Problems, artifacts and solutions in the INADEQUATE NMR experiment

Abstract

The INADEQUATE experiment can provide unequalled, detailed information about the carbon skeleton of an organic molecule. However, it also has the reputation of requiring unreasonable amounts of sample. Modern spectrometers and probes have mitigated this problem, and it is now possible to get good structural data on a few milligrams of a typical organic small molecule. In this paper, we analyze the experiment step by step in some detail, to show how each part of the sequence can both contribute to maximum overall sensitivity and can lead to artifacts. We illustrate these methods on three molecules: 1-octanol, the steroid 17α-ethynylestradiol and the isoquinoline alkaloid β-hydrastine. In particular, we show that not only is the standard experiment powerful, but also a version tuned to small couplings can contribute vital structural information on long-range connectivities. If the delay in the spin echo is long, pairs of carbons with small couplings can create significant double-quantum coherence and show correlations in the spectrum. These are two-and three-bond correlations in a carbon chain or through a heteroatom in the molecule. All these mean that INADEQUATE can play a viable and important role in routine organic structure determination.

Sensitivity enhancement for maximally resolved two‐dimensional NMR by nonuniform sampling

“…Therefore, it is highly desirable to resort to twodimensional heteronuclear correlation 1 H(X) experiments to provide the needed spectral dispersion to aid in completing assignments. It can be difficult to obtain concentrations of these molecules on the scale of several millimolar, which would be sufficient for 1 H NMR studies but can still impair multi-dimensional heteronuclear NMR such as observing 13 C-1 H correlations. Unfortunately, and in contrast to biopolymers, there are no general routes to enrich small biomolecules in rare isotopes such as 13 C or 15 N. Importantly, cryogenic probe technologies provide overall sensitivity enhancement and are increasingly available in configurations which optimize the signal-to-noise ratio (SNR) for X nucleus (e.g.…”

Use of continuous optimization methods to find carbon links in 2D INADEQUATE spectra

“…The correlations in the INADEQUATE plots all appear as simple AB spectra. Since both parts of a correlation come from the same double-quantum coherence, the two parts of the correlation should be mirror images [22], although pathological offset effects [23] may slightly distort the symmetry. These key facts allow us to build penalty functions who guide the optimization toward the global minimum.…”

Broadband Continuous Nuclear Magnetic Resonance Signal in a Pulsed Magnetic Field: Numerical Solutions of Bloch Equations under Radio Frequency Irradiation

“…The Bloch equations are a set of macroscopic equations used to calculate the nuclear magnetization M = (M x , M y , M z ) as a function of time. Up until now, these equations were solved by the application of a Laplace transform [13], a multiple-derivative method [14], numerical integration [15], and a Lagrange interpolation method [16]. Despite the availability of these solutions, as far as we know, there are no solutions under the condition of pulsed magnetic fields, especially when the RF excitation field is a broadband continuous wave.…”