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Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N ‐Oxides Using 1 H– 15 N HMBC NMR Spectroscopy
Author(s) -
Sheehy Kevin J.,
Bateman Lorraine M.,
Flosbach Niko T.,
Breugst Martin,
Byrne Peter A.
Publication year - 2020
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202000329
Subject(s) - alkylation , chemistry , pyridine , azine , nuclear magnetic resonance spectroscopy , chemical shift , medicinal chemistry , carbon 13 nmr , nmr spectra database , organic chemistry , spectral line , catalysis , physics , astronomy
A series of representative diazines and pyridine N ‐oxides were subjected to alkylation using several different alkylating agents. The 15 N NMR chemical shifts (δ N values) of the diazines, pyridine N ‐oxides and derived alkylation products were determined using 1 H‐ 15 N HMBC NMR spectroscopy at natural 15 N abundance. The changes in the 15 N NMR chemical shifts (Δ(δ N ) values) that occurred on going from starting materials to products in these reactions were analyzed. N‐alkylation of diazines resulted in large upfield shifts of the δ N values of the alkylated nitrogen (of the order of 100 ppm or greater). While O‐alkylation of pyridine N ‐oxides resulted in upfield shifts of the δ N values of the N ‐(alkoxy)pyridinium nitrogen, the Δ(δ N ) values were of a much smaller magnitude ( ca . –42 ppm) than those observed for N‐alkylations of diazines. Nitrogen NMR spectroscopic data from the literature of relevance to alkylation of azines, diazines, azine N ‐oxides and diazine N ‐oxides was gathered together, and using this in tandem with our 15 N NMR spectroscopic data, we have been able to corroborate our observations on the trends observed in the Δ(δ N ) values associated with N‐ and O‐alkylation reactions of aromatic N‐heterocycles and N ‐oxides. An analysis protocol that relies on synergistic evaluation of 1 H‐ 15 N HMBC and 1 H‐ 13 C HMBC NMR spectra has been developed that enables unambiguous diagnosis of the occurrence of N‐alkylation of aromatic N‐heterocycles and O‐alkylation of aromatic N ‐oxides.