Specificity of 15N NMR chemical shifts to the nature of substituents and tautomerism in substituted pyridine N-oxides

Abstract

1 H, 13 C, and 15 N 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). d( 15 N) 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, d( 15 N) 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, 1 H and 13 C NMR spectral data are in agreement with 15 N 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.

Towards an Accurate Prediction of Nitrogen Chemical Shifts by Density Functional Theory and Gauge‐Including Atomic Orbital

“…Based on our data, Methods 5 and 6 with geometry optimization at M062X/6-31+G(d,p) or M062X/6-31+G(2d,p) in the gas phase and NMR GIAO calculations at mPW1PW91/6-311+G(2d,p) with the Solvation Model based on Density (SMD) solvent model and Method 7 with geometry optimization and NMR GIAO calculation at B3LYP/cc-pVDZ with the conductorlike polarizable continuum model (CPCM) solvent model provide the best performance for predictions. The advantage of Methods 5 and 6 lies in providing the chemical shift prediction for 1 H, 13 C, and 13 N in one set of calculations taking advantage of previous work. [17] We also note that the fitted empirical scaling factors provide a better prediction for 15 N chemical shifts in CHCl 3 than those in DMSO in terms of RMSDs (Table 2).…”

“…[1] Development of accurate, yet practically with low to moderate computational costs by applying an empirical scaling to minimize the systematic errors in the adopted models. The success of such empirical scaling is demonstrated by the superior performance of predictions of chemical shifts for 1 H and 13 C, which has been recently reviewed by Lodewyk et al [1] It has been noted that the major benefit of this empirical scaling is that the slope can be used as an empirical correction to correct the computed chemical shifts for systematic errors. Such a procedure can reduce error from various sources such as solvation effects, rovibratory effects, and other methodological limitations.…”

“…It has been suggested that the high sensitivity of the nitrogen lone pair to changes in the molecular environment makes 15 N NMR an exceptionally useful tool. [11][12][13] However, compared to 1 H and 13 C, the range of 15 N chemical shifts is much larger (up to 1200 ppm), making it very challenging to develop an empirical scaling that works satisfactorily across all the 15 N chemical shift ranges. Moreover, oxidation states, conformational variations, and protonation states pose additional challenges for theoretical predictions of 15 N chemical shifts.…”

“…We compiled a database with small and relatively rigid molecules covering most common nitrogen containing functional groups and developed empirical scaling parameters for linear regression approaches with seven levels of theory. As a complement to previous experimental and computational work on 1 H and 13 C, [1,14,15] our protocol will assist in the full realization of predictions of chemical shifts in structural elucidations of many important natural products and pharmaceutical related NMR compounds. Furthermore, to the best of our knowledge, the transferability for the linear regression models between different solvents was investigated for the first time.…”

NMR Spectroscopic Study of Tautomerism in Solution and in the Solid State

“…chemical shifts are again the most sensitive NMR parameters to the effects of substituents and tautomerism in a large variety of substituted pyridine N-oxides[105].5.3.9 Tautomeric Structures in Nucleosides, Nucleotides, and ProteinsBecause of the low sensitivity of 15 N NMR spectroscopy, in playing a dominant role in the study of the tautomeric structures of nucleosides and nucleotides, 15 Nlabeled amino bases are very useful to enable recording of the high-resolution 15 N NMR spectra. Full 15 N labeling of adenine, for instance, suggested the existence of the N(3)-H species in the tautomeric equilibrium, in addition to the well-reported major N(9)-H and minor N(7)-H tautomers (Figure 5.5)[107].…”