Identification of a dimerization product of a pharmaceutically relevant organic molecule based on NMR chemical shifts calculation
Ab-initio calculations / NMR spectra / Density Functional Theory (DFT)
Barbituric acid derivatives, also called barbiturates, were long time used as soporifics and tranquilizer and are nowadays mainly administered as antiepilectic, anticonvulsant, and narcotic agents. Apart from the pharmaceutical use, barbituric acid is of importance in supramolcular chemistry.
In this case study, we will study the dimerization product of a methylated barbituric acid derivative which is illustrated in Fig. 1.
Figure 1: Structure of monomeric barbituric acid derivative and atom numbering. Color code: C - carbon, N - blue, O - red, H - white.
The dimerization of 1,3-dimethyl-5-methylenebarbituric acid can in principle lead to two possible products, a 1,2- and a 1,3-dimer (structures are shown in Fig. 2). This reaction is very interesting from chemical point of view, since the dimerization of the methylene groups to a cyclobutane unit was a rather surprisingly observation . Kuhn et al.  had synthesized a pyridine adduct of 1,3-dimethyl-5-methylenebarbituric acid whose presence was confirmed by X-ray diffraction of sublimated material, while characteristic methylene shifts were missing in the recorded NMR spectra. A possible reason for this finding is the dimerization of the methylene groups to a cyclobutane unit, which is a rather unexpected reaction according to the Woodward-Hoffmann rules , though. The dimerization can, however, be rationalized by the zwitterionic nature of the monomer which could induce the formation of the dimer at room temperature .
In order to determine the structure of the dimerization product, nuclear magnetic resonance (NMR) spectroscopy has been used experimentally. Though NMR is a powerful analytical technology and routinely applied for structure determination of organic molecules, NMR spectra can be very complex or ambiguous to interpret. In the current case, it could not be clearly deduced from the experimental data which dimer, i.e. the 1,2- or a 1,3-dimer, is present. In the following, we will show how theory can efficiently complement experimentation and demonstrate how the dimer structure can be identified based on the calculation of NMR chemical shifts.
The structures of the 1,2- and the 1,3-dimer of 1,3-dimethyl-5-methylenebarbituric acid were created using MAPS  building tools. First principles calculations were performed using MAPS NWChem plugin. The structures of both dimers were geometry optimized using the density functional PBE0  with the def2-SVP  basis set and applying the dispersion correction developed by Grimme et al. . Based on the geometry optimized structures, NMR chemical shieldings s were calculated using gauge including atomic orbitals (GIAO)  at HF/def2-SVP level. Commonly, NMR spectroscopic studies refer to chemical shifts, usually denoted as δ. The chemical shift δ is defined as the difference in the chemical shielding σ between the nucleus of the compound of interest and the shielding of the same nucleus in a reference compound, see e.g. . Therefore, the chemical shieldings σ of a reference compound need to be calculated additionally. Since we are interested in 13C-NMR chemical shifts, tetramethylsilane (TMS) is used as reference sample, which is typically used as reference standard in NMR spectroscopy for determining 1H and 13C chemical shifts and which is also recommended by the IUPAC . For reasons of consistency, TMS was treated at the same level of theory, which means that chemical shieldings are calculated at GIAO-HF/def2-SVP level based on a structure optimized at PBE0-D3/def2-SVP level.
Results and Discussion
Prior to the calculation of NMR chemical shieldings, the structures of the 1,2- and the 1,3-dimer of 1,3-dimethyl-5-methylenebarbituric acid were fully geometry optimized at DFT level. The optimized structures of both dimers are illustrated in Fig. 2.
Figure 2: Geometry optimized structures of the 1,2-dimer (left) and 1,3 dimer (right). Color code: C - carbon, N - blue, O - red, H - white.
NMR chemical shieldings s were then calculated at Hartree-Fock level using a split-valence basis set (def2-SVP). Chemical shifts δ are obtained as the difference in the shieldings between the sample σs and a reference compound : δ / ppm ≈ 106 * (σref – σs). As it is common practice and recommended by the IUPAC, the chemical shifts δ for obtaining the 13C-NMR spectrum were calculated relative to TMS.
The isotropic shielding constants σ of the dimers are listed in Tab. 1.
|Atom||σ / ppm|
|1,2 dimer||1,3 dimer|
Table 1: Shielding constants σ (ppm) of the 1,2-dimer and 1,3-dimer. For labelling see Fig. 1.
In Tab. 2, the difference Δ in the relative chemical shifts δ between the 1,3- and the 1,2-dimer are listed for comparison with literature data which were computed at a higher level of theory (GIAO-MP2) and for which a larger basis set (TZP) was used .
|Atom||Δδ / ppm|
Table 2: Difference Δδ = δ(1,3-dimer) – δ(1,2-dimer) in relative chemical shifts d between the 1,2-dimer and 1,3-dimer. For labelling see Fig. 1.
A rather larger difference Δδ between the 1,2- and 1,3-dimer is found for C1 and C2. C1 of the 1,3-dimer is shifted upfield, while C2 is shifted downfield compared to the 1,2-dimer. Comparably small differences Δδ are observed for C3-C5. Similar differences Dd are observed for C3 and C4, while a slightly different trend is found for C5 compared to literature data. Overall, the results are in line with published results .
For analyzing which of the dimers fits in better with the experimental data , the chemical shifts were calculated relative to C2. The corresponding values are listed in Tab. 3.
|Atom||Δδ / ppm|
|1,2 dimer||1,3 dimer||Exp.|
Table 3: Chemical shifts δ relative to C2 calculated at GIAO-HF/def2-SVP level. For labeling see Fig. 1.
In this case study, ab initio calculation of 13C-NMR chemical shifts have been presented. The simulations allowed to identify the dimerization product of 1,3-dimethyl-5-methylenebarbituric acid. In line with published results, the better agreement between experimental data and calculated NMR chemical shifts is obtained for the 1,3-dimer than for the 1,2-dimer. We have shown how computational approaches can be leveraged to reveal structural properties and complement efficiently experimentation.
- Klärner, F.-G.; Kahlert, B.; Nellesen, A.; Zienau, J.; Ochsenfeld, C.; Schrader, T. J. Am. Chem. Soc. 2006, 128, 4831-4841.
- Mulder, F. A. A.; Filatov, M. Chem. Soc. Rev. 2010, 39, 578-590.
- Doser, B., Sweidan, K., Kuhn, N., Ochsenfeld, C. J. Phys. Org. Chem. 2015, 28, 354-357.
- MAPS, Version 4.0, Scienomics, Paris, France, 2016, http://www.scienomics.com/.
- Perdew, J. P.; Ernzerhof, M.; Burke, K. J. Chem. Phys. 1996, 105, 9982-9985.
- Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297-3305.
- (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comp. Chem. 2011, 32, 1456-1465.
- (a) London, F. J. Phys. Radium 1937, 8, 397-409. (b) Ditchfield, R. Mol. Phys. 1974, 27, 789-807. (c) Wolinski, K.; Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251-8260.
- Kuhn, N.; Kuhn, A.; Niquet, E.; Steimann, M.; Sweidan, K. Z. Naturforsch. 2005, 60b, 924.