Abstract
1H, 13C, and 15N NMR chemical shifts have been measured for 2-aminopyridine N-oxide (1), its eleven derivatives (2–10, 13, 14), and 3-Cl and 3-Br substituted 4-nitropyridine N-oxides (11, 12). δ(15N) of pyridine ring nitrogen in 2-acetylaminopyridine N-oxides are 5.9–11.5 ppm deshielded from those in 2-aminopyridine N-oxides. When amino and acetylamino substituents are in 4-position, δ(15N) of ring nitrogen is 21.3 ppm deshielded in the acetylated derivative. The strong resonance interaction between 2-amino and 5-nitro groups reflects in the decrease of amino nitrogen shielding about 5.3–17.9 ppm. Also, 1H and 13C NMR spectral data are in agreement with 15N NMR results reflected as deshielded amino protons and carbons C-2 and C-5. The pyridine nitrogen chemical shift in all amino- and acetylamino derivatives vary between −101.2 and −126.7 ppm, which has been connected with the tautomeric balance in our earlier studies.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
15N isotope is the most sensitive NMR nucleus to the effect of a substituent introduced to pyridine N-oxide (2- and 4-amino, 2- and 4-acetylamino, methyl group in different positions together with 2-amino and/or 2-acetylamino, 5-nitro with 2-amino, 4-nitro together with 3-chloro and 3-bromo e.g.). Pyridine N-oxides possess an N–O-moiety, a dual resonance functionality, that can act as both a π-electron donor and a π-electron acceptor [1]. Acceptors in the ring decrease and donors increase the shielding of 15N. A linear relationship has been observed between the substituent chemical shifts of 15N and 13C for the related substituted benzenes.
Only few research reports on 15N and 14N NMR studies of aminopyridine N-oxides are found in the literature [2–5]. In this paper, we present our studies regarding the possible tautomerism in amino and acetylaminopyridine N-oxides because this problem has not yet been unambiguously solved. Another interest lies in the 5-nitro-substituted compounds (10, 13, 14), where the electron lone pair of amino moiety is involved in the π-electron conjugation with the aromatic ring the nitro group acting as an electron acceptor.
Recently, 2-amino-5-nitropyridine derivatives have been shown to be very interesting owing to their promising non-linear optical properties as these molecules possess high hyperpolarizability and highly delocalised π-electron system for reason that acceptor and donor group are situated in para-position to each other [6].
Experimental
2-Aminopyridine N-oxide and its 3- and 5-methyl derivatives were obtained by protecting the primary amino group by acetylation during the oxidation of ring nitrogen. Otherwise, oxidation would have transformed aminopyridines into nitropyridines [7–15]. In hydrolysis, acetylamino derivatives of pyridine N-oxide gave the corresponding amino compounds [7]. 2-Amino- and 2-acetylaminopyridine N-oxides as well as their 3-, 4-, 5-, and 6-methyl derivatives are reported in literature [8, 9], but their synthesis were greatly improved [14] compared to the earlier reported methods [8–13].
Synthesis
The modified synthesis of 2-acetylaminopyridine N-oxides (2, 4) and 4-, 5-, and 6-methyl-(2-acetylaminopyridine-N-oxides) (7, 8, 9) [8–10, 13] has been presented previously [14]. By modification of methods by Brown and Adam et al. [9, 10], a remarkable shortening in reaction time (9 to 2 h) was achieved by substituting acetic acid by acetic anhydride in the reaction.
The syntheses of 2-amino- (1), 4-amino- (3), 2-amino-3-methyl- (5), 2-amino-5-methylpyridine N-oxide (6) have also been reported earlier [16]. These compounds were obtained by hydrolysis of the corresponding acetylaminopyridine N-oxides [13]. By Herz’s hydrolysis method [13] with 50 % H2SO4 instead of 10 % NaOH decreases, the reaction time varied from 5 to 1 h [9, 10].
The syntheses of 2-amino-5-nitro- (10), 2-amino-5-nitro-3-methyl- (13) and 2-amino-5-nitro-6-methylpyridine N-oxides (14) have been presented previously [16, 17]. These compounds were obtained in rearrangement reaction of the corresponding nitraminopyridine N-oxides [16, 17].
3-Chloro- (11) and 3-bromo-4-nitropyridine N-oxides (12) were prepared by oxidation of 3-chloro- and 3-bromopyridine by 30 % H2O2 in the presence of acetic anhydride followed by nitration of the crude products after the excess acid was removed [18]. The modification of this synthesis in comparison with earlier applied methods [7] consists an improvement of N-oxidation (using acetic anhydride instead of acetic acid) and separation of final product from reaction mixture (using 25 % NH4OH and NH4HCO3 instead of NaOH) giving the pure product due to low temperature during the neutralization process.
NMR spectroscopy
The 1H, 13C and PFG [19] 1H, 13C HMQC [20, 21], and PFG 1H,X (X = 13C or 15N) HMBC [22] spectra were recorded for 0.5 M DMSO-d6 solution in a 5-mm sample tube at 30 °C on a Bruker Avance DRX 500 spectrometer working at 500.13 MHz (proton), 125.77 MHz (carbon-13) and 50.70 MHz (nitrogen-15), respectively.
In 1H NMR experiments, the number of data points was 64 K giving a spectral resolution of 0.05 Hz, the number of scans was 8 and the flip angle 30°. An exponential window function of the spectral resolution was used before FT. The 1H NMR chemical shifts are referenced to the signal of residual DMSO-d5 (δ = 2.50 ppm from TMS).
In 13C experiments, the number of data points was 32 K giving a spectral resolution of 0.5 Hz, the number of scans was 64, and flip angle 30°. A composite pulse decoupling, Waltz-16, was used to remove proton couplings. An exponential window function of the spectral resolution was used before FT. The 13C NMR chemical shifts are referenced to the center peak of the solvent DMSO-d6 (δ = 39.50 ppm from TMS). The number of data points in PFG 1H,13C HMQC, and HMBC measurements were 1,024 (f 2) × 256 (f 1). This matrix was zero filled to 2,048 × 1,024 and apodized by a shifted sine bell window function along both axes before FT.
In PFG 1H, 15N HMBC experiments, the digital resolution was <0.5 ppm and a 50-ms delay was used for the evolution of long-range couplings. The number of data points were 1,024 (f 2) × 512/450 ppm (f 1 = 15N). This matrix was zero filled to 1,024 × 1,024 and apodized by a shifted sine bell window function along both axes before FT. 15N NMR chemical shifts are referenced to the signal of an external CH3NO2 (δ = 0.0 ppm).
Results and discussion
The structures of compounds 1–14 are presented in Fig. 1. The 1H, 13C, and 15N NMR chemical shifts are collected in Tables 1, 2, and 3.
Regarding 15N NMR shifts, we can use our previous papers for comparison [6, 23, 24].
1H NMR shifts
The 1H NMR data reveal the electron acceptor ability of the acetyl group via δ(H-3) (ortho to acetylamino). In 2, δ(H-3) is 1.49 ppm and in 7–9 1.34–1.38 ppm deshielded in comparison with 1 showing the strong electron withdrawing property of acetylamino group. In 4-acetylamino substituted derivative, δ(H-3/5) are just 1.08 ppm deshielded from that of 4-amino derivative (3). In 5-nitro derivatives, the greatest deshieldings, 0.89 and 0.88 ppm for H-6 and H-4, respectively (10), 0.82 ppm for both protons (13) and 0.79 ppm for H-4 (14), are observed. Joint with these effects, one can observe deshieldings of amino protons by 1.31 ppm (10), 1.20 ppm (13), and 1.16 ppm (14) which refer to resonance interaction between amino and nitro group.
13C NMR shifts
The assignments of 13C NMR chemical shifts (Table 2) are based on literature data and substituent induced chemical shifts [6, 23–25] as well as homo- and heteronuclear 2D chemical shift correlation measurements. When C-2 in pyridine N-oxide is substituted with an amino group the ipso carbon chemical shift changes from 138.2 ppm [25] to 150.69 ppm (1). In its methylated derivatives (5) and (6), the 2-ipso carbon is 1.11 (5) and 2.18 ppm (6) shielded from that of 1. The substitution of hydrogen in amino group by acetyl group (2) increases the shielding in ipso carbon C-2 ppm by 6.97 ppm and in the methylated derivatives by ca. 4–9 ppm (7, 8, and 9). When the methyl group locates at C-5 (8), the deshielding of C-5 is 17.0 ppm due to hyperconjugation with the methyl group. When a 5-nitro group is introduced into 2-amino-pyridine N-oxide (10) and its 3- (13) and 6-methyl (14) derivatives, the increase in δ(C-2) is 3.0–4.4 ppm and in δ(C-5) 21–23 ppm. Again these changes are due to resonance interaction between the 2-amino and 5-nitro group.
15N NMR shifts
Our earlier studies on pyridine N-oxides show that in nitraminopyridine and N-alkylamino-4-nitro derivatives possessing a tertiary amino group at C-2, δ(15N) of the ring nitrogen varies from −92.7 to −93.0 ppm. It means that these compounds exist mainly as amino tautomers [6, 23, 24]. In neat pyridine N-oxide, the corresponding δ(15N) is −86.8 ppm [25]. Also, in a compound with a secondary amino substituent at C-3 δ(15N) is −86.9 ppm revealing its tautomeric preference as an amino form. In 3-methyl-2-nitraminopyridine N-oxide, the corresponding value of δ(15N) is −94.4 ppm. The predominance of the amino tautomer is in agreement with quantum chemical ab initio HF/6-311G** structure optimization and energy calculations [6]. The greater stability of the amino tautomer can be explained that while the N–NO2 group is twisted to one side of the plane of the aromatic ring the spatial vicinity of two substituents inhibit the conjugation between the 2-nitramino and pyridine ring increasing the energy of the amino form, which, however, is slightly more stable than the imino form. When the molar ratio of the imino form in the tautomer balance is increasing, the δ(15N) of ring nitrogen becomes more shielded varying from −124.1 to −168.7. In 4-nitro derivatives with secondary 2-amino substituent, δ(15N) of ring varies from −112.8 to −120.9 ppm [22] and in 5-nitro derivatives with secondary 2-amino substituent from −128.4 to −129.5 [24]. δ(15N) of ring in pyridine N-oxide and 2-aminopyridine N-oxide are −86.6 ppm [6] and −126.1 ppm, respectively. In all other derivatives, the aromatic nitrogen chemical shifts from 114.6 to 126.7 ppm mean that the molar ratio of the imino form in the tautomer balance is increasing.
In 2-aminopyridine N-oxide (1), δ(15N) of amino is −315.8 ppm. Introduction of methyl group to 2-aminopyridine to C-3 (5) or to C-5 (6) has a minimal effect on the amino shift differing from that of 5-nitro group (10), i.e., 17.7 ppm. The p-nitro group together with 3- and 6-methyl substituents (13, 14) decreases the amino nitrogen shift 17.9 and 5.3 ppm, respectively.
In conclusion, taking into account the large chemical shift range and sensitivity to substituents of 15N, we can state that there are characteristic δ(15N) ranges for pyridine-N oxides possessing NH2, NHCOCH3, and NO2 substituents. δ(15N) of ring vary from −74.7 to −126.7 ppm, δ(15N) of primary amino from −297.9 to −318.9 ppm, δ(15N) of amino in acetyl derivatives from −246.7 to −255.2 ppm, and δ(15N) of nitro group from −16.7 to −19.2 ppm. δ(15N) of ring is somewhat sensitive to the nature of substituent at C-2. When the NH2 is substituted by NHCOCH3, δ(15N) of ring becomes slightly deshielded, while the deshielding in amino nitrogen is larger being 61–69 ppm. As a whole, the 15N NMR shifts manifest a strong resonance interaction between 2-amino and 5-nitro groups by 17.7 ppm (10), 19.9 ppm (13), and 5.3 ppm (14) deshielding in δ(15N) of the amino group.
Conclusions
Among NMR parameters for fifteen substituted pyridine N-oxides reported in this study, 15N NMR chemical shifts are the most sensitive to the effects of substituent and tautomerism.
δ(15N) of the pyridine ring nitrogen in 2-acetylaminopyridine N-oxides are 5.9–11.5 ppm deshielded from those in 2-aminopyridine N-oxides. When amino and acetylamino substituents are in 4-position, δ(15N) of ring nitrogen is 21.3 ppm deshielded in the acetylated derivative. The strong resonance interaction between 2-amino and 5-nitro groups reflects in the decrease of amino nitrogen shielding about 5.3–17.9 ppm. The pyridine nitrogen chemical shift in all amino- and acetylamino derivatives vary between −101.2 and −126.7 ppm, which has been connected with the tautomeric balance in our earlier studies. Also, 1H and 13C NMR spectral data are in agreement with 15N NMR results.
References
Sawada M, Takai Y, Yamano S, Misumi S, Hanafusa T, Tsuno Y (1988) J Org Chem 53:191
Stefaniak L (1976) Spectrochim Acta 32A:345
Stefaniak L, Witanowski M, Webb GA (1983) Bull Acad Pol Sci Ser Sci Chim 29:489 and references cited therein
Paudler WW, Jovanovic M (1982) Heterocycles 19:93
Crabtree KN, Hostetler KJ, Munsch TE, Neuhaus P, Lahti PM, Sander W, Poole JS (2008) J Org Chem 73:3441
Laihia K, Kolehmainen E, Virtanen E, Nissinen M, Puszko A, Talik Z (2003) Magn Reson Chem 41:721
Abramovitch RA, Smith EM (1974) In: Abramovitch RA (ed) Pyridine and its derivatives, vol 2. Interscience, New York, p 96 and references cited therein
Bernstein J, Losee K, Lott WA (1950) J Am Chem Soc 72:4362
Brown EV (1957) J Am Chem Soc 79:3565
Adam M, Miyano S (1954) J Am Chem Soc 76:2785
Taylor EC, Driscoll JS (1960) J Org Chem 25:1716
Taylor EC, Driscoll JS (1961) J Org Chem 26:3001
Herz W, Murty DKR (1960) J Org Chem 25:2242
Talik Z, Talik T, Ban-Oganowska H, Puszko A (1982) Prace Naukowe AE 191:97
Dehn JW, Salina AJ (1966) Patent USA 3 249 597. Chem Abstr 65(90):61b
Talik T, Talik Z (1982) Prace Naukowe AE 199:145
Talik T, Talik Z (1987) Prace Naukowe AE 397:141
Talik T, Talik Z (1962) Roczniki Chemii 36:539
Hurd RE, John BK (1991) J Magn Reson 91:648
Bax A, Griffey RH, Hawkins BL (1983) J Magn Reson 55:301
Bax A, Subramanian S (1986) J Magn Reson 67:565
Bax A, Summers MF (1986) J Am Chem Soc 108:2093
Laihia K, Puszko A, Linnanto J, Kolehmainen E (2006) J Mol Struct 783:73
Laihia K, Kolehmainen E, Kauppinen R, Lorenc J, Puszko A (2002) Spectrochim Acta A 58:1425
Laihia K, Puszko A, Kolehmainen E, Lorenc J (2008) J Mol Struct 889:371
Open Access
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Author information
Authors and Affiliations
Additional information
Z. Talik: Deceased.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Puszko, A., Laihia, K., Kolehmainen, E. et al. Specificity of 15N NMR chemical shifts to the nature of substituents and tautomerism in substituted pyridine N-oxides. Struct Chem 24, 333–337 (2013). https://doi.org/10.1007/s11224-012-0069-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11224-012-0069-0