Article pubs.acs.org/jchemeduc
Using 1H NMR Spectra of Polymers and Polymer Products To Illustrate Concepts in Organic Chemistry Mary L. Harrell and David E. Bergbreiter* Department of Chemistry, Texas A&M University, College Station, Texas 77842-3012, United States S Supporting Information *
ABSTRACT: The use of 1H NMR spectroscopy to analyze the number-average molecular weight of a methoxy poly(ethylene glycol) (MPEG) and an acetate derivative of this MPEG is described. These analyses illustrate NMR principles associated with the chemical shift differences of protons in different environments, NMR integration, and the effect of the natural abundance of 13C carbons in a polymer and the resulting low but predictable intensity of the satellite peaks due to 13C−1H spin−spin coupling. Also included in this discussion is an example of end-group analysis of the product of an acetylation reaction. In the discussion of the acetylation product, an 1H NMR spectrum of a crude product mixture where the small peaks due to end groups can be seen along with a set of impurities due to catalyst, solvents, and byproducts is included because, in practice, chemists often first see these sorts of spectra. KEYWORDS: Second-Year Undergraduate, Spectroscopy, Analytical Chemistry, Organic Chemistry, Polymer Chemistry, Inquiry-Based/Discovery Learning, NMR Spectroscopy, Isotopes
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INTRODUCTION In research laboratories, synthetic chemists routinely use 1H NMR spectroscopy to characterize both crude reaction mixtures and purified products. 1H NMR spectroscopy is similarly useful in characterizing polymers and their reaction products. NMR spectroscopy is an integral part of the introductory organic chemistry curriculum, while polymers are often considered an “extra” part of an introductory organic class, an “enriching” activity for the more active learners. However, using polymers does not have to be only an extra “enriching” activity. Polymers can be integrated into an introductory organic course to provide a broader context for the precepts of organic chemistry and to illustrate concepts that are otherwise not always apparent to students. This article describes how end-group analysis and analysis of the products of modification of a common polymer can be used in lecture or in a problem set to illustrate concepts in NMR spectroscopy related to chemical shifts, spin−spin coupling, macromolecule degree of polymerization, isotopic abundance, and byproduct formation. These concepts are introduced using a common polymer, methoxy poly(ethylene glycol) (MPEG), whose derivatives are important in biological and medical applications that are relevant to many students’ interests.1
py and polymer chemistry. First, 1H NMR spectroscopic analysis of the small peaks of a starting methoxy-terminated MPEG derivative’s end groups relative to the 13C satellite peaks due to 13C−1H coupling is used to verify the molecular weight of the starting polymer. This is one method to determine molecular weight. Other methods such as gel permeation chromatography,2 mass spectrometry,3 viscosity measurements,4 and vapor pressure osmometry5 have also been used to determine molecular weights of polymers. In addition, this paper also uses the product of esterification of the hydroxyl end group of this MPEG polymer to illustrate the change in chemical shift of the end group upon esterification. Similar esterification reactions are used in applications of PEG derivatives in biology and medicine, and the chemical shift changes seen are like those seen for conversions of other alcohols into esters. In the esterification reaction, both an 1H NMR spectrum of a crude reaction product along with an 1H NMR spectrum of the purified MPEG monoester product are provided and discussed. The crude product contains small amounts of impurities. The 1H NMR spectra that students most often see are of purified products. In practice, crude products are also analyzed. These 1H NMR spectra of crude
STUDY OF METHOXY POLY(ETHYLENE GLYCOL) The discussion below uses 1H NMR spectra of a ca. 2000 Da MPEG (MPEG2000) polymer and the products of an end-group esterification to illustrate several concepts in NMR spectrosco-
Special Issue: Polymer Concepts across the Curriculum
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© XXXX American Chemical Society and Division of Chemical Education, Inc.
Received: October 24, 2016 Revised: April 28, 2017
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DOI: 10.1021/acs.jchemed.6b00801 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Scheme 1. Synthesis of Methoxy Poly(ethylene glycol) (MPEG) from Ethylene Oxide Using Sodium Methoxide as an Initiator Followed by 4-N,N-Dimethylaminopyridine-Catalyzed Esterification of a Terminal Hydroxyl Group by Acetic Anhydride To Form an Acetate-Terminated MPEG Derivative
converted into a high-molecular-weight polymer with n monomer units.8 This reaction can be accomplished using an alkoxide such as sodium methoxide as an initiator. In this reaction, a small amount of sodium methoxide (MeO−Na+) is added to a large excess of ethylene oxide. In the initial step, this methoxide behaves as a nucleophile, attacking a −CH2− group of the ethylene oxide, opening the epoxide. While strongly basic and nucleophilic oxygen anions are not usually good leaving groups, this process occurs readily because of the ring strain of the epoxide three-membered ring. This initial product has an alkoxide anion at its terminus that is as reactive as the sodium methoxide and can react with another ethylene oxide to form the dimer 2. This dimer has two −CH2CH2O− groups derived from the starting monomer. Further reactions with more of the excess molecules of ethylene oxide lead to trimers, tetramers, etc. Eventually this polymerization produces a polymer with n units derived from the ethylene oxide monomer. After the monomer is consumed, the polymer poly(ethylene glycol) (3) that is formed has n repeat units (n − 1 −CH2CH2O− units with a methoxy (CH3O−) group at one end and a −CH2CH2ONa as the other end group). Workup with water protonates the alkoxide end group of the polymer to form the product monomethyl poly(ethylene glycol) (4). Polymers like this with a methoxy group on one end are often identified with the shorthand name MPEG. There are also some other similar product polymers with −OH groups at both ends that are poly(ethylene glycol)s (PEGs). The term PEG is typically used for polymers with 200 monomer units are sometimes called poly(ethylene oxide) (PEO). These PEG, MPEG, and PEO materials are manufactured and sold by a number of companies, including BASF, The Dow Chemical Company, INEOS, and several companies in India and Asia.9 Not surprisingly, these polymers have many industrial applications. For example, a Web site for Dow’s PEG and MPEG polymers lists applications for these polymers that include uses as adhesives, inks, mold release agents, paints, toilet bowl cleaners, and wood treatment agents.10 Polymers such as PEG and MPEG also have specialty applications in biological chemistry, pharmaceuticals, and medicine, where the water solubility and biological compatibility of these polymers lead to greater bioavailability of drugs or to greater biocompatibility of medical devices.8,11−14 These biological or medical applications of PEG or MPEG typically use PEG or MPEG to functionalize surfaces or biologically active molecules. Such chemistry most often involves chemical modifications of the MPEG or PEG hydroxyl end groups, often via esterification or ether-forming reactions.
products contain signals due to trace amounts of solvents, catalyst residues, and byproducts. This material has been used in an introductory organic chemistry lecture course three times as an in-class example and twice as a homework problem. While the material has been used in various ways, the approach that worked very well was to use the analysis of the starting MPEG as a lecture example. In this case, the students performed well because the lecture had highlighted the low natural abundance of 13C and noted that 13 C couples to protons just as is the case in 1H−1H spin−spin splitting. With this background, the 1H NMR spectrum of the crude product or the purified product was then analyzed by students. In two of the lecture courses, students were also given the crude product’s 1H NMR spectrum and were tasked with identifying the impurities. In that case they were given an experimental procedure that listed the solvents, catalysts, and reagents used in the esterification. This experimental procedure and these 1H NMR spectroscopy end-group analyses have also been used to introduce new undergraduates to polymer derivatization and analysis in our research laboratory, but only with fewer than 10 undergraduates at the onset of their research experience. The Supporting Information contains the details of the 1H NMR spectroscopy end-group analysis based on the relative size of the integrals of the satellite peaks and other end-group peaks or based on the integrals of the satellite peaks and main MPEG signal. In a lecture class or problem set, students would simply be given the integral data for the satellite peaks and other end-group peaks along with the equations for a calculation. The worksheet with its example in the Supporting Information has a detailed procedure for students to use in these calculations that allows them to use the estimate of 13C natural abundance to determine the number-average molecular weight (Mn)6,7 of the MPEG or acetylated MPEG polymer and to show that the polymer does indeed have a molecular weight of about 2000 Da. The students beginning undergraduate research use the detailed experimental procedure to make their own derivative and do their own 1H NMR spectroscopic analyses. In those cases, students would use the expanded portions of the 1H NMR spectrum and calculate the integrals of the satellite and end-group signals. While the amounts different students do can vary, the overall goal is to show students how simple chemistry can modify a polymer and how to do endgroup analysis to determine Mn. A key feature of polymers is their size or degree of polymerization. The monomer ethylene oxide (1) in the polymerization reaction (Scheme 1) has a molecular weight of 44 Da. By means of the reactions of epoxides discussed in any introductory organic text, n molecules of ethylene oxide can be B
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An 1H NMR spectrum of the nominally 2000 Da MPEG starting material 4 obtained on a 500 MHz NMR spectrometer has one dominant signal due to the ca. 100 −OCH2− groups of the ca. 50 −OCH2CH2O− units in the polymer that appears as a broad peak at δ 3.64. While 4 has a MeO− on one end and a −OH on the other end that makes each of these ca. 100 −CH2− groups in principle different, the differences are negligible. Thus, all but two of the −CH2− peaks are superimposed on one another, producing a broad, large peak at δ 3.64. As shown in Figure 1a, this single peak is essentially
ANALYSIS OF THE MOLECULAR WEIGHT OF MPEG The utility of polymers in general and the uses of polymers such as PEG, MPEG, and their derivatives often depends on their molecular weight.15 However, unlike the situation with many organic molecules, the calculation of a molecular weight is more complicated with polymers because polymers including PEG, MPEG and their derivatives are not uniform collections of molecules. A one mole sample of ethylene oxide contains Avogadro’s number of individual molecules, all of which have the same structure. Each of the 6 × 1023 molecules of ethylene oxide in 1 mole of ethylene oxide has a molecular weight of 44 Da. In contrast, while a mole of MPEG too contains Avogadro’s number of individual molecules, the molecules in a 1 mole sample of MPEG that has on average of 45 monomers are not as uniform in terms of their sizes and molecular weights. A 1 mole sample of an MPEG polymer is actually a statistical distribution of molecules with a varying number of incorporated monomer units and varying molecular weight. For example, a 2.0 kg sample of MPEG2000 that has an average degree of polymerization of 45 contains MPEG molecules with a degree of polymerization that would include molecules with 42, 43, 44, . . . 46, 47, and 48 monomer units. Indeed, an MPEG polymer with an average degree of polymerization of 45 likely contains some polymer molecules that have fewer than 30 or more than 60 repeat units. This distribution of molecules can be very broad, and there can be slight changes in the distribution of molecules during purifications (see Figures S15 and S16 in the Supporting Information for models of distributions of different-sized molecules of both MPEG2000 and an acetate derivative of MPEG2000). Thus, while purification of a low-molecular-weight compound does not change its molecular weight, if only a few percent of the lowermolecular-weight polymer chains were removed during a precipitation or recrystallization process, the molecular weight of the polymer can slightly increase. Because polymers are a distribution of different-sized molecules, properties such as molecular weight for polymers are only discussed in terms of an average molecular weight. There are several ways to discuss this molecular weight. The discussion below is focused on an average molecular weight called the number-average molecular weight (Mn), which is simply the number-average degree of polymerization times the molecular weight of the monomer plus any mass due to added end groups.1,6,7 The degree of polymerization, the molecular weight Mn, and the identity of a polymer’s end groups can all be important for a polymer’s eventual application.15 There are a number of ways to analyze polymer molecular weight. Some of these methods are discussed in analytical, physical, or polymer chemistry courses. Methods such as viscosity, gel permeation chromatography, and vapor pressure osmometry have been used as examples in the chemical education literature.2,4,5 A molecular weight analysis that can be discussed in an introductory organic chemistry course is end-group analysis, which can be accomplished by using quantitative 1H NMR spectroscopy. This is illustrated in this paper using as an example a commercially available MPEG polymer that has an average degree of polymerization of ca. 45 and a nominal molecular weight of ca. 2000 Da (MPEG2000). A second example uses a derivative of this MPEG polymer where the free hydroxyl end group is modified to form an ester. These MPEG polymers that have hydroxyl and methoxy (4) or acetate ester and methoxy end groups (5) are shown in Scheme 1.
Figure 1. 1H NMR spectra of the MPEG ether 4 obtained on a 500 MHz NMR spectrometer: (a) normal spectrum of 4 showing a single peak for the roughly equivalent ca. 50 −OCH2CH2O− groups in the repeat units of 4 at δ 3.64; (b) spectrum at higher gain with the large peak at δ 3.64 offscale but showing the −OCH3 end group and 13C satellite peaks.
the only peak seen if an 1H NMR spectrum with the peak at δ 3.64 is scaled to fit on a standard 8.5 × 11 inch piece of paper. However, if the expanded spectrum is carefully examined (Figure 1b), several other peaks can be seen in the vicinity of the δ 3.64 peak. These other peaks include a singlet at δ 3.38, two multiplets on the shoulder of the large peak at δ 3.64 that are at δ 3.55 and δ 3.72, and two equal-sized but smaller multiplets at δ 3.50 and δ 3.78. These latter two multiplets are separated from one another by 140 Hz. When this NMR spectrum was obtained on a 300 MHz NMR spectrometer instead of on a 500 MHz NMR spectrometer, the δ 3.64 signal is still seen as the dominant signal. On an expanded spectrum (see the Supporting Information for a 300 MHz NMR spectrum of 4), the singlet at δ 3.38 can still be seen, though the multiplets at δ 3.55 and δ 3.72 are more poorly resolved. However, the two equal-sized smaller multiplets originally at δ 3.50 and δ 3.78 now appear at δ 3.41 and δ 3.88. These latter two peaks seem to be at a different chemical shift. However, they are still separated by 140 Hz. Since chemical shifts are identical regardless of the field strength of an NMR spectrometer, these latter two peaks are C
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not due to different chemical functionality. The lack of change in their separation in hertz indicates that they are due to spin− spin coupling. These two multiplets that are separated by 140 Hz arise because there is a natural abundance of ca. 1% of 13C in this starting PEG. 13C has a spin of 1/2 just like a proton. Thus, an sp3-hybridized 13C carbon couples to protons attached to it to produce a spin−spin splitting pattern. However, >99% of the naturally occurring carbon is 12C, which has no nuclear spin and does not couple to attached protons. Thus, this 13C−1H coupling is usually not readily seen in 1H NMR spectroscopy. The peak due to the 13C−1H coupling is only present for the ca. 1% of carbons that are in the form of the 13C carbon isotope. While this spin−spin coupling produces two peaks with 13C−1H coupling constants that are 115−140 Hz for an sp3-hybridized carbon, the peaks have only ca. 0.5% of the intensity of the peaks seen for the 99% of the carbons that are 12 C and thus are too small to notice. However, in the case of this polymer, the signal at δ 3.64 is derived from ca. 100 carbons. Since the natural abundance of 13C is ca. 1%, this means that ca. 1% of the −OCH2− methylenes will have a 13C. As a result, two satellite signals with a 140 Hz 13C−1H coupling constant are seen at δ 3.50 and δ 3.78 in the spectrum in Figure 1b. NMR spectroscopy can be used to determine the Mn of 4 in several ways. First, one can integrate the large peak at δ 3.64 and the singlet due to the terminal −OCH3 group at δ 3.38. In the case of the spectrum in Figure 1b, the ratio of these two peaks is 208.22/3.00. Since the singlet due to −OCH3 at δ 3.38 is due to three protons, the larger peak has to be due to 208 protons. The means that this larger peak contains 52 −OCH2CH2− groups and that 4 has an Mn of 2322 Da. Such end-group analyses of PEG derivatives have been reported previously by others and work well with PEGs having Mn values below 5000 Da.16 Second, integration of the 13C satellites at δ 3.55 and δ 3.72 in the 1H NMR spectrum in Figure 1b using the NMR software showed that these signals had an average integral of 0.94. Integration of the signal of the −OCH3 at δ 3.38 showed that this signal had an integral of 3.00. The ratio of the singlet at δ 3.38 to the average integration of the satellite peaks at δ 3.55 and δ 3.78 is 3.19. That corresponds to a ratio of 3 protons to 0.97% of the 2n protons of the −OCH2− groups in the larger δ 3.64 peak. A simple algebraic calculation using eqs 1 and 2 shows that there are 194 protons, corresponding to 48 − OCH2CH2− groups and an Mn of 2164 Da. An example of this calculation is provided in the Supporting Information. Similar analyses of 13C satellite peaks due to J13C−1H coupling have been used by us and others to analyze organic reaction products or polymer solvent impurities.17,18 This second analysis has the advantage of comparing the integrals of two similarly sized peaks. integral of the methoxy peak three proton equivalents integral of a satellite peak = x proton equivalents on each satellite peak
MPEG M n [proton equiv. in both sat. peaks][repeat unit weight] = [nat. abundance of 13C][proton equiv. in a repeat unit] + end‐group weight
(2)
There are two other multiplets in the spectrum in Figure 1b that are due to −CH2O− groups near each end of the polymer. These multiplets are difficult to integrate as they are on the shoulder of the broader δ 3.64 peak. However, if a copy of this spectrum were expanded such that the multiplet at δ 3.55 and the singlet at δ 3.38 are on the same page and large enough, these two peaks can be cut and weighed. The relative integrals of these two peaks are ca. 2.2:3.0. This same cut-and-weigh technique can be used to measure the relative integrals of the −OCH2− satellite peaks and the −OCH3 peaks. Some expanded spectra are included in the Supporting Information for this purpose. The molecular weight calculated in this way is quite comparable to the molecular weights calculated using the main peak at δ 3.64 and the −OCH3 peak at δ 3.38.
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FORMATION OF A MONOESTERIFIED MPEG DERIVATIVE As noted above, derivatives of MPEG and PEG polymers are often used in biological applications.8,11−14 Such derivatization reactions use the chemistry of alcohol functional groups discussed in an introductory organic chemistry course. This can involve a variety of reactions, including esterification and amidation of MPEGs with terminal hydroxyl or amine groups.19,20 Acetylation is a simple example of esterification of MPEG. This reaction is shown in Scheme 1. In this chemistry, acetylation with acetic anhydride forms a product polymer 5 with an acetate ester end group as well as the original methoxy end group. This product 5 can be easily isolated by filtration, and the purified product 5 can be characterized by 1H NMR spectroscopy (Figure 2). In practice, the crude product formed
Figure 2. 1H NMR spectrum of the purified MPEG acetate ester 5 obtained on a 500 MHz NMR spectrometer.
in a reaction is often analyzed first. This crude product contains mostly 5. However, traces of solvent, catalyst, adventitious water (PEG and MPEG derivatives are hygroscopic) and byproducts are also present. An 1H NMR spectrum of this crude reaction product is shown in Figure 3. The purified acetylated MPEG derivative 5 has the 1H NMR spectrum shown in Figure 2. While the spectrum of the crude product contains peaks due to impurities, the spectrum of either the crude or purified product 5 has the same set of peaks
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numbers of repeat units from the original statistical mixture of polymer molecules that made up 4.
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CONCLUSIONS The 1H NMR spectra and the chemistry described can be used in various places in a lecture course. In our case, it has been used in 1H NMR spectroscopy lectures as a way to illustrate the natural abundance of 13C, the presence of spin−spin coupling, diamagnetic chemical shifts, and quantitative 1H NMR spectroscopy end-group analysis of polymer molecular weight. It could however also be used in discussions of alcohols or esters. In view of the importance of MPEG and PEG polymers, the polymer synthesis itself could merit mention as an example in lecture when discussing epoxide chemistry. The chemistry used in the esterification and the role of the 4-N,Ndimethylaminopyridine organocatalyst are also relevant to the chemistry of alcohol functional groups. Finally, esterification of MPEG can be used in context with a discussion of applications of MPEG esters in medicine and biology. The greatest value of these ideas, though, is probably in the context of discussing NMR spectroscopy, chemical shifts, coupling constants, and the relative abundances of magnetically active nuclei.
Figure 3. 1H NMR spectrum of the crude MPEG acetate esterterminated product 5 (500 MHz) containing as trace impurities acetic acid, protonated triethylamine, and protonated 4-N,N-dimethylaminopyridine.
for the bulk of the −CH2CH2O− groups of 5, for the end groups of 5, and for the 13C satellites of the main −CH2CH2O− peak. Specifically, a singlet due to the CH3− group of the acetate ester appears at δ 2.05, a multiplet due to the −OCH2− that is next to the ester end group appears at δ 4.19, and a singlet due to the −OCH3 group appears at δ 3.35. The bulk of the protons resulting from the −OCH2CH2O− protons are seen as a large peak at δ 3.62. Small multiplets due to −OCH2− groups near the terminus of the main chain also appear on the shoulder of this δ 3.62 peak. As was true for the MPEG starting material 4, this large peak at δ 3.62 is due to the −OCH2CH2O− protons. Finally, as in the case of 4, there are two −CH2O− satellite peaks separated by 140 Hz that appear at δ 3.47 and δ 3.75. Integration of the methyl singlets at δ 2.05 and δ 3.35 and the AcOCH2− multiplet at δ 4.19 for the ester terminus using the NMR software shows that these protons are present in a 3.1:3.0:2.1 ratio, consistent with a 3:3:2 ratio of these protons in 5. Using the NMR software to compare the integral for the larger peak at δ 3.62 with the integral for the three-, three-, or two-proton peak for the methyl singlet at δ 2.05 or δ 3.35 or the AcOCH2− multiplet at δ 4.19, respectively, leads to the conclusion that there are 208 protons or 52 −OCH2CH2− groups giving rise to the main peak at δ 3.62. This calculation suggests that the Mn of 5 is 2365 Da. The Mn of 5 can also be calculated from integrals of the 13C satellite peaks at δ 3.47 and δ 3.75 either using the 1H NMR spectrometer software or the cut-and-weigh procedure described above. These calculations used the same methodology as the analysis of the Mn of 4 and showed that the purified product 5 had an Mn value of 2318 Da (cut-and-weigh method) or 2229 Da (NMR integration of the satellite peaks). These three methods of calculation yielded slightly different Mn values depending on whether the calculation used the NMR software integration of the −OCH3 end group and the integral of the main −OCH2CH2− peak, the NMR software integration of the −OCH3 group and the satellite −CH2− peak due to the 0.97% 13C in 5 to estimate the integral of the main −OCH2CH2− peak, or the cut-and-weigh analysis of peaks using the −OCH3 group and the satellite −CH2− peak due to the 0.97% 13C in 5 to estimate the integral of the main −OCH2CH2− peak. The slightly higher molecular weight of 5 versus 4 in this reaction sequence is consistent with the addition of the acetyl group and could also reflect the fact that the purification procedures remove some polymers with smaller
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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.6b00801. Expanded regions of the spectra in Figures 1, 2, and 3 showing the regions for peaks used in the cut-and-weigh analyses; detailed experimental procedure; sample calculation of Mn; worksheet to use as a lecture exercise to incorporate these concepts; comparison of the spectra of MPEG 4 obtained using 300 and 500 MHz instruments (PDF, DOCX) FID data (ZIP)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
David E. Bergbreiter: 0000-0002-1657-0003 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Support of our research by the National Science Foundation (Grant CHE-1362735) and the Robert A. Welch Foundation (Grant A-0639) is gratefully acknowledged, as is a gift of MPEG2000 from Michael Killough of INEOS.
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REFERENCES
(1) Zalipsky, S.; Harris, J. M. Introduction to Chemistry and Biological Applications of Poly(ethylene glycol). ACS Symp. Ser. 1997, 680, 1−14. (2) Marson, G. A.; Torres, B. B. Principles of Gel Permeation Chromatography: Interactive Software. J. Chem. Educ. 2006, 83 (10), 1567−1568. (3) Chakraborty, A. B.; Chen, W.; Gebler, J. C. Improved Mass Determination of Poly(ethylene glycols) by Electrospray Ion-Mobility Time-of-Flight Mass Spectrometry Coupled with Ion−Molecule Reactions. Pharm. Technol. 2008, 32 (7), 84−87.
E
DOI: 10.1021/acs.jchemed.6b00801 J. Chem. Educ. XXXX, XXX, XXX−XXX
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(4) Smith, D. R.; Raymonda, J. W. Polymer Molecular Weight Distribution: An Undergraduate Chemistry Experiment. J. Chem. Educ. 1972, 49 (8), 577−578. (5) Schwinefus, J. J.; Checkal, C.; Saksa, B.; Baka, N.; Modi, K.; Rivera, C. Molar Mass and Second Virial Coefficient of Polyethylene Glycol by Vapor Pressure Osmometry. J. Chem. Educ. 2015, 92 (12), 2157−2160. (6) Horta, A.; Pastoriza, M. A. The Molecular Weight Distribution of Polymer Samples. J. Chem. Educ. 2007, 84 (7), 1217−1221. (7) Izunobi, J. U.; Higginbotham, C. L. Polymer Molecular Weight Analysis by 1H NMR Spectroscopy. J. Chem. Educ. 2011, 88 (8), 1098−1104. (8) Herzberger, J.; Niederer, K.; Pohlit, H.; Seiwert, J.; Worm, M.; Wurm, F. R.; Frey, H. Polymerization of Ethylene Oxide, Propylene Oxide, and Other Alkylene Oxides: Synthesis, Novel Polymer Architectures, and Bioconjugation. Chem. Rev. 2016, 116 (4), 2170− 2243. (9) Grand View Research, Inc. Global Polyethylene Glycol (PEG) Market by Application (Medical, Personal Care, Industrial) Is Expected to Reach USD 1.68 Billion by 2020. http://www. grandviewresearch.com/press-release/global-polyethylene-glycol-pegmarket (accessed April 2017). (10) Dow. Polyethylene Glycol. http://www.dow.com/polyglycols/ polyethylene/applications/index.htm (accessed April 2017). (11) Li, J.; Kao, W. J. Synthesis of Polyethylene Glycol (PEG) Derivatives and PEGylated-Peptide Biopolymer Conjugates. Biomacromolecules 2003, 4 (4), 1055−1067. (12) Harding, J. L.; Reynolds, M. M. Combating Medical Device Fouling. Trends Biotechnol. 2014, 32 (3), 140−146. (13) Turecek, P. L.; Bossard, M. J.; Schoetens, F.; Ivens, I. A. PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs. J. Pharm. Sci. 2016, 105 (2), 460−475. (14) Nischan, N.; Hackenberger, C. P. R. Site-Specific PEGylation of Proteins: Recent Developments. J. Org. Chem. 2014, 79 (22), 10727− 10733. (15) Odian, G. Principles of Polymerization, 4th ed.; Wiley: Hoboken, NJ, 2004; Chapter 1. (16) Dust, J. M.; Fang, Z.-H.; Harris, J. M. Proton NMR Characterization of Poly(ethylene glycols) and Derivatives. Macromolecules 1990, 23 (16), 3742−3746. (17) Claridge, T. D. W.; Davies, S. G.; Polywka, M. E. C.; Roberts, P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D. Pure by NMR. Org. Lett. 2008, 10 (23), 5433−5436. (18) Harrell, M. L.; Malinski, T. J.; Torres-Lopez, C.; Gonzalez, K.; Suriboot, J.; Bergbreiter, D. E. Alternatives for Conventional Alkane Solvents. J. Am. Chem. Soc. 2016, 138 (44), 14650−14657. (19) Wikipedia. PEGylation. https://en.wikipedia.org/wiki/ PEGylation (accessed April 2017). (20) Grigoletto, A.; Maso, K.; Mero, A.; Rosato, A.; Schiavon, O.; Pasut, G. Drug and Protein Delivery by Polymer Conjugation. J. Drug Delivery Sci. Technol. 2016, 32 (PartB), 132−141.
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