Spectroscopy 14 (2000) 121–126 121 IOS Press Solution and solid state (CPMAS) NMR studies of the tautomerism of six-membered heterocyclic compounds related to 2-pyridones Concepción López a,* , Rosa María Claramunt a,* , Ibon Alkorta b and José Elguero b a Departamento de Química Orgánica y Biología, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain b Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain Received October 1999 Accepted January 2000 Abstract. Several 13 C and 15 N chemical shifts of 2-pyridone (1), 4(3H)-pyrimidone (2), uracil (3) and cytosine (4) have been measured in solution and in the solid state. These data have been discussed in relation with the tautomerism of the four hete- rocycles. GIAO ab initio calculations of absolute shieldings have been carried out to identify the predominant tautomers in the case of compounds (1) and (2). 1. Introduction A recent survey of the physical methods to study tautomerism [1] reveals that there are no examples of the use of solid state NMR ( 13 C and 15 N) to establish the tautomer present in the solid state in the case of six-membered heterocyclic rings (azines). On the contrary, examples of application to five-membered rings (azoles) abound [2–8]. To demonstrate the possibilities of CPMAS NMR for the study of the tau- tomerism of azines, four “classical” compounds were selected: 2-pyridone (1), 4(3H)-pyrimidone (2), uracil (3) and cytosine (4). These compounds can exist in several tautomeric forms: two for pyridone, three for pyrimidone and six for uracil and cytosine (Scheme 1). Previous information [9] indicates that pyridone exists in solution as tautomer 1b, 4(3H)-pyrimidone in water is a 50 : 50 mixture of 2b and 2c (in other solvents, 2c seems predominant); uracil both in solution and in solid state exists as pyrimidine-2,4-dione (3f) [10], finally, cytosine both in solution and in solid state exists in the oxo-amino structure (4e) [11]. More recent diffraction studies of these compounds show that in the solid state tautomer 1b of pyridone is present (neutron study, 295 K and 120 K [12]), and confirm the structure of tautomers 3f and 4e (hydrate, X-ray, 97 K) [13,14]. No data are available for 4(3H)-pyrimidone (2). * Corresponding authors. E-mail: [email protected]. 0712-4813/00/$8.00 2000 – IOS Press. All rights reserved
Transcript
Spectroscopy 14 (2000) 121–126 121IOS Press
Solution and solid state (CPMAS) NMRstudies of the tautomerism of six-memberedheterocyclic compounds related to2-pyridones
Concepción Lópeza,∗, Rosa María Claramunta,∗, Ibon Alkortab and José ElguerobaDepartamento de Química Orgánica y Biología, Facultad de Ciencias, UNED, Senda del Rey 9,E-28040 Madrid, Spainb Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
Received October 1999Accepted January 2000
Abstract. Several13C and15N chemical shifts of 2-pyridone (1), 4(3H)-pyrimidone (2), uracil (3) and cytosine (4) have beenmeasured in solution and in the solid state. These data have been discussed in relation with the tautomerism of the four hete-rocycles. GIAOab initio calculations of absolute shieldings have been carried out to identify the predominant tautomers in thecase of compounds (1) and (2).
1. Introduction
A recent survey of the physical methods to study tautomerism [1] reveals that there are no examplesof the use of solid state NMR (13C and15N) to establish the tautomer present in the solid state in the caseof six-membered heterocyclic rings (azines). On the contrary, examples of application to five-memberedrings (azoles) abound [2–8]. To demonstrate the possibilities of CPMAS NMR for the study of the tau-tomerism of azines, four “classical” compounds were selected: 2-pyridone (1), 4(3H)-pyrimidone (2),uracil (3) and cytosine (4).
These compounds can exist in several tautomeric forms: two for pyridone, three for pyrimidone andsix for uracil and cytosine (Scheme 1). Previous information [9] indicates that pyridone exists in solutionas tautomer1b, 4(3H)-pyrimidone in water is a 50 : 50 mixture of2b and2c (in other solvents,2cseemspredominant); uracil both in solution and in solid state exists as pyrimidine-2,4-dione (3f) [10], finally,cytosine both in solution and in solid state exists in the oxo-amino structure (4e) [11].
More recent diffraction studies of these compounds show that in the solid state tautomer1b of pyridoneis present (neutron study, 295 K and 120 K [12]), and confirm the structure of tautomers3f and 4e(hydrate, X-ray, 97 K) [13,14]. No data are available for 4(3H)-pyrimidone (2).
0712-4813/00/$8.00 2000 – IOS Press. All rights reserved
122 C. López et al. / Tautomerism of six-membered heterocyclic compounds
Scheme 1.
2. Experimental
Compounds1–4 are commercially available and were used without further purification.13C NMR (100.62 MHz) and15N NMR (40.56 MHz) spectra in solution were obtained using a Bruker
DRX-400 instrument. Chemical shifts (δ) in ppm are referred to Me4Si and CH3NO2 as external stan-dards. Solid state13C and15N CPMAS NMR spectra were recorded using a Bruker AC-200 instrument(50.32 and 20.28 MHz) and standard CP pulse sequences were employed. All spectra were recorded at300 K.
Full geometry optimization of all the compounds has been carried out with the B3LYP method [15]and the 6-31G* basis set [16] as implemented in the Gaussian-98 package [17]. For the computation ofthe isotropic nuclear magnetic shieldings, a single point calculation using the B3LYP/6-31G* optimizedgeometries at the B3LYP/6-311++G** level [18] and the GIAO perturbation method has been used [19].
3. Results and discussion
The information available on13C and15N (or 14N) data of these compounds is relatively scarce [20–25]. Some of these references contain only indirect information, for instance, ref [23] describes15N la-belled uracil but reports only1H NMR chemical shifts and1H–15N coupling constants and references [24,25] reports14N NQR results. Therefore, we decided first to record the13C and15N NMR spectra of thefour compounds in DMSO-d6. Our results, together with those of the literature are collected in Table 1.The numbering is reported in Fig. 1 using the most abundant tautomers (1b, 2c, 3f, 4e) according to ourprecedent summary of the available information. There are no references concerning pyrimidone2.
We have calculated theoretically the chemical shifts of pyridine as reference compound and of bothtautomers in the case of compound2, the corresponding absolute shieldings being gathered in Table 2.We have advocated the use of theoretical calculations together with experimental determination of aver-age values as a powerful method to determine the structure of the major tautomer [1]. Other authors
C. López et al. / Tautomerism of six-membered heterocyclic compounds 123
Table 113C and15N chemical shifts and1H–13C coupling constants of compounds1–5
a 14N and13C [22]; b 13C [21]; cThis work (DMSO-d6); dThis work (CPMAS);e 13C [26];f 13C [27] (the underlined values for cytosine are probably wrong);gThe assignment (2J or3J) of the small coupling constants is only tentative.
Fig. 1.
have shown that GIAO calculations were useful to assign the signals of pyridine-2(1H)-thione and2-mercaptopyridine [28]. Note that17O NMR should be an excellent tool to identify tautomers sincethe17O chemical shifts are very sensitive to the oxygen hybridization.
124 C. López et al. / Tautomerism of six-membered heterocyclic compounds
On the contrary, using tautomer1a the regressions were much worse and the correlation coefficientsdrop to 0.971 and 0.963, respectively. These results illustrate the usefulness of this approach.13C CPMASchemical shifts obtained in the solid state are also consistent with1b, the tautomer found in neutrondiffraction analysis [12] (r2 = 0.997).
The slightly more complex case of pyrimidone [three tautomers (2a–2c)], where according to literaturetautomers2b and2c seem predominant in water and2c in other solvents [9], was examined next. Wesummarize in Table 3 the results of the GIAO calculations.
Treating both tautomers1b and2c together, the plot represented in Fig. 2 was obtained. To these linescorrespond Eqs. (3) and (4):
We also tried a combination of two tautomers for pyrimidonein solution(in the solid state it is very rarethat two tautomers coexist and, in that case in CPMAS the signals of each tautomer are observed), oneof them2cand the other one either2aor 2b. The results correspond to a mixture of2b and2c, accordingto the13C NMR chemical shifts there is (81± 14)% of2c and (19± 14)% of2b; and according to the15N NMR chemical shifts to (94± 1)% of 2cand (6± 1)% if 2b.
The cases of uracil and cytosine, six tautomers each, were not theoretically approached.
4. Conclusions
We can summarize the results we have obtained by describing each case:
C. López et al. / Tautomerism of six-membered heterocyclic compounds 125
Fig. 2. Plots of experimentalδ values against theoreticalσ values.
(1) Pyridone1: total agreement with the fact that pyridone exists in solution and in the solid state asthe 2-oxo tautomer1b.
(2) Pyrimidone2: total (in solid state) or partial (in DMSO solution) predominance of tautomer2c.Interpolation shows that the ratio between tautomer2c and tautomer2b is about 90/10, whiletautomer2a is absent.
(3) Uracil3: since chemical shifts in the solid state (tautomer3f [13]) and in solution are very similarwe can conclude that tautomer3f is also the predominant tautomer in solution.
(4) Cytosine4: since chemical shifts in the solid state (tautomer4e [14]) and in solution are verysimilar we can conclude that tautomer4e is also the predominant tautomer in solution.
Acknowledgments
We thank Dr C. Foces-Foces for a search of X-ray and neutron diffraction structures of the four com-pounds reported in the Cambridge Structural Data Base. We thank Dr Stefan Steuernagel (Bruker Spec-trospin GmbH) for recording some spectra with a DSX 500 MHz instrument (13C at 125.77 MHz and15N at 50.70 MHz). Financial support has been provided by the Spanish DGICYT (project number PB96-0001-C03) and Comunidad de Madrid (07N/0001/1999).
126 C. López et al. / Tautomerism of six-membered heterocyclic compounds
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