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The Relationship Between Molecular Symmetry and Physicochemical Properties Involving Boiling and Melting of Organic Compounds

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Abstract

Objective and Methods

The reliable estimation of phase transition physicochemical properties such as boiling and melting points can be valuable when designing compounds with desired physicochemical properties. This study explores the role of external rotational symmetry in determining boiling and melting points of select organic compounds. Using experimental data from the literature, the entropies of boiling and fusion were obtained for 541 compounds. The statistical significance of external rotational symmetry number on entropies of phase change was determined by using multiple linear regression. In addition, a series of aliphatic hydrocarbons, polysubstituted benzenes, and di-substituted napthalenes are used as examples to demonstrate the role of external symmetry on transition temperature.

Results

The results reveal that symmetry is not well correlated with boiling point but is statistically significant in melting point.

Conclusion

The lack of correlation between the boiling point and the symmetry number reflects the fact that molecules have a high degree of rotational freedom in both the liquid and the vapor. On the other hand, the strong relationship between symmetry and melting point reflects the fact that molecules are rotationally restricted in the crystal but not in the liquid. Since the symmetry number is equal to the number of ways that the molecule can be properly oriented for incorporation into the crystal lattice, it is a significant determinant of the melting point.

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Data Availability

The database created for this current study is available from the corresponding author on reasonable request.

References

  1. Dearden JC. Quantitative structure-property relationships for prediction of boiling point, vapor pressure, and melting point. Environ Toxicol Chem. 2003;22(8):1696–709.

    Article  CAS  PubMed  Google Scholar 

  2. Sepassi K, Yalkowsky SH. Simplified estimation of the Octanol−Air partition coefficient. Ind Eng Chem Res. 2007;46(7):2220–3.

    Article  CAS  Google Scholar 

  3. Ran Y, Yalkowsky SH. Prediction of drug solubility by the general solubility equation (GSE). J Chem Inf Comput Sci. 2001;41(2):354–7.

    Article  CAS  PubMed  Google Scholar 

  4. Wyttenbach N, Niederquell A, Kuentz M. Machine estimation of drug melting properties and influence on solubility prediction. Mol Pharm. 2020;17(7):2660–71.

    Article  CAS  PubMed  Google Scholar 

  5. Myrdal PB, Krzyzaniak JF, Yalkowsky SH. Modified trouton’s rule for predicting the entropy of boiling. Ind Eng Chem Res. 1996;35(5):1788–92.

    Article  CAS  Google Scholar 

  6. Wyttenbach N, Kirchmeyer W, Alsenz J, Kuentz M. Theoretical considerations of the Prigogine-Defay ratio with regard to the glass-forming ability of drugs from undercooled melts. Mol Pharm. 2016;13(1):241–50.

    Article  CAS  PubMed  Google Scholar 

  7. Stein SE, Brown RL. Estimation of normal boiling points from group contributions. J Chem Inf Comput Sci. 1994;34(3):581–7.

    Article  CAS  Google Scholar 

  8. Kolska Z, Zabransky M, Randov A. Group contribution methods for estimation of selected physico-chemical properties of organic compounds. In: Morales-Rodriguez R, editor. Thermodynamics - Fundamentals and Its Application in Science. London: InTech; 2012.

    Google Scholar 

  9. Constantinou L, Gani R. New group contribution method for estimating properties of pure compounds. AIChE J. 1994;40(10):1697–710.

    Article  CAS  Google Scholar 

  10. Joback KG, Reid RC. Estimation of pure-component properties from group-contributions. Chem Eng Commun. 1987;57(1–6):233–43.

    Article  CAS  Google Scholar 

  11. Ma P, Zhao X. Modified group contribution method for predicting the entropy of vaporization at the normal boiling point. Ind Eng Chem Res. 1993;32(12):3180–3.

    Article  CAS  Google Scholar 

  12. Hoshino D, Nagahama K, Hirata M. Prediction of the entropy of vaporization at the normal boiling point by the group contribution method. Ind Eng Chem Fundam. 1983;22(4):430–3.

    Article  CAS  Google Scholar 

  13. Chickos JS, Acree WE Jr. Total phase change entropies and enthalpies. An update on fusion enthalpies and their estimation. Thermochim Acta. 2009;495(1–2):5–13.

    Article  CAS  Google Scholar 

  14. Krzyzaniak JF, Myrdal PB, Simamora P, Yalkowsky SH. Boiling Point and melting point prediction for aliphatic, non-hydrogen-bonding compounds. Ind Eng Chem Res. 1995;34(7):2530–5.

    Article  CAS  Google Scholar 

  15. Dannenfelser R-M, Yalkowsky SH. Estimation of entropy of melting from molecular structure: a non-group contribution method. Ind Eng Chem Res. 1996;35(4):1483–6.

    Article  CAS  Google Scholar 

  16. Lian B, Yalkowsky SH. Molecular geometry and melting point related properties. Ind Eng Chem Res. 2012;51(51):16750–4.

    Article  CAS  Google Scholar 

  17. Lian B, Yalkowsky SH. Unified physicochemical property estimation relationships (UPPER). J Pharm Sci. 2014;103(9):2710–23.

    Article  CAS  PubMed  Google Scholar 

  18. Admire B, Lian B, Yalkowsky SH. Estimating the physicochemical properties of polyhalogenated aromatic and aliphatic compounds using UPPER: part 1. Boiling point and melting point. Chemosphere. 2015;119:1436–40.

    Article  CAS  PubMed  Google Scholar 

  19. Alantary D, Yalkowsky SH. Estimating the physicochemical properties of polysubstituted aromatic compounds using UPPER. J Pharm Sci. 2018;107(1):297–306.

    Article  CAS  PubMed  Google Scholar 

  20. Bondi A. A correlation of the entropy of fusion of molecular crystals with molecular structure. Chem Rev. 1967;67(5):565–80.

    Article  CAS  Google Scholar 

  21. Weiss A. Arnold Bondi: Physical properties of molecular crystals, liquids, and glasses. John Wiley and Sons, New York, London, Sydney 1968. 502 Seiten. Preis: 175 s. 1968;72:1242–3.

  22. Trouton F IV. On molecular latent heat. Lond Edinb Dublin Philos Mag J Sci. 1884;18(110):54–7.

    Article  Google Scholar 

  23. Walden P. Über die Schmelzwärme, spezifische Kohäsion und Molekulargrösse bei der Schmelztemperatur. Z Elektrotech Elektrochem. 1908;14(43):713–24.

    CAS  Google Scholar 

  24. Wunderlich B. The detection of conformational disorder by thermal analysis. Pure Appl Chem. 1989;61(8):1347–51.

    Article  CAS  Google Scholar 

  25. Johnson JLH, Yalkowsky SH. Two new parameters for predicting the entropy of melting: Eccentricity (ε) and spirality (μ). Ind Eng Chem Res. 2005;44(19):7559–66.

    Article  CAS  Google Scholar 

  26. Yalkowsky SH, Alantary D. Estimation of melting points of organics. J Pharm Sci. 2018;107(5):1211–27.

    Article  CAS  PubMed  Google Scholar 

  27. Chickos JS, Hesse DG, Liebman JF. Estimating vaporization enthalpies of organic compounds with single and multiple substitution. J Org Chem. 1989;54(22):5250–6.

    Article  CAS  Google Scholar 

  28. Sanghvi R, Yalkowsky SH. Estimation of the normal Boiling Point of organic compounds. Ind Eng Chem Res. 2006;45(8):2856–61.

    Article  CAS  Google Scholar 

  29. Martin E, Yalkowsky SH, Wells JE. Fusion of disubstituted benzenes. J Pharm Sci. 1979;68(5):565–8.

    Article  CAS  PubMed  Google Scholar 

  30. Yalkowsky SH. Carnelley’s rule and the prediction of melting point. J Pharm Sci. 2014;103(9):2629–34.

    Article  CAS  PubMed  Google Scholar 

  31. Tsakanikas PD, Yalkowsky SH. Estimation of melting point of flexible molecules: Aliphatic hydrocarbons. Toxicol Environ Chem. 1988;17(1):19–33.

    Article  CAS  Google Scholar 

  32. Chan L, Morris GM, Hutchison GR. Understanding conformational entropy in small molecules. J Chem Theory Comput. 2021;17(4):2099–106.

    Article  CAS  PubMed  Google Scholar 

  33. Wu Y, Brooks CL 3rd. Flexible CDOCKER: Hybrid searching algorithm and scoring function with side chain conformational entropy. J Chem Inf Model. 2021;61(11):5535–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wicker JGP, Cooper RI. Will it crystallise? Predicting crystallinity of molecular materials. CrystEngComm. 2015;17(9):1927–34.

    Article  CAS  Google Scholar 

  35. Wei J. Molecular symmetry, rotational entropy, and elevated melting points. Ind Eng Chem Res. 1999;38(12):5019–27.

    Article  CAS  Google Scholar 

  36. Carnelley TXIII. Chemical symmetry, or the influence of atomic arrangement on the physical properties of compounds. Lond Edinb Dublin Philos Mag J Sci. 1882;13(79):112–30.

    Article  Google Scholar 

  37. Brown RJC, Brown RFC. Melting point and molecular symmetry. J Chem Educ. 2000;77(6):724.

    Article  CAS  Google Scholar 

  38. Butler PH. Point group symmetry applications: Methods and tables. 1981st ed. New York: Springer; 2012.

    Google Scholar 

  39. Rumble JR. CRC Handbook of Chemistry and Physics. 101st ed. CRC Press/Taylor & Francis; 2020.

    Google Scholar 

  40. Wei J. Boiling points and melting points of chlorofluorocarbons. Ind Eng Chem Res. 2000;39(8):3116–9.

    Article  CAS  Google Scholar 

  41. Gavezzotti A. Molecular symmetry, melting temperatures and melting enthalpies of substituted benzenes and naphthalenes. J Chem Soc Perkin Trans 2. 1995;(7):1399–404.

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Acknowledgements

The authors gratefully acknowledge Honghu Luo for his help with construction of the database and data analysis. D.H.L. acknowledges Great Minds in STEM (GMIS) and The University of Arizona Graduate College for their funding and support. D.H.L. acknowledges the technical support from Dr. Patrick Walters, Dr. Carlos Lizarraga, Dr. Greg Chism, and the educators at the University of Arizona Data Science Institute and Cyverse.

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Authors and Affiliations

  1. Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA

    David Humberto Lopez & Samuel Hyman Yalkowsky

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  1. David Humberto Lopez
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  2. Samuel Hyman Yalkowsky
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Correspondence to David Humberto Lopez.

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Lopez, D.H., Yalkowsky, S.H. The Relationship Between Molecular Symmetry and Physicochemical Properties Involving Boiling and Melting of Organic Compounds. Pharm Res 40, 2801–2815 (2023). https://doi.org/10.1007/s11095-023-03576-z

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