The Distribution of Macromolecular Principles throughout Introductory

Article pubs.acs.org/jchemeduc

The Distribution of Macromolecular Principles throughout Introductory Organic Chemistry Joel I. Shulman* Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States ABSTRACT: Many of the principles of organic polymer chemistry are direct extensions of the information contained in the standard introductory organic chemistry course. Often, however, the discussion of macromolecules is relegated to a chapter at the end of the organic chemistry text and is covered briefly, if at all. Connecting the organic-chemical principles of macromolecules to those of small molecules at the time these principles are first presented demonstrates some of the practical implications of organic chemistry, including medical applications. Making these connections can serve as a motivator to many students who are interested in medical applications of organic chemistry. Several examples of how macromolecular principles can be distributed throughout an introductory organic chemistry course to connect basic concepts to everyday life are discussed. KEYWORDS: Second-Year Undergraduate, Curriculum, Organic Chemistry, Polymer Chemistry, Analogies/Transfer, Polymerization, Synthesis, Applications of Chemistry • Learning about the applications of chemistry to everyday life can be motivating for students. • The many medical/biological applications of synthetic polymers have pertinence to the large cohort of organic students who are interested in health-care professions. Beyond the introduction of chain-growth and step-growth polymerizations when discussing alkenes and carboxylic acid derivatives, there are abundant opportunities throughout an organic course to use polymers to illustrate basic principles. What follows are some examples that illustrate basic principles of organic chemistry but do not appear in most current textbooks.3 These examples can be used to supplement discussions of small-molecule principles at appropriate times in a course.

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he American Chemical Society Guidelines for Undergraduate Professional Education in Chemistry, published in 2015 by the ACS Committee on Professional Training, state that “...the principles that govern [macromolecular] systems must be part of the curriculum required for certified graduates” in chemistry.1,2 Because only a small minority of undergraduate chemistry programs teach a dedicated macromolecular/ polymer chemistry course, “[c]overage of these topics may be distributed across multiple courses.”1 The introductory course in organic chemistry provides an obvious opportunity to discuss the synthesis and physical properties of macromoleculessynthetic organic polymers in particularcomparing and contrasting them with small molecules. Most texts used for introductory organic chemistry dedicate a chapter to synthetic polymers. However, such a chapter is usually found at the end of the book and therefore is often not covered in the already crowded organic curriculum. In addition, leaving polymer chemistry to an appended topic in the course disassociates the material from the chemical principles to which polymers are related. In addition to or instead of a dedicated organic polymer chapter, some texts cover radical chain-growth and cationic polymerization during discussion of alkenes and step-growth polymerization during discussion of carboxylic acid derivatives. Embedding polymer chemistry into the curriculum in this wayin the context of the basic principles students are learningprovides several advantages: • Polymer syntheses and reactions are a natural extension of the principles that students learn throughout the course and demonstrate some of the practical implications of organic chemistry. © XXXX American Chemical Society and Division of Chemical Education, Inc.

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RELATIVE REACTIVITIES OF CARBOXYLIC ACID DERIVATIVES AND RELATION TO BIODEGRADABILITY Organic chemistry students learn the relative reactivities of carboxylic acid derivatives with water, e.g., anhydride > ester > amide. This carries over to the corresponding polymers (Figure 1). Thus, polyanhydrides hydrolyze rapidly and can be used to encapsulate drugs for controlled in vivo release.4 Talking about polyanhydrides provides the opportunity to introduce the concept of mixed anhydrides, which are integral to the synthesis of such polymers (Scheme 1). The rate of hydrolysis of Special Issue: Polymer Concepts across the Curriculum Received: September 9, 2016 Revised: March 12, 2017

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DOI: 10.1021/acs.jchemed.6b00673 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

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Figure 1. Polymers with anhydride, ester, and amide bonds.

Scheme 1. Synthesis of a Polyanhydride via a Mixed Anhydride

biodegradability avoids any danger of a foreign material remaining in the body and causing an inflammatory response. The idea of polyester hydrolysis can lead to a discussion of green chemistry. A particularly useful poly(hydroxyalkanoate) is poly(3-hydroxybutyrate) (Figure 3), which can be used to

polyanhydrides such as this depends on the length of the alkyl chain and determines the rate of release of the encapsulated drug in the body. Polyesters will also hydrolyze, though much more slowly than polyanhydrides. The rate of hydrolysis of polyesters is highly dependent upon their structure. Thus, poly(ethylene terephthalate) (PET) (Figure 2) can be molded into containers

Figure 3. Poly(3-hydroxybutyrate). Figure 2. Poly(ethylene terephthalate).

Scheme 2. Formation and Hydrolysis of a Poly(αhydroxyalkanoate)

replace polypropylene in many applications. Whereas polypropylene is very stable in the environment, films made from poly(3-hydroxybutyric acid) are degraded to carbon dioxide and water by microorganisms in landfills.6 Even though poly(3hydroxybutyrate) is several times more expensive than polypropylene, environmental regulations in several European countries, particularly Germany, favor the use of this and other biodegradable polymers.

the stereochemistry around the chiral center, have a variety of biomedical applications such as sutures, stents, and drug delivery devices.5 Traditional suture materials such as catgut must be removed after they have served their purpose, whereas biodegradable polyester sutures derived from α-hydroxycarboxylic acids can be degraded and absorbed by the body in 2 weeks to about 90 days, depending on the nature of R. When R = CH3, the polyester degrades to lactic acid, a compound found naturally in the body that is metabolized to CO2 and H2O. This

NATURE LOVES FIVE- AND SIX-MEMBERED RINGS At several points during an introductory organic chemistry coursefor example, during the discussion of aldol and Dieckmann condensationsstudents are told that the formation of five- and six-membered rings is kinetically favored over the formation of either smaller or larger rings. A good way to drive home this concept when discussing the intramolecular aldol condensation and the Dieckmann condensation is to compare the formation of six- and seven-membered-ring lactones from the corresponding ω-hydroxycarboxylic acids. Whereas 5-hydroxypentanoic acid readily lactonizes to form the six-membered ring, 6-hydroxyhexanoic acid generally fails to form a lactone unless the reaction is run under high-dilution conditions (Scheme 3). In fact, the formation of sevenmembered-ring lactones occurs 104 times more slowly than the formation of five-membered-ring lactones.7 Rather than

that are unreactive toward hydrolysis and can be used as beverage containers as well as being drawn into polyester fibers. However, polyesters can be engineered to hydrolyze at a desirable rate. For example, polymers of α-hydroxycarboxylic acids (Scheme 2), depending on the nature of the R group and

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Scheme 3. Comparison of the Formation of Six- and SevenMembered Rings

Scheme 4. Anionic Polymerization via Repeated Michael Addition

Scheme 5. Curing of Super Glue via Repeated Michael Additions

(Figure 5), when R = butyl, isobutyl, n-octyl, or 2-octyl (Dermabond), this monomer can be used to replace stitches to

lactonizing under the conditions usually used to form an ester, 6-hydroxyhexanoic acid forms polycaprolactone. Indeed, caprolactone itself readily undergoes ring-opening polymerization to give the same polymer.8

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PRACTICAL USES OF THE MICHAEL REACTION The Michael reaction (1,4-addition, conjugate addition; Figure 4) is discussed, inter alia, in the context of being a valuable way

Figure 5. Cyanoacrylates in general have a variety of medical uses.

close wounds. GluSeal90 (blend of R = butyl and R = 2-octyl) is a “liquid adhesive bandage intended to cover minor cuts, scrapes, burns, and minor irritations of the skin and help protect them from infection”.9 PeriAcryl90 is the same blend formulated for use in periodontal surgery.9

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RING-OPENING POLYMERIZATION: RING OPENING OF EPOXIDES Students learn fairly early in organic chemistry that nucleophiles can attack epoxides via an SN2 mechanism, resulting in the opening of the three-membered ring. Less obvious to students is that the intermediate alkoxide can itself act as a nucleophile, attacking excess epoxide to form a polymer in a process known as ring-opening polymerization (Scheme 6).

Figure 4. Nucleophiles will attack the carbonyl carbon of unconjugated carbonyl compounds (1,2-addition). With α,β-unsaturated carbonyls, either 1,2-addition or Michael addition (1,4-addition, conjugate addition) can occur.

Scheme 6. Ring Opening via SN2 Attack on an Epoxide Leading to a Polymer

to introduce substituents β to a carbonyl group or to form a new six-membered ring (Robinson annulation). Polymer chemistry provides the opportunity to demonstrate a practical application of the Michael reaction that all students can appreciate. Specifically, many examples of anionic polymerization involve repeated Michael additions (Scheme 4). An example to which everyone can relate is super glue. In this case, the Michael acceptor is the monomer methyl cyanoacrylate. The two strongly electron-withdrawing substituents on this monomer allow it to undergo rapid anionic polymerization initiated by a weak nucleophile (Scheme 5). In the case of super glue, the nucleophile is water, either from the air or on the surface to be glued. Thus, super glue does not “air dry”; rather, it cures via anionic polymerization initiated by water. In addition to their myriad household uses, cyanoacrylates can be designed for many medical applications, all mediated by anionic polymerization. Thus, in a generic cyanoacrylate

In the case where the epoxide is simply ethylene oxide, the resulting polymer is poly(ethylene glycol) (PEG), a highly water-soluble macromolecule. PEG is used in many creams and lotions. Of importance from a medical standpoint is the fact that PEG can be attached covalently to a larger molecule (a process termed PEGylation) to improve its delivery kinetics.10 C



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Scheme 7. Formation of a Carbamic Acid and Resulting Loss of Carbon Dioxide in the Hofmann Rearrangement and in the Removal of the Benzyloxycarbonyl Protecting Group from an Amine

Scheme 8. Synthesis of a Polyurethane

Scheme 9. Production of Carbon Dioxide as a Blowing Agent during the Synthesis of a Polyurethane Foam

For example, PEGylation of interferon, used to treat hepatitis C, increases the circulatory lifetime of the parent protein.

bonds, formed by oxidation of cysteine to cystine (Scheme 10), to the tertiary structure of peptides.

INSTABILITY OF CARBAMIC ACIDS: RELATION TO POLYURETHANE FOAMS Students in organic chemistry may be exposed to two different examples of carbamic acids decomposing to an amine and carbon dioxide: the Hofmann rearrangement and the use of the benzyloxycarbonyl (Z) protecting group (Scheme 7). An application of the release of carbon dioxide by carbamic acid decomposition is seen in the production of foams during the synthesis of polyurethanes from diisocyanates (Scheme 8). For example, the addition of a small amount of water into the reaction of 2,4-toluene diisocyanate with a diol causes some of the diisocyanate to hydrolyze to a carbamic acid, which decomposes to release carbon dioxide (and a minor amount of adventitious diamine) simultaneously with the formation of the polyurethane (Scheme 9). The release of this “blowing agent” gas during polymerization causes the polyurethane to foam as it is formed. Polyurethane foams can be used as furniture stuffing, carpet backing, packaging material, and insulation.

Scheme 10. Mild Oxidation of Thiols To Create Disulfide Bonds

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An excellent illustration of the manipulation of disulfide linkages in everyday life is the process of giving hair a permanent wave. Hair derives its body in large part from disulfide bonds in the protein that constitutes the hair structure. Treatment of hair with a mild reducing agent such as 2mercaptoethanol (HS−CH2−CH2−OH) will reduce the disulfide bridges, causing the hair to “lose its shape”. Wrapping the hair around curlers into a desired new shape and then reforming disulfide bonds by mild oxidation (e.g., with hydrogen peroxide) completes the “permanent” wave (Figure 6).11

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PRACTICAL IMPLICATIONS OF THE FORMATION OF DISULFIDE BONDS Organic chemistry students are usually exposed briefly to the formation of disulfide bonds by mild oxidation of thiols. Students may be told further about the importance of disulfide D



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Figure 6. Disulfide bonds help provide body to hair (diagram, upper left). Reduction of disulfide bonds causes the hair to lose shape, allowing hair to be curled into a desired new shape (diagram, upper right). Reformation of disulfide bonds by mild oxidation (lower diagram, with new positioning of thiol groups on polymer chains denoted by letter markers) completes the permanent-wave process. Reproduced with permission from ref 11. Copyright Charles Ophardt.

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Programs. ACS Committee on Professional Training, Spring 2015. https://www.acs.org/content/dam/acsorg/about/governance/ committees/training/2015-acs-guidelines-for-bachelors-degreeprograms.pdf (accessed February 2017). (2) Wenzel, T. J.; McCoy, A. B.; Landis, C. R. An Overview of the Changes in the 2015 ACS Guidelines for Bachelor’s Degree Programs. J. Chem. Educ. 2015, 92 (6), 965−968. (3) Introduction of Macromolecular Science/Polymeric Materials into the Foundational Course in Organic Chemistry; Howell, B. A., Ed.; ACS Symposium Series, Vol. 1151; American Chemical Society: Washington, DC, 2013. (4) Tamada, J.; Langer, R. The Development of Polyanhydrides for Drug Delivery Applications. J. Biomater. Sci., Polym. Ed. 1992, 3 (4), 315−353. (5) Handbook of Biodegradable Polymers: Synthesis, Characterization and Applications; Lendlein, A., Sisson, A., Eds.; ChemTec Publishing: Toronto, ON, 2011. (6) Tokiwa, Y.; Calabia, B. P.; Ugwu, C. U.; Aiba, S. Biodegradability of Plastics. Int. J. Mol. Sci. 2009, 10 (9), 3722−3742. (7) Galli, C.; Illuminati, G.; Mandolini, L.; Tamborra, P. Ring Closure Reactions. 7. Kinetics and activation parameters of lactone formation in the range of 3- to 23-membered rings. J. Am. Chem. Soc. 1977, 99 (8), 2591−2597. (8) Labet, M.; Thielemans, W. Synthesis of polycaprolactone: a review. Chem. Soc. Rev. 2009, 38, 3484−3504.

BOTTOM LINE Much of the polymer world is “just organic chemistry”. Introductory organic chemistry is an appropriate place to introduce many of the principles of macromolecular chemistry. Including these principles in the context of where they appear for small molecules demonstrates to students some of the practical implications of organic chemistry. It also demonstrates to students with a strong biological interest that organic chemistry is pertinent to these interests.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Joel I. Shulman: 0000-0003-1259-948X Notes

The author declares no competing financial interest.

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REFERENCES

(1) Undergraduate Professional Education in Chemistry. ACS Guidelines and Evaluation Procedures for Bachelor’s Degree E



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(9) GluSeal90 and PeriAcryl90 are products of GluStitch Inc. http:// www.glustitch.com/productsList.php?region=USA (accessed February 2017). (10) Veronese, F. M.; Pasut, G. PEGylation, successful approach to drug delivery. Drug Discovery Today 2005, 10 (21), 1451−1458. (11) Diagrams from: Ophardt, C. E. Virtual Chembook; Elmhurst College: Elmhurst, IL, 2003; see http://chemistry.elmhurst.edu/ vchembook/568hairwave.html (accessed February 2017).

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The Distribution of Macromolecular Principles throughout Introductory

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