Rethinking Reactivity: How Structure, Energy, and Entropy Drive Chemical Transformations
DOI:
10.29303/jpm.v20i4.8795Published:
2025-06-26Issue:
Vol. 20 No. 4 (2025): Special IssueKeywords:
Duality; Potential Energy; Reaction Mechanism; Reactivity; ThermodynamicsArticles
Downloads
How to Cite
Downloads
Metrics
Abstract
This work introduces a new way to understand chemical and biological reactivity by connecting molecular structure directly to potential energy and entropy. Moving beyond traditional views, where potential energy is merely “stored energy” and entropy a measure of “disorder”, this structural-thermodynamic framework defines both properties through the lens of constitution, configuration, and conformation. By analyzing diverse mechanisms, including nucleophilic substitutions, eliminations, and cycloadditions, the study shows how structure drives energy storage and release, as well as entropic expansion. The framework highlights how organization increases potential energy while dissociation and flexibility enhance entropy. This structural view not only clarifies the thermodynamic basis of reaction pathways but also offers a predictive model for molecular design in drug development, catalysis, and computational chemistry. By linking structure to thermodynamic behavior, the approach helps students and researchers move from memorization to mechanistic reasoning, providing a unified tool to interpret and anticipate chemical transformations.References
Atkins, P. W., and J. De Paula, Physical Chemistry, W. H. Freeman and Company, New York, NY, 2010.
S. E. Harris and C. R. Bertozzi, Molecular Thermodynamics: A Second Look at the Fundamentals of Physical Chemistry, Springer, New York, NY, 2021.
K. J. Laidler, The World of Physical Chemistry, Oxford University Press, New York, NY, 1987.
R. Gould, Statistical and Thermal Physics: Fundamentals and Applications, Cengage Learning, New York, NY, 2007.
D. A. McQuarrie, Statistical Mechanics, University Science Books, Sausalito, CA, 2008.
S. A. Kauffman et al., Chemistry: A Molecular Approach, Pearson Education, Boston, MA, 2021.
R. F. W. Bader, Atoms in Molecules: A Quantum Theory, Clarendon Press, 1990.
P. W. Atkins and R. Friedman, Molecular Quantum Mechanics, Oxford University Press, 2011.
J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 1985.
J. Alzeer, “Lifestylopathy as personalized medicine: A holistic approach to health,” Medical Research Archives, vol. 13, no. 1, 2025. https://doi.org/10.18103/mra.v13i1.6209.
J. Alzeer, “Balancing potential energy and entropy: The foundations of lifestylopathy and homeostasis,” J Public Health Emerg, vol. 8, p. 8, 2024. https://doi.org/10.21037/jphe-23-140.
J. Alzeer, “Entropy and potential energy as a key role of Halalopathy in disease prevention and cure,” Longhua Chinese Medicine, vol. 3, p. 20, 2020. https://doi.org/10.21037/lcm-20-40
N. Levine, Physical Chemistry, McGraw-Hill Education, 2014.
J. Alzeer, “Directionality of chemical reaction and spontaneity of biological process in the context of entropy,” International Journal of Regenerative Medicine, vol. 5, no. 2, pp. 1–7, 2022. https://doi.org/10.31487/j.rgm.2022.02.06.
J. W. Moore and C. L. Stanitski, Principles of Chemistry: A Molecular Approach, Prentice Hall, 2009.
J. W. Gibbs, “On the equilibrium of heterogeneous substances,” Transactions of the Connecticut Academy of Arts and Sciences, vol. 3, pp. 108-248, 1878.
F. A. Miller and J. A. McGowan, Thermodynamics and Kinetics in Materials Science, Springer, 2017.
C. Tanner, Quantum Chemistry: A Unified Approach, Oxford University Press, 2016.
X. Wang et al., Chemical Thermodynamics and Kinetics, Oxford University Press, 2017.
C. Schmid and C. Griesinger, NMR and Chemistry: A Practical Guide, Wiley-VCH, 2009.
C. J. Cramer, Essentials of Computational Chemistry: Theories and Models, John Wiley & Sons, 2004.
J. Alzeer, “Beyond disorder: A new perspective on entropy in chemistry,” American Journal of Medicinal Chemistry, vol. 5, no. 1, p. 1-5, 2024. https://doi.org/10.31487/j.ajmc.2024.01.01.
J. Alzeer, “Exploring the dynamics of nucleophilic substitution reactions: Understanding the role of entropy and potential energy in SN1 and SN2 pathways,” American Journal of Medicinal Chemistry, vol. 4, no. 1, pp. 1-4, 2023. https://doi.org/10.31487/j.ajmc.2023.01.02.
L. Chan, G. Morris, and G. Hutchison, “Understanding conformational entropy in small molecules,” 2021. https://doi.org/10.26434/chemrxiv.12671027.v2.
U. Lucia, “The Gouy-Stodola theorem in bioenergetic analysis of living systems (irreversibility in bioenergetics of living systems),” Energies, vol. 7, no. 9, pp. 5717-5739, 2014. https://doi.org/10.3390/en7095717.
B. Chen, S. Wong, and C. Li, “On the calculation of system entropy in nonlinear stochastic biological networks,” Entropy, vol. 17, no. 10, pp. 6801-6833, 2015. https://doi.org/10.3390/e17106801.
R. Fenwick, S. Esteban-Martín, and X. Salvatella, “Understanding biomolecular motion, recognition, and allostery by use of conformational ensembles,” European Biophysics Journal, vol. 40, no. 12, pp. 1339-1355, 2011. https://doi.org/10.1007/s00249-011-0754-8.
S. Cushman, “Entropy, ecology and evolution: Toward a unified philosophy of biology,” Entropy, vol. 25, no. 3, p. 405, 2023. https://doi.org/10.3390/e25030405.
M. He et al., “Structural analysis of biomolecules through a combination of mobility capillary electrophoresis and mass spectrometry,” ACS Omega, vol. 4, no. 1, pp. 2377-2386, 2019. https://doi.org/10.1021/acsomega.8b03224.
J. Alzeer, “The role of buffers in establishing a balance of homeostasis and maintaining health,” American Journal of Medicinal Chemistry, vol. 4, no. 1, pp. 1–6, 2023. http://dx.doi.org/10.31487/j.AJMC.2023.01.01.
P. W. Atkins and J. de Paula, Physical Chemistry, 10th ed., Oxford University Press, 2014.
E. A. Meyer, “Weak interactions in organic chemistry,” Chemical Reviews, vol. 115, no. 19, pp. 1501-1587, 2015.
R. M. Bishop, “Entropy changes for chemical systems,” Journal of Chemical Education, vol. 94, no. 2, pp. 184-189, 2017.
F. A. Carey and R. J. Sundberg, Advanced Organic Chemistry, Part A: Structure and Mechanisms, Springer, New York, 2014.
M. D. Green and J. R. Rinehart, Environmental Chemistry and Organic Chemistry, Wiley, New York, 2020.
V. Vlasov, “Activation parameter changes as a mechanistic tool in SN2 reactions in solution,” European Journal of Chemistry, vol. 6, no. 2, pp. 225-236, 2015. https://doi.org/10.5155/eurjchem.6.2.225-236.1246.
F. Ruff and Ö. Farkas, “Concerted SN2 mechanism for the hydrolysis of acid chlorides: Comparisons of reactivities calculated by the density functional theory with experimental data,” Journal of Physical Organic Chemistry, vol. 24, no. 6, pp. 480-491, 2010. https://doi.org/10.1002/poc.1790.
J. Handgraaf, J. Reek, and E. Meijer, “Iridium(I) versus ruthenium(II): A computational study of the transition metal catalyzed transfer hydrogenation of ketones,” Organometallics, vol. 22, no. 15, pp. 3150-3157, 2003. https://doi.org/10.1021/om030104t.
C. Peng, J. Kong, F. Seeliger, and K. Matyjaszewski, “Mechanism of halogen exchange in ATRP,” Macromolecules, vol. 44, no. 19, pp. 7546–7557, 2011. https://doi.org/10.1021/ma201035u.
J. Mohrig, “Stereochemistry of 1,2-elimination and proton-transfer reactions: Toward a unified understanding,” Accounts of Chemical Research, vol. 46, no. 7, pp. 1407–1416, 2013. https://doi.org/10.1021/ar300258d.
S. Nettey, C. Swift, R. Joviliano, D. Oliveira, and S. Gronert, “The impact of substituents on the transition states of SN2 and E2 reactions in aliphatic and vinylic systems: Remarkably facile vinylic eliminations,” Journal of the American Chemical Society, vol. 134, no. 22, pp. 9303–9310, 2012. https://doi.org/10.1021/ja301557a.
Y. Kim, J. Mohrig, and D. Truhlar, “Free-energy surfaces for liquid-phase reactions and their use to study the border between concerted and nonconcerted α,β-elimination reactions of esters and thioesters,” Journal of the American Chemical Society, vol. 132, no. 32, pp. 11071–11082, 2010. https://doi.org/10.1021/ja101104q.
O. Diels and K. Alder, “Die optische Aktivität der Diels-Alder-Reaktion,” Die Naturwissenschaften, vol. 16, no. 2, pp. 641–643, 1928.
L. G. López, H. F. Pérez-Peralta, and J. J. Rodríguez, “Entropy considerations in the Diels-Alder reaction,” Journal of Molecular Modeling, vol. 26, no. 4, p. 90, 2020.
J. E. Baldwin, “The Diels-Alder reaction,” The Chemical Society Reviews, vol. 5, no. 2, pp. 173–187, 1976.
B. Chen, J. Zhang, W. Xu, S. Yan, and X. Zhu, “Thermodynamic and kinetic studies of mononuclear non-heme high-valent (FeO)2+ complexes,” ACS Omega, vol. 10, no. 4, pp. 3718–3728, 2025. https://doi.org/10.1021/acsomega.4c08847.
Y. Peng, “Universal relation between thermodynamic driving force and one-way fluxes in a nonequilibrium chemical reaction with complex mechanism,” arXiv preprint, 2019. https://doi.org/10.48550/arxiv.1911.11956.
T. Yıldırım, “Trends in PhD theses in Turkish chemistry education (1999–2019),” Eurasian Journal of Educational Research, vol. 20, no. 89, pp. 1–40, 2020. https://doi.org/10.14689/ejer.2020.89.10.
P. Mahaffy, S. Matlin, J. Whalen, and T. Holme, “Integrating the molecular basis of sustainability into general chemistry through systems thinking,” Journal of Chemical Education, vol. 96, no. 12, pp. 2730–2741, 2019. https://doi.org/10.1021/acs.jchemed.9b00390.
Author Biography
Jawad Alzeer, Palestine Polytechnic University
License
Copyright (c) 2025 Jawad Alzeer

This work is licensed under a Creative Commons Attribution 4.0 International License.
The following terms apply to authors who publish in this journal:
1. Authors retain copyright and grant the journal first publication rights, with the work simultaneously licensed under a Creative Commons Attribution License 4.0 International License (CC-BY License) that allows others to share the work with an acknowledgment of the work's authorship and first publication in this journal.
2. Authors may enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., posting it to an institutional repository or publishing it in a book), acknowledging its initial publication in this journal.
3. Before and during the submission process, authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website), as this can lead to productive exchanges as well as earlier and greater citation of published work (See The Effect of Open Access).