 ⁇ m, outer diameter ⁇ fraction (1/16) ⁇ -in, and length 10 cm) containing a PS-DVB monolith was used for the alkylation.
  • the monolith was prepared from heating the solution sealed inside the capillary containing 20% v/v styrene, 20% v/v DVB (80%, mixture of isomers), 40% v/v 1-propanol, 20% v/v formamide, and 0.3% w/v 2′2-azobisisobutyronitrile (AlBN), for 24 hours at 70° C. After the residual mixture was removed, the porous monolith was thoroughly washed with methylene chloride and N,N-dimethylformamide.
  • a screw top glass vial (1.5- to 3-ml) having an open-top cap with a Teflon-faced plastic septum was used for delivering liquid into the monolithic column.
  • a liquid contained in the vial was pressurized by a nitrogen source of 60-100 psi introduced with a fused silica capillary inserted through the septum.
  • Each end of the monolithic column was extended with a fused silica capillary by using a connection union. With one end (the fused silica capillary) inserted into the capped vial containing 1.0 ml nitrobenzene, the column was rinsed with nitrobenzene for 1 hour before the alkylation.
  • This example illustrates a typical application of the monolithic capillary column prepared from Example 1. Peptides from a tryptic digest of cytochrome c were separated and analyzed by LC-ESI/MS using the octadecylated monolithic column.
  • the octadecylated PS-DVB monolithic column (125 ⁇ m in inner diameter and 10 cm in length) produced from Example 1 was used as a reversed-phase liquid chromatographic column.
  • the column was attached to a Micromass LCT mass spectrometer with a tapered fused silica capillary (tip end inner diameter, 10 ⁇ m, flame-pulled from a fused silica capillary having 150 ⁇ m outer diameter and 50 ⁇ m inner diameter) as the electrospray interface.
  • a micro gradient pump, Eldex MicroPro 1000 syringe pumping system was used to deliver the mobile phase to the column.
  • a Valco micro-electric two position valve actuator with 1 ⁇ L injection volume was connected after the pump.
  • a split valve was connected after the sample injector and right before the column inlet, which split ⁇ fraction (1/100) ⁇ of the main flow into the column while the remainder went into the waste. All connection capillaries were nonconductive fused silica capillaries.
  • the mobile phase flow rate before the split was typically 30 ⁇ L/min.
  • the flow rate for the column was maintained at 300 nL/min.
  • the applied high voltage for the electrospray ionization was 3.5 kV.
  • Peptide mass spectra were recorded in the range of 380 to 1700 m/z.
  • the separation results are presented as the chromatogram and the mass spectra shown in FIGS. 1 and 2.
  • the gradient elution was programmed as: 0 ⁇ 10 ⁇ 15 min; 5% ⁇ 40% ⁇ 70% B (i.e., acetonitrile concentration 5% ⁇ 40% ⁇ 70% v/v).
  • This example illustrates a process for octadecylating a porous PS-DVB monolith covalently bonded in a fused silica capillary.
  • a fused silica capillary (inner diameter 75 ⁇ m, outer diameter 375 ⁇ m, and length 20 cm) containing covalently bonded PS-DVB monolith was prepared as described above and used for the octadecylation.
  • This example illustrates the use of the surface-alkylated porous PS-DVB monolith in a fused silica capillary prepared from Example 3.
  • column standard peptides were separated and characterized in liquid chromatography hyphenated with electrospray ionization mass spectrometry (LC-ESI/MS).
  • Example 3 The monolithic capillary column with octadecyl groups as the stationary phase produced from Example 3 was cut to 10 cm in length. The testing system and procedure were the same as that of Example 2.
  • a synthetic mixture containing 7 Sigma standard peptides (14 pmol each in water, injected before the 1:100 split valve) was separated in reversed-phase LC mode under gradient elution conditions.
  • the injected sample mixture contained: 1) methionine enkephalin, 2) leucine enkephalin, 3) oxytocin, 4) bradykinin, 5) LH-RH, 6) angiotensin II, and 7) angiotensin I.
  • the separation results are presented as the chromatogram and the mass spectra shown in FIGS. 4 and 5.
  • the gradient elution was completed in 10 minutes while the mobile phase was changed from 1 0%B to 50%B (i.e., acetonitrile concentration from 10 to 50% v/v).
  • This example illustrates a process for alkylating a porous PS-DVB monolith molded in a micro-opening of a silicon or polymer chip.
  • a porous PS-DVB monolith was formed in situ in a vertical cylindrical through-opening with a diameter of 100 ⁇ m in a silicon chip or wafer.
  • the process for preparing the chip-molded monoliths was modified from that for capillary monoliths.
  • a liquid was forced into the monolith by using a liquid delivery probe as shown in FIG. 6.
  • the liquid in the probe was driven by a nitrogen source with a pressure of up to 30 psi.
  • the chip-molded monolith was wetted, treated, and washed with the liquid delivery probe as described in Example 1.

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  • Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Manufacture Of Porous Articles, And Recovery And Treatment Of Waste Products (AREA)
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US20060057556A1 (en) * 2002-10-21 2006-03-16 The Government Of The United States Of America Department Of Health And Human Services Contiguous capillary electrospray sources and analytical devices
US7169298B2 (en) 2000-01-26 2007-01-30 Transgenomic, Inc. Method and apparatus for separating polynucleotides using monolithic capillary columns
WO2007092227A3 (fr) * 2006-02-02 2008-06-26 Battelle Memorial Institute emetteurs monolithiques d'ionisation par electronebulisation et leurs procedes de fabrication
US20100145626A1 (en) * 2001-03-02 2010-06-10 Ecker David J Systems for rapid forensic analysis of mitochondrial DNA and characterization of mitochondrial DNA heteroplasmy

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JP2005099015A (ja) * 2003-09-05 2005-04-14 Sumitomo Chemical Co Ltd 液体クロマトグラフィー装置
JP4613002B2 (ja) * 2003-10-29 2011-01-12 株式会社日立ハイテクノロジーズ エレクトロスプレイ用カラム一体型チップの製造方法
US20080190840A1 (en) * 2004-06-24 2008-08-14 Agilent Technologies Inc. Microfluidic Device with at Least One Retaining Device
WO2006049333A1 (fr) * 2004-11-04 2006-05-11 Gl Sciences Incorporated Aiguille de pulverisation pour esi et procede pour sa production
JP4919318B2 (ja) * 2005-12-07 2012-04-18 オルガノ株式会社 官能基導入用反応カラム、官能基導入装置及び官能基導入方法
JP5386805B2 (ja) * 2007-08-10 2014-01-15 三菱化学株式会社 多孔質架橋重合体の製造方法、多孔質架橋重合体、多孔質架橋重合体粒子および吸着剤
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US7169298B2 (en) 2000-01-26 2007-01-30 Transgenomic, Inc. Method and apparatus for separating polynucleotides using monolithic capillary columns
US20100145626A1 (en) * 2001-03-02 2010-06-10 Ecker David J Systems for rapid forensic analysis of mitochondrial DNA and characterization of mitochondrial DNA heteroplasmy
US20060057556A1 (en) * 2002-10-21 2006-03-16 The Government Of The United States Of America Department Of Health And Human Services Contiguous capillary electrospray sources and analytical devices
US7544932B2 (en) 2002-10-21 2009-06-09 The United States Of America, As Represented By The Secretary, Of The Department Of Health And Human Services Contiguous capillary electrospray sources and analytical devices
US20050056321A1 (en) * 2003-09-16 2005-03-17 Rehm Jason E. Composite polymer microfluidic control device
US7296592B2 (en) 2003-09-16 2007-11-20 Eksigent Technologies, Llc Composite polymer microfluidic control device
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WO2007092227A3 (fr) * 2006-02-02 2008-06-26 Battelle Memorial Institute emetteurs monolithiques d'ionisation par electronebulisation et leurs procedes de fabrication

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EP1309381A4 (fr) 2003-08-27
US20030111418A1 (en) 2003-06-19
EP1309381A1 (fr) 2003-05-14

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