CIGAR-HMBC experiment

As a final piece of data to further support the structure of 15, a 3-6-Hz optimized CIGAR-HMBC experiment was also acquired over a weekend... 

One of the examples shown by Kline and Cheatham compares the correlations observed in a GNHMBC experiment with those from a N-optimized CIGAR-HMBC experiment performed on 5-chloro-l,3-dimethylpyrazole (2). When conventional, statically optimized GNHMBC data were acquired, then only a correlation from the H4 resonance to the NMe N1 resonance at 196.7 ppm was observed. In contrast, when a 3-10 Hz optimized CIGAR-HMBC spectrum was recorded, a correlation was also observed to the N2 resonance at 309.5 ppm. 

HMBC experiment. However as already discussed decreasing the corresponding free precession period prior to the coherence transfer reintroduces splitting due to IH, IH coupling in the fl dimension. So alternative experiments such as IMPEACH-HMBC and CIGAR-HMBC experiment have been designed to suppress this splitting [5.173, 5.174, 5.175]. 

In the early days of heteronuclear correlation spectroscopy, a gradient free version of the double low-pass filter was proposed [5.212, 5.213], but the necessity to suppress unwanted coherences, particularly in INADEQUATE experiments, has forced the design of a gradient version [5.214]. The application of this filter is not just restricted to INADEQUATE experiments it has also become the element of choice in ACCORD-HMBC and ACCORD-CIGAR-HMBC experiments to reduce residual one-bond correlations. These experiments are very sensitive to the suppression of one-bond... 

Retrospectively, after demonstrating in the implementation of the IMPEACH-MBC experiment that it is possible to suppress F skew, it was evident that the skew of responses in F, while a nuisance if uncontrolled, could serve as a useful means of response authentication if Fi skew was under user control. The CIGAR-HMBC experiment aeeomplishes this task. While the constant time variable delay of the IMPEACH-MBC experiment (see Eq. (8)) renders the duration of the variable delay constant, the CIGAR-HMBC pulse sequence modifies the variable delay interval of the experiment still further, as shown below the complete puLse sequence is shown in Fig. 17. 

Fig. 19. Pulse sequence for the J, J-HMBC experiment described by Krishnamurthy ei This experiment represents the most refined version of the accordion-optimized experiments to be developed thus far and allows the differentiation of Jxh from Jxh long-range correlations to protonated heteroatoms ( - C and N). The experiment further modifies the concept of the constant time variable delay used in the IMPEACH-MBC and CIGAR-HMBC experiments to even more selectively manipulate various components of magnetization. This is done using the pulse sequence operator given the acronym STAR (Selectively Tailored Accordion F Refocusing) (.see also Fig. 20). Differentiation of various components of heteronuclear long-range magnetization is accomplished within the STAR operator, with the balance of the pulse sequence similar to that of the IMPEACH-MBC and CIGAR-HMBC experiments.

Fig. 8.27 F] skew inherent to responses in ACCORD-HMBC spectra is only partially user controllable. These properties prompted the development of the IMPEACH-MBC experiment [146], which suppresses F skew. Further modification to re-introduce user-controlled F skew was incorporated into the CIGAR-HMBC experiment using a parameter called jg aie [147]. The effect of adjusting the Js aie pai a-meter in the CIGAR-HMBC experiment is shown for the 3-methylene group of 2-penta-none over a range ofJscaie settings from 0 to 24.

M. Kline, S. Cheatham, A robust method for determining H—optimized CIGAR-HMBC experiments, Magn. Reson. Chem. 41 (2003) 307—314. 

In 2000, Krishnamurthy et al. have presented the 2/,3/-HMBC experiment (Figure 20), that affords for the first time the means of unequivocally differentiating between 2/ch from 3Jch correlations.59 Their approach is based on a further derivative of the constant-time variable delay introduced in the IMPEACH-MBC experiment. The user-definable /-scaling factor of the CIGAR-HMBC is used in the new experiment, the 2J,3J-HMBC experiment, to differentiate between 2/CH from 3Jch correlations. This new pulse sequence element has been given the acronym STAR (Selectively Tailored Accordion F1 Refocused) operator. 

Figure 20 Timing diagram of the suggested 2y,3y-HMBC experiment, including a LPJF3 for efficient 1JCH suppression. The sequence is virtually identical to the CIGAR-HMBC pulse sequence. The STAR operator is also a constant-time variable element. In this fashion, scalable F, modulation can be specifically introduced for 2JCH cross-peaks into the spectrum independently of the digitization employed in the second frequency domain.

Investigation of the robustness of optimized CIGAR-HMBC. Kline and Cheatham in developing a N-optimized variant of CIGAR-HMBC (see Section 2.2) extensively applied the experiment in an effort to determine its robustness relative to conventional HMBC for structural characterization. assignments reported by... 

In contrast to the IMPEACH-HMBC experiment, the CIGAR experiment incorporates into the constant-time variable delay incrementation of dO, the f 1 increment. A further development is the STARR operator whereby in a 2J, 3J-HMBC experiment it is possible to label the 2J(C, H) correlation peaks by a tilt due to 3J(H, H). A pre-requisite for this labelling is that the I3c nucleus is neither a quaternary atom or completely substituted. The STARR operator is shown below and it is left as an exercise for the reader [5.175]. 

Looking at this second edition in a little more detail chapter 5.3.1 has been extended to include simulations of multiple offset selective pulse experiments whilst chapter 5.5.2 examines ACCORDION-principle based HMBC experiments. Multiple offset selective pulse experiments are now an important application in LC-NMR and biomolecular NMR spectroscopy whilst the discussion of the CIGAR and the IMPEACH-HMBC experiment in chapter 5.5.2 are an invitation to use NMR-SIM to trace complex pulse sequences back to their origin. There is now a more comprehensive discussion of filter elements, which are now a vital element in the latest pulse sequences, in chapter 5.8.2. Finally the new chapter 5.9 is subdivided into two subsections. The first subsection 5.9.1 is a collection of some of the latest published ideas to improve existing sequences. Section... 

While uncontrolled F response skew of the type encountered in the ACCORD-HMBC experiment is undesirable [145], user-defined Fj skew can be a useful determinant of response authenticity. A further generation accordion-optimized long-range experiment, CIGAR-HMBC, was developed to provide this flexibility. The constant time variable delay from the IMPEACH-MBC experiment was further modified as follows ... 

A 2002 review by Reynolds and Enriquez describes the most effective pulse sequences for natural product structure elucidation.86 For natural product chemists, the review recommends HSQC over HMQC, T-ROESY (transverse rotating-frame Overhauser enhancement) in place of NOESY (nuclear Over-hauser enhancement spectroscopy) and CIGAR (constant time inverse-detected gradient accordion rescaled) or constant time HMBC over HMBC. HSQC spectra provide better line shapes than HMQC spectra, but are more demanding on spectrometer hardware. The T-ROESY or transverse ROESY provides better signal to noise for most small molecules compared with a NOESY and limits scalar coupling artefacts. In small-molecule NMR at natural abundance, the 2D HMBC or variants experiment stands out as one of the key NMR experiments for structure elucidation. HMBC spectra provide correlations over multiple bonds and, while this is desirable, it poses the problem of distinguishing between two- and three-bond correlations. 

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