Introducing Students to Surface Modification and Phase Transfer of

Laboratory Experiment pubs.acs.org/jchemeduc

Introducing Students to Surface Modification and Phase Transfer of Nanoparticles with a Laboratory Experiment Alaaldin M. Alkilany,*,† Sara Mansour,† Hamza M. Amro,† Beatriz Pelaz,‡ Mahmoud G. Soliman,‡ Joshua G. Hinman,§ Jordan M. Dennison,§ Wolfgang J. Parak,‡ and Catherine J. Murphy§ †

Department of Pharmaceutics & Pharmaceutical Technology, School of Pharmacy, The University of Jordan, Amman 11942, Jordan Fachbereich Physik, Philipps Universität Marburg, 35037 Marburg, Germany § Department of Chemistry, University of Illinois at UrbanaChampaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States ‡

S Supporting Information *

ABSTRACT: A simple, reliable, and cost-effective experiment is presented in which students synthesized citrate-capped gold nanoparticles (GNPs), functionalized them with poly(ethylene glycol) (PEG), and transferred the PEG-GNPs from water to the organic phase dichloromethane. The experiment introduces students to nanotechnology with foci on important concepts including surface modification of nanoparticles, colloidal stability, and phase transfer. The proposed experiment was evaluated at three different universities to confirm its reproducibility and versatility. Collectively, the proposed experiment is suitable to be implemented into colloid- or nanoscience-related curricula. KEYWORDS: Upper-Division Undergraduate, Laboratory Instruction, Hands-On Learning/Manipulatives, Demonstrations, Nanotechnology, Colloids

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INTRODUCTION There is a growing interest in the field of nanotechnology across both academia and industry because of the unique physical, chemical, optical, electrical, and magnetic properties that inorganic solids exhibit at the nanoscale; these properties bear tremendous promise for future applications.1 As a result, there is a need to develop educational materials to be implemented in modern chemical curricula for students to gain proper theoretical and practical knowledge related to nanoscience.2 For example, in the past decade (2005−2016), this Journal has published more than 170 papers on various topics highlighting nanoparticle synthesis (gold,3 silver,4 iron oxides,5 and quantum dots6), shape-controlled synthesis,7 sizedependent optical properties,8 sensing applications of nanoparticles,9 and nanotoxicology.10 In alignment with theses topics, appropriate surface chemistry is required to provide colloidal stability and, in many cases, to add specific functionalities.11 Surprisingly, detailed educational demonstrations of the surface modification and/or phase transfer of nanoparticles from aqueous to organic solution are lacking. Herein we report a simple, reliable, and cost-effective experiment in which undergraduate students learn to synthesize gold nanoparticles (GNPs) using the simple Frens method, functionalize the nanoparticle surfaces with a polymer (poly(ethylene glycol) methyl ether thiol, PEG-SH), and transfer the © XXXX American Chemical Society and Division of Chemical Education, Inc.

PEGylated gold nanoparticles (PEG-GNPs) from the aqueous phase to an organic phase (dichloromethane, DCM). This experiment supports specific learning outcomes related to the field of nanoscience, highlighting the ability of student to (1) prepare nanoparticles following standard procedures; (2) explain the optical properties of GNPs and their dependence on aggregation; (3) explain the two major routes of colloidal stability of GNPs (electrostatic and steric stabilization); (4) perform simple surface functionalization chemistry on the surface of GNPs, and observe how this chemistry facilitates the transfer from water to an immiscible organic solvent (phase transfer of nanoparticles); (5) calculate the efficiency of the observed phase transfer. The validity and applicability of this demonstration was evaluated independently at three institutions: University of Jordan (Jordan), Philipps Universität Marburg (Germany), and University of Illinois at UrbanaChampaign (USA). Student feedback and instructor evaluations confirmed that this experiment can be conducted in a typical laboratory session, Received: December 21, 2016 Revised: April 18, 2017

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DOI: 10.1021/acs.jchemed.6b01003 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

(3) the ligand exchange concept and the formation of a selfassembled monolayer of thiolated molecules on GNPs, with discussion of the differences between well-ordered small-molecule thiols and large polymers containing thiol end groups; (4) colloidal stability (electrostatic repulsion and steric hindrance as routs of stabilization);15 (5) aggregation of GNPs and resulting optical response, including an introduction to surface plasmons; (6) the dual solubility of PEG in water and DCM and the dual stability of PEG-GNPs in both solvents; (7) the role of methanol in the phase transfer of PEG-GNPs from water to the organic solvent. Students found this theoretical introduction to be extremely helpful in understanding important concepts related to the experimental part, as evidenced by their responses to assigned homework that contained a series of questions (a sample is included in the SI). More details regarding this introduction can be found in the instructor lab manual. Immediately after the theoretical introduction, students were distributed into groups (2−3 students/group). To ensure that the experiments could be performed by students in the allotted time, stock solutions were prepared prior to the lab by the instructor. Moreover, the lab instructor cleaned glass flasks (100 mL) with aqua regia prior to the lab to avoid exposure of students to these strong acids. The availability of all chemicals, glassware, and supplies (as detailed in the instructor lab manual) was checked prior to the lab. Brief instructions on the proper use of micropipettes, hot-plate stirrers, and the UV−vis spectrophotometer were delivered prior to the experimental part. Each group worked together in all stages. However, each student was asked to prepare his/her own lab report. The experimental part (as detailed below) lasted for another 2 hours, resulting in a total of ca. 3 hours for both theoretical and experimental parts.

and suggest the suitability of this experimental material to be incorporated into colloid- or nanoscience-related chemistry curricula.

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EXPERIMENTAL PROCEDURE The procedure for this laboratory experiment involves several main steps, each of which is briefly summarized below. Synthesis of Citrate-Capped Gold Nanoparticles (Cit-GNPs)

Citrate-capped gold nanoparticles (Cit-GNPs) were synthesized using the well-documented Frens method12 with minor modifications. Briefly, an aqueous solution of gold chloride salt (HAuCl4, 50 mL, 2.5 × 10−4 M) was brought to boiling with stirring, followed by addition of sodium citrate solution (1.25 mL, 5% w/w) to reduce the gold salt to the elemental metal and to form Cit-GNPs. Full experimental details are included in the instructor lab manual in the Supporting Information (SI). PEGylation of Cit-GNPs (PEG-GNPs)

The surface modification of as-prepared Cit-GNPs with a thiolated poly(ethylene glycol) polymer (PEG-SH, Mn = 5000 Da) was carried out using simple published protocols.13 Briefly, an aqueous solution of PEG-SH (0.2 mL, 50 mg/mL) was added to 10 mL of a Cit-GNPs aqueous solution in a 15 mL centrifuge tube and mixed gently. The mixture was left to stand for 20 min to allow for the replacement of citrate anions by PEG-SH chains on the surface of the GNPs. Full experimental details are included in the instructor lab manual. Salt-Induced Nanoparticle Aggregation (Cit-GNPs versus PEG-GNPs)

The colloidal stability of gold nanoparticles was evaluated by observing the aggregation upon the addition of NaCl solution (1.0 mL, 5% w/w) to 1.0 mL of either Cit-GNPs or PEG-GNPs in a plastic cuvette. Color changes from red (well-dispersed) to blue (aggregated) were used to evaluate nanoparticle aggregation.

Synthesis of Cit-GNPs

Phase Transfer of PEG-GNPs from Water to Dichloromethane

The Frens method is employed in this experiment to prepare Cit-GNPs because of its simplicity and reproducibility. Figure 1

Phase transfer of PEG-GNPs from water to an organic layer (DCM) was carried out using a published protocol with minor modifications.14 Briefly, 2.0 mL of DCM was placed in a glass vial, followed by the addition of 2.0 mL of the as-prepared PEG-GNPs solution. Phase transfer then was facilitated by the addition of 3.0 mL of methanol. Full experimental details are included in the instructor lab manual.

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HAZARDS Gloves, goggles, and laboratory coats should be worn. During the nanoparticle synthesis step, the flask with boiling water should be handled carefully with lab tongs. Steps involving the use of dichloromethane should be performed in a fume hood away from potential ignition sources.

Figure 1. Cartoon demonstrating the synthesis of Cit-GNPs using the Frens protocol.

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RESULTS AND DISCUSSION The lab starts with a theoretical introduction (∼1 h) to familiarize students with the following topics: (1) brief introduction to the field of nanotechnology; (2) gold nanoparticle synthesis using the Frens method with a simplified mechanistic discussion to highlight the redox chemistry that is involved in the synthesis of Cit-GNPs and the role of citrate ions in the synthesis;

shows the synthesis of Cit-GNPs by boiling an aqueous solution of gold chloride (HAuCl4) followed by addition of sodium citrate solution. A typical Cit-GNPs synthesis takes around 30 min. The resulting nanoparticle solution showed a typical ruby red color indicating the formation of GNPs (see the video in the SI). The students were asked to take a picture of the GNP solution (using their cell phone cameras) and to record its UV−vis extinction spectrum using a laboratory spectrophotometer. B




PEGylation of GNPs

detailed to the students in the theoretical introduction session and can be found in the instructor lab manual.

PEGylation (assembly of the PEG polymer on the surface of GNPs) is a well-documented, simple, and relatively fast surface modification of GNPs.13 The aim of this procedure is to introduce students to different types of colloidal stabilization routes in solution (electrostatic repulsion for Cit-GNPs vs steric hindrance for PEG-GNPs)15 and their sensitivity to added salt. Moreover, PEGylation is necessary to facilitate the phase transfer from water to DCM because of the hydrophilicity/hydrophobicity of this unique polymer. PEGylation was carried out by addition of PEG-SH aqueous solution to Cit-GNPs with stirring for 20 min to replace citrate ions on the GNPs with PEG (see Figure 2 and the video in the

Phase Transfer of PEG-GNPs from Water to Dichloromethane

There are various published protocols to transfer GNPs from water to organic phases.17 We recently developed a protocol to transfer GNPs from water to dichloromethane using methanol as a common solvent and thiolated PEG as a phase-transfer agent.14 We observed that this protocol is simple, fast, and highly reproducible, which motivated us to employ it as an educational material in nanochemistry. Figure 4 summarizes the phase-transfer process, which is explained in the instructor lab manual. Mixing DCM with PEG-GNPs in water resulted in a twolayer system with the red phase containing PEG-GNPs on the top, as shown in Figure 4 (DCM is denser than water). Students were instructed to shake the vials gently and to notice that the two phases are immiscible and no phase transfer occurs. Efficient and spontaneous phase transfer was initiated by the addition of methanol (a common solvent that is miscible with both water and DCM), as shown in Figure 4 and in the video in the SI. The roles of methanol and the PEG coating in the phase-transfer process were discussed in detail in the theoretical introduction session and can be found in the instructor lab manual. To calculate the phase-transfer efficiency, students obtained the UV−vis extinction spectra of (1) PEG-GNPs aqueous solution before phase transfer and (2) the aqueous upper layer after phase transfer. The phase-transfer efficiency was calculated using the equation

Figure 2. Cartoon demonstrating the surface functionalization of CitGNPs with PEG-SH polymer to prepare PEG-GNPs. The displacement of citrate ions on the surface of the GNPs by the thiolated polymer molecules (PEG-SH) should be noted.

SI). Students were instructed to test the colloidal stability of GNPs before and after PEGylation by addition of NaCl solution, as detailed in Experimental Procedure.

⎛ ⎞ A efficiency = ⎜1 − after ⎟ × 100% Abefore ⎠ ⎝

Nanoparticle Aggregation Test (Cit-GNPs versus PEG-GNPs)

where Abefore and Aafter are the absorbance values at the wavelength of the plasmon peak λmax obtained from the UV−vis extinction spectra of the PEG-GNPs solution before phase transfer and the aqueous upper layer after phase transfer, respectively. To confirm that the lower layer after phase transfer (the red layer in Figure 5a) is the organic phase (DCM-rich phase) with PEG-GNPs, students were instructed to pour the lower layer after phase transfer into a beaker filled with tap water. The formation of red droplets at the bottom of the beaker supported the phase transfer of PEG-GNPs from water to DCM, as shown in Figure 5b.

It is well-known that PEGylation of nanoparticles enhances their colloidal stability via steric hindrance.16 Students were instructed to compare the colloidal stabilities of Cit-GNPs and PEG-GNPs upon the addition of salt solution, as detailed in Experimental Procedure and the SI. A clear, spontaneous, and reproducible aggregation of Cit-GNPs was observed upon salt addition, as evidenced by the change of solution color from red to blue (Figure 3A). In contrast, PEG-GNPs showed excellent colloidal stability without aggregation, as evidenced by the constant red color before and after salt addition (Figure 3B). An explanation regarding the observed different colloidal stabilities of Cit-GNPs (electrostatic repulsion stabilization) and PEG-GNPs (steric repulsion by the hydrophilic shell) was

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FORMATIVE ASSESSMENT

Methodology

After the experiment was conducted, formative assessment was conducted using a homework assignment, written student feedback, and short interviews with participating students. For example, all of the students handed in lab reports (templates were provided and can be found in the SI) in which they summarized their results. Moreover, every student was instructed to hand in a homework assignment including his/ her answers to five thematic questions that cover the most important concepts taught in this lab (a copy can be found in the SI). A feedback sheet that includes eight questions (a copy can be found in the SI) was completed by each student to assess the validity of this lab, the achievement of the learning

Figure 3. Representative example of the student results on the aggregation test. (A) Addition of NaCl to Cit-GNPs resulted in aggregation, as evidenced by the color change from red to blue. (B) PEG-GNPs showed a stable colloid upon addition of salt. C




Figure 4. Phase transfer of PEG-GNPs from water to dichloromethane upon the addition of methanol. Note: The red line at the top of the vial to the right is a common optical reflection of the red layer in the bottom and does not represent a true layer.

(3) relate the colloidal stability of Cit-GNPs to the electrostatic repulsion mechanism and explain the aggregation upon salt addition; (4) functionalize the surface of Cit-GNPs with PEG polymer, evaluate the different colloidal stabilities of Cit-GNPs and PEG-GNPs upon salt addition, and provide an explanation for this observation; (5) carry out an efficient phase transfer of PEG-GNPs from water to DCM and discuss the roles of the PEG shell and methanol in this process; (6) obtain UV−vis spectra of the GNP solutions and calculate the phase-transfer efficiency. Achievement of ILOs of the proposed laboratory was evaluated using multiple formative assessment methods, including (1) inlab evaluation looking for the ability of student to perform the reaction properly, (2) lab reports, and (3) questions in the form of a homework assignment. For each ILO, methods of learning, methods of assessment, results of the assessment, and a final conclusion regarding the achievement of the ILO are listed in Table S3 in the SI. Collectively, our results suggested satisfactory achievement of the ILOs.

Figure 5. Beaker test. The lower red layer in the glass vial after the phase transfer (a) is added to a beaker filled with water. The formation of red droplets at the bottom of the beaker confirms the transfer of PEG-GNPs to the organic layer (DCM layer).

Observed Deviation/Difficulties

Generally, all lab stages (theoretical orientation, synthesis of Cit-GNPs, surface modification with PEG, and phase transfer) were carried out by students with satisfactory reproducibility and rate of success at the three institutions. However, for one student group, the prepared Cit-GNPs solution appeared lighter than the typical color. After investigation, it was found that the students did not pipet the proper amount of gold solution. With this in mind, we suggest that lab instructors demonstrate the proper use of pipettes to students prior to the laboratory. Another observed difficulty was related to calculating the transfer efficiency of PEG-GNPs from water to DCM. The

outcomes, and how it compares to typical and related laboratories in their curriculum. Achieved Student Learning Outcomes

The presented laboratory is designed to provide students with the following intended learning outcomes (ILOs), which ensure their ability to (1) prepare Cit-GNPs and identify the role of the reactants used (e.g., sodium citrate as a reducing agent and a capping agent simultaneously); (2) explain why GNPs are red (understanding optical properties of metals at the nanoscale);

Figure 6. UV−vis spectra of PEG-GNP solution in dichloromethane (red dashed lines) and of the aqueous upper layer (blue solid lines) (A) without and (B) with dilution with methanol (1:1 v/v). D



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protocol instructs the students to compare the absorbance values at λmax for PEG-GNPs solution before phase transfer (Abefore) and the aqueous upper layer after transfer (Aafter). The more efficient the phase transfer is, the more color will disappear from the aqueous upper layer as a result of the transfer of PEG-GNPs from water to DCM. In all of the student experiments, the phase transfer of PEG-GNPs from the aqueous layer to the DCM layer was very efficient, as evidenced by the complete disappearance of the red color of the upper layer. However, the upper layers in some cases were colorless and turbid instead of colorless and clear as a result of the formation of an unstable water/DCM emulsion. This turbidity resulted in light scattering during the collection of the UV−vis extinction spectra, thus resulting in spectra with elevated baselines (Figure 6A). This elevated baseline resulted in a false high Aafter and ultimately a false low phase-transfer efficiency. To prevent the formation of a stable emulsion and thus to eliminate the observed turbidity, a 1:1 dilution with methanol for both solutions (PEG-GNPs solutions before phase transfer and the aqueous upper layer after phase transfer) was necessary. This simple remedy was found to be extremely beneficial to eliminate turbidity and thus an erroneous determination of the phase-transfer efficiency (Figure 6B). In principle, the instructor could use this kind of data to start a discussion about the limits of UV−vis spectroscopy and how scattering can produce what appears to be “absorbance”. All of the students calculated high phase-transfer efficiency values (>90%). UV−vis extinction spectra and calculation examples are available in the student report samples in the SI.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alaaldin M. Alkilany: 0000-0001-9004-7256 Beatriz Pelaz: 0000-0002-4626-4576 Wolfgang J. Parak: 0000-0003-1672-6650 Catherine J. Murphy: 0000-0001-7066-5575 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the funding support by Scientific Research Fund-Jordan and Erasmus Mundus Mobility Award for A.M.A. Part of this work was funded by the European Commission (Grant FutureNanoNeeds to W.J.P.). M.G.S. acknowledges funding from the FAZIT-Stiftung Germany. The concept of this lab class was tested within the master class “Functional Materials” (summer semester 2016) at Fachbereich Physik of Philipps Universität Marburg.

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REFERENCES

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CONCLUSION This combined laboratory/lecture exercise introduced students to a simple method to prepare GNPs and to functionalize their surfaces with thiolated polymers. The comparison between the colloidal stabilities of Cit-GNPs and PEG-GNPs upon the addition of salt allowed students to visually understand important concepts related to colloidal stability and the effect of different surface chemistries and stabilization mechanisms. Moreover, students were introduced to a simple and reproducible method to transfer GNPs from an aqueous phase to an organic phase, which can be used as a springboard to cover important concepts related to interfacial tension, hydrophilicity/hydrophobicity, hydration shells, and phase transfer. Students found this lab to be informative, covering new exciting avenues, and enjoyable. Instructors from the three different institutions found this lab to be safe, short (total of 3 hours with the theoretical lecture introduction), cost-effective (∼$1.4/student; see Table S1 for details), and highly reproducible. Collectively, we believe that this laboratory is suitable as an educational exercise that can be implemented in chemistry or possibly physics curricula related to the emerging field of nanoscience.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b01003. Instructor lab manual, template of student lab report, template of student homework, template of student feedback sheets, and selected samples of student lab reports (PDF, DOCX) Taped demonstration in video format (MPG) E




Introduction to Nanotoxicity and Interdisciplinary Science. J. Chem. Educ. 2013, 90 (4), 475−478. (11) Rivera-Gil, P.; Jimenez De Aberasturi, D.; Wulf, V.; Pelaz, B.; Del Pino, P.; Zhao, Y.; De La Fuente, J. M.; Ruiz De Larramendi, I.; Rojo, T.; Liang, X.-J.; Parak, W. J. The Challenge To Relate the Physicochemical Properties of Colloidal Nanoparticles to Their Cytotoxicity. Acc. Chem. Res. 2013, 46 (3), 743−749. (12) Frens, G. Controlled Nucleation for the Regulation of the Particle Size in Monodisperse Gold Suspensions. Nature, Phys. Sci. 1973, 241 (105), 20−22. (13) del Pino, P.; Yang, F.; Pelaz, B.; Zhang, Q.; Kantner, K.; Hartmann, R.; Martinez de Baroja, N.; Gallego, M.; Möller, M.; Manshian, B. B.; Soenen, S. J.; Riedel, R.; Hampp, N.; Parak, W. J. Basic Physicochemical Properties of Polyethylene Glycol Coated Gold Nanoparticles that Determine Their Interaction with Cells. Angew. Chem., Int. Ed. 2016, 55 (18), 5483−5487. (14) Alkilany, A. M.; Yaseen, A. I. B.; Park, J.; Eller, J. R.; Murphy, C. J. Facile phase transfer of gold nanoparticles from aqueous solution to organic solvents with thiolated poly(ethylene glycol). RSC Adv. 2014, 4 (95), 52676−52679. (15) Pellegrino, T.; Kudera, S.; Liedl, T.; Muñoz Javier, A.; Manna, L.; Parak, W. J. On the Development of Colloidal Nanoparticles towards Multifunctional Structures and their Possible Use for Biological Applications. Small 2005, 1 (1), 48−63. (16) Brandenberger, C.; Mühlfeld, C.; Ali, Z.; Lenz, A.-G.; Schmid, O.; Parak, W. J.; Gehr, P.; Rothen-Rutishauser, B. Quantitative Evaluation of Cellular Uptake and Trafficking of Plain and Polyethylene Glycol-Coated Gold Nanoparticles. Small 2010, 6 (15), 1669−1678. (17) (a) Soliman, M. G.; Pelaz, B.; Parak, W. J.; del Pino, P. Phase Transfer and Polymer Coating Methods toward Improving the Stability of Metallic Nanoparticles for Biological Applications. Chem. Mater. 2015, 27 (3), 990−997. (b) Sperling, R. A.; Parak, W. J. Surface modification, functionalization and bioconjugation of colloidal inorganic nanoparticles. Philos. Trans. R. Soc., A 2010, 368 (1915), 1333−83.

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Introducing Students to Surface Modification and Phase Transfer of

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