Recent Advances in Conformational Analysis and Spectral techniques, Compiled with Quantum Mechanical Calculations for Some Compounds

Currently, quantum mechanical (QM) calculations are essential to support diverse chemical investigations by predicting electronic structures, reaction energies, and spectroscopic properties. Precise analysis of molecular conformations enables a comprehensive understanding of the structural, physicochemical properties of molecular systems. This decade has witnessed significant advancements in computational chemistry and spectroscopic techniques that have revolutionized conformational analysis, providing more accurate structural elucidation. Combination of QM calculations with experimental spectrum data (IR, NMR, UV-Vis, and Raman) has markedly improved the precision of conformational analysis and interpretation of spectral data. This review highlights significant advancements in conformational analysis, spectroscopic techniques, and their synergistic application with QM calculations, particularly density functional theory (DFT). The review presents case studies of chemically and biologically relevant molecules to illustrate the effectiveness of integrating experimental spectra and computational methods for conformational analysis and structural elucidation. This review also highlights the current limitations and proposes suggestions for future methodological improvements.

[1] B. Dittrich, J. Lübben, S. Mebs, A. Wagner, P. Luger, and R. Flaig, “Accurate Bond Lengths to Hydrogen Atoms from Single?Crystal X?ray Diffraction by Including Estimated Hydrogen ADPs and Comparison to Neutron and QM/MM Benchmarks,” Chemistry – A European Journal, vol. 23, no. 19, pp. 4605–4614, Mar. 2017, doi: 10.1002/chem.201604705.

[2] M. Monti, L. Biancorosso, and E. Coccia, “Time-Resolved Circular Dichroism in Molecules: Experimental and Theoretical Advances,” Molecules, vol. 29, no. 17, p. 4049, Aug. 2024, doi: 10.3390/molecules29174049.

[3] G. J. Sharman, “Conformation and Stereochemical Analysis of Drug Molecules,” eMagRes, pp. 105–116, Mar. 2015, doi: 10.1002/9780470034590.emrstm1392.

[4] S. G. Podkolzin, G. B. Fitzgerald, and B. E. Koel, “Combining Vibrational Spectroscopies with Quantum Chemical Calculations for Molecular-Level Understanding of Reaction Mechanisms on Catalytic Surfaces,” Applications of Molecular Modeling to Challenges in Clean Energy, pp. 153–176, Jan. 2013, doi: 10.1021/bk-2013-1133.ch009.

[5] S. Maeda, Y. Harabuchi, Y. Ono, T. Taketsugu, and K. Morokuma, “Intrinsic reaction coordinate: Calculation, bifurcation, and automated search,” International Journal of Quantum Chemistry, vol. 115, no. 5, pp. 258–269, Sep. 2014, doi: 10.1002/qua.24757.

[6] J. Anan, E. Adu Fosu, C. Obuah, M. Kojo Ainooson, A. Aniagyei, L. Hamenu, A. Oppong, A. Muller, “A DFT and TD-DFT studies of the photosensitizing capabilities of thiophene-based dyes,” Computational and Theoretical Chemistry, vol. 1237, p. 114633, Jul. 2024, doi: 10.1016/j.comptc.2024.114633.

[7] H. Etabti, M. Er-Rajy, A. Fitri, A. Ammasi, M. Shkir, A.T. Benjelloun, M. Benzakour, M. McHarfi, “Computational Analysis of Triazolone-Based Dyes in DSSCs: Exploring Acceptor Terminal for Enhanced Photovoltaic Performance,” Journal of Fluorescence, vol. 35, no. 10, pp. 9333–9357, Mar. 2025, doi: 10.1007/s10895-025-04231-z.

[8] R. Diana, U. Caruso, F. S. Gentile, L. Di Costanzo, P. Musto, and B. Panunzi, “Structural feature of thermo-induced fluorochromism in a 1D zinc coordination polymer. A cross-analysis by PL and FTIR spectroscopy, and DFT formalism,” Dyes and Pigments, vol. 202, p. 110247, Jun. 2022, doi: 10.1016/j.dyepig.2022.110247.

[9] F. H. Allen, “The Cambridge Structural Database: a quarter of a million crystal structures and rising,” Acta Crystallographica Section B Structural Science, vol. 58, no. 3, pp. 380–388, May 2002, doi: 10.1107/s0108768102003890.

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[12] J. CAVANAGH, W. J. FAIRBROTHER, A. G. PALMER, M. RANCE, and N. J. SKELTON, “SEQUENTIAL ASSIGNMENT, STRUCTURE DETERMINATION, AND OTHER APPLICATIONS,” Protein NMR Spectroscopy, pp. 781–817, 2007, doi: 10.1016/b978-012164491-8/50012-9.

[13] B. Smith, “Spectral Interpretation Aids,” Infrared Spectral Interpretation, pp. 195–205, Feb. 2018, doi: 10.1201/9780203750841-9.

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[15] T. Bally and P. R. Rablen, “Quantum-Chemical Simulation of ¹H NMR Spectra. 2. Comparison of DFT-Based Procedures for Computing Proton–Proton Coupling Constants in Organic Molecules,” The Journal of Organic Chemistry, vol. 76, no. 12, pp. 4818–4830, May 2011, doi: 10.1021/jo200513q.

[16] V. Barone, S. Alessandrini, M. Biczysko, J.R. Cheeseman, D.C. Clary, A.B. McCoy, R.J. Dirisio, F. Neese, M. Melosso, C. Puzzarini, “Computational molecular spectroscopy,” Nature Reviews Methods Primers, vol. 1, no. 1, May 2021, doi: 10.1038/s43586-021-00034-1.

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[18] P. Atkins, J. de Paula, and J. Keeler, “Computational chemistry,” Atkins’ Physical Chemistry, Dec. 2022, doi: 10.1093/hesc/9780198847816.003.0049.

[19] G. Singh and S. Kumar, “Computational Chemistry: Exploring Molecular Properties and Reactivity,” Innovations in Science and Technology: Shaping a Sustainable Future (Vol. 1), pp. 87–97, May 2024, doi: 10.9734/bpi/mono/978-81-973809-6-9/ch8.

[20] J. Hénin, T. Lelièvre, M. R. Shirts, O. Valsson, and L. Delemotte, “Enhanced Sampling Methods for Molecular Dynamics Simulations [Article v1.0],” Living Journal of Computational Molecular Science, vol. 4, no. 1, p. 1583, Dec. 2022, doi: 10.33011/livecoms.4.1.1583.

[21] T. A. Mohamed, I. A. Shaaban, U. A. Soliman, and W. M. Zoghaib, “Computational studies, NMR, Raman and infrared spectral analysis of centrosymmetric (2Z,4Z)-Hexa-2,4-dienedinitrile,” Journal of Theoretical and Computational Chemistry, vol. 18, no. 02, p. 1950011, Mar. 2019, doi: 10.1142/s0219633619500111.

[22] I. A. Shaaban, A. Karoyo, L. D. Wilson, and T. A. Mohamed, “Raman and DRIFT spectra, vibrational assignments and quantum mechanical calculations of centrosymmetric meso -2,3-Dimercaptosuccinic acid,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 183, pp. 275–283, Aug. 2017, doi: 10.1016/j.saa.2017.04.017.

[23] G. Lauro, P. Das, R. Riccio, D. S. Reddy, and G. Bifulco, “DFT/NMR Approach for the Configuration Assignment of Groups of Stereoisomers by the Combination and Comparison of Experimental and Predicted Sets of Data,” The Journal of Organic Chemistry, vol. 85, no. 5, pp. 3297–3306, Jan. 2020, doi: 10.1021/acs.joc.9b03129.

[24] A. M?ndi, J. Wu, and T. Kurt?n, “TDDFT-ECD and DFT-NMR studies of thaigranatins A–E and granatumin L isolated from Xylocarpus granatum” RSC Advances, vol. 10, no. 53, pp. 32216–32224, 2020, doi: 10.1039/d0ra03725g.

[25] M. Habgood, T. James, and A. Heifetz, “Conformational Searching with Quantum Mechanics,” Quantum Mechanics in Drug Discovery, pp. 207–229, 2020, doi: 10.1007/978-1-0716-0282-9_14.

[26] R. Fouad, I. A. Shaaban, T. E. Ali, M. A. Assiri, and S. S. Shenouda, “Co( ii ), Ni( ii ), Cu( ii ) and Cd( ii )-thiocarbonohydrazone complexes: spectroscopic, DFT, thermal, and electrical conductivity studies” RSC Advances, vol. 11, no. 60, pp. 37726–37743, 2021, doi: 10.1039/d1ra06902k.

[27] I. A. Shaaban, T. E. Ali, M. A. Assiri, A. M. Fouda, S. M. Eledfawy, and N. M. Hassanin, “Regioselective cyclization reaction of 2-imino-2H-chromene-3-carboxamide with triethyl phosphonoacetate; a combined spectral and computational studies,” Journal of Molecular Structure, vol. 1199, p. 126935, Jan. 2020, doi: 10.1016/j.molstruc.2019.126935.

[28] S. Bondock, T. Albarqi, I.A. Shaaban, M.M. Abdou, “Novel asymmetrical azines appending 1,3,4-thiadiazole sulfonamide: synthesis, molecular structure analyses, in silico ADME, and cytotoxic effect,” RSC Advances, vol. 13, no. 15, pp. 10353–10366, 2023, doi: 10.1039/d3ra00123g.

[29] F.L.P. Costa, A.C.F. De Albuquerque, R.G. Fiorot, L.M. Li?o, L.H. Martorano, G.V.S. Mota, A.L. Valverde, J.W.M. Carneiro, F.M. Dos Santos Junior, “Structural characterisation of natural products by means of quantum chemical calculations of NMR parameters: new insights,” Organic Chemistry Frontiers, vol. 8, no. 9, pp. 2019–2058, 2021, doi: 10.1039/d1qo00034a.

[30] C. B. Braga and R. Rittner, “Combined Utilization of ¹H NMR, IR, and Theoretical Calculations To Elucidate the Conformational Preferences of Some l-Histidine Derivatives,” The Journal of Physical Chemistry A, vol. 121, no. 3, pp. 729–740, Jan. 2017, doi: 10.1021/acs.jpca.6b12515.

[31] I. A. Shaaban, “Conformational analysis, infrared/Raman spectral assignment, and electronic structural studies of 1,3-dimethyl-2-imidazolidinone using quantum chemical calculations,” Journal of Molecular Structure, vol. 1175, pp. 708–720, Jan. 2019, doi: 10.1016/j.molstruc.2018.08.015.

[32] S. G. Smith and J. M. Goodman, “Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability,” Journal of the American Chemical Society, vol. 132, no. 37, pp. 12946–12959, Aug. 2010, doi: 10.1021/ja105035r.

[33] S. TOYOTA, “Discovery of internal rotation and conformers of 1,2-dichloroethane: the dawn of the concept of conformation,” Proceedings of the Japan Academy, Series B, vol. 100, no. 2, pp. 101–113, Feb. 2024, doi: 10.2183/pjab.100.003.

[34] G. A. Morrison, “Conformational Analysis of Some Alkaloids,” Fortschritte der Chemie Organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products / Progrès dans la Chimie des Substances Organiques Naturelles, pp. 269–317, 1967, doi: 10.1007/978-3-7091-8164-5_9.

[35] V. Dragojlovic, “Conformational analysis of cycloalkanes,” ChemTexts, vol. 1, no. 3, Aug. 2015, doi: 10.1007/s40828-015-0014-0.

[36] S. Hayward, “A Retrospective on the Development of Methods for the Analysis of Protein Conformational Ensembles,” The Protein Journal, vol. 42, no. 3, pp. 181–191, Apr. 2023, doi: 10.1007/s10930-023-10113-9.

[37] Y. Zhou, I. Limbu, M. J. Garson, and E. H. Krenske, “Conformational Sampling in Computational Studies of Natural Products: Why Is It Important?,” Journal of Natural Products, vol. 87, no. 10, pp. 2543–2549, Sep. 2024, doi: 10.1021/acs.jnatprod.4c00852.

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[1] B. Dittrich, J. Lübben, S. Mebs, A. Wagner, P. Luger, and R. Flaig, “Accurate Bond Lengths to Hydrogen Atoms from Single?Crystal X?ray Diffraction by Including Estimated Hydrogen ADPs and Comparison to Neutron and QM/MM Benchmarks,” Chemistry – A European Journal, vol. 23, no. 19, pp. 4605–4614, Mar. 2017, doi: 10.1002/chem.201604705.

[2] M. Monti, L. Biancorosso, and E. Coccia, “Time-Resolved Circular Dichroism in Molecules: Experimental and Theoretical Advances,” Molecules, vol. 29, no. 17, p. 4049, Aug. 2024, doi: 10.3390/molecules29174049.

[3] G. J. Sharman, “Conformation and Stereochemical Analysis of Drug Molecules,” eMagRes, pp. 105–116, Mar. 2015, doi: 10.1002/9780470034590.emrstm1392.

[4] S. G. Podkolzin, G. B. Fitzgerald, and B. E. Koel, “Combining Vibrational Spectroscopies with Quantum Chemical Calculations for Molecular-Level Understanding of Reaction Mechanisms on Catalytic Surfaces,” Applications of Molecular Modeling to Challenges in Clean Energy, pp. 153–176, Jan. 2013, doi: 10.1021/bk-2013-1133.ch009.

[5] S. Maeda, Y. Harabuchi, Y. Ono, T. Taketsugu, and K. Morokuma, “Intrinsic reaction coordinate: Calculation, bifurcation, and automated search,” International Journal of Quantum Chemistry, vol. 115, no. 5, pp. 258–269, Sep. 2014, doi: 10.1002/qua.24757.

[6] J. Anan, E. Adu Fosu, C. Obuah, M. Kojo Ainooson, A. Aniagyei, L. Hamenu, A. Oppong, A. Muller, “A DFT and TD-DFT studies of the photosensitizing capabilities of thiophene-based dyes,” Computational and Theoretical Chemistry, vol. 1237, p. 114633, Jul. 2024, doi: 10.1016/j.comptc.2024.114633.

[7] H. Etabti, M. Er-Rajy, A. Fitri, A. Ammasi, M. Shkir, A.T. Benjelloun, M. Benzakour, M. McHarfi, “Computational Analysis of Triazolone-Based Dyes in DSSCs: Exploring Acceptor Terminal for Enhanced Photovoltaic Performance,” Journal of Fluorescence, vol. 35, no. 10, pp. 9333–9357, Mar. 2025, doi: 10.1007/s10895-025-04231-z.

[8] R. Diana, U. Caruso, F. S. Gentile, L. Di Costanzo, P. Musto, and B. Panunzi, “Structural feature of thermo-induced fluorochromism in a 1D zinc coordination polymer. A cross-analysis by PL and FTIR spectroscopy, and DFT formalism,” Dyes and Pigments, vol. 202, p. 110247, Jun. 2022, doi: 10.1016/j.dyepig.2022.110247.

[9] F. H. Allen, “The Cambridge Structural Database: a quarter of a million crystal structures and rising,” Acta Crystallographica Section B Structural Science, vol. 58, no. 3, pp. 380–388, May 2002, doi: 10.1107/s0108768102003890.

[10] James W. Robinson, Eileen Skelly Frame, George M. Frame II, “Introduction to Spectroscopy,” Undergraduate Instrumental Analysis, pp. 92–143, Jul. 2014, doi: 10.1201/b15921-6.

[11] J. Drenth, Principles of Protein X-Ray Crystallography. Springer New York, 2007. doi: 10.1007/0-387-33746-6.

[12] J. CAVANAGH, W. J. FAIRBROTHER, A. G. PALMER, M. RANCE, and N. J. SKELTON, “SEQUENTIAL ASSIGNMENT, STRUCTURE DETERMINATION, AND OTHER APPLICATIONS,” Protein NMR Spectroscopy, pp. 781–817, 2007, doi: 10.1016/b978-012164491-8/50012-9.

[13] B. Smith, “Spectral Interpretation Aids,” Infrared Spectral Interpretation, pp. 195–205, Feb. 2018, doi: 10.1201/9780203750841-9.

[14] A. D. Becke, “Density-functional thermochemistry. III. The role of exact exchange,” The Journal of Chemical Physics, vol. 98, no. 7, pp. 5648–5652, Apr. 1993, doi: 10.1063/1.464913.

[15] T. Bally and P. R. Rablen, “Quantum-Chemical Simulation of ¹H NMR Spectra. 2. Comparison of DFT-Based Procedures for Computing Proton–Proton Coupling Constants in Organic Molecules,” The Journal of Organic Chemistry, vol. 76, no. 12, pp. 4818–4830, May 2011, doi: 10.1021/jo200513q.

[16] V. Barone, S. Alessandrini, M. Biczysko, J.R. Cheeseman, D.C. Clary, A.B. McCoy, R.J. Dirisio, F. Neese, M. Melosso, C. Puzzarini, “Computational molecular spectroscopy,” Nature Reviews Methods Primers, vol. 1, no. 1, May 2021, doi: 10.1038/s43586-021-00034-1.

[17] J. H. Jensen, “Computational Chemistry,” Jan. 2017, doi: 10.14293/s2199-1006.1.sor-chem.clywqk5.v1.

[18] P. Atkins, J. de Paula, and J. Keeler, “Computational chemistry,” Atkins’ Physical Chemistry, Dec. 2022, doi: 10.1093/hesc/9780198847816.003.0049.

[19] G. Singh and S. Kumar, “Computational Chemistry: Exploring Molecular Properties and Reactivity,” Innovations in Science and Technology: Shaping a Sustainable Future (Vol. 1), pp. 87–97, May 2024, doi: 10.9734/bpi/mono/978-81-973809-6-9/ch8.

[20] J. Hénin, T. Lelièvre, M. R. Shirts, O. Valsson, and L. Delemotte, “Enhanced Sampling Methods for Molecular Dynamics Simulations [Article v1.0],” Living Journal of Computational Molecular Science, vol. 4, no. 1, p. 1583, Dec. 2022, doi: 10.33011/livecoms.4.1.1583.

[21] T. A. Mohamed, I. A. Shaaban, U. A. Soliman, and W. M. Zoghaib, “Computational studies, NMR, Raman and infrared spectral analysis of centrosymmetric (2Z,4Z)-Hexa-2,4-dienedinitrile,” Journal of Theoretical and Computational Chemistry, vol. 18, no. 02, p. 1950011, Mar. 2019, doi: 10.1142/s0219633619500111.

[22] I. A. Shaaban, A. Karoyo, L. D. Wilson, and T. A. Mohamed, “Raman and DRIFT spectra, vibrational assignments and quantum mechanical calculations of centrosymmetric meso -2,3-Dimercaptosuccinic acid,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 183, pp. 275–283, Aug. 2017, doi: 10.1016/j.saa.2017.04.017.

[23] G. Lauro, P. Das, R. Riccio, D. S. Reddy, and G. Bifulco, “DFT/NMR Approach for the Configuration Assignment of Groups of Stereoisomers by the Combination and Comparison of Experimental and Predicted Sets of Data,” The Journal of Organic Chemistry, vol. 85, no. 5, pp. 3297–3306, Jan. 2020, doi: 10.1021/acs.joc.9b03129.

[24] A. M?ndi, J. Wu, and T. Kurt?n, “TDDFT-ECD and DFT-NMR studies of thaigranatins A–E and granatumin L isolated from Xylocarpus granatum” RSC Advances, vol. 10, no. 53, pp. 32216–32224, 2020, doi: 10.1039/d0ra03725g.

[25] M. Habgood, T. James, and A. Heifetz, “Conformational Searching with Quantum Mechanics,” Quantum Mechanics in Drug Discovery, pp. 207–229, 2020, doi: 10.1007/978-1-0716-0282-9_14.

[26] R. Fouad, I. A. Shaaban, T. E. Ali, M. A. Assiri, and S. S. Shenouda, “Co( ii ), Ni( ii ), Cu( ii ) and Cd( ii )-thiocarbonohydrazone complexes: spectroscopic, DFT, thermal, and electrical conductivity studies” RSC Advances, vol. 11, no. 60, pp. 37726–37743, 2021, doi: 10.1039/d1ra06902k.

[27] I. A. Shaaban, T. E. Ali, M. A. Assiri, A. M. Fouda, S. M. Eledfawy, and N. M. Hassanin, “Regioselective cyclization reaction of 2-imino-2H-chromene-3-carboxamide with triethyl phosphonoacetate; a combined spectral and computational studies,” Journal of Molecular Structure, vol. 1199, p. 126935, Jan. 2020, doi: 10.1016/j.molstruc.2019.126935.

[28] S. Bondock, T. Albarqi, I.A. Shaaban, M.M. Abdou, “Novel asymmetrical azines appending 1,3,4-thiadiazole sulfonamide: synthesis, molecular structure analyses, in silico ADME, and cytotoxic effect,” RSC Advances, vol. 13, no. 15, pp. 10353–10366, 2023, doi: 10.1039/d3ra00123g.

[29] F.L.P. Costa, A.C.F. De Albuquerque, R.G. Fiorot, L.M. Li?o, L.H. Martorano, G.V.S. Mota, A.L. Valverde, J.W.M. Carneiro, F.M. Dos Santos Junior, “Structural characterisation of natural products by means of quantum chemical calculations of NMR parameters: new insights,” Organic Chemistry Frontiers, vol. 8, no. 9, pp. 2019–2058, 2021, doi: 10.1039/d1qo00034a.

[30] C. B. Braga and R. Rittner, “Combined Utilization of ¹H NMR, IR, and Theoretical Calculations To Elucidate the Conformational Preferences of Some l-Histidine Derivatives,” The Journal of Physical Chemistry A, vol. 121, no. 3, pp. 729–740, Jan. 2017, doi: 10.1021/acs.jpca.6b12515.

[31] I. A. Shaaban, “Conformational analysis, infrared/Raman spectral assignment, and electronic structural studies of 1,3-dimethyl-2-imidazolidinone using quantum chemical calculations,” Journal of Molecular Structure, vol. 1175, pp. 708–720, Jan. 2019, doi: 10.1016/j.molstruc.2018.08.015.

[32] S. G. Smith and J. M. Goodman, “Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability,” Journal of the American Chemical Society, vol. 132, no. 37, pp. 12946–12959, Aug. 2010, doi: 10.1021/ja105035r.

[33] S. TOYOTA, “Discovery of internal rotation and conformers of 1,2-dichloroethane: the dawn of the concept of conformation,” Proceedings of the Japan Academy, Series B, vol. 100, no. 2, pp. 101–113, Feb. 2024, doi: 10.2183/pjab.100.003.

[34] G. A. Morrison, “Conformational Analysis of Some Alkaloids,” Fortschritte der Chemie Organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products / Progrès dans la Chimie des Substances Organiques Naturelles, pp. 269–317, 1967, doi: 10.1007/978-3-7091-8164-5_9.

[35] V. Dragojlovic, “Conformational analysis of cycloalkanes,” ChemTexts, vol. 1, no. 3, Aug. 2015, doi: 10.1007/s40828-015-0014-0.

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