Solvent Compatibility of Poly(dimethylsiloxane)-Based Microfluidic Devices Jessamine Ng Lee, Cheolmin Park,�� and George M. Whitesides* Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138 This paper describes the compatibility of poly(dimethyl- siloxane) (PDMS) with organic solvents this compatibility is important in considering the potential of PDMS-based microfluidic devices in a number of applications, includ- ing that of microreactors for organic reactions. We con- sidered three aspects of compatibility: the swelling of PDMS in a solvent, the partitioning of solutes between a solvent and PDMS, and the dissolution of PDMS oligo- mers in a solvent. Of these three parameters that deter- mine the compatibility of PDMS with a solvent, the swelling of PDMS had the greatest influence. Experimen- tal measurements of swelling were correlated with the solubility parameter, �� (cal1/2 cm-3/2), which is based on the cohesive energy densities, c (cal/cm3), of the materi- als. Solvents that swelled PDMS the least included water, nitromethane, dimethyl sulfoxide, ethylene glycol, per- fluorotributylamine, perfluorodecalin, acetonitrile, and propylene carbonate solvents that swelled PDMS the most were diisopropylamine, triethylamine, pentane, and xylenes. Highly swelling solvents were useful for extracting contaminants from bulk PDMS and for changing the surface properties of PDMS. The feasibility of performing organic reactions in PDMS was demonstrated by perform- ing a Diels-Alder reaction in a microchannel. Several characteristics make poly(dimethylsiloxane) (PDMS) useful in fabricating microfluidic devices intended for bioanaly- sis: ease of fabrication (rapid prototyping, sealing, interfacing with the user), transparency in the UV-visible regions, chemical inertness, low polarity, low electrical conductivity, and elasticity.1,2 PDMS does not swell in contact with water. The cost of fabrication in PDMS is low compared to that for many materials (e.g., glass or silicon) commonly used in microdevices and MEMs.3 There is a growing interest in using microfluidic systems for functions other than bioanalysis in water, including organic synthesis in organic solvents.4-6 PDMS swells in contact with nonpolar solvents (e.g., hydrocarbons, toluene, and dichloro- methane) and is not useful for manipulations requiring these solvents. The objective of this work was to define the solvent compatibility of PDMS as a first step in discerning what types of solvents (other than water) can be used in microfluidic systems fabricated in this material. It is clear that PDMS is not a universal material and that other classes of polymers (or perhaps even glass, despite the inconvenience of fabricating devices in rigid, brittle materials) will be required for non- and less-polar solvents. What are not clear are the characteristics of the solvents that are required for a solvent to be compatible with PDMS. The problem of solvent compatibility has three aspects: (1) the solubility of a solvent in PDMS, since this solubility influences the swelling of the PDMS (2) the solubility of solutes in PDMS (or more properly, the partition of solute between a solution and PDMS), since loss of solute from the solvent is a concern and (3) the dissolution of PDMS oligomers in solvent, since these oligomers (present as contaminants in cross-linked PDMS) are potential contaminants in the products of reactions carried out in PDMS. Background on Solubility. Many parameters have been used in calculating solubilities.7,8 We have arbitrarily chosen to use cohesive energy density, c (cal/cm3), the energy associated with the intermolecular attractive interactions within a unit volume of material.8-10 The cohesive energy density can be expressed as c ) -U/V, where U is the molar internal energy (cal/mol) and V is the molar volume (cm3/mol). For two materials to be soluble, their cohesive energy densities must be similar, since this energy must be overcome to separate the molecules of the solute to allow the molecules of solvent to insert. For materials such as cross- linked polymers that do not dissolve, solubility is measured by the degree of swelling. The cohesive energy density is often expressed in terms of the solubility parameter, or Hildebrand value: �� ) c1/2 ) (-U/V)1/2 (cal1/2 cm-3/2).8,11 The solubility parameter is useful for predicting the swelling behavior of a polymer in a solvent without knowing any other information about the solvent. * Corresponding author. Phone: 617-495-9430. Fax: 617-495-9857. E-mail: gwhitesides@gmwgroup.harvard.edu. �� Current address: Department of Metallurgical System Engineering, Yonsei University, Seoul, 120-749, Korea. (1) McDonald, J. C. Whitesides, G. M. Acc. Chem. Res. 2002, 35, 491-499. (2) Ng, J. M. K., Gitlin, I., Stroock, A. D., and Whitesides, G. M. Electrophoresis 2002, 23, 3461-3473. (3) Becker, H. Locascio, L. E. Talanta 2002, 56, 267-287. (4) Salimi-Moosavi, H. Tang, T. Harrison, D. J. J. Am. Chem. Soc. 1997, 119, 8716-8717. (5) Kakuta, M., Bessoth, F. G. Manz, A. Chem. Rec. 2001, 1, 395-405. (6) Tokeshi, M. Minagawa, T. Uchiyama, K. Hibara, A. Sato, K. Hisamoto, H. Kitamori, T. Anal. Chem. 2002, 74, 1565-1571. (7) Burke, J. AIC Book Pap. Group Annu. 1984, 3, 13-58. (8) Du, Y. Xue, Y. Frisch, H. L. Physical Properties of Polymers Handbook AIP Press: Woodbury, NY, 1996. (9) Mark, J. E. Eisenberg, A. Graessley, W. W. Mandelkern, L. Koenig, J. L. Physical Properties of Polymers American Chemical Society: Washington DC, 1984. (10) Abboud, J.-L. M. Notario, R. Pure Appl. Chem. 1999, 71, 645-718. (11) The units for �� can be expressed as the square root of the cohesive energy density (cal1/2 cm-3/2) or as the square root of a pressure (MPa1/2), where 1 cal1/2 cm-3/2 ) 0.488 88 MPa1/2. Anal. Chem. 2003, 75, 6544-6554 6544 Analytical Chemistry, Vol. 75, No. 23, December 1, 2003 10.1021/ac0346712 CCC: $25.00 �� 2003 American Chemical Society Published on Web 10/11/2003

For a binary system, the Hildebrand-Scatchard equation relates the solubility parameters of nonpolar liquids to the enthalpy change on mixing them: ���Hm ) Vm(��1 - ��2)2 1 2 , where Vm is the volume of the mixture, ��i is the solubility parameter of the component i, and i is the volume fraction of i in the mixture.8 For two components to be soluble in one another (i.e., for swelling to occur in a polymer-solvent system), the free energy of mixing must be favorable, that is, ���Gm 0. Since ���Gm ) ���Hm - T���Sm, and ���Hm ��� (��p - ��s)2, swelling is maximal when (��p - ��s)2 is 0, where ��p and ��s are the solubility parameters of the polymer and solvent.8 Table 1 shows values of �� for a range of solvents often used in organic synthesis.8,10,12 Although the Hildebrand-Scatchard equa- tion suggests that solvents with �� similar to that of PDMS (�� ) 7.3 cal1/2 cm-3/2) will swell PDMS effectively, the relationship between �� and swelling is not linear and differs for each polymer- solvent system. We therefore wished to calibrate this ranking experimentally. Many research groups have used gravimetric methods to determine the degree of swelling of a polymer by a solvent.13-17 The degree of swelling is measured by the ratio of the mass of the swollen network and solvent combined to the mass of the dry extracted solid. This method has two major disadvantages. First, the mass of the combined swollen network and solvent must be measured while in equilibrium with the solvent in the vapor phase, so that evaporation of the solvent does not effect the measurement. Second, the gravimetric technique requires extra steps in its protocol compared to length measure- ments (described below), because the unpolymerized PDMS oligomers must first be extracted before measurement. In this research, we measured swelling by placing a solid piece of PDMS in a solvent for 24 h and then measuring the change in dimensions (e.g., length) of the solid while the PDMS was still submersed in the solvent in the liquid phase. The amount of un-cross-linked oligomers in solid PDMS is small (���0-5%, w/w see later discussion) compared to the cross-linked network, and the oligomers do not significantly affect the shape or length of the cross-linked PDMS. We, therefore, did not need to extract the oligomers from the PDMS before measuring the swollen length. The degree of swelling is expressed by the swelling ratio:9,18 S ) D/D0, where D is the length of the solid PDMS in the solvent and D0 is the length of the dry, solid PDMS.19 RESULTS AND DISCUSSION Swelling of PDMS in Organic Solvents. Prediction of swelling of PDMS by a solvent is important when considering which solvents to use in performing organic syntheses in micro- fluidic devices made in PDMS, which cosolvents to use in separations, or which nonpolar components to expect to lose from aqueous solution by contact with PDMS. Swelling of micro- channels has many implications. Swelling changes the cross- sectional area of the channel and, therefore, the rate and profile of flow. Changes in channel dimensions due to swelling can effect integration of the channel with components such as membranes, detectors, mixers, or electrodes. Swelling also changes surface properties and may cause the microfluidic device to deseal if the PDMS is bonded to a glass substrate. Here, we calibrate the relation of the solubility parameter, ��, of each solvent listed in Table 1 to the extent of swelling of PDMS. The degree of swelling is measured by the swelling ratio, S Table 1 also reports the values of these ratios. Figure 1 plots the swelling ratio observed for each solvent against its solubility parameter. The inset lists the solvents in descending order of solubility in PDMS.20 As expected, solvents that have a solubility parameter similar to that of PDMS (�� ) 7.3 cal1/2 cm-3/2) generally swell PDMS more than solvents that have a solubility parameter (12) Lide, D. R. In Handbook of Chemistry and Physics, 74th ed. Lide, D. R., Ed. CRC Press: Boca Raton, FL, 1994. (13) Favre, E. Eur. Polym. J. 1996, 32, 1183-1188. (14) Yoo, J. S. Kim, S. J. Choi, J. S. J. Chem. Eng. Data 1999, 44, 16-22. (15) Horkay, F. Waldron, W. K. McKenna, G. B. Polymer 1995, 36, 4525- 4527. (16) Hedden, R. C. Wong, C. Cohen, C. Macromolecules 1999, 32, 5154-5158. (17) Hedden, R. C. Saxena, H. Cohen, C. Macromolecules 2000, 33, 8676- 8684. (18) Van Krevelen, D. W. Properties of Polymers Elsevier: New York, 1990. (19) Swelling in terms of volume is calculated by ���V ) S3. (20) In this paper, the number associated with the solvent, e.g., hexanes (8) indicates the rank of the solvent from Figure 1, in descending order of solvability in PDMS. Table 1. Solubility Parameters, Swelling Ratios, and Dipole Moments of Various Solvents Used in Organic Synthesis solvent ��a Sb �� (D) refc rankd perfluorotributylamine 5.6 1.00 0.0 10 32 perfluorodecalin 6.6 1.00 0.0 10 33 pentane 7.1 1.44 0.0 10 3 poly(dimethylsiloxane) 7.3 ��� 0.6-0.9 8, 14 diisopropylamine 7.3 2.13 1.2 10 1 hexanes 7.3 1.35 0.0 10 8 n-heptane 7.4 1.34 0.0 10 10 triethylamine 7.5 1.58 0.7 8,10 2 ether 7.5 1.38 1.1 10 6 cyclohexane 8.2 1.33 0.0 10 11 trichloroethylene 9.2 1.34 0.9 10 9 dimethoxyethane (DME) 8.8 1.32 1.6 10 12 xylenes 8.9 1.41 0.3 10 4 toluene 8.9 1.31 0.4 10 13 ethyl acetate 9.0 1.18 1.8 8,10 19 benzene 9.2 1.28 0.0 10 14 chloroform 9.2 1.39 1.0 10 5 2-butanone 9.3 1.21 2.8 10 18 tetrahydrofuran (THF) 9.3 1.38 1.7 10 7 dimethyl carbonate 9.5 1.03 0.9 8,10 25 chlorobenzene 9.5 1.22 1.7 10 15 methylene chloride 9.9 1.22 1.6 10 16 acetone 9.9 1.06 2.9 8,12 22 dioxane 10.0 1.16 0.5 10 20 pyridine 10.6 1.06 2.2 10 23 N-methylpyrrolidone (NMP) 11.1 1.03 3.8 10 26 tert-butyl alcohol 10.6 1.21 1.6 8,12 17 acetonitrile 11.9 1.01 4.0 10 31 1-propanol 11.9 1.09 1.6 8,10 21 phenol 12.0 1.01 1.2 8,12 29 dimethylformamide (DMF) 12.1 1.02 3.8 8,10 27 nitromethane 12.6 1.00 3.5 10 34 ethyl alcohol 12.7 1.04 1.7 8,12 24 dimethyl sulfoxide (DMSO) 13.0 1.00 4.0 10 35 propylene carbonate 13.3 1.01 4.8 10 30 methanol 14.5 1.02 1.7 8,12 28 ethylene glycol 14.6 1.00 2.3 8,12 36 glycerol 21.1 1.00 2.6 13,15 37 water 23.4 1.00 1.9 8,12 38 a �� in units of cal1/2 cm-3/2. b S denotes the swelling ratio that was measured experimentally S ) D/D0, where D is the length of PDMS in the solvent and D0 is the length of the dry PDMS. c References refer to literature values of �� and ��. d Rank refers to the order of the solvent in decreasing swelling ability (see Figure 1). 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