The Structural Details of Aspirin Molecules and Crystals

Author(s): Ana Maria Toader, Snezana D. Zarić, Christina M. Zalaru, Marilena Ferbinteanu*

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 1 , 2020

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We revisit, in the key of structural chemistry, one of the most known and important drugs: the aspirin. Although apparently simple, the factors determining the molecular structure and supramolecular association in crystals are not trivial. We addressed the problem from experimental and theoretical sides, considering issues from X-ray measurements and results of first-principle reconstruction of molecule and lattices by ab initio calculations. Some puzzling problems can give headaches to specialists and intrigue the general public. Thus, the reported polymorphism of aspirin is disputed, a so-called form II being alleged as a result of misinterpretation. At the same time, were presented evidences that the structure of common form I can be disrupted by domains where the regular packing is changed to the pattern of form II. The problems appear even at the level of independent molecule: the most stable conformation computed by various techniques of electronic structure differs from those encountered in crystals. Because the energy difference between the related conformational isomers (computed as most stable vs. the experimental structure) is small, about 1 kcal/mol, comprised in the error bars of used methods, the unresting question is whether the modelling is imprecise, or the supramolecular factors are mutating the conformational preferences. By a detective following of the issue, the intermolecular effects were made responsible for the conformation of the molecule in crystal. The presented problems were gathered from literature results, debates, glued with modelling and analysis redone by ourselves, in order to secure the unitary view of the considered prototypic topic.

Keywords: Aspirin, molecular structure, polymorphism, supramolecular structure, intermolecular effects, computational modelling.

Lehn, J.M. Perspectives in supramolecular chemistry-from molecular recognition towards molecular information processing and self-organization. Angew. Chem. Int. Ed. Engl., 1990, 29(11), 1304-1319.
Lehn, J.M. Supramolecular chemistry. Science, 1993, 260(5115), 1762-1763.
[] [PMID: 8511582]
Rowan, S.J.; Cantrill, S.J.; Cousins, G.R.L.; Sanders, J.K.M.; Stoddart, J.F. Dynamic covalent chemistry. Angew. Chem. Int. Ed. Engl., 2002, 41(6), 898-952.
[ 6<898:AID-ANIE898>3.0.CO;2-E] [PMID: 12491278]
Jeffrey, G.A. An Introduction to Hydrogen Bonding (Topics in Physical Chemistry); Oxford University Press: New York, 1997.
Desiraju, G.; Steiner, T. The Weak Hydrogen Bond.Structural Chemistry and Biology; Oxford University Press: Oxford, 2001.
Rowland, R.S.; Taylor, R. Intermolecular nonbonded contact distances in organic crystal structures: comparison with distances expected from van der waals radii. J. Phys. Chem., 1996, 100(18), 7384-7391.
Steiner, T.; Desiraju, G.R. Distinction between the weak hydrogen bond and the van der Waals interaction. Chem. Commun. (Camb.), 1998, 891-892.
Desiraju, G.R. Supramolecular synthons in crystal engineering-a new organic synthesis. Angew. Chem. Int. Ed. Engl., 1995, 34(21), 2311-2327.
Desiraju, G.R. Crystal engineering: a holistic view. Angew. Chem. Int. Ed. Engl., 2007, 46(44), 8342-8356.
[] [PMID: 17902079]
Webber, M.J.; Appel, E.A.; Meijer, E.W.; Langer, R. Supramolecular biomaterials. Nat. Mater., 2016, 15(1), 13-26.
[] [PMID: 26681596]
Bertrand, N.; Gauthier, M.A.; Bouvet, C.; Moreau, P.; Petitjean, A.; Leroux, J.C.; Leblond, J. New pharmaceutical applications for macromolecular binders. J. Control. Release, 2011, 155(2), 200-210.
[] [PMID: 21571017]
Leach, A.R. Molecular modelling: principles and applications, 2nd ed; Prentice Hall: Englewood Cliffs, N.J., 2001.
Massa, W. Crystal Structure Determination; Springer -Verlag: Berlin, 2004.
Usón, I.; Sheldrick, G.M. Advances in direct methods for protein crystallography. Curr. Opin. Struct. Biol., 1999, 9(5), 643-648.
[] [PMID: 10508770]
Ducruix, A.; Giegé, R. Crystallization of Nucleic Acids and Proteins: A Practical Approach, 2nd ed; Oxford University Press: Oxford, 1999.
Hanson, B.L.; Harp, J.M.; Bunick, G.J. The well-tempered protein crystal: annealing macromolecular crystals. Methods Enzymol., 2003, 368, 217-235.
[] [PMID: 14674276]
Rupp, B. Biomolecular Crystallography: Principles, Practice and Application to Structural Biology; Rupp, , B., Ed.; Garland Science: New York, 2009.
Hansch, C.; Kurup, A.; Garg, R.; Gao, H. Chem-bioinformatics and QSAR: a review of QSAR lacking positive hydrophobic terms. Chem. Rev., 2001, 101(3), 619-672.
[] [PMID: 11712499]
Selassie, C.D. Burger’s medicinal Chemistry and Drug Discovery, 6th ed; Abraham, D.J., Ed.; Wiley New York, 2003, Vol. 1, pp. 1-48.
Allinger, N.L.; Burkert, U. Molecular Mechanics; American Chemical Society Publication: Washington, DC, 1982.
Mackerell, A.D. Jr. Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem., 2004, 25(13), 1584-1604.
[] [PMID: 15264253]
Becker, O.M. Computational biochemistry and biophysics; Marcel Dekker, Inc.: New York, 2001.
Koch, W.; Holthausen, M.C. A Chemist’s Guide to Density Functional Theory; Wiley-VCH Verlag GmbH: Weinheim, 2001.
Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A Gen. Phys., 1988, 38(6), 3098-3100.
[] [PMID: 9900728]
Lee, C.; Yang, W.; Parr, R.G. Development of the colle-salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.
[] [PMID: 9944570]
Van Lenthe, E.; Baerends, E.J. Optimized Slater-type basis sets for the elements 1-118. J. Comput. Chem., 2003, 24(9), 1142-1156.
[] [PMID: 12759913]
Hehre, W.J.; Stewart, R.F.; Pople, J.A. Self-consistent molecular orbital methods. 1. Use of Gaussian expansions of Slater-type atomic orbitals. J. Chem. Phys., 1969, 51, 2657-2664.
Vane, J.R.; Bottling, R.M. Aspirin and Other Salicylates; Chapman and Hall Medical: London, 1992.
Wheatley, P.J. The crystal and molecular structure of aspirin. J. Chem. Soc., 1964, 6036-6048.
Kim, Y.; Machida, K.; Taga, T.; Osaki, K. Structure redetermination and packing analysis of aspirin crystal. Chem. Pharm. Bull. (Tokyo), 1985, 33(7), 2641-2647.
[] [PMID: 4085037]
Bond, A.D.; Boese, R.; Desiraju, G.R. On the polymorphism of aspirin: crystalline aspirin as intergrowths of two “polymorphic” domains. Angew. Chem. Int. Ed. Engl., 2007, 46(4), 618-622.
[] [PMID: 17139692]
Bauer, J.D.; Haussuhl, E.; Winkler, B.; Arbeck, D.; Milman, V.; Robertson, S. Elastic properties, thermal expansion, and polymorphism of acetylsalicylic acid cryst. Growth Des., 2010, 10(7), 3132-3140.
Chan, E.J.; Welberry, T.R.; Heerdegen, A.P.; Goossens, D.J. Diffuse scattering study of aspirin forms (I) and (II). Acta Crystallogr. B, 2010, 66(Pt 6), 696-707.
[] [PMID: 21099031]
Varughese, S.; Kiran, M.S.R.N.; Solanko, K.A.; Bond, A.D.; Ramamurty, U.; Desiraju, G.R. Interaction anisotropy and shear instability of aspirin polymorphs established by nanoindentation. Chem. Sci. (Camb.), 2011, 2, 2236-2242.
Arputharaj, D.S.; Hathwar, V.R.; Row, T.N.G.; Kumaradhas, P. Topological electron density analysis and electrostatic properties of aspirin: an experimental and theoretical study. Cryst. Growth Des., 2012, 12(9), 4357-43.
Wilson, C.C. Interesting proton behaviour in molecular structures. Variable temperature neutron diffraction and ab initio study of acetylsalicylic acid: characterising librational motions and comparing protons in different hydrogen bonding potentials. New J. Chem., 2002, 26(12), 1733-1739.
Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: New York, 2002.
Peverati, R.; Truhlar, D.G. Quest for a universal density functional: the accuracy of density functionals across a broad spectrum of databases in chemistry and physics. Philos. Trans.- Royal Soc., Math. Phys. Eng. Sci., 2014, 372(2011) 20120476
[] [PMID: 24516178]
Yu, L.; Stephenson, G.A.; Mitchell, C.A.; Bunnell, C.A.; Snorek, S.V.; Bowyer, J.J.; Borchardt, T.B.; Stowell, J.G.; Byrn, S.R. Thermochemistry and conformational polymorphism of a hexamorphic crystal system. J. Am. Chem. Soc., 2000, 122(4), 585-591.
Vishweshwar, P.; McMahon, J.A.; Oliveira, M.; Peterson, M.L.; Zaworotko, M.J. The predictably elusive form II of aspirin. J. Am. Chem. Soc., 2005, 127(48), 16802-16803.
[] [PMID: 16316223]
Desiraju, G.R. The C-H-O hydrogen bond in crystals: what is it? Acc. Chem. Res., 1991, 24(10), 290-296.
Desiraju, G.R. The C-h···o hydrogen bond: structural implications and supramolecular design. Acc. Chem. Res., 1996, 29(9), 441-449.
[] [PMID: 23618410]
Veljković, D.Ž.; Janjić, G.V.; Zarić, S.D. Are the C-H•••O interactions linear? Case of the aromatic CH donors. CrystEngComm, 2011, 13, 5005-5010.
Nishioa, M. CH/π hydrogen bonds in crystals. CrystEngComm, 2004, 6, 130-158.
Stojanović, S.Đ.; Medaković, V.B.; Predović, G.; Beljanski, M.; Zarić, S.D. XH/pi interactions with the pi system of porphyrin ring in porphyrin-containing proteins. J. Biol. Inorg. Chem., 2007, 12(7), 1063-1071.
[] [PMID: 17659366]
Bond, A.D.; Boese, R.; Desiraju, G.R. On the polymorphism of aspirin. Angew. Chem. Int. Ed. Engl., 2007, 46(4), 615-617.
[] [PMID: 17131435]
D’Ascenzo, L.; Auffinger, P. A comprehensive classification and nomenclature of carboxyl-carboxyl(ate) supramolecular motifs and related catemers: implications for biomolecular systems. Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater., 2015, 71(Pt 2), 164-175.
[] [PMID: 25827369]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M. Li. X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A. Jr.; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, Ö.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. In: Gaussian 09; Gaussian; Inc.: Wallingford, CT, 2009.
Choudhary, A.; Kamer, K.J.; Raines, R.T. An n→π* interaction in aspirin: implications for structure and reactivity. J. Org. Chem., 2011, 76(19), 7933-7937.
[] [PMID: 21842865]
Reed, A.E.; Curtiss, L.A.; Weinhold, F. Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem. Rev., 1988, 88(6), 899-926.
Bürgi, H.B.; Dunitz, J.D. From crystal statics to chemical dynamics. Acc. Chem. Res., 1983, 16(5), 153-161.
Glaser, R. Aspirin. An ab initio quantum-mechanical study of conformational preferences and of neighboring group interactions. J. Org. Chem., 2001, 66(3), 771-779.
[] [PMID: 11430095]
Yurtsever, Z.; Erman, B.; Yurtsever, E. Competitive hydrogen bonding in aspirin-aspirin and aspirin-leucine interactions. Turk. J. Chem., 2012, 36, 383-395.
Møller, C.; Plesset, M.S. Note on an approximation treatment for many-electron systems. Phys. Rev., 1934, 46(7), 618-622.
Frisch, M.J.; Head-Gordon, M.; Pople, J.A. Direct MP2 gradient method. Chem. Phys. Lett., 1990, 166, 275-280.
Cížek, J. On the correlation problem in atomic and molecular systems. calculation of wavefunction components in ursell-type expansion using quantum-field theoretical methods. J. Chem. Phys., 1966, 45(11), 4256.
Stanton, J.F. Why CCSD(T) works: a different perspective. Chem. Phys. Lett., 1997, 281(1-3), 130-134.
Dunning, T.H. Jr. Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen. J. Chem. Phys., 1989, 90, 1007-1023.
Ouvrard, C.; Price, S.L. Toward crystal structure prediction for conformationally flexible molecules: the headaches illustrated by aspirin. Cryst. Growth Des., 2004, 4(6), 1119-1127.
Dunitz, J.D. Are crystal structures predictable? Chem. Commun. (Camb.), 2003, (5), 545-548.
[] [PMID: 12669825]
Beyer, T.; Lewis, T.; Price, S.L. Which organic crystal structures are predictable by lattice energy minimisation? CrystEngComm, 2001, 3(44), 178-212.
Lommerse, J.P.M.; Motherwell, W.D.S.; Ammon, H.L.; Dunitz, J.D.; Gavezzotti, A.; Hofmann, D.W.M.; Leusen, F.J.J.; Mooij, W.T.M.; Price, S.L.; Schweizer, B.; Schmidt, M.U.; Verwer, P.; Williams, D.E.; Williams, D.E. van Eijck BP. A test of crystal structure prediction of small organic molecules. Acta Crystallogr. B, 2000, 56(Pt 4), 697-714.
[] [PMID: 10944263]
Motherwell, W.D.S.; Ammon, H.L.; Dunitz, J.D.; Dzyabchenko, A.; Erk, P.; Gavezzotti, A.; Hofmann, D.W.M.; Leusen, F.J.J.; Lommerse, J.P.M.; Mooij, W.T.M.; Price, S.L.; Scheraga, H.; Schweizer, B.; Schmidt, M.U.; van Eijck, B.P.; Verwer, P.; Williams, D.E. Crystal structure prediction of small organic molecules: a second blind test. Acta Crystallogr. B, 2002, 58(Pt 4), 647-661.
[] [PMID: 12149555]
Verwer, P.; Leusen, F.J.J. Computer Simulation to Predict Possible Crystal Polymorphs; Wiley-VCH: New York, 1998, Vol. 12, pp. 327-365.
Brodersen, S.; Wilke, S.; Leusen, F.J.J.; Engel, G. A study of different approaches to the electrostatic interaction in force field methods for organic crystals. Phys. Chem. Chem. Phys., 2003, 5(21), 4923-4931.
Mayo, S.L.; Olafson, B.D.; Goddard, W.A. DREIDING: a generic force field for molecular simulations. J. Phys. Chem., 1990, 94(26), 8897-8909.
Payne, R.S.; Rowe, R.C.; Roberts, R.J.; Charlton, M.H.; Docherty, R. Potential polymorphs of aspirin. J. Comput. Chem., 1999, 20(2), 262-273.
Mooij, W.T.M.; van Eijck, B.P.; Kroon, J. Ab initio crystal structure predictions for flexible hydrogen-bonded molecules. J. Am. Chem. Soc., 2000, 122(4), 3500-3505.
van Eijck, B.P. Ab initio crystal structure predictions for flexible hydrogen-bonded molecules. Part II. Accurate energy minimization. J. Comput. Chem., 2001, 22(8), 805-815.
Allen, F.H.; Harris, S.E.; Taylor, R. Comparison of conformer distributions in the crystalline state with conformational energies calculated by ab initio techniques. J. Comput. Aided Mol. Des., 1996, 10(3), 247-254.
[] [PMID: 8808740]
Holden, J.R.; Du, Z.Y.; Ammon, H.L. Prediction of possible crystal structures for C-, H-, N-, O-, and F-containing organic compounds. J. Comput. Chem., 1993, 14(4), 422-437.
ADF2010. SCM, Theoretical Chemistry, Vrije Universiteit, Amsterdam, The Netherlands. Available at:.
te Velde, G.; Bickelhaupt, F.M.; Baerends, E.J.; Guerra, C.F.; van Gisbergen, S.J.A.; Snijders, J.G.; Ziegler, T. Cemistry with ADF. J. Comput. Chem., 2001, 22(9), 931-967.
Bickelhaupt, F.M.; Baerends, E.J. Reviews of Computational Chemistry, Boyd, D.B; Lipkowitz, K.B., Ed.; Wiley-VCH: New York, 2000, Vol. 15, pp. 1-86.
Wilson, C.C. Hydrogen atoms in acetylsalicylic acid (Aspirin): the librating methyl group and probing the potential well in the hydrogen-bonded dimer. Chem. Phys. Lett., 2001, 335(1-2), 57-63.
Cabezas, C.; Alonso, J.L.; López, J.C.; Mata, S. Unveiling the shape of aspirin in the gas phase. Angew. Chem. Int. Ed. Engl., 2012, 51(6), 1375-1378.
[] [PMID: 22223259]

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Year: 2020
Published on: 18 February, 2020
Page: [99 - 120]
Pages: 22
DOI: 10.2174/0929867325666181031132823
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