Measurement of long‐range heteronuclear coupling constants using the peak intensity in classical 1D HMBC spectra

In this contribution, we show that the magnitude of heteronuclear long‐range coupling constants can be directly extracted from the classical 1D HMBC spectra, as all multiplet lines of a cross‐peak always and exclusively vanish for the condition Δ = k/ⁿJ_CH. To the best of our knowledge, this feature of the classical HMBC has not yet been noticed and exploited. This condition holds true, irrespective of the magnitude and numbers of additional active and passive homonuclear ⁿJ_HH′ couplings. Alternatively, the ⁿJ_CH value may also be evaluated by fitting the peak's intensity in the individual spectra to its simple sin(πⁿJ_CHΔ)exp(−Δ/T_2eff) dependence. Compared to the previously proposed J‐HMBC sequences that also use the variation of the cross‐peak's intensity for extracting the coupling constants, the classical HMBC pulse sequence is significantly more sensitive.     

Compensating for variation in 1JCH coupling constants in HSQC spectra acquired on small organic molecules

The HSQC sequence provides a sensitive way of determining the ¹³C chemical shift of protonated carbons. It uses INEPT elements for magnetization transfer, which can only be optimized for one value of ¹J_CH, but small organic molecules contain a wide range of ¹J_CH values. One popular method of compensating for ¹J_CH variation is to incorporate adiabatic pulses into the INEPT elements. This article shows that this method fails for a significant subset of functional groups. It also shows that the effects of this failure can be reduced by avoiding refocusing delays and by using a J‐compensated excitation element. Copyright © 2010 John Wiley & Sons, Ltd.     

Unequivocal total assignment of 13C and 1H NMR spectra of some pyrido[1,2‐a]pyrimidine derivatives by 2D‐NMR

We report the total assignments of the ¹³C and ¹H NMR spectra of some 4‐methyl‐2‐oxo‐(2H)‐pyrido[1,2‐a]pyrimidine and 2‐methyl‐4‐oxo‐(4H)‐pyrido[1,2‐a]pyrimidine derivatives. The products were characterized by ¹H and ¹³C NMR and reported data for similar compounds. No comparative data for the two sets of isomeric compounds with respect to ¹³C and ¹H NMR have been reported to date. We made some detailed studies of the 2D NMR spectra of these compounds and observed that assignments made for non‐protonated carbon atoms by us and those reported in the literature for similar compounds need correction. The revised assignments were made on the basis of heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) techniques. Copyright © 2003 John Wiley & Sons, Ltd.     

Frequency-swept HSQC sequences for high-throughput NMR analysis

This article describes new versions of the DEPT phase-edited heteronuclear single quantum correlation (HSQC) pulse sequence with sensitivity enhancement. The sequences incorporate frequency-swept carbon and proton pulses. The new experiments are inherently robust, well-suited for a high-throughput setting in which sample-to-sample variations may be ignored. The observed signal has the obvious benefit of sensitivity enhancement resulting from the preservation of two magnetization transfer pathways. The two pathways are maintained even in the version of the sequence in which all pulses are frequency-swept. There is an additional signal gain of roughly 10% that derives from the use of both proton and carbon frequency-swept pulses. Furthermore, the sequences use J compensation to provide optimal signal over a range of heteronuclear coupling constants. We demonstrate that the new sequences offer good sensitivity and perform well even when the NMR probe is deliberately mistuned.     

3‐Methylflavones characterization revisited: complete assignment of 1H and 13C NMR data

Ten 3‐methylflavone derivatives were studied. Previously reported NMR data of some derivatives were corrected and/or completed, including the complete assignment of the two known natural derivatives. The complete ¹H and ¹³C NMR assignments were achieved by combination of one‐dimensional and two‐dimensional NMR experiments. Copyright © 2013 John Wiley & Sons, Ltd.     

Complete assignment of 1H and 13C NMR spectra of α‐phenylsulfinyl‐N‐methoxy‐ N‐methylpropionamide and some p‐substituted derivatives

The complete assignment of the ¹H and ¹³C NMR spectra of the diastereomeric pairs of some α‐arylsulfinyl‐substituted N‐methoxy‐N‐methylpropionamides with the substituents methoxy, methyl, chloro, nitro is reported. Copyright © 2008 John Wiley & Sons, Ltd.     

Towards the automatic analysis of NMR spectra: part 6. Confirmation of chemical structure employing both 1H and 13C NMR spectra

A method of comparing predicted and experimental chemical shifts was used to confirm or refute postulated structures. 1H NMR spectra returned all true positives with a false positive rate of 4%. When an analogous procedure was adopted for 13C NMR spectra, the false positive rate dropped to 1%, whereas the more practical HSQC data yielded a false positive rate of 2%. If the HSQC results were combined with 1H results, a false positive rate of 1% resulted, 4 times more accurate than 1H alone.     

A toolbox of HSQC experiments for small molecules at high 13C‐enrichment. Artifact‐free,fully 13C‐homodecoupled and JCC‐encoding pulse sequences

A set of modified HSQC experiments designed for the study of ¹³C‐enriched small molecules is introduced. It includes an improved sensitivity‐enhanced HSQC experiment eliminating signal artifacts because of high‐order ¹³C magnetization terms generated at high ¹³C enrichment. A broadband homonuclear ¹³C decoupling sequence based on Zangger and Sterk's method simplifies the complex ¹³C–¹³C multiplet structure in the F1 dimension of HSQC. When recording spectra at high resolution, the combination with a multiple‐site modulation of the selective pulse outperforms the constant‐time HSQC in terms of sensitivity and reliability. Finally, two pulse sequences reintroducing selected J_CC couplings with selective pulses facilitate their assignments and measurements either in the splitting of the resulting doublets or by modulation of the signal amplitude. A sample of uniformly 92% ¹³C‐enriched cholesterol is used as an example. Copyright © 2013 John Wiley & Sons, Ltd.     

1H and 13C NMR spectral assignments of pyridinium salts linked to a N‐9 or N‐3 adenine moiety

¹H and ¹³ C NMR spectral data of 13 new compounds containing a 4‐(dimethylamino)‐ or 4‐(pyrrolidin‐1‐yl)pyridinium moiety linked to the N‐9 or N‐3 nitrogen atom of an adenine moiety were assigned. 1D and 2D NMR experiments (DEPT, HSQC and HMBC) allowed the unequivocal identification of N‐9 and N‐3 isomers. Copyright © 2012 John Wiley & Sons, Ltd.     

D-HMBC versus LR-HSQMBC: Which experiment provides theoretically and experimentally the best results?

The long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) experiment is the experiment of choice for visualizing heteronuclear long-range coupling interactions ⁿJ_CH across 4–6-bonds and is experimentally superior to the decoupled heteronuclear multiple-bond correlation (D-HMBC) experiment. Yet, the exact reasons have not been fully understood and established. On the basis of our recent investigation of the nonrefocused variants LR-HSQC and HMBC, we have extended a J_HH′-dedicated investigation to the D-HMBC and LR-HSQMBC experiments. Unlike the nonrefocused variants, the influence of homonuclear couplings J_HH′ on the intensity of long-range ⁿJ_CH cross-peaks is not easily predictable and may be summarized as follows: (a) irrespective of the magnitude and number of J_HH′ interactions long-range ⁿJ_CH cross-peaks are more intense in D-HMBC spectra as long as the evolution delay Δ is not too large, because in contrast to LR-HSQMBC no J_HH′-caused intensity zeroes will occur. (b) If J_HH′ is small and Δ large, the intensity of cross peaks in D-HMBC spectra may be weakened or may even vanish at Δ = (0.25+0.5k)/J_HH′, whereas for the LR-HSQMBC this unwanted effect occurs at Δ = k + 0.5/J_HH′. Consequently, when Δ is adjusted to visualize weak ⁿJ_CH long-range correlations, our findings corroborate that there are potentially more cross-peaks expected to show up in a LR-HSQMBC spectrum compared with a D-HMBC spectrum. This has been indeed noticed experimentally, even though the intensity of a many long-range ⁿJ_CH cross-peaks may still be higher in the spectra of the D-HMBC experiment correspondingly adjusted for detecting weak ⁿJ_CH correlations.     

Complete assignment of the 1H and 13C NMR spectra of four 2‐substituted 4a,8a‐cis‐endo‐5,8‐methano‐4a,5,8,8a‐tetrahydronaphthalene‐1,4‐diones

The complete assignment of the ¹H and ¹³C NMR spectra of the title enediones, bearing as substituents N‐aziridinyl (a novel compound), methoxy, chloro and methylsulfanyl, is reported. Copyright © 2002 John Wiley & Sons, Ltd.     

Automated compound verification using 2D-NMR HSQC data in an open-access environment

Since the introduction of NMR prediction software, medicinal chemists have imagined submitting their compounds to corporate compound registration systems that would ultimately display a simplified pass/fail result. We initially implemented such a system based on HPLC and liquid chromatography mass spectrometry (LCMS) data that is embedded within our industry standard sample submission and registration process. By using gradient-heteronuclear single quantum coherence (HSQC) experiments, we have extended this concept to NMR data through a comparison of experimentally acquired data against predicted (1)H and (13)C NMR data. Integration of our compound registration system with our analytical instruments now provides our chemists unattended and automated NMR verification for collections of submitted compounds. The benefits achieved from automated processing and interpretation of results produced enhanced confidence in our compound library and released the chemists from the tedium of manipulating large amounts of data. This allows scientists to focus more of their attention to the drug discovery process.     

Spectroscopic separation of 13C NMR spectra of complex isomeric mixtures by the CSSF‐TOCSY‐INEPT experiment

Isomeric mixtures from synthetic or natural origins can pose fundamental challenges for their chromatographic separation and spectroscopic identification. A novel 1D selective NMR experiment, chemical shift selective filter (CSSF)‐TOCSY‐INEPT, is presented that allows the extraction of ¹³C NMR subspectra of discrete isomers in complex mixtures without physical separation. This is achieved via CSS excitation of proton signals in the ¹H NMR mixture spectrum, propagation of the selectivity by polarization transfer within coupled ¹H spins, and subsequent relaying of the magnetization from ¹H to ¹³C by direct INEPT transfer to generate ¹³C NMR subspectra. Simple consolidation of the subspectra yields ¹³C NMR spectra for individual isomers. Alternatively, CSSF‐INEPT with heteronuclear long‐range transfer can correlate the isolated networks of coupled spins and therefore facilitate the reconstruction of the ¹³C NMR spectra for isomers containing multiple spin systems. A proof‐of‐principle validation of the CSSF‐TOCSY‐INEPT experiment is demonstrated on three mixtures with different spectral and structural complexities. The results show that CSSF‐TOCSY‐INEPT is a versatile, powerful tool for deconvoluting isomeric mixtures within the NMR tube with unprecedented resolution and offers unique, unambiguous spectral information for structure elucidation. Copyright © 2014 John Wiley & Sons, Ltd.     

Complete assignment of NMR data of 22 phenyl‐1H‐pyrazoles' derivatives

Complete assignment of ¹H and ¹³C NMR chemical shifts and J(¹H/¹H and ¹H/¹⁹F) coupling constants for 22 1‐phenyl‐1H‐pyrazoles' derivates were performed using the concerted application of ¹H 1D and ¹H, ¹³C 2D gs‐HSQC and gs‐HMBC experiments. All 1‐phenyl‐1H‐pyrazoles' derivatives were synthesized as described by Finar and co‐workers. The formylated 1‐phenyl‐1H‐pyrazoles' derivatives were performed under Duff's conditions. Copyright © 2011 John Wiley & Sons, Ltd.     

Discrimination of pseudo‐meta and pseudo‐para diamino‐octafluoro[2.2]paracyclophanes by 1H, 19F,and 13C NMR

Pseudo‐meta and pseudo‐para diamino‐octafluoro[2.2]paracyclophanes are challenging to separate either by chromatography or recrystallization, but through the use of a mixture of the two isomers, the ¹H, ¹⁹F, and ¹³C NMR spectra of these compounds have been fully and unambiguously assigned using ¹H COSY, ¹H‐¹⁹F HOESY, ¹H‐¹³C HSQC, ¹H‐¹³C HMBC, and ¹⁹F‐¹³C HSQC techniques. This permits the easy identification of either of the individual isomers. In addition, the ¹³C spectrum of the pseudo‐ortho analogue is reported and assigned for the first time. The gem shift effect in this series of bridge‐fluorinated paracyclophanes serves to deshield ¹H resonances and shield ¹³C. Copyright © 2012 John Wiley & Sons, Ltd.     

1H and 13C NMR analysis of 2‐acetamido‐3‐mercapto‐3‐methyl‐N‐aryl‐butanamides and 2‐acetamido‐3‐methyl‐3‐nitrososulfanyl‐N‐aryl‐butanamide derivatives

The complete assignment of the ¹H and ¹³C NMR spectra of various 2‐acetamido‐3‐mercapto‐3‐methyl‐N‐aryl‐butanamides and 2‐acetamide‐3‐methyl‐3‐nitrososulfanyl‐N‐aryl‐butanamides with p‐methoxy, o‐chloro and m‐chloro substituents is reported. Copyright © 2013 John Wiley & Sons, Ltd.     

Photo‐induced cross‐linking mechanism in azide–novolac negative photoresists: molecular level investigation using NMR spectroscopy

Negative photoresists are composed of a photoactive component (aromatic azides/bisazides) and cyclized rubber or novolac resin dissolved in an organic solvent. Hydrogen abstraction and/or insertion reaction of the reactive nitrene intermediate formed during photoirradiation of the azide result in a cross‐linked network of the novolac resin. The molecular weight of novolac resin in the exposed part of the photoresist film thus increases compared with that of the unexposed part. This makes the exposed part insoluble in the alkaline developer. Exploiting this change in physical property, a pattern can be transferred to a substrate from a mask. A better understanding of the exact mechanism of cross‐linking reactions is very important to the design of a high‐performing negative photoresist. A quinone–imine‐type complex has been proposed earlier involving the aromatic moiety of novolac resin as the reaction site. A more recent study focuses the attack of nitrene on the methylenic bridge and hydroxyl group of novolac resins, which were found to be responsible for the cross‐linking reaction along with the aromatic moiety of novolac resin. However, in our study no evidence was found for the involvement of a methylenic hydrogen or aromatic moiety of novolac resin in the cross‐linking reaction. The ¹H NMR, ¹³C NMR and DEPT‐135 spectra before and after photolysis indicate that the cross‐linking site is predominantly the hydroxyl group of novolac resin. Multiple reaction sites of attack for the nitrene intermediate have been demonstrated in cashew nut shell liquid (CNSL)‐based novolac resin by ¹H NMR spectroscopy, which in turn further increases the cross‐linked network in the exposed part of a negative photoresist. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and structure elucidation of three series of nitro‐2‐styrylchromones using 1D and 2D NMR spectroscopy

2‐Styrylchromones, although scarce in nature, constitute a group of oxygen heterocyclic compounds which have shown significant biological activities. New nitro‐2‐styrylchromones have been synthesised by the Baker–Venkataraman method, and the structure elucidation was accomplished using extensive 1D (1H, 13C) and 2D NMR spectroscopic studies (COSY, HSQC and HMBC experiments). Copyright © 2009 John Wiley & Sons, Ltd.     

Radiofrequency‐induced temperature increase as a function of cross polarization contact time in 8CB

In this work we analyse the non‐negligible heating effect that can be produced by the radiofrequency during the contact time in Hartmann–Hahn cross polarization experiments in liquid crystals. We perform the analysis in the nematic phase of 4‐n‐octyl‐4′‐cyanobiphenyl (8CB). The heating effect is quantified through the chemical shifts of the carbon resonances, which move towards their respective positions in the isotropic phase when increasing the contact time. The calibration procedure involves an independent measurement of chemical shift dependence on externally controlled bath temperature. This variation was performed in the range between 300 and 313 K covering the smectic A and nematic mesophases. An overall heating rate of 0.16 K ms^?1 is observed during the contact time in a cross polarization experiment performed at ω₁/2π ? 80 kHz. This rate goes to approximately one‐half for ω₁/2π ? 60 kHz and becomes unobservable for ω₁/2π < 50 kHz under typical experimental conditions. Copyright © 2002 John Wiley & Sons, Ltd.     

The advantages of forward linear prediction over multiple aliasing for obtaining high‐resolution HSQC spectra in systems with extreme spectral crowding

The resolution obtained for the highly crowded ¹³C–¹H HSQC spectrum of a mixture of three trisaccharides using forward linear prediction is compared with that recently reported for the same mixture but using multiple (100‐fold or greater) aliasing of HSQC spectra in combination with a computer program to unfold the aliased spectra. It is shown that forward linear prediction gives slightly superior resolution while avoiding the significant sensitivity loss associated with the very narrow spectral windows and consequent long evolution times required for the multiple aliasing method. Copyright © 2003 John Wiley & Sons, Ltd.