Entropic Considerations in Molecular Design - ACS Sustainable

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Entropic Considerations in Molecular Design John C Warner, and Jennifer K. Ludwig ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.6b02096 • Publication Date (Web): 04 Oct 2016 Downloaded from http://pubs.acs.org on October 9, 2016

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ACS Sustainable Chemistry & Engineering

Entropic Considerations in Molecular Design ‡John C. Warner* and ‡Jennifer K. Ludwig *[email protected] The Warner Babcock Institute for Green Chemistry 100 Research Drive, Wilmington, MA 01887 KEYWORDS: Green Chemistry, Entropy, Molecular Design, Entropic Control, Self-Assembly

ABSTRACT

New information on the safety of chemicals, combined with threats of dwindling natural resources, increased pollution, and evidence of climate change have created a new environment for chemical innovation. In this new environment, traditional elements of chemical and material syntheses, such as high energy input and waste output, are no longer suitable. Scientists and engineers can instead gain insight from nature, where entropy facilitates reactions at room temperature and ambient pressure, using water as a solvent. This paper addresses five general considerations based on entropy to guide and inspire scientists and engineers in designing more efficient and benign chemicals, materials, and processes.

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Introduction

The second decade of the new millennium marks a crucial era in chemical innovation. Contemporary research on chemical safety, paired with dwindling stocks of natural resources, increasing pollution, and clear evidence of climate change have encouraged demand for chemicals and products that are better for the public and environment.1 In this new domain of innovation, traditional design methods dependent on high energy input and waste output are no longer suitable. As an alternative to methods drawing from “enthalpic” energy, scientists and engineers can learn from nature, where “entropic” energy facilitates reactions at room temperature and ambient pressure, using for the most part, water as a solvent. Focus on entropy in design has appeared countless times in the past literature, and is often associated with the terms “self-assembly”2 or “biomimicry”3. In chemistry and materials science, self-assembly and biomimicry principles have been used widely in the development of nano4, biological5, and metal-organic materials6. Although the precedence of entropic design concepts is well demonstrated in the literature, the following discussion organizes the concepts into five simple design considerations that can be used to guide and inspire scientists and engineers in the development of more efficient and benign chemicals, materials, and processes.

Collaborative Structures


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Throughout the history of chemistry, the molecules and materials that have shaped modern industrial society have been based predominantly on the formation of covalent bonds. Although covalent bonds are essential components of a chemist’s design toolbox, a situation in which they may not be the ideal solution is in the modification of target molecules. Disadvantages to the formation of covalent bonds, such as high energy and solvent use, coproducts and byproducts, and many separation and purification steps can make the modification of target molecules expensive, time-consuming, and wasteful. Furthermore, covalently altering the target molecule may interfere with established, favorable physical or chemical properties. As a more efficient alternative, target molecules can be non-covalently associated with other molecules exhibiting desirable characteristics through ionic forces, hydrogen-bonding, Van der Vaals forces, lipophilic-lipophilic interactions, or pi-pi interactions to form non-covalent derivatives (NCDs) or co-crystals.7 The ability to alter physical properties such as stability, melting points, optical properties, solubility, and bioavailability, while offering a potentially less toxic, wasteful, labor-intensive, and expensive preparation, have made NCDs an attractive solution for a variety of applications.8-9 Pharmaceuticals, cosmetics, agrochemicals, and food additives have utilized NCD co-crystals to improve properties. In addition, a number of methods for NCD screening and scale-up have been explored with successful results10-14, creating more opportunities for commercialization. A notable early example of an NCD application is the hydroquinone-bis-(N,Ndiethyl)terepthalamide cocrystal, used as an auxiliary developer in Polaroid’s instant film technology in the 1990s.15 In an effort to stabilize and water-solubilize the hydroquinones, (N,Ndiethyl)terepthalamide was added as a hydrogen-bond acceptor. The hydrogen bonding in the co-


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crystal tethered hydroquinone to two (N,N-diethyl)terepthalamide molecules at neutral pH, but allowed for dissociation at elevated pH.

Equilibrium Discontinuities

In the context of chemistry and materials science, manipulating tipping points, or points in which steady trends change drastically, can be a useful strategy in the design of new material properties and reaction mechanisms. To illustrate this concept, imagine a pile of sand where one grain at a time is added to the top of the pile. At a critical point, a catastrophic grain shift occurs, causing the pile to fall apart into an amorphous, flat pile. In this scenario, the pre- and postcatastrophic states serve as metaphors for different equilibrium states. If we are able to control the tipping points of certain systems, pushing them towards either equilibrium state or stabilizing the transition, new design opportunities emerge. This concept can be extrapolated to the product design and development process. In order to have a successful product, shelf-life stability, functional performance, and product longevity must be optimized. In terms of the sand pile example, shelf-life stability is the in-tact pile, functional performance is the action of falling apart, and product longevity is the dissociated pile. In order to improve all three aspects, it is essential to first fully understand how the tipping point relates to each state. For example, to enhance a paint in all three aspects, one would need to delve into the mechanism that initiates the curative process, the curative process itself, and the mechanism of termination. Once all three phenomena are understood, modifications can be made to inhibit or promote each mechanism.


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As a more situation-specific example, a tipping point is observed in thymine photopolymer solubility by UV light dosage.16-17 When exposed to increasing dosages of UV light, thymine photopolymers act as crosslinkers, branching intermolecular gaps through a 2π + 2π photocyclodimerization. However, at a certain dosage of UV light, the solubility of the crosslinked thymine photopolymers rapidly decreases, indicating a tipping point. The solubility tipping point can be manipulated to produce different functionalities or physical properties, and has been previously used in photoresist technology18, templated formation of conductive polymers19, dissolution control in release systems20, and hair curling21.

Pre-Associative Reactivity

The reason traditional syntheses of organic compounds employ high temperatures and pressures is typically to increase the probability of molecular collisions. The geometry of molecular orbitals imposes specific reaction trajectories, rendering the vast majority of molecular collisions non-product producing. By applying heat and pressure, the frequency of molecular collisions is increased indiscriminately, providing no preferential orientation of reactive species. In contrast, nature enhances the success of molecular collisions using much less energy by creating local reaction environments. Using enzymes22 and compartmentalization through lipid barriers, nature confines and orients molecules to promote efficient transformations. In the laboratory, catalysts and manipulations of solubility interfaces demonstrate examples of this concept. Since the late 18th century, catalysts have been extensively explored, yielding many different types varying in size, composition, and mechanism. Apart from using catalysts to orient molecules, another way promote reactivity is to spatially confine molecules. From using water as


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a solvent in Diels-Alder reactions23, to the newer use of designer surfactants24, creating local environments enables faster kinetic rearrangement, thereby reducing or eliminating the need for applied heat or pressure.

Synchronous Orthogonal Mechanisms

Inside a cell, many processes occur simultaneously. Molecules are synthesized, taken apart, transported, imported, exported, stored, and coordinated with other molecules. Despite all of the concurrent molecular processes, the cell still accomplishes tasks with high efficiency. In contrast, the majority of human-made syntheses, processes, and products require pure feedstocks to function properly or at all. Synchronous orthogonal mechanisms, or non-interfering reactions that occur simultaneously, typically appear in “one-pot” syntheses and are powerful strategies that incorporate all reactants in one or few reaction steps, require minimal purification, and reduce the amount of necessary resources.25 An example of a synchronous orthogonal mechanism is demonstrated in the one-pot, four-component synthesis of substituted pyrroles in gluconic acid aqueous solution26. The proposed

mechanism

suggests

that

two

intermediates

are

formed:

(Z)-4-

((4-

methoxyphenyl)amino)pent-3-en-2-one (A) from 4-methox yaniline and acetylacetone; and (E)1-methoxy-4-(2-nitrovinyl)benzene (B) from 4-methoxybenzaldehyde and nitromethane. The two intermediates then react via a Michael addition, followed by a cyclization, eliminating a nitroxyl group and H2O to yield the product (90%).

Resilience and Molecular Diversity


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In the two hundred plus years since the Industrial Revolution, the materials used in products have progressed from molecularly complex, bio-based, and minimally processed to molecularly complex, synthetic, often petroleum-based, and highly processed. It is now commonplace for the materials that go into any manufacturing process to first be extracted, then isolated, then purified, then either mixed or reacted with other materials to make the final product. This is a big difference in energy expenditure than simply going out to chop down a tree. A good question to ask is how manufacturing has become so dependent on highly pure starting materials. One answer is that chemists have made use of available feedstocks and optimized each material to serve a certain purpose. Refining petroleum has produced an abundant source of waste that has been transformed into various pure feedstocks. Another answer is the concern of quality control. If there are unknown compounds in products, there is more of a chance of failure. However, the missing piece of the puzzle is why efforts have not been focused on developing reliably reproducible processes that give inherent diversity of structure. Materials in natural systems rarely exist in high purity. One finds within the tissues and membranes of physiological organisms a wide diversity of molecular compositions. Often various stereo and region-isomers coexist within structures. Mechanistically, the existence of this molecular diversity provides the benefit of affording resilience of properties. For example, the presence of a variety of fatty acids within cell membranes allows for homeostatic maintenance within organisms across a broad temperature differential.27


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Ironically, the dependence on highly pure feedstocks has limited the ability to design resilient products. If a bio-based material has within it a variety of isomers, rather than incurring significant cost to separate the isomers out, products should be designed to take advantage of this “built in” diversity. Rather than require a highly purified material, what is actually necessary is a natural, diverse feedstock that is reliably reproducible. Resilience and molecular diversity in the current literature is exemplified by the use of natural extracts. Instead of using pure materials, plant-based extracts containing many substances have been tested for use as catalysts for nanoparticle synthesis28, corrosion inhibitors29, food additives30-31, and dyes32. For these materials to become more mainstream, inherent molecular diversity and reliable, reproducible processes to support it must be seen as an advantage.

Conclusion

Chemists throughout history have successfully used traditional methods of synthesis to provide countless beneficial products for society. As the future unfolds, we can expect even more discoveries of materials and processes that accomplish additional unmet needs. It is not suggested that the five “enthalpic” considerations presented here call for some required shift of thinking among practitioners of chemistry. The spirit of this discussion is to offer a different mindset when considering molecular design. By considering the concepts of collaborative structures, equilibrium discontinuities, pre-associative reactivity, synchronous orthogonal mechanisms, and resilience and molecular diversity, chemists might approach issues of sustainability in design from a different perspective, as additional innovative tools in the chemist’s toolbox.


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Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. ACKNOWLEDGMENT The authors wish to thank the various people throughout our careers that have contributed to the balance of entropy and enthalpy in our lives. References 1. Anastas, P. T.; Warner, J. C., Green Chemistry: Theory and Practice. Oxford University Press: New York, 1998. 2. Whitesides, G. M.; Grzybowski, B., Self-assembly at all scales. Science 2002, 295 (5564), 24182421. 3. Benyus, J. M., Biomimicry. William Morrow: New York, 1997. 4. Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Molecular self-assembly and nanochemistry: a chemical strategy for the synthesis of nanostructures; DTIC Document: 1991. 5. Zhang, S., Fabrication of novel biomaterials through molecular self-assembly. Nat. Biotechnol. 2003, 21 (10), 1171-1178. 6. Zhang, M.; Gu, Z.-Y.; Bosch, M.; Perry, Z.; Zhou, H.-C., Biomimicry in metal–organic materials. Coord. Chem. Rev. 2015, 293, 327-356. 7. Stoler, E.; Warner, J. C., Non-covalent derivatives: cocrystals and eutectics. Molecules 2015, 20 (8), 14833-14848. 8. Warner, J. C., Pollution prevention via molecular recognition and self-assembly: non-covalent derivatization. In Green Chemistry: Frontiers in Benign Chemical Syntheses and Processes, Oxford University Press: London, England, 1998; pp 336-346. 9. Cannon, A. S.; Warner, J. C., Noncovalent derivatization: green chemistry applications of crystal engineering. Cryst. Growth Des. 2002, 2 (4), 255-257. 10. Daurio, D.; Nagapudi, K.; Li, L.; Quan, P.; Nunez, F.-A., Application of twin screw extrusion to the manufacture of cocrystals: scale-up of AMG 517–sorbic acid cocrystal production. Faraday Discuss. 2014, 170, 235-249. 11. Duarte, I.; Pereira, M. J.; Padrela, L.; Temtem, M., Synthesis and Particle Engineering of Cocrystals. 2014. 12. Salan, J.; Anderson, S. R., Method to Produce and Scale-Up Cocrystals and Salts Via Resonant Acoustic Mixing. 2014. 13. Leung, D. H.; Lohani, S.; Ball, R. G.; Canfield, N.; Wang, Y.; Rhodes, T.; Bak, A., Two novel pharmaceutical cocrystals of a development compound–screening, scale-up, and characterization. Cryst. Growth Des. 2012, 12 (3), 1254-1262. 14. Zhao, L.; Raval, V.; Briggs, N. E.; Bhardwaj, R. M.; McGlone, T.; Oswald, I. D.; Florence, A. J., From discovery to scale-up: α-lipoic acid: nicotinamide co-crystals in a continuous oscillatory baffled crystalliser. CrystEngComm 2014, 16 (26), 5769-5780.


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15. Taylor, L. D.; Warner, J. C. Process and composition for use in photographic materials containing hydroquinones. 1994. 16. Warner, J. C., Entropic control in green chemistry and materials design. Pure Appl. Chem. 2006, 78 (11), 2035-2041. 17. Trakhtenberg, S.; Cannon, A.; Warner, J., Non-Catalytic Photo-Induced Immobilization Processes in Polymer Films. In Thin Films and Nanostructures: Physico-Chemical Phenomena in Thin Films and at Solid Surfaces, Elsevier: 2007; Vol. 34, pp 665-695. 18. Grasshoff, J. M.; Taylor, L. D.; Warner, J. C. Vinylbenzyl thymine monomers. 1995. 19. Trakhtenberg, S.; Hangun-Balkir, Y.; Warner, J. C.; Bruno, F. F.; Kumar, J.; Nagarajan, R.; Samuelson, L. A., Photo-cross-linked immobilization of polyelectrolytes for enzymatic construction of conductive nanocomposites. J. Am. Chem. Soc. 2005, 127 (25), 9100-9104. 20. Whitfield, J. R.; Morelli, A.; Warner, J. C., Enzymatic reversal of polymeric thymine photocrosslinking with E. coli DNA photolyase. J. Macromol. Sci., Pure Appl. Chem. 2005, 42 (11), 15411546. 21. Warner, J. C.; Cannon, A. S.; Raudys, J.; Undurti, A. Photo-reactive polymers and devices for use in hair treatments. 2009. 22. Fersht, A., Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding. Macmillan: 1999. 23. Rideout, D. C.; Breslow, R., Hydrophobic acceleration of Diels-Alder reactions. J. Am. Chem. Soc. 1980, 102 (26), 7816-7817. 24. Lipshutz, B. H.; Ghorai, S., “Designer”-Surfactant-Enabled Cross-Couplings in Water at Room Temperature. Aldrichimica acta 2012, 45 (1), 3-16. 25. Hayashi, Y., Pot economy and one-pot synthesis. Chem. Sci. 2016, 7 (2), 866-880. 26. Li, B.-L.; Li, P.-H.; Fang, X.-N.; Li, C.-X.; Sun, J.-L.; Mo, L.-P.; Zhang, Z.-H., One-pot four-component synthesis of highly substituted pyrroles in gluconic acid aqueous solution. Tetrahedron 2013, 69 (34), 7011-7018. 27. Zhang, Y.-M.; Rock, C. O., Membrane lipid homeostasis in bacteria. Nat. Rev. Microbiol. 2008, 6 (3), 222-233. 28. Iravani, S., Green synthesis of metal nanoparticles using plants. Green Chem. 2011, 13 (10), 2638-2650. 29. Abdel-Gaber, A.; Abd-El-Nabey, B.; Khamis, E.; Abd-El-Khalek, D., A natural extract as scale and corrosion inhibitor for steel surface in brine solution. Desalination 2011, 278 (1), 337-342. 30. Amakura, Y.; Umino, Y.; Tsuji, S.; Ito, H.; Hatano, T.; Yoshida, T.; Tonogai, Y., Constituents and their antioxidative effects in eucalyptus leaf extract used as a natural food additive. Food Chem. 2002, 77 (1), 47-56. 31. Xu, W.; Qu, W.; Huang, K.; Guo, F.; Yang, J.; Zhao, H.; Luo, Y., Antibacterial effect of grapefruit seed extract on food-borne pathogens and its application in the preservation of minimally processed vegetables. Postharvest Biol. Technol. 2007, 45 (1), 126-133. 32. Selvi, A. T.; Aravindhan, R.; Madhan, B.; Rao, J. R., Studies on the application of natural dye extract from Bixa orellana seeds for dyeing and finishing of leather. Ind. Crops. Prod. 2013, 43, 84-86.


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Entropic Considerations in Molecular Design John C. Warner and Jennifer K. Ludwig The design of more sustainable molecular systems requires the manipulation of entropy over enthalpy. This paper describes five general entropic considerations for molecular design.


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Entropic Considerations in Molecular Design - ACS Sustainable

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