Revealing the Local Proton Network through Three-Dimensional 13C

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Revealing the Local Proton Network Through ThreeDimensional C/H Double Quantum/H Single Quantum and H Double Quantum/ C/H Single Quantum Correlations Fast MAS Solid-State NMR Spectroscopy at Natural Abundance 13

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Michal Malon, Manoj Kumar Pandey, and Yusuke Nishiyama J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b06203 • Publication Date (Web): 07 Aug 2017 Downloaded from http://pubs.acs.org on August 12, 2017

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The Journal of Physical Chemistry

Revealing the Local Proton Network Through Three-Dimensional 13C/1H Double Quantum/1H Single Quantum and 1H Double Quantum/13C/1H Single Quantum Correlations Fast MAS Solid-State NMR Spectroscopy at Natural Abundance Michal Malon1,2, Manoj Kumar Pandey3 and Yusuke Nishiyama1,2* 1

RIKEN CLST-JEOL Collaboration Center, Yokohama, Kanagawa 230-0045, Japan

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JEOL RESONANCE Inc., Akishima, Tokyo 196-8558, Japan

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Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India

* Corresponding author: tel +81-42-542-2236, email [email protected]

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Abstract 1

H double quantum (DQ)/1H single quantum (SQ) correlation solid-state NMR spectroscopy is

widely used to obtain internuclear 1H-1H proximities, especially at fast magic angle spinning (MAS) rate > 60 kHz. However, 1H signals are not well-resolved due to intense 1H-1H homonuclear dipolar interactions even at the attainable maximum MAS frequencies of ~100 kHz to date and/or under 1

H-1H homonuclear dipolar decoupling irradiations. Here we introduce novel three-dimensional (3D)

experiments to resolve the 1H DQ/1H SQ correlation peaks using the additional Although the low natural abundance of

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C dimension.

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C (1.1%) significantly reduces the sensitivities, the 1H

indirect measurements alleviate this issue and make this experiment possible even at naturally abundant samples. The two different implementations of

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C/1H DQ/1H SQ correlations and 1H

DQ/13C/1H SQ correlations are discussed and demonstrated using L-histidine.HCl.H2O at natural abundance to reveal the local 1H-1H networks nearby each

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C. In addition, the complete 1H

resonance assignments are achieved from a single 3D 13C/1H DQ/1H SQ experiment. We have also demonstrated the applicability of our proposed method on a biologically relevant molecule capsaicin.


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Introduction Protons are the first choice of nuclei for solution NMR studies because of high abundance and gyromagnetic ratio, thus enhanced sensitivity. Moreover, rapid isotropic tumbling of the molecules in solution results in the averaging of the orientation dependent anisotropic interactions that lead to well-resolved NMR spectra. On the other hand, broad and featureless lineshapes due to intense 1H-1H homonuclear dipolar interactions hamper the observation of 1H using the solid-state NMR1. In the past, many research groups have put tremendous efforts in developing methods to improve the 1H resolution of rigid solids 2,3,4 . The 1H-1H homonuclear decoupling sequences combined with magic-angle spinning (MAS) are the widely used methods for 1H resolution enhancement in one and higher dimensional manner. Especially, the 1H double quantum (DQ)/1H single quantum (SQ) 2D correlation experiment recorded with

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H-1H homonuclear dipolar

decoupling gives direct evidence of 1H-1H proximities and hence, the hydrogen bonding network as well 5 . Major disadvantage of 1H-1H decoupling is the complexity associated with the pulse sequences and thus 1H-1H decoupling requires careful setting of the experimental conditions, while a few simple and systematic approaches have also been proposed earlier to alleviate such complexity6. Moreover, the 1H spectra are associated with experimental condition dependent scaling factor, which should be taken into account to analyze the chemical shift values. Alternatively, fast MAS (> 60 kHz) can be used to improve the resolution and sensitivity of rigid solids. Recent development of fast MAS equipment has allowed the spinning rate faster than 100 kHz which dramatically improves the 1H NMR resolution7,8,9,10,11,12. The fast MAS greatly reduces the difficulty associated with the setup of the 1H-1H decoupling pulse sequences and moreover, 1H spectra are not accompanied with any 1H chemical shift scaling. Consequently, fast MAS technique is rapidly emerging as the method of choice for 1H-based measurements. In addition to the 1H DQ/1H SQ correlation experiments, various single channel 1H-detected experiments have been developed in the past13. For example, 2D 1H chemical shift anisotropy (CSA)/1H SQ14,15, 3D 1H SQ/1H DQ/1H SQ16,17, 3D 1H CSA/1H DQ/1H SQ18, 3D 1H DQ/1H DQ/1H SQ19, etc. Although these homonuclear multi-dimensional experiments greatly improve the 1H resolution, the practical 1H resolution is still limited due to residual 1H-1H dipolar broadening, limited 1H chemical shift range (typically 0-20 ppm), and MAS rate independent inhomogeneous broadenings including structural distributions, anisotropic bulk magnetic susceptibility (ABMS) broadening, residual dipolar splitting (RDS), etc. Recently, constant-time acquisition approaches are demonstrated to remove the broadening due to residual 1H-1H dipolar broadening but fail to remove the broadening originating from the other sources20. The poor resolution due to the limited 1H resolution is dramatically alleviated by the introduction of the heteronuclear (X) dimension. In addition to the resolution improvement, the indirect observation of X nuclei via 1H also enhances the sensitivity21,22,23. Here, X nuclei can either 3 ACS Paragon Plus Environment


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be spin-1/2 or quadrupolar nuclei24,25,26,27. Such method is not only restricted to 2D experiments rather higher dimensional experiments (> 2) can also be designed with various combinations of building blocks. Especially, 3D 1H DQ/14N/1H SQ28 is particularly useful to observe 1H/1H/14N networks because of the importance of 14N in chemistry, biology, pharmaceutical sciences, etc., and the high abundance of

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N (>99%). However, the

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N resolution is somewhat limited compared to

spin-1/2 nuclei, because the presence of the quadrupolar interactions broadens the 14N lineshape via second order broadening, which cannot be removed by MAS. Nonetheless, the quadrupolar interactions can partially improve the resolution through isotropic quadrupolar shift at the same time. In this paper, we demonstrate the 3D

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C/1H DQ/1H SQ correlation experiments on

naturally abundant samples. Since 13C is a spin-1/2 system, it offers much higher resolution than 14N due to the absence of quadrupolar broadening. On the other hand, the low abundance of 13C (1.1%) largely reduces the sensitivity. Fortunately, the sensitivity enhancement via 1H-detection together with high efficiencies of DQ filtering and two-way 1H→13C→1H magnetization transfer allows the 3D experiment in the reasonable measurement time even for naturally abundant samples. The 1H DQ/1H SQ planes at each 13C peak reveal local 1H-1H spin networks. We also demonstrate the 3D 1H DQ/13C/1H SQ correlation experiment by interchanging the 1H DQ dimension with the

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dimension and discuss the pros and cons of the two 3D experiments. Due to the limitation of

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C C

sensitivity and resolution, the methods presented are suitable for analyzing organic samples such as pharmaceutical compounds and natural products at natural abundance with molecular weight less than c.a. 500 Da. Most importantly complexities associated with isotopic labeling due to the high cost and practical difficulties can be avoided. The methods are demonstrated on the hydrochloride salt of amino acid, L-histidine (L-histidine.HCl.H2O) at natural abundance. The proposed 3D 13C/1H DQ/1H SQ correlation method is further applied to a biologically relevant molecule capsaicin to get partial assignment of 1H and

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C signals. Capsaicin is an active ingredient of red pepper and also

responsible for the hot taste. It acts as a pain reliever by activating a heat-sensitive ion channel, the transient receptor potential vanilloid 1 (TRPV1).

Pulse sequence The pulse sequences for 2D 1H DQ/1H SQ (Figure 1a), 2D 13C/1H SQ (Figure 1b), 3D 1H DQ/13C/1H SQ (Figure 1c) and 3D

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C/1H DQ/1H SQ (Figure 1d) experiments are shown. The 3D

sequences shown are constructed from simple combinations of the highly sensitive 13C/1H SQ cross polarization (CP)- heteronuclear single quantum correlation (HSQC)21 (Figure 1b) and 1H DQ/1H SQ BABA sequences (Figure 1a)29,30. It should be noted that 13C/1H CP-HSQC sequence in the 2D and 3D sequences can be replaced with CP/INEPT-HSQC sequence to reveal through-bond connectivities instead of through-space correlations31. Similarly, 1H DQ recoupling can also be replaced with other recoupling sequences32,33,34. The above pulse sequences demonstrated for 4 ACS Paragon Plus Environment

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C

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can also be used for the other spin-1/2 heteronuclei like 15N, 31P, etc. to get additional assignment.

Figure 1 Pulse schemes for (a) 2D 1H DQ/1H SQ (BABA), (b) 2D DQ/13C/1H SQ (BABA/CP-HSQC), and (d) 3D

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C/1H SQ (CP-HSQC), (c) 3D 1H

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C/1H DQ/1H SQ (CP-HSQC/BABA) correlation

experiments. The BABA-xy16 sequence is used to excite and reconvert the 1H DQ coherence and CP-HSQC scheme is used for 1H→13C→1H magnetization transfer. Phase cyclings for the above sequences are provided in the Supporting Information (Figure S1).

Experimental 5 ACS Paragon Plus Environment


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All the NMR experiments were carried out using JNM-ECZ600R spectrometer (JEOL RESONANCE Inc., Japan) operating at a magnetic field of 14.1 T (1H Larmor frequency of 599.67 MHz) and equipped with 1 mm HXMAS double resonance solid-state NMR probe (JEOL RESONANCE Inc., Japan). About 0.8 mg of the L-histidine.HCl.H2O and capsaicin samples (Sigma Aldrich) were separately packed into a 1 mm zirconia MAS rotor. The MAS rate was actively controlled to 70,000±20 Hz by the pneumatic controller in order to establish its long-term stability. Since the two BABA recoupling blocks should be precisely synchronized to the sample spinning, short-term stability of MAS rate as monitored by the oscilloscope in the time scale of t1 is also quite important to get rid of strong t1 noise. The rf field strength of the hard pulses were set to ν1,H = 270 kHz and ν1,C = 238 kHz. The BABA-xy16 homonuclear recoupling sequence with a cycle time of 8 tr was used for excitation and reconversion period in the 1H DQ dimension, where tr is the cycle time of sample spinning. While the 1H pulse lengths in the BABA sequences were experimentally optimized to 0.55-0.60 μs to maximize the DQ filtering efficiency using the sequence shown in Figure 1(a) with t1 = 0, the other 90° degree pulses were set to 1.1 μs for 1H and 1.05 μs for 13C. The CP conditions were optimized using 13C3, 15N L-alanine at the MAS rate of 70 kHz by maximizing the 1H NMR signal intensity after 1H → 13C → 1H transfer using the sequence shown in Figure 1(b) with t1 = 0. The DQ CP condition with 1,H = 17 kHz and ν1,C = 54 kHz with ramp ±14 kHz on the 13

C channel was used. The contact times were set to 1 ms for the 1H → 13C transfer, and 0.3 ms for

the

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C → 1H transfer. HORROR rf field strength was separately optimized by minimizing the 1H

NMR signal intensity after 1 ms spinlock. The 100 and 25 ms HORROR irradiation was applied to suppress uncorrelated

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H signals, for L-histidine.HCl.H2O and capsaicin, respectively. The

heteronuclear decoupling was achieved by 10 kHz 1H WALTZ decoupling during the 13C evolution period and 10 kHz 13C WALTZ decoupling during the 1H DQ evolution and the 1H acquisition35. No 13

C decoupling was applied during BABA, since it slightly reduces the BABA filtering efficiencies.

The sign discrimination in the indirect dimension was performed by the States-TPPI method. 12 (16), 8 (4), and 32 (16) transients were accumulated for each FID in 2D 1H DQ/1H SQ, 2D 13C/1H SQ, and 3D experiments for L-histidine.HCl.H2O (capsaicin), respectively. The 12 (16) and 32 increments in the 1H DQ for 3D (2D) and the 13C dimensions, respectively, were acquired for L-histidine.HCl.H2O. The 16 (32) and 128 increments in the 1H DQ for 3D (2D) and the

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C dimensions, respectively,

were acquired for capsaicin. A repetition delay of 5 s for L-histidine.HCl.H2O and 3 s for capsaicin was used, resulting in 0.4, 0.7, and 68 hour experimental time for 2D 1H DQ/1H SQ, 2D 13C/1H SQ, and 3D experiments, respectively, for L-histidine.HCl.H2O and 0.8, 1.7, and 108 hours for capsaicin. The coherence selection was achieved by the phase cycling. While no z-filtering was applied to avoid unwanted spin diffusion for L-histidine.HCl.H2O, z-filtering of tz = 1 ms was applied for capsaicin.


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Results and discussion First, we separately measured the filtering efficiency of BABA and CP-HSQC units using the sequence shown in Figures 1(a) and (b) with t1 = 0, respectively (Figure 2), with respect to the spin echo signal intensity (Figure 2a) for L-histidine.HCl.H2O. The filtering efficiency of peaks of interest is evaluated from the peak height, which lies in the range from 31 to 44% for BABA (Figure 2b) and from 25 to 33% for CP-HSQC (Figure 2c) by taking the 1.1% abundance of 13C into account. Since the contact time of the second CP is intentionally set short (0.3 ms), the 1H nuclei that are not directly bonded to

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C (H2O, NH3+, NH(5) and NH(7)) give negligible signal intensities in the

CP-HSQC filtered spectrum (Figure 2(c)). The pseudo through-bond correlation and absence of long-range correlations are further demonstrated in the 2D

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C/1H SQ CP-HSQC correlation

spectrum (vide infra, see Figure 3(b)). About 0.1% 1H signal survives after 1D 1H DQ/13C/1H SQ (BABA/CP-HSQC: Figure 2(d)) and 13C/1H DQ/1H SQ (CP-HSQC/BABA: Figure 2(e)) filtering with t1 = t2 = 0, using the pulse sequence shown in Figure 1(c) and (d), respectively. This corresponds to 12% filtering efficiency after incorporating the correction due to the natural abundance of 13C. The overall filtering efficiency is slightly higher than the simple multiplication of BABA and CP-HSQC filtering efficiencies. The higher efficiency may be attributed to the selection of a suitable set of crystalline orientations for both BABA and CP-HSQC filtering units. While the peaks observed in the 1H DQ/13C/1H SQ (BABA/CP-HSQC) filtered spectrum are same as one in the CP-HSQC filtered spectrum, higher intensities are observed for NH and NH3+ peaks in the 13C/1H DQ/1H SQ (CP-HSQC/BABA) filtered spectrum due to the BABA mixing after the CP-HSQC filtering. Consequently, a reduction in the signal intensities of 1Hs directly bonded to 13C is observed. Nonetheless, the overall integral signal intensities are similar to each other for BABA/CP-HSQC and CP-HSQC/BABA. This is because the order of BABA and CP-HSQC units only affects the distribution of 1H signal as discussed below in detail.



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Figure 2 Comparison of 1D 1H NMR between (a) spin echo, (b) 1H DQ/1H SQ (BABA) filtered, (c) 13C/1H SQ (CP-HSQC) filtered, (d) 1H DQ/13C/1H SQ (BABA/CP-HSQC) filtered, and (e) 13C/1H DQ/1H SQ (CP-HSQC/BABA) filtered spectra of L-histidine.HCl.H2O. Each spectra were magnified with (b) 3, (c) 270, (d) 810, and (e) 810 times with respect to (a). The averaged filtering efficiency is shown in each figure. The efficiency divided by the abundance of 8 ACS Paragon Plus Environment

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C is also shown in the

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parentheses. The spectra were observed with (a) 3, (b) 12, (c) 512, (d) 4096, and (e) 4096 transients, and displayed after averaging by the number of scans so that the signal intensities can be directly compared. 1

H DQ/1H SQ (Figure 3a) and

The 2D

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C/1H SQ (Figure 3b) spectra of

L-histidine.HCl.H2O are shown. While, in the 1D 1H spectra, the CH(2) and CH2(3) peaks are completely overlapped and CH(6), CH(8) and NH3+ are partially overlapped because of the limited 1

H resolution, 2D expansion enhances the resolution, giving resolved peaks for suitable cases. For

example, 1H DQ/1H SQ correlation alleviate the overlap of CH(6), CH(8) and NH3+ and the 2D 13

C/1H SQ correlation clearly resolves CH(6) and CH(8) both in the 1H and

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C dimension due to

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suppression of NH3 signal. On the other hand, CH(2) and CH2(3) signals are still fully overlapped in the 1H DQ/1H SQ spectrum. This introduces uncertainty in the interpretation of 1H DQ/1H SQ correlation spectra as it is not possible to assign the cross peak at 2.9 ppm in the 1H SQ dimension. Interestingly, by introducing the 13C dimension, CH(2) signal is completely separated from CH2(3) in the 13C dimension. It is expected that the combination of 1H DQ/1H SQ and 13C/1H SQ correlation spectra should provide the separated 1H DQ/1H SQ correlation for each 1

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C. As discussed above,

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cross peaks between non-bonded H and C in the C/ H SQ spectrum were not observed (Figure 3(b)).

Figure 3 (a) 1H SQ/1H DQ and (b) 13C/1H SQ 2D correlation spectra of L-histidine.HCl.H2O at 70 kHz MAS. Figure 4 shows the 3D 1H DQ/13C/1H SQ and

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C/1H DQ/1H SQ correlation spectra of

L-histidine.HCl.H2O (Figure 4 (a1) and (a2)) together with projections onto the 13C, 1H DQ and 1H SQ dimensions, and slices. The projections onto the 13C dimension (Figure 4 (b1) and (b2)) give 2D 9 ACS Paragon Plus Environment


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H DQ/1H SQ correlation with reduced number of peaks as compared to the conventional 2D 1H

DQ/1H SQ correlation spectrum (Figure 3(a)). The 1H→13C→1H magnetization transfer in the 3D experiments acts as a filter and resembles that of the selective excitation and suppression pulse-based methods wherein the peak selection relies on the frequency difference36. The effect of selective excitation and suppression pulses in 1H DQ/1H SQ experiments have previously been demonstrated using DANTE and WATERGATE sequences together with pulsed field gradient (PFG) pulses36. Nevertheless, the utility of such selective-pulse approaches is rather limited in the cases where spectral resolution in the 1H dimension is poor. Alternatively, 1H→13C→1H filtering, which does not rely on the chemical shift separation in the 1H dimension, can be effectively utilized. For instance, overlapped 1H resonances from CH(2) and CH2(3) can easily be resolved using this approach. Therefore, the 3D 1H DQ/13C/1H SQ (BABA/CP-HSQC) and 13C/1H DQ/1H SQ (CP-HSQC/BABA) experiments should provide simplified spectra vital for the resonance assignment purposes. The 1H→13C→1H filtering mechanism in 1H DQ/13C/1H SQ and

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C/1H DQ/1H SQ

experiments is found to be different. For example, the 1H→13C→1H filtering after the BABA sequence (BABA/CP-HSQC) results in the SQ signal only from 1Hs that are directly bonded to 13C (Figure 4 (b1)). Whereas, additional cross peaks between 1Hs that are not bonded to 1

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C during

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BABA emerge in the H→ C→ H filtering followed by the BABA sequence (CP-HSQC/BABA) (Figure 4 (b2)).. In the 1H DQ/13C/1H SQ spectrum, first the DQ coherence at ωA + ωB is observed in the 1H DQ dimension, and then transferred to 1HA and 1HB magnetizations. The 1HB magnetization is finally observed after 1H→13C→1H filtering, giving cross peak only at (1H SQ, 1H DQ) = (ωB, ωA + ωB). On the other hand, in the 13C/1H DQ/1H SQ experiment, first the 1HB magnetization is selected by the 1H→13C→1H filtering and then converted into the 1HA-1HB coherence as the DQ coherence can be generated from the single spin magnetization. This results in (1H SQ, 1H DQ) at (ωA, ωA + ωB) and (ωB, ωA + ωB) chemical shifts. It should be noted that the DQ coherence thus produced has the 50% intensity compared to those originated from both the 1HA and 1HB magnetizations. As discussed above, the

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C/1H DQ/1H SQ experiment gives all those 1H DQ/1H SQ correlation peaks that are

partially suppressed in the 1H DQ/13C/1H SQ experiment. However, the

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C/1H DQ/1H SQ

experiment suffers from sensitivity loss as compared to the 1H DQ/13C/1H SQ experiment. In other words, the choice between

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C/1H DQ/1H SQ and 1H DQ/13C/1H SQ experiments relies on the

compromise between readability of the spectra and sensitivity. Theoretically the signal intensity in the 13C/1H DQ/1H SQ spectrum should be half of that in the 1H DQ/13C/1H SQ spectrum; however, the former normally gives higher sensitivity than the expected theoretical value due to the presence of the third spin and hence more preferred over the latter. Barring non 13C-bonded proton peaks such as NH3+-NH3+, NH-NH, NH3+-NH, H2O-H2O, the 2D 1H DQ/1H SQ projection (Figure 4 (b2)) taken from the 13C/1H DQ/1H SQ spectrum contains all the 1H peaks that are bonded to 13C. This partially resolves the ambiguity in cross peaks due to signal overlap. For example, the presence of 10 ACS Paragon Plus Environment

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CH(6)-NH3+ correlation is not clear in the conventional 2D 1H DQ/1H SQ spectrum (Figure 3(a)) due to the overlap with NH3+-NH3+ correlation. On the other hand, the

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C/1H DQ/1H SQ clearly

gives CH(6)-NH3+ correlation at the position of the 1H SQ frequency of NH3+ because of the absence of NH3+-NH3+ auto-correlation peak (Figure 4 (b2); marked with the arrow). The 13C/1H SQ projections (Figure 4 (c1) and (c2)) that are obtained from the projection onto the 1H DQ dimension look mostly similar to the conventional 13C/1H SQ CP-HSQC spectrum giving only pseudo through-bond correlations (Figure 3(b)). No additional cross peaks appear in the projection of the 1H DQ/13C/1H SQ spectrum. This is because the addition of the DQ filtering before the 1H→13C→1H magnetization transfer mixes the longitudinal 1H magnetizations before 13C/1H SQ measurements, having no visible effect on the resultant projection. On the other hand, cross peaks resulting from the remote three spin connectivities of 1H-1H-13C appear in the 13C/1H SQ projection of the 13C/1H DQ/1H SQ spectrum because of the 1H mixing during DQ filtering between the 13C and 1

H SQ dimensions. These correlations give similar information to the heteronuclear multiple bond

correlation (HMBC) experiments in solution NMR 37 , although the mechanism is completely different. The projections onto the 1H SQ dimension give the 13C/1H DQ correlation spectra (Figure 4 (d1) and (d2)) which is similar to the 13C-detected 13C/1H DQ correlation experiment proposed at moderate MAS rate38. In principle,

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C/1H DQ projections from 1H DQ/13C/1H SQ and

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C/1H

DQ/1H SQ correlation spectra should result in identical spectra. Nevertheless, signal intensities are found different which may be attributed to the difference in magnetization transfer efficiencies of the two pulse sequences. The power of the 3D experiments presented here is fully appreciated by taking 2D slices. 1

The H DQ/1H SQ slices taken along each

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C resonance are shown in Figure 4 (e-h). Each slice

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represents the local H spin network in the vicinity of each 13C. Interestingly, the 2D slices obtained from two 3D experiments (1H DQ/13C/1H SQ and 13C/1H DQ/1H SQ) show fairly different pattern. As discussed above, the 13C/1H DQ/1H SQ spectrum gives more cross peaks at the cost of intensity but is more informative. Since our experimental observation shows that the sensitivity loss in the 13

C/1H DQ/1H SQ experiment is much less than the theoretical expectation (50%), it is preferable

over 1H DQ/13C/1H SQ experiments if the moderate sensitivity loss is acceptable. For example, the 1

H DQ/1H SQ slice at the

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C chemical shift of CH(6) in the

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C/1H DQ/1H SQ spectrum shows

CH(6)-NH3+ and CH(6)-CH(8) cross peaks, and CH(6)-CH(6) autocorrelation peak resulting from the intermolecular 1H proximities (Figure 4 (e2)). The CH(6)-NH3+ and CH(6)-CH(8) connectivities are identified by the correlations at the 1H SQ frequencies of NH3+ and CH(8), since their counter parts at the 1H SQ frequency of CH(6) are overlapped with the CH(6)-CH(6) autocorrelation peak. Thus, these correlations cannot be extracted from the 1H DQ/13C/1H SQ spectrum, where correlation peaks only appear at the 1H SQ frequency of CH(6). The slice at CH(8) (Figure 4 (f2)) gives no 11 ACS Paragon Plus Environment


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CH(8)-CH(8) autocorrelation peak due to the longer internuclear distance than the CH(6)-CH(6) distance (4.2 Å for CH(6)-CH(6) and 5.0 Å for CH(8)-CH(8)). In the conventional 1H DQ/1H SQ spectrum (Figure 3(a)), the presence and absence of CH(6)-CH(6) and CH(8)-CH(8) peaks are not clear because of the partial overlaps, which are only resolved in the 3D experiments. These slices are also useful for the spectral assignments. While the 1H of CH(6) gives strong correlation to both NH signals (Figure 4 (e2)), the 1H of CH(8) correlates only to single NH signal (Figure 4 (f2)). Hence, CH(6) can be assigned as the carbon between two nitrogens of imidazole ring. CH(8) is unambiguously assigned to the other CH in the imidazole ring. In addition, the NH resonance at 12 ppm (1H) is assigned to the nitrogen between two CH. The unambiguous 1H assignments are completed with the help of the CH(2) and CH2(3) assignments from the 13C/1H SQ projection of the 1

H DQ/13C/1H SQ spectrum, hence complete spectral assignments are made. The slices at CH(2) and

CH2(3) are more informative (Figure 4 (g) and (h); data processed with larger broadening is available in Figure S2 of the Supporting Information). Although the 1H peaks of CH(2) and CH2(3) are completely overlapped in the 1H SQ dimension, they are clearly separated in the 13C dimension, giving isolated 1H DQ/1H SQ correlation spectra for each carbon. The higher signal intensity in the 1

H DQ/13C/1H SQ spectrum is beneficial to identify the correlation between CH(8)-NH3+ and

CH(2)-CH2(3) (circled in Figure 4 (g, h)), which are less significant in the

13

C/1H DQ/1H SQ

spectrum as discussed above. Interestingly, both slices look similar reflecting close internuclear distances (3.4 Å for CH(2)-CH(8) and 3.1 Å for CH2(3)-CH(8), and 2.3 Å for CH(2)-NH3+ and 2.5 Å for CH2(3)-NH3+). Diagonal peaks appear both in slices at CH(2) and CH2(3). While the peak represents the cross peak between CH(2) and CH2(3) in case of Figure 4(g), autocorrelation peak of CH2(3) is also overlapped in case of Figure 4(h).


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Figure 4 (a1 and a2) 3D spectra, projections onto (b1 and b2) 13C, (c1 and c2) 1H DQ, and (d1 and d2) 1H SQ dimensions, and slices at (e1 and e2) CH(6), (f1 and f2) CH(8), (g1 and g2) CH(2), and (h1 and h2) CH2(3) of 3D 1H DQ/13C/1H SQ and 13C/1H DQ/1H SQ correlation spectra of L-histidine.HCl.H2O, respectively. The spectra for each 3D spectrum are plotted with the same contour level so that direct comparison of spectral intensities between the 3D experiments can be made.

The importance of the presented 3D methods is demonstrated on capsaicin at natural abundance. The 3D

13

C/1H DQ/1H SQ spectrum together with its

DQ/1H SQ slice are shown in Figure 5. The 2D

13

C/1H SQ projection and 1H

13

C/1H SQ correlation spectra measured with two

different second CP contact times and 2D 1H DQ/1H SQ spectrum are also shown. While only bonded 1H-13C correlations appear in the 2D 13C/1H SQ spectrum with the short second CP contact time of 0.3 ms (Figure 5d), additional long-range

13

C-1H correlations (1H-1H-13C three spin

connectivity) originating from 1H-1H mixing by the BABA recoupling appear in the 13 ACS Paragon Plus Environment

13

C/1H SQ


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projection (Figure 5b). Since the 1H-13C correlations are established through the second CP with short contact time, only

13

C signals that are directly bonded to 1Hs appear in the spectrum.

Interestingly, the use of long second CP (1 ms) results in a different set of long-range correlations in the 13C/1H SQ spectrum (Figure 5f) as compared to the 13C/1H SQ projection from 3D 13C/1H DQ/1H SQ spectrum due to the difference in the spin dynamics. In the

13

C/1H SQ projection of the 3D

13

C/1H DQ/1H SQ spectrum (Figure 5b), all the correlation peaks are associated with protonated 13Cs,

and the long-range correlations are between protonated additional long-range correlations in the

13

C and non-bonded 1Hs. In contrast, the

13

C/1H SQ spectrum (Figure 5f: 1 ms) originate from

through-space 1H-13C dipolar interactions between non-bonded 1H-13C pair including quaternary 13

Cs. Indeed, the long-range correlations between 1H and quaternary carbons are clearly observed.

More interestingly, the additional correlations observed in Figure 5b are absent in the

13

C/1H SQ

spectra with the long second CP (Figure 5f: 1 ms). This is because the dipolar interactions between protonated carbons to remote 1Hs, which essentially give additional correlations appear in Figure 5b, are truncated by the intense dipolar interactions between bonded

13

C-1H pair. For example, in the

13

C/1H SQ projection, the 13C resonance at 114.5 ppm gives correlations to 6.1 ppm and 1.0 ppm in

addition to the directly bonded 1H at 6.5 ppm. Similar correlations are also observed at the

13

C

1

resonance at 117.2 ppm. These correlations clearly show the three spin connectivity among H(6.1 ppm) – 1H(6.5 ppm) – 1

13

C(114.5 ppm and 117.2 ppm). The other three spin correlations among

1

H(1.0 ppm) – H(6.1 ppm) – 13C(117.2 ppm) and 1H(1.0 ppm) – 1H(6.5 ppm) – 13C(114.5 ppm) are

also identified. These correlations are made through 1H-1H connectivity among 1H(6.1 ppm) – 1H(6.5 ppm), 1H(1.0 ppm) – 1H(6.1 ppm) and 1H(1.0 ppm) – 1H(6.5 ppm). It is worth noting that some of the bonded 1H-13C correlations disappear in the

13

C/1H SQ projection because of sensitivity loss

during the BABA mixing. On the other hand, a different set of correlations is observed in the 2D 13

C/1H SQ spectrum with the long second CP (Figure 5f: 1 ms). Most notably, the correlations

between 1Hs and quaternary carbons, which are not observed in Figure 5b, are established. The quaternary carbon at 116.2 ppm, 128.4 ppm, and 145.3 ppm shows correlations to 1Hs at 6.1 ppm, (5.5 and 6.1) ppm, and (7.7 and 6.5) ppm, respectively. Since these quaternary carbons belong to the aromatic ring, the correlated 1Hs are assigned to the aromatic ring. While three 1H resonances are overlapped at 5.5 ppm, the 1Hs at 6.1 and 6.5 ppm are solely assigned to aromatic 1Hs. Thus, 13C resonances at 114.5 ppm and 117.2 ppm are assigned to aromatics through its 1H counter parts at 6.5 and 6.1 ppm, respectively. As shown above, the two 13C/1H SQ correlation spectra complement each other in terms of remote 1H-13C correlations and highlight the importance of two methods for the assignment purpose. Moreover, the 1H DQ/1H SQ slices along each 13C resonance give more detailed correlations which are sometimes obscured in the 1H/13C SQ projection. For example, the 1H DQ/1H SQ slice at

13

C shift of 108.1 ppm gives an attractive correlation pattern (Figure 5c). The directly

1

bonded H at 5.5 ppm gives strong correlation to 1H at 2.6 ppm, which is assigned to OCH3 protons 14 ACS Paragon Plus Environment

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from correlation (13C, 1H SQ) = (53.7 ppm, 2.6 ppm). In addition, autocorrelation peak and correlation to 1H at 8.0 ppm are observed. These correlations are also observed in 2D 1H DQ/1H SQ spectrum shown in Figure 5e, however, it is not possible to separately assign the correlations because of severe signal overlaps. We are now investigating all the correlations together with additional measurements of 14N/1H, 1H DQ/1H DQ/1H SQ, etc., which is out of the scope of the current paper and will be published elsewhere.

Figure 5 (a) 3D

13

C/1H DQ/1H SQ correlation spectrum of capsaicin at 70 kHz MAS, (b) its

projection onto the 1H DQ axis, and (c) 1H DQ/1H SQ slices at 114.5 ppm.

13

C/1H SQ

13

C/1H SQ CP-HSQC

correlation spectra with short (d: 0.3ms) and long (f: 1 ms) second CP contact time and (e) 1H DQ/1H SQ correlation spectrum are also shown.

Conclusion 3D 1H DQ/13C/1H SQ and 13C/1H DQ/1H SQ correlation experiments are demonstrated on 15 ACS Paragon Plus Environment


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small organic molecules at naturally abundant spite of low natural abundance of

13

Page 16 of 19

13

C under ultrafast MAS conditions of 70 kHz. In

C (1.1%) and small sample amount < 1 mg, the 1H detection

allows successful measurement of 3D experiments in the realistic measurements time of several days. Although there are several overlaps of 1H resonances even for such small molecules at ultrafast MAS conditions, the additional

13

C dimension resolves the 1H DQ/1H SQ patterns, revealing the

local 1H networks. While 1H DQ/13C/1H SQ experiments offer better sensitivity,

13

C/1H DQ/1H SQ

experiments are generally recommended because of simplicity of spectral analysis provided the sensitivity allows. In cases where the sensitivity is quite limited, the 13C/1H DQ/1H SQ experiment is beneficial over the 1H DQ/13C/1H SQ experiment. The 3D experiments are useful to analyze the local molecular structures of small organic molecules in addition to spectral assignments.

Supporting Information Phase cyclings of the pulse sequences. 1H DQ/1H SQ slices of 3D 1H DQ/13C/1H SQ and

13

C/1H

DQ/1H SQ correlation spectra for L-histidine.HCl.H2O. References 1

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TOC Graphic


Revealing the Local Proton Network through Three-Dimensional 13C

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