Research article Received: 25 November 2014

Revised: 26 January 2015

Accepted: 2 March 2015

Published online in Wiley Online Library: 17 April 2015

(wileyonlinelibrary.com) DOI 10.1002/mrc.4239

Simultaneous determination of the magnitude and the sign of multiple heteronuclear coupling constants in 19 F or 31P-containing compounds Josep Saurí, Pau Nolis and Teodor Parella* The presence of a highly abundant passive nucleus (Z = 19 F or 31P) allows the simultaneous determination of the magnitude and the sign of up to three different heteronuclear coupling constants from each individual cross-peak observed in a 2D 1H-X selHSQMBC spectrum. Whereas J(HZ) and J(XZ) coupling constants are measured from E.COSY multiplet patterns, J(XH) is independently extracted from the complementary IPAP pattern generated along the detected F2 dimension. The incorporation of an extended TOCSY transfer allows the extraction of a complete set of all these heteronuclear coupling constants and their signs for an entire 1H subspin system. 1H-X/1H-Y time-shared versions are also proposed for the simultaneous measurement of five different couplings (J(XH), J(YH), J(XZ), J(YZ), and J(ZH)) for multiple signals in a single NMR experiment. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: Heteronuclear coupling constants; NMR; HSQMBC; IPAP; E.COSY

Introduction

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Results and discussion Scheme 1 illustrates the different spin systems and coupling pathways studied in this work, and Table 1 summarizes the different coupling constants (magnitude and/or sign) that can be established in selHSQMBC experiments as a function of the presence of a passive spin, the use of a TOCSY transfer, or the application to the TS version. When the original selHSQMBC scheme (Fig. 1A without the TOCSY mixing) is applied on molecules containing a passive highly abundant spin Z, the corresponding J(HZ) and J(XZ) couplings can be measured from the complementary E.COSY coupling pattern,

* Correspondence to: Teodor Parella, Servei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Barcelona, Catalonia, Spain. E-mail: [email protected] Servei de Ressonància Magnètica Nuclear, Facultat de Ciències, Universitat Autònoma de Barcelona, Bellaterra, E-08193, Barcelona, Catalonia, Spain

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The determination of both the magnitude and the sign of heteronuclear coupling constants is fundamental in the structural characterization of organic, organometallic, and inorganic compounds.[1–3] Recently, a family of 1H frequency-selective HSQMBC (selHSQMBC) experiments has been proposed to obtain long-range proton-carbon J coupling constants (nJ(CH); n > 1) in a very straightforward way.[4–8] The CLIP-selHSQMBC experiment allows the easy measurement of the magnitude of nJ(CH) from pure in-phase (IP) multiplets,[5] whereas a more powerful IPAP approach can be applied to more complex multiplets by determining the relative displacement of separate α/β multiplet components along the highly resolved F2 dimension.[6] Related selHSQMBC-COSY[7] and selHSQMBC-TOCSY[8] experiments extend the measurement to other protons belonging to the same spin system, and in addition, the positive/negative sign of nJ(CH) can be obtained by comparing the relative right/left or left/right sense of the α/β signal displacement. It has also been shown that multiple and different J couplings can be simultaneously determined from the analysis of a single 2D cross-peak in modified selHSQMBC experiments involving passive 1H spins.[9] The main advantages to measure correlated coupling constants in a one-shot way compared with the sequential measurement of each individual coupling constant using different NMR experiments are for economizing spectrometer time and, most importantly, such measurements can afford the sign information that, in many cases, is not available using conventional techniques. One illustrative example is the E.COSY principle[10] that allows the measurement of two different J coupling values from the same cross-peak without interference between them, one along the F2 dimension and another from the indirect F1 dimension, whereas the slope of the tilted multiplet pattern indicates the relative positive/negative sign between these two J values. A number of different NMR solutions have been reported for the

simultaneous measurement of multiple heteronuclear coupling constants in small molecules.[11–16] Here, we show how the application of the previously reported 1 H-X selHSQMBC and selHSQMBC-TOSY experiments (X = 13C or 15 N) to molecules containing passive highly abundant spins (Z = 19 F or 31P) allows the measurement of the magnitude and the size of multiple heteronuclear coupling constants from complementary in-phase E.COSY and IPAP multiplet patterns. Additionally, time-shared (TS) versions of these selHSQMBC experiments[17] are also proposed for the simultaneous determination of multiple coupling constants for two different heteronuclei, namely X and Y, and examples for the extraction of a complete set of the magnitude and/or the sign of different heteronuclear coupling constants in nitrogen-containing molecules are provided.

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1

1

Scheme 1. Spin systems that can be studied with the H-X selHSQMBC techniques as a function of the directly involved ( H and X) and the passive (marked as Z) spins. J(HX) is determined from IPAP multiplets along the detected dimension, whereas couplings involving the passive Z spin (J(HZ) and J(XZ)) are measured from complementary E.COSY multiplet patterns. More complex spin systems involving the simultaneous detection of two heteronuclei (X and Y) can also be studied using time-shared versions.

Table 1. Magnitude and/or sign information that can be established in a family of selHSQMBC experiments as a function of the presence of passive spin, the use of the TOCSY transfer, or the application of time-shared methodology NMR experiment 1

(A) H-X selHSQMBC 1 (B) H-X selHSQMBC-TOCSY 1 (C) H-X selHSQMBC-{Z}

1

(D) H-X selHSQMBCTOCSY-{Z} 1

(E) H-X-Y-Time-sharedselHSQMBC 1 (F) H-X-Y-Time-sharedselHSQMBC-TOCSY 1 (G) H-X-Y-Time-sharedselHSQMBC-{Z}

1

(H) H-X-Y-Time-sharedselHSQMBC-TOCSY-{Z}

J and multiplet pattern

Magnitude

J(XH) via IPAP J(XH) via IPAP n J(XH) via IPAP n J(ZH) via E.COSY n J(ZX) via E.COSY n J(XH) via IPAP n J(ZH) via E.COSY n J(ZX) via E.COSY n J(XH) via IPAP n J(YH) via IPAP n J(XH) via IPAP n J(YH) via IPAP n J(XH) via IPAP n J(YH) via IPAP n J(ZX) via E.COSY n J(ZY) via E.COSY n J(ZH) via E.COSY n J(XH) via IPAP n J(YH) via IPAP n J(ZX) via E.COSY n J(ZY) via E.COSY n J(ZH) via E.COSY

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

n n

Sign No Yes No Yes Yes Yes Yes Yes No No Yes Yes No No Yes Yes Yes Yes Yes Yes Yes Yes

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independently of the determination of J(XH) from the IPAP pattern. Assuming the three-spin system represented in Fig. 1B, the corresponding H2-X cross-peak in a 1H-X selHSQMBC experiment would present a fully in-phase E.COSY multiplet pattern (Fig. 1B). The positive/negative sign and the magnitude of J(HZ) and J(XZ) could be extracted from the relative slope and the component displacement, respectively. However, the IPAP technique allows a much better cross-peak editing, enabling the additional measurement of J(XH) by analyzing the relative displacement of the resulting α/β components along the F2 dimension.

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As an example, Fig. 2 shows the 2D 1H–13C selHSQMBC spectrum corresponding to allyltriphenylphosphonium bromide (1), a molecule containing a single 31P as a passive spin, from which the simultaneous measurement of the relative sign and the magnitude of J (CP) and J(HP) coupling constants involving the selected H1 proton is achieved.[12,13] It is shown that the application of the IPAP technique simplifies and improves the peak appearance along the detected dimension, allowing the additional measurement of the small nJ(CH) coupling constants, which was not evident from the IP spectrum (compare Fig. 2B vs 2C). Otherwise, selHSQMBC experiments involve pure IP magnetization, and therefore, the incorporation of a TOCSY transfer allows the investigator to extend the determination of all J(HP), J(CP), and nJ(CH) coupling constants to an entire 1H spin system (for an example, see Fig. S2). The reported selHSQMBC methods can be successfully applied to other nuclei than X = 13C. For instance, the application of equivalent 1 H–15N selHSQMBC and selHSQMBC-TOCSY counterparts on molecules containing nitrogen and fluorine nuclei permits the simultaneous measurement of a complete set of J(NH), J(NF), and J(HF) coupling constants.[14–16] The 1H–15 N selHSQMBC spectrum of 2-fluoropyridine (2) after selective excitation of the H6 proton displays a strong cross-peak due to the large two-bond J(N-H6) value (11.3 Hz), where the small four-bond J(H6-F) (1.1 Hz) and the two-bond J(NF) (50.8 Hz) can be additionally measured into the same 2D cross-peak. Additionally, all J(NH) and J(HF) coupling constants for the relayed H3, H4, and H5 protons can be obtained in a related 1H–15 N selHSQMBC-TOCSY (Fig. 3). Note that these cross-peaks will exhibit very small intensity or they will not be observed in conventional selHSQMBC spectra due to the low nJ(NH) value. It is shown that under good digital resolution conditions, nJ (NH) values even smaller than 2 Hz can be measured along the F2 dimension using the IPAP technique, mainly because the intensity of the corresponding relayed cross-peaks depends of the efficiency of the starting N-H6 coupling and the subsequent TOCSY transfer. From the expanded area of the N-H5 cross-peak, it is shown that all magnitude and relative signs can be easily established. The tilt direction into the E.COSY pattern affords the relative sign of J(FH) with respect to the J(NF) coupling. On the other hand, the relative displacement along the F2 dimension affords the sign of nJ(NH), taking as a reference the same displacements in other cross-peaks into the same row.

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Magnitude and sign of multiple heteronuclear coupling constants

Figure 1. (A) General pulse scheme of the selHSQMBC (without the optional TOCSY mixing) and selHSQMBC-TOCSY experiments. All experimental details 1 can be found in the Supporting Information. (B) Schematic representation showing the IPAP methodology in a selHSQMBC H-X cross-peak involving a passive Z spin. Two complementary IP (Ψ = y and ε = on) and AP (Ψ = x and ε = off) datasets are initially acquired and then combined (IP + AP) to obtain α/β edited subspectra. Coupling constant values are extracted from the E.COSY and IPAP patterns as shown in the panels. The relative tilting of the E. COSY pattern provides information about the relative signs.

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Figure 2. (A) 2D H- C selHSQMBC spectrum after selective excitation of H1 proton of allyltriphenylphosphonium bromide, 1. (B) IP data yields J(HP) in the n F2 dimension as well as J(CP) in the F1 dimension. The arrows indicate the relative sign of J(CP) from the E.COSY pattern generated in the F1 dimension 31 thanks to the passive P spin. (C) The relative displacement between α (black) and β (red) cross-peaks in separate IPAP spectra allows the additional n measurement of J(CH) along the F2 dimension.

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Figure 3. Expanded area showing α/β spectra corresponding to 2D H– N selHSQMBC-TOCSY experiment after selective excitation of H6 proton of 219 fluoropyridine, 2. The passive F nucleus allows the determination of the sign and the magnitude of J(NF) and J(FH) from the relative E.COSY pattern n generated along the F1 dimension, while the sign and the magnitude of each J(NH) are measured from the relative displacement of the α/β spectra as it is shown in the overlaid 1D slices.

The different experiments described here can be further enhanced in several ways. For instance, the resolution in the F1 dimension can be improved by the use of nonlinear uniform sampling[18] and the J(HH) multiplet structure along the F2 dimension can be further simplified using broadband homodecoupled techniques such as the homonuclear decoupled band-selective selHSQMBC,[19] obtaining better resolved cross-peaks, and facilitating the extraction of 1H-X values from simplified doublet patterns (Fig. S3). The proposed methods can also be modified by implementing the time-shared (TS) evolution concept (see pulse sequence details in the Supporting Information).[17] For instance, the simultaneous measurement of small nJ(CH) and nJ(NH) coupling

1

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1

15

constants can be accomplished from a single TS-(1H,X-1H,Y)selHSQMBC experiment (X = 13C and Y = 15 N) in nitrogen-containing molecules. Figure 4 shows a practical example after selection of the H6 proton in 2. Figure 4A shows the pure IP TS-selHSQMBC spectrum where all cross-peaks belonging to 13C and 15 N present the same relative IP character, while Fig. 4B is exactly the same spectrum but with inversion of 15 N cross-peaks. Two equivalent spectra showing anti-phase (AP) character with respect to nJ(CH) and nJ(NH) are also required (Fig. S5). Combination of these four datasets affords separate spin-state selective 1H–13C and 1H–15 N spectra. Figure 4C and 4D show two expanded areas corresponding to the IPAP H6C2 and H6-N cross-peaks, where the different α (black) and β (red)

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Figure 4. 2D TS-( H, C– H, N)-selHSQMBC spectra of 2. (A) and (B) IP datasets where both C nucleus and N nucleus have the same (A) and opposite relative phases (B). Expanded areas showing the superposed α/β components corresponding to the (C) H6-C2 and (D) H6-N cross-peaks after IP ± AP data combination. Three different J couplings can be determined from each cross-peak.

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Magn. Reson. Chem. 2015, 53, 427–432

Magnitude and sign of multiple heteronuclear coupling constants spectra are shown superimposed and slightly shifted for the sake of clarity. The equivalent TS-selHSQMBC-TOCSY experiment affords an increased number of cross-peaks from which a complete set of magnitudes and signs of heteronuclear nJ(CH), nJ(NH), J(CF), J(NF), and J(FH) coupling constants can be extracted from the same dataset (Fig. S6). More and detailed information about the general concepts, experimental details, and successful implementation of the TS concepts in conventional NMR experiments are found in the supporting information and Ref. [17]. The success of the proposed experiments depends on several practical aspects: (i) the choice of the proton to be selectively refocused; (ii) the efficiency of the TOCSY transfer; (iii) good resolution along the detected dimension is needed for both IPAP and E. COSY multiplet patterns; and (iv) the number of t1 increments to be acquired will only depend of the resolution needed to resolve J(XZ) in the indirect F1 dimension. In cases where J(XZ) is not resolved, the inclusion of a J-scaling element during the t1 period, in the form of k*t1 180°(C,Z) k*t1, could be incorporated in spectrometers with a triple channel configuration.[13a] In conclusion, the success of selHSQMBC experiments for the precise determination of heteronuclear coupling constants relies on the simple analysis of the pure IP nature of their cross-peaks. It has been shown that, for molecules containing highly abundant passive spins (31P or 19 F), the high levels of digital resolution easily reached in the detected dimension and the spread of the resulting E.COSY and IPAP multiplets allow a simple measurement of both the magnitude and the sign of multiple heteronuclear coupling constants from a unique dataset. In addition, the use of an extended TOCSY transfer improves the limitation for singlefrequency proton excitation, allowing the measurement of small J values even for those protons appearing in overcrowded resonances. As an example, a complete set of magnitudes and signs of heteronuclear J(CH), J(NH), J(CF), J(NF), and J(FH) coupling constants have been extracted from the single TS NMR experiment of 2 (Table S1).

Methods and materials

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Acknowledgements Financial support for this research provided by MINECO (project CTQ2012-32436) is gratefully acknowledged. We also thank the Servei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona, for allocating instrument time to this project.

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NMR experiments were recorded on a BRUKER DRX-500 spectrometer equipped with a three-channel 5-mm cryoprobe incorporating a z-gradient coil and on a Bruker Avance 600 spectrometer equipped with TXI HCN z-gradient probes. The test samples were 30 mg of allyltriphenylphosphonium bromide dissolved in 0.6 ml of CDCl3 (1) and 25 mg of 2-fluoropyridine dissolved in 0.6 ml of CDCl3 (2). All pulse sequences used in this work are individually shown in Fig. S1: selHSQMBC (Fig. S1A), selHSQMBC-TOCSY (Fig. S1B), TSselHSQMBC (Fig. S1C), and TS-selHSQMBC-TOCSY (Fig. S1D). Thin and thick bars represent 90° and 180° non-selective pulses and are applied along the x-axis unless otherwise stated. Smoothed CHIRP adiabatic pulses were used as inversion (500 μs) and refocusing (2 ms) 13C 180° pulses. The duration of z-filtered DIPSI2 scheme was set to 30–40 ms depending on the case. A basic two-step phase cycle was employed, ϕ 1 = ϕ 2 = (x, x) and ϕ rec = (x, x), and phase-sensitive data were obtained using the gradient echo/antiecho protocol. IPAP procedure: Two independent IP and AP datasets are separately collected as a function of the pulses marked with ε: IP (Ψ = y and ε = on) and AP (Ψ = x and ε = off). Separate α/β datasets are obtained after time-domain data addition/subtraction according to AP ± IP. All data were acquired and processed with the TOPSPIN software package.

In general, a recycle delay of 1 s and a selective 180° pulse with a Gaussian shape of 20 ms of duration were used on the specified proton frequency. The interpulse INEPT delays were optimized to Δ′ + p(180°sel)/2 = 1/4*nJ(XH), and δ′ and δ″ delays compensate evolution during the variable t1 and t1′ periods. Gradients G3 and G4 flank the simultaneous 1H and 13C 180° pulses to generate pure refocusing elements. The zero-quantum filter incorporated into the TOCSY transfer consists of a G5 gradient simultaneous to a CHIRP pulse (30 ms). G1 and G2 are used for coherence selection using echo/antiecho protocol in conventional selHSQMBC experiments. All gradients had a sine shape with a duration (δ) of 1 ms followed by a recovery delay of 100 μs, and the gradient ratios G1 : G2 : G3 : G4 : G5 were set to 80 : 20.1 : 33 : 50 : 3 (% with respect to the maximum strength of 53.5 G/cm) for X = 13C or 80 : 8.1 : 33 : 50 : 3 for X = 15 N in sequences of Fig. S1A and B. In time-shared experiments (Fig. S1C and D), the t1 and t1′ increments were set to Δt1 = 1/SW(C) and Δt′1 = 1/[SW(N) 1/SW(C)], the gradients G6, G7, and G8 are used for coherence selection using echo/antiecho, and gradient strength ratios between G3 : G4 : G5 : G6 : G7 : G8 were set to 33 : 50 : 3 : 47.63 : 32.37 : 8.14. The 2D 1H-13C selHSQMBC-IPAP experiment of Fig. 2 was recorded at 500.13 MHz using the pulse sequence of Fig. S1A. The interpulse INEPT delays (Δ′ + p(180°sel)/2 = 1/4*nJ(CH)) were optimized to 8 Hz. Two scans were accumulated for each one of the 128 t1 increments; the number of data points in t2 was set to 2048, and the spectral window in both dimensions were 1502 (F2) and 1866.5 (F1) Hz, respectively. The overall acquisition time was 8 min. Zero filling to 1024 in F1, 4096 points in F2, and a sine-squared function in both dimensions were applied prior to Fourier transformation, giving a digital resolution in the F2 and F1 dimensions of 0.36 and 1.84 Hz/Pt, respectively. The 2D 1H–15 N selHSQMBC-TOCSY-IPAP experiment in Fig. 3 was recorded at 500 MHz using the pulse sequence of Fig. S1B. The interpulse INEPT delays (Δ′ + p(180°sel)/2 = 1/4*nJ(NH)) were optimized to 8 Hz, with a TOCSY mixing time of 30 ms. Sixteen scans were accumulated for each one of the 64 t1 increments; the number of data points in t2 was set to 4096, and the spectral window in both dimensions were 2500 (F2) and 2500 (F1) Hz, respectively. The overall acquisition time was 35 min. Zero filling to 1024 in F1, 4096 points in F2, and a sine-squared function in both dimensions were applied prior to Fourier transformation, giving a digital resolution in the F2 and F1 dimensions of 0.25 and 2.85 Hz/Pt, respectively. The 2D-TS-selHSQMBC-IPAP experiment in Fig. 4 was recorded at 500 MHz using the pulse sequence of Fig. S1C. The interpulse INEPT delays (Δ′ + p(180°sel)/2 = 1/4*nJ(XH)) were optimized to 10 Hz. Eight scans were accumulated for each one of the 128 t1 increments; the number of data points in t2 was set to 4096, and the spectral window in both dimensions were 2500 (F2) and 8804 (F1) Hz, respectively. The overall acquisition time was 35 min. Zero filling to 1024 in F1, 4096 points in F2, and a sine-squared function in both dimensions were applied prior to Fourier transformation, giving a digital resolution in the F2 and F1 dimensions of 0.25 and 8.60 Hz/Pt, respectively. The Bruker pulse program codes for all selHSQMBC experiments described in this work are available in our website (http://sermn. uab.cat).

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Supporting information Additional supporting information may be found in the online version of this article at the publisher’s web-site.

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Magn. Reson. Chem. 2015, 53, 427–432

Simultaneous determination of the magnitude and the sign of multiple heteronuclear coupling constants in 19F or 31P-containing compounds.

The presence of a highly abundant passive nucleus (Z = 19F or 31P) allows the simultaneous determination of the magnitude and the sign of up to three ...
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