Conformational Analysis, Experimental and GIAO-DFT <sup>13</sup>C NMR Chemical Shift Calculation on 2’-Hydroxy-3,4,5-trimethoxy-chalcone

Costa, Fabio Luiz P.; Gomes, Paulo F.; Silva, Andressa K.; Lião, Luciano M.

doi:10.21577/0103-5053.20170060

Abstract

In this paper we investigated the ability of the GIAO-mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level of theory to predict the ¹³C nuclear magnetic resonance (NMR) chemical shifts of the 2’-hydroxy-3,4,5-trimethoxy-chalcone molecule. Two different approaches were used. First: the absolute shieldings σ for all carbon atoms in each geometrically optimized conformers of the 2’-hydroxy-3,4,5-trimethoxy-chalcone molecule were calculated at the GIAO-mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level of theory. This approach is further used to generate weighted average values for each atom considering the previously obtained conformational distribution. Second: only the σ for the lowest energetic conformer will be taken to account. The robustness of the method was evaluated for two other chalcones: (E)-1-(4-hydroxy-3-methoxyphenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)prop-2-en-1-one and (E)-1-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one, corroborating the ability of the method in chemical shift prevision. Although, both approaches were able to reproduce the chemical shifts of the 2’-hydroxy-3,4,5-trimethoxy-chalcone, significant differences in the calculated values for C-4 and methoxy carbons were observed. The best results were obtained using the second approach (II).

Keywords:
chalcone; 2’-hydroxy-3,4,5-trimethoxy-chalcone; GIAO-NMR; scaling factor; NMR spectroscopy

Introduction

Chalcones (1,3-diaryl-2-propen-1-ones) are important intermediates for the synthesis of compounds such as flavonoids, isoflavonoids and their derivatives.¹1 Daskiewicz, J.-B.; Depeint, F.; Viornery, L.; Bayet, C.; Comte-Sarrazin, G.; Comte, G.; Gee, J. M.; Johnson, I. T.; Ndjoko, K.; Hostettmann, K.; Barron, D.; J. Med. Chem. 2005, 48, 2790. Besides having a physiological role in plants, flavonoids have also been reported to have a wide variety of biological activities, including antioxidant,²2 Stevens, J. F.; Miranda, C. L.; Frei, B.; Buhler, D. R.; Chem. Res. Toxicol. 2003, 16, 1277.

3 Nishida, J.; Kawabata J.; J. Biosci. Biotechnol. Biochem. 2006, 70, 193.

4 Gacche, R. N.; Dhole, N. A.; Kamble, S. G.; Bandgar, B. P. J.; Enzyme Inhib. Med. Chem. 2007, 23, 28.

5 Vogel, S.; Ohmayer, S.; Brunner, G.; Heilmann, J.; Bioorg. Med. Chem. 2008, 16, 4286.^-⁶6 Jung, J.-C.; Jang, S.; Lee, Y.; Min, Y.; Lim, E.; Jung, H.; Oh, M.; Oh, S.; Jung, M.; J. Med. Chem. 2008, 51, 4054. antibacterial,⁷7 Sugamoto, K.; Kurogi, C.; Matsushita, Y.; Matsui, T.; Tetrahedron Lett. 2008, 49, 6639.^,⁸8 Avila, H. P.; Smania, E.; Monache, F. D.; Smania, A.; Bioorg. Med. Chem. 2008, 16, 9790. anticancer,⁹9 Lawrence, N. J.; Patterson, R. P.; Ooi, L. L.; Cook, D.; Ducki, S.; Bioorg. Med. Chem. Lett. 2006, 16, 5844.^,¹⁰10 Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M. L.; Piro, O. E.; Castellano, E. E.; Vidal, A.; Azqueta, A.; Monge, A.; de Cerain, A. L.; Sagrera, G.; Seoane, G.; Cerecettoand, H.; Gonzalez, M.; Bioorg. Med. Chem. 2007, 15, 3356. antiangiogenic ones.¹¹11 Boumendjel, A.; Boccard, J.; Carrupt, P.-A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.; Wouessidjewe, D.; Matera, E.-L.; Dumontet, C.; J. Med. Chem. 2008, 51, 2307. The growing interest in these compounds and their potential use in medicinal applications is indicated by the increasing number of publications concerning the synthesis and biological evaluation of chalcone analogues.¹1 Daskiewicz, J.-B.; Depeint, F.; Viornery, L.; Bayet, C.; Comte-Sarrazin, G.; Comte, G.; Gee, J. M.; Johnson, I. T.; Ndjoko, K.; Hostettmann, K.; Barron, D.; J. Med. Chem. 2005, 48, 2790.

2 Stevens, J. F.; Miranda, C. L.; Frei, B.; Buhler, D. R.; Chem. Res. Toxicol. 2003, 16, 1277.

3 Nishida, J.; Kawabata J.; J. Biosci. Biotechnol. Biochem. 2006, 70, 193.

4 Gacche, R. N.; Dhole, N. A.; Kamble, S. G.; Bandgar, B. P. J.; Enzyme Inhib. Med. Chem. 2007, 23, 28.

5 Vogel, S.; Ohmayer, S.; Brunner, G.; Heilmann, J.; Bioorg. Med. Chem. 2008, 16, 4286.

6 Jung, J.-C.; Jang, S.; Lee, Y.; Min, Y.; Lim, E.; Jung, H.; Oh, M.; Oh, S.; Jung, M.; J. Med. Chem. 2008, 51, 4054.

7 Sugamoto, K.; Kurogi, C.; Matsushita, Y.; Matsui, T.; Tetrahedron Lett. 2008, 49, 6639.

8 Avila, H. P.; Smania, E.; Monache, F. D.; Smania, A.; Bioorg. Med. Chem. 2008, 16, 9790.

9 Lawrence, N. J.; Patterson, R. P.; Ooi, L. L.; Cook, D.; Ducki, S.; Bioorg. Med. Chem. Lett. 2006, 16, 5844.

10 Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M. L.; Piro, O. E.; Castellano, E. E.; Vidal, A.; Azqueta, A.; Monge, A.; de Cerain, A. L.; Sagrera, G.; Seoane, G.; Cerecettoand, H.; Gonzalez, M.; Bioorg. Med. Chem. 2007, 15, 3356.^-¹¹11 Boumendjel, A.; Boccard, J.; Carrupt, P.-A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.; Wouessidjewe, D.; Matera, E.-L.; Dumontet, C.; J. Med. Chem. 2008, 51, 2307. Their properties are related, among other factors, to its great conformational freedom as well as to the several patterns of substitution of A and B rings.¹²12 Larsen, M.; Kromann, H.; Kharazmi, A.; Nielsen, S. F.; Bioorg. Med. Chem. Lett. 2006, 15, 4858. Thus, the correct structural determination and the knowledge about three-dimensional (3D) atomic structure of chalcones are crucial to understand their properties. In this context, the complete assignments of ¹³C nuclear magnetic resonance (NMR) chemical shifts for chalcones, even using computation methodology, can help in identifying the chemical structures of new chalcone derivatives. The 2’-hydroxy-3,4,5-trimethoxy-chalcone (Figure 1) has shown in vitro inhibitory effects on PGE2 (prostaglandin E2) production from RAW 264.7 cells induced by LPS (lipopolysaccharide).¹³13 Tran, T.-D.; Park, H.; Kim, H. P.; Ecker, G. F.; Thai, K.-M.; Bioorg. Med. Chem. 2009, 19, 1650. At 10 μM 2’-hydroxychalcones proved strong effect to inhibit the PGE2 production (102.3%). However, these compounds also indicated the effect on cell viability with potential for anti-inflammation and anticancer activity.¹³13 Tran, T.-D.; Park, H.; Kim, H. P.; Ecker, G. F.; Thai, K.-M.; Bioorg. Med. Chem. 2009, 19, 1650.

Our research group has worked with quantum mechanics using computational tools to better understand the interpretation of the ¹³C NMR chemical shift experimental data. Recently, we published the applicability of the empirical equations for conversion of quantum mechanically calculated chemical shielding tensors into chemical shift values.¹⁴14 Costa, F. L. P.; de Albuquerque, A. C. F.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Phys. Org. Chem. 2010, 23, 972.

15 Costa, F. L. P.; de Albuquerque, A. C. F.; Borges, R. M.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2014, 11, 219.^-¹⁶16 Costa, F. L. P.; de Albuquerque, A. C. F.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2015, 12, 2195. In these papers, it was pointed out the importance of a linear conversion formula in order to achieve great ¹³C NMR chemical shift experimental data reproduction and prediction. In this context, the goal of this work was to investigate the ability of the scaling factor protocol at the GIAO-mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level of theory to predict the ¹³C NMR chemical shifts (d) of the 2’-hydroxy-3,4,5-trimethoxy-chalcone molecule (Figure 1). Moreover, two different approaches for determining the d of the 2’-hydroxy-3,4,5-trimethoxy-chalcone were compared.

Figure 1
Structure of the 2’-hydroxy-3,4,5-trimethoxy-chalcone.

Methodology

Chemicals

The 2’-hydroxy-3,4,5-trimethoxy-chalcone was obtained from Sigma-Aldrich Chemical Co.

NMR system and operating conditions

NMR analyses were acquired on a Bruker Avance III 11.75 Tesla spectrometer at 298 K using a 5 mm triple resonance broadband inverse (TBI) probehead. The spectra were obtained at 125.77 MHz for ¹³C using CDCl₃ as the solvent. The ¹³C spectra (Figure S1, Supplementary Information (SI)) were acquired with spectral window of 37,878 Hz, 32,768 digitalized points and accumulation of 3,926 FIDs. The heteronuclear single-quantum correlation (HSQC, Figure S2, SI) and heteronuclear multiple-bond correlation (HMBC, Figure S3, SI) experiments were acquired with a spectral window of 10,000 and 37,731 Hz for ¹H and ¹³C, respectively. The phase and baseline were corrected with the TopSpin software (version 3.2 Bruker BioSpin). NMR assignments are based on ¹H,¹³C and ¹H-¹³C HSQC/HMBC experiments. ¹H NMR (500 MHz, CDCl₃) d 12.85 (s, OH), 7.93 (dd, J 8.1, 1.6 Hz, H-6’), 7.84 (d, J 15.4 Hz, H-β), 7.53 (d, J 15.4 Hz, H-α), 7.50 (ddd, J 8.4, 7.2, 1.6 Hz, H-4’), 7.03 (dd, J 8.4, 1.2 Hz, H-3’), 6.95 (ddd, J 8.1, 7.2, 1.2 Hz, H-5’), 6.88 (s, H-2/H-6), 3.93 (s, OMe-3/OMe-5), 3.92 (s, OMe-4); HMBC/HSQC crosspeaks: OMe-3/OMe-5 (C-2, C-3, C-5, C-6), OMe-4 (C-4), H-2/H-6 (C-1, C-3, C-4, C-5, C-β), H-β (C-1, C-2, C-6, C-α, C=O), H-α (C-1, C=O), H-3’ (C-1’, C-2’, C-5’, C=O), H-4’ (C-2’, C-3’, C-5’, C-6’), H-5’ (C-2’, C-3’, C4’, C-6’), H-6’ (C-1’, C-2’, C-4’, C-5’, C=O).

Computational details

The ¹³C NMR chemical shifts of the three chalcones were calculated with two different approaches. In the first one, the absolute shieldings (σ) of all carbon atoms in each geometrically optimized conformer of molecule were calculated using the GIAO (gauge-independent atomic orbital) approximation at the mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) (NMR//optimization) level of theory, and further used to generate weighted average values for each atom considering the previously obtained conformational distribution, σ_aver. In the second one, only the σ for the lowest energetic conformer was taken to account, σ_lowe. Molecular mechanics calculations were performed using the Spartan’08 modeling software,¹⁷17 Spartan'08, Wavefunction Inc., Irvine, California, USA, 2010. whereas DFT (density functional theory) calculations were performed using the Gaussian 09 W software package.¹⁸18 Frisch, A. E.; Frisch, M. J.; Trucks, G.; Gaussian 09 User's Reference, Gaussian Inc., Pittsburgh, USA, 2009. Solvent effects were not taken into account in any calculation.

Statistical validation

In order to perform a statistical validation of our results the mean deviation (MD) and the root mean square deviation (RMSD) errors (in ppm) were calculated.

Results and Discussion

A randomized conformational search of the 2’-hydroxy-3,4,5-trimethoxy-chalcone molecule was performed (Figure 2) using the Monte Carlo (MC) method with a search limit of 200 structures. Merck molecular force field (MMFF) as implemented in the Spartan’08 software package, considering an initial energy cutoff of 10 kcal mol^-1, was employed.

Figure 2
Superposition of the three lowest energy conformations of the 2’-hydroxy-3,4,5-trimethoxy-chalcone molecule.

The 28 more significant conformations of 2’-hydroxy-3,4,5-trimethoxy-chalcone molecule were saved, which are responsible for more than 99.99% of the total Boltzmann population in the first 10 kcal mol^-1. This was followed by single-point energy calculations at the B3LYP/6-31G(d) and level of theory. The 21 more significant conformations within the range of 0.0-5.0 kcal mol^-1 were selected by energy minimization calculations carried out at the mPW1PW91/6-31G(d) level of theory. The relevant results are given in Table 1. Frequency calculations carried out at the mPW1PW91/6-31G(d) level of theory confirmed the optimized geometries to be local minima and delivered values of free energy at 298 K and 1 atm. In this step, the three most significant conformations within the range of 0.0-3.0 kcal mol^-1 were selected (Figure 3).

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Table 1
DFT, thermo chemical parameter and DFT population for the 28 more significant conformations of 2'-hydroxy-3,4,5-trimethoxy-chalcone molecule

Figure 3
DFT-optimized structures of the three more stable conformers, 1, 2 and 3, respectively, of 2’-hydroxy-3,4,5-trimethoxy-chalcone. For relative energies and abundances of the conformers, see .

In the approach (I), for each optimized conformer geometry, the ¹³C atomic chemical shielding tensors (σ) were computed at the mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level of theory. Isotropic atomic chemical shifts d in units of ppm were computed as differences between the atomic isotropic shielding of the solutes and corresponding reference atoms in tetramethylsilane (TMS). Thus, the population-averaged chemical shifts for the selected conformers were computed assuming Boltzmann statistics, according to equation 1, based on mPW1PW91/6-31G(d) free energies. Finally, the ¹³C NMR chemical shifts were scaled according to Costa et al. protocols.¹⁵15 Costa, F. L. P.; de Albuquerque, A. C. F.; Borges, R. M.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2014, 11, 219.

(1)

⟨δ⟩ = \sum_{i} \frac{δ_{i} e^{- Δ E_{i} / k T}}{\sum_{i} e^{- Δ E_{i} / k T}}

DE_i is the relative energy of the i^th conformer to the lowest energy, k is the Boltzmann constant, and the temperature T is set to 298 K. In the approach (II), only the lowest-energetic conformer was used to obtain the scaled chemical shifts.

Figure 3 shows the three most significant conformations conformers of 2’-hydroxy-3,4,5-trimethoxy-chalcone according to the geometry optimization calculations carried out at the mPW1PW91/6-31G(d) level of theory. The two more significant factors that determine the stability of the 2’-hydroxy-3,4,5-trimethoxy-chalcone conformers are apparently the intramolecular hydrogen bond between the OH and C=O and steric effects of methoxyl groups in the B-ring.

Table 2 shows the calculated (d_calc), scaled (d_scal) and experimental (d_exp) ¹³C NMR chemical shifts of the 2’-hydroxy-3,4,5-trimethoxy-chalcone as well as the differences (≠) among them. The data comparison demonstrated a great agreement between experimental and calculated NMR chemical shifts.

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Table 2
Calculated (scaled) and differences between experimental ¹³C NMR chemical shifts (in ppm) in the 2'-hydroxy-3,4,5-trimethoxy-chalcone relative to TMS, for approaches (I) and (II)

The main differences between experimental and scaled chemical shifts, for both approaches, were observed in carbons C-4, OMe-3, OMe-4 and OMe-5. These differences are consistent with the three selected conformers (Figure 3) to obtain the chemical shifts at the approach (I). The reason is that they have different orientations of the OCH₃ group (atoms C-3, C-4 and C-5) with respect to the aromatic ring and their chemical shifts are systematically dependent on the orientation of the methoxyl group.

For evaluating the robustness of the method, the chemical shift for two other chalcones: (E)-1-(4-hydroxy-3-methoxyphenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)prop-2-en-1-one and (E)-1-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (Figure S4, SI), were calculated. The results presented in Table 3 demonstrate an excellent predictive ability of the method. The experimental and theoretical calculation of the NMR data for these two chalcones are presented in the Supplementary Information.

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Table 3
Statistical data illustrating the performance of two approaches for the GIAO calculation of ¹³C NMR chemical shifts (δ, in ppm) for the 2'-hydroxy-3,4,5-trimethoxy-chalcone (a), (E)-1-(4-hydroxy-3-methoxyphenyl)-3-(3,5-di-tert-butyl-4 hydroxyphenyl)prop-2-en-1-one (b) and (E)-1-(4-aminophenyl)- 3-(3,4-dimethoxyphenyl)prop-2-en-1-one (c)

Conclusions

In this work, we investigated the ability of the scaling factor protocol at the GIAO-mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level of theory to predict the ¹³C NMR chemical shifts of the 2’-hydroxy-3,4,5-trimethoxy-chalcone. The robustness of the method was evaluated for two other chalcones: (E)-1-(4-hydroxy-3-methoxyphenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)prop-2-en-1-one and (E)-1-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one, corroborating the ability of the method in chemical shift prevision. After using the scale factor, the two approaches were able to correctly reproduce the chemical shifts, despite the differences in the conditions of the experimental measurements and computational predictions. Both approaches had similar performance. These findings suggest that, in this case, either the approach (I) or the approach (II) could be chosen and that further analysis of the methoxychalcones is therefore justified.

Supplementary Information

Supplementary information is available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgments

The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) and Financiadora de Estudos e Projetos (FINEP) for the financial support. The authors also thanks Prof Dr Guilherme Roberto de Oliveira for the chalcone samples.

References

¹
Daskiewicz, J.-B.; Depeint, F.; Viornery, L.; Bayet, C.; Comte-Sarrazin, G.; Comte, G.; Gee, J. M.; Johnson, I. T.; Ndjoko, K.; Hostettmann, K.; Barron, D.; J. Med. Chem. 2005, 48, 2790.
²
Stevens, J. F.; Miranda, C. L.; Frei, B.; Buhler, D. R.; Chem. Res. Toxicol. 2003, 16, 1277.
³
Nishida, J.; Kawabata J.; J. Biosci. Biotechnol. Biochem. 2006, 70, 193.
⁴
Gacche, R. N.; Dhole, N. A.; Kamble, S. G.; Bandgar, B. P. J.; Enzyme Inhib. Med. Chem. 2007, 23, 28.
⁵
Vogel, S.; Ohmayer, S.; Brunner, G.; Heilmann, J.; Bioorg. Med. Chem. 2008, 16, 4286.
⁶
Jung, J.-C.; Jang, S.; Lee, Y.; Min, Y.; Lim, E.; Jung, H.; Oh, M.; Oh, S.; Jung, M.; J. Med. Chem. 2008, 51, 4054.
⁷
Sugamoto, K.; Kurogi, C.; Matsushita, Y.; Matsui, T.; Tetrahedron Lett. 2008, 49, 6639.
⁸
Avila, H. P.; Smania, E.; Monache, F. D.; Smania, A.; Bioorg. Med. Chem 2008, 16, 9790.
⁹
Lawrence, N. J.; Patterson, R. P.; Ooi, L. L.; Cook, D.; Ducki, S.; Bioorg. Med. Chem. Lett. 2006, 16, 5844.
¹⁰
Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M. L.; Piro, O. E.; Castellano, E. E.; Vidal, A.; Azqueta, A.; Monge, A.; de Cerain, A. L.; Sagrera, G.; Seoane, G.; Cerecettoand, H.; Gonzalez, M.; Bioorg. Med. Chem. 2007, 15, 3356.
¹¹
Boumendjel, A.; Boccard, J.; Carrupt, P.-A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.; Wouessidjewe, D.; Matera, E.-L.; Dumontet, C.; J. Med. Chem. 2008, 51, 2307.
¹²
Larsen, M.; Kromann, H.; Kharazmi, A.; Nielsen, S. F.; Bioorg. Med. Chem. Lett. 2006, 15, 4858.
¹³
Tran, T.-D.; Park, H.; Kim, H. P.; Ecker, G. F.; Thai, K.-M.; Bioorg. Med. Chem. 2009, 19, 1650.
¹⁴
Costa, F. L. P.; de Albuquerque, A. C. F.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Phys. Org. Chem. 2010, 23, 972.
¹⁵
Costa, F. L. P.; de Albuquerque, A. C. F.; Borges, R. M.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2014, 11, 219.
¹⁶
Costa, F. L. P.; de Albuquerque, A. C. F.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2015, 12, 2195.
¹⁷
Spartan'08, Wavefunction Inc., Irvine, California, USA, 2010.
¹⁸
Frisch, A. E.; Frisch, M. J.; Trucks, G.; Gaussian 09 User's Reference, Gaussian Inc., Pittsburgh, USA, 2009.

Publication Dates

Publication in this collection
Nov 2017

History

Received
26 Dec 2016
Accepted
31 Mar 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] ¹
Daskiewicz, J.-B.; Depeint, F.; Viornery, L.; Bayet, C.; Comte-Sarrazin, G.; Comte, G.; Gee, J. M.; Johnson, I. T.; Ndjoko, K.; Hostettmann, K.; Barron, D.; J. Med. Chem. 2005, 48, 2790.

[2] ²
Stevens, J. F.; Miranda, C. L.; Frei, B.; Buhler, D. R.; Chem. Res. Toxicol. 2003, 16, 1277.

[3] ³
Nishida, J.; Kawabata J.; J. Biosci. Biotechnol. Biochem. 2006, 70, 193.

[4] ⁴
Gacche, R. N.; Dhole, N. A.; Kamble, S. G.; Bandgar, B. P. J.; Enzyme Inhib. Med. Chem. 2007, 23, 28.

[5] ⁵
Vogel, S.; Ohmayer, S.; Brunner, G.; Heilmann, J.; Bioorg. Med. Chem. 2008, 16, 4286.

[6] ⁶
Jung, J.-C.; Jang, S.; Lee, Y.; Min, Y.; Lim, E.; Jung, H.; Oh, M.; Oh, S.; Jung, M.; J. Med. Chem. 2008, 51, 4054.

[7] ⁷
Sugamoto, K.; Kurogi, C.; Matsushita, Y.; Matsui, T.; Tetrahedron Lett. 2008, 49, 6639.

[8] ⁸
Avila, H. P.; Smania, E.; Monache, F. D.; Smania, A.; Bioorg. Med. Chem 2008, 16, 9790.

[9] ⁹
Lawrence, N. J.; Patterson, R. P.; Ooi, L. L.; Cook, D.; Ducki, S.; Bioorg. Med. Chem. Lett. 2006, 16, 5844.

[10] ¹⁰
Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M. L.; Piro, O. E.; Castellano, E. E.; Vidal, A.; Azqueta, A.; Monge, A.; de Cerain, A. L.; Sagrera, G.; Seoane, G.; Cerecettoand, H.; Gonzalez, M.; Bioorg. Med. Chem. 2007, 15, 3356.

[11] ¹¹
Boumendjel, A.; Boccard, J.; Carrupt, P.-A.; Nicolle, E.; Blanc, M.; Geze, A.; Choisnard, L.; Wouessidjewe, D.; Matera, E.-L.; Dumontet, C.; J. Med. Chem. 2008, 51, 2307.

[12] ¹²
Larsen, M.; Kromann, H.; Kharazmi, A.; Nielsen, S. F.; Bioorg. Med. Chem. Lett. 2006, 15, 4858.

[13] ¹³
Tran, T.-D.; Park, H.; Kim, H. P.; Ecker, G. F.; Thai, K.-M.; Bioorg. Med. Chem. 2009, 19, 1650.

[14] ¹⁴
Costa, F. L. P.; de Albuquerque, A. C. F.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Phys. Org. Chem. 2010, 23, 972.

[15] ¹⁵
Costa, F. L. P.; de Albuquerque, A. C. F.; Borges, R. M.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2014, 11, 219.

[16] ¹⁶
Costa, F. L. P.; de Albuquerque, A. C. F.; dos Santos Jr., F. M.; de Amorim, M. B.; J. Comput. Theor. Nanosci. 2015, 12, 2195.

[17] ¹⁷
Spartan'08, Wavefunction Inc., Irvine, California, USA, 2010.

[18] ¹⁸
Frisch, A. E.; Frisch, M. J.; Trucks, G.; Gaussian 09 User's Reference, Gaussian Inc., Pittsburgh, USA, 2009.

Conformer	ΔE^a a Relative MMFF energy of conformers obtained from Monte Carlo analysis; / (kcal mol^-1)	Bolt. dist.^b b MMFF Boltzmann population of the conformers; / %	ΔE^c c relative B3LYP/6-31G(d) single point energy of conformers obtained from Monte Carlo analysis; / ( kcal mol^-1)	Bolt. dist.^d d B3LYP/6-31(g) single point energy Boltzmann population of the conformers; / %	ΔE^e e relative mPW1PW91/6-31G(d) energy minimization of the conformers; / (kcal mol^-1)	Bolt. dist.^f f mPW1PW91/6-31G(d) energy minimization Boltzmann population of the conformers; / %	ΔG^g g relative mPW1PW91/6-31G(d) sum of electronic and free energy of the conformers; / (kcal mol^-1)	Bolt. dist.^h h mPW1PW91/6-31G(d) Boltzmann population calculated from ΔG values of the conformers. / %
001	0.00	34.6	0.00	40.8	0.00	79.2	0.00	80.9
002	0.09	29.7	0.09	35.1	1.01	12.3	1.06	11.4
003	0.62	12.1	0.62	14.2	1.21	8.5	1.27	7.7
004	0.67	11.2	1.30	4.5	2.60	-	-	-
005	1.30	3.8	2.22	1	3.00	-	-	-
006	1.31	3.8	2.30	0.8	4.01	-	-	-
007	2.22	0.8	2.35	0.8	4.05	-	-	-
008	2.30	0.7	2.39	0.7	4.23	-	-	-
009	2.35	0.7	2.68	0.4	4.31	-	-	-
010	2.39	0.6	2.74	0.4	-	-	-	-
011	2.68	0.4	2.85	0.3	-	-	-	-
012	2.70	0.2	2.89	0.3	-	-	-	-
013	2.74	0.3	3.38	0.1	-	-	-	-
014	2.74	0.2	3.48	0.1	-	-	-	-
015	2.85	0.3	3.50	0.1	-	-	-	-
016	2.89	0.1	3.65	0.1	-	-	-	-
017	3.38	0.1	3.73	0.1	-	-	-	-
018	3.48	0.1	3.76	0.1	-	-	-	-
019	3.50	0.1	4.42	0	-	-	-	-
020	3.63	0.1	4.47	0	-	-	-	-
021	3.65	0.1	4.99	0	-	-	-	-
022	3.73	0.1	-	-	-	-	-	-
023	3.76	0.1	-	-	-	-	-	-
024	4.42	0	-	-	-	-	-	-
025	4.47	0	-	-	-	-	-	-
026	4.99	0	-	-	-	-	-	-
027	5.52	0	-	-	-	-	-	-
028	6.87	0	-	-	-	-	-	-

Nuclei	δ_exp / ppm	Approach (I)		Approach (II)
Nuclei	δ_exp / ppm	δ_calc^a a Calculated chemical shifts (δcalc = σTMS - σaver or σlowe) obtained by TMS subtraction; (δ_scal)^b b scaled chemical shifts (δscal = 1.05δcalc - 1.22) obtained by the generated universal scaling factor;15 / ppm	≠ δ_calc (δ_scal) / ppm	δ_calc^a a Calculated chemical shifts (δcalc = σTMS - σaver or σlowe) obtained by TMS subtraction; (δ_scal)^b b scaled chemical shifts (δscal = 1.05δcalc - 1.22) obtained by the generated universal scaling factor;15 / ppm	≠ δ_calc (δ_scal) / ppm
C-1	130.07	124.46 (129.46)	-5.61 (-0.61)	124.18 (129.17)	-5.89 (-0.90)
C-2^c c the δcalc and δscal for C-2 and C-6 were arithmetically averaged.	106.03	103.56 (107.52)	-2.47 (1.49)	101.93 (105.81)	4.10 (-0.22)
C-3	153.55	148.18 (154.37)	-5.37 (0.82)	148.05 (154.23)	-5.50 (0.68)
C-4	140.92	137.56 (143.22)	-3.36 (2.30)	136.44 (142.04)	-4.48 (1.12)
C-5	153.55	148.19 (155.38)	-5.41 (0.78)	147.90 (154.08)	-5.70 (-0.48)
C-6^c c the δcalc and δscal for C-2 and C-6 were arithmetically averaged.	106.03	103.56 (107.52)	-2.47 (1.49)	101.93 (105.81)	4.10 (-0.22)
C-α	119.29	143.30 (149.24)	-2.34 (3.60)	143.27 (149.21)	-2.37 (3.57)
C-β	145.64	111.42 (115.77)	-7.88 (-3.53)	111.21 (115.55)	-8.09 (-3.75)
C-1'	120.05	183.25 (191.19)	-10.29 (-2.35)	183.22 (191.16)	-10.32 (-2.38)
C-2'	163.60	115.05 (119.58)	-4.95 (-0.42)	114.85 (119.37)	-5.15 (-0.63)
C-3'	118.65	159.43 (166.18)	-4.17 (2.58)	159.34 (166.08)	-4.26 (2.48)
C-4'	136.35	114.30 (118.79)	-4.35 (0.14)	114.09 (118.57)	-4.56 (-0.08)
C-5'	118.81	130.59 (135.90)	-5.76 (-0.45)	130.43 (135.73)	-5.92 (-0.62)
C-6'	129.61	111.37 (115.72)	-7.44 (-3.09)	111.17 (115.51)	-7.64 (-3.30)
C=O	193.54	124.40 (129.40)	-5.21 (-0.21)	124.24 (129.23)	-5.37 (-0.38)
OMe-3	56.29	54.25 (55.75)	-2.46 (-0.99)	52.98 (54.41)	-3.32 (-1.89)
OMe-4	61.03	57.26 (58.80)	-3.77 (-2.13)	57.42 (59.07)	-3.61 (-1.96)
OMe-5	56.29	53.84 (55.31)	-2.04 (-0.54)	52.96 (54.39)	-3.33 (-1.90)

Chalcone	Approach (I)		Approach (II)
Chalcone	MD (RMSD)^a a Calculated chemical shifts (δcalc = TMS - δ) obtained by TMS subtraction; / ppm	MD (RMSD)^b b scaled chemical shifts (δscal = 1.05δcalc - 1.22) obtained by the generated universal scaling factors.15 MD: mean deviation; RMSD: root mean square deviation. / ppm	MD (RMSD)^a a Calculated chemical shifts (δcalc = TMS - δ) obtained by TMS subtraction; / ppm	MD (RMSD)^b b scaled chemical shifts (δscal = 1.05δcalc - 1.22) obtained by the generated universal scaling factors.15 MD: mean deviation; RMSD: root mean square deviation. / ppm
a	4.75 (5.20)	0.06 (1.90)	5.21 (5.54)	0.55 (1.89)
b	4.73 (5.75)	0.19 (1.89)	5.54 (6.26)	0.87 (1.56)
c	5.56 (6.63)	0.80 (2.87)	7.17 (7.82)	2.49 (3.54)

Brasil

Brasil

Conformational Analysis, Experimental and GIAO-DFT ¹³C NMR Chemical Shift Calculation on 2’-Hydroxy-3,4,5-trimethoxy-chalcone

Abstract

Introduction

Methodology

Chemicals

NMR system and operating conditions

Computational details

Statistical validation

Results and Discussion

Conclusions

Supplementary Information

Acknowledgments

References

Publication Dates

History

Brasil

Brasil

Conformational Analysis, Experimental and GIAO-DFT 13C NMR Chemical Shift Calculation on 2’-Hydroxy-3,4,5-trimethoxy-chalcone

Abstract

Introduction

Methodology

Chemicals

NMR system and operating conditions

Computational details

Statistical validation

Results and Discussion

Conclusions

Supplementary Information

Acknowledgments

References

Publication Dates

History

Conformational Analysis, Experimental and GIAO-DFT ¹³C NMR Chemical Shift Calculation on 2’-Hydroxy-3,4,5-trimethoxy-chalcone