13C NMR Signal Enhancement Using Parahydrogen-Induced

Article Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

pubs.acs.org/JACS

13

C NMR Signal Enhancement Using Parahydrogen-Induced Polarization Mediated by a Cobalt Hydrogenation Catalyst

Kenan Tokmic, Rianna B. Greer, Lingyang Zhu, and Alison R. Fout* School of Chemical Sciences, University of Illinois at Urbana−Champaign, 600 S. Mathews Avenue, Urbana, Illinois 61801, United States

Downloaded via UNIV OF LOUISIANA AT LAFAYETTE on October 25, 2018 at 14:12:36 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: The use of a cobalt-based catalyst for the generation of hyperpolarized 13C NMR resonances by parahydrogenation of ethyl acrylate is presented herein. Comparisons of the carboxylate 13C NMR signal enhancement factor of ethyl propionate between using (MesCCC)Co-py and a commonly utilized cationic diphosphine rhodium complex demonstrates that the cobalt system is a viable PHIP catalyst alternative. Furthermore, the operative hydrogenation mechanism of the cobalt system was examined by using 1H, 13C, and parahydrogen-induced polarization NMR spectroscopies to elucidate reaction intermediates affiliated with the observed 1H and 13C NMR signal enhancements in ethyl propionate.

■

INTRODUCTION Nuclear magnetic resonance (NMR) spectroscopy is one of the most widely used techniques for the routine characterization of a variety of compounds whereas magnetic resonance imaging is a vital diagnostic tool in the biomedical field. While both techniques have wide applicability, accessing the full potential has been limited due to their inherent low sensitivity. Approaches which generate a non-Boltzmann distribution of magnetic spins can increase the sensitivity of these analytical methods. Among these approaches,1−3 dynamic nuclear polarization (DNP) has advanced significantly over the past few decades,4,5 where it has been applied in clinical studies for metabolic imaging.6 However, the excessive cost and time requirements for generating hyperpolarized material remain a limitation for the widespread use of DNP. Parahydrogen-induced polarization (PHIP) offers a cheaper and faster alternative for the generation of hyperpolarized substances compared to DNP. The generation of hyperpolarization involves the pairwise addition of parahydrogen (pH2) to a substrate’s carbon−carbon multiple bond7,8 or through reversible exchange of p-H2 and a substrate,9 both using a transition metal catalyst. To prolong the signal enhancement gained from PHIP, which has enabled its use in biomedical applications, the transfer of the polarization from the added protons to slow-relaxing heteronuclei (such as a 13C of a carboxylate or 15N groups) is required since the T1 relaxation time of protons is generally a few seconds.10−19 Although this requirement is certainly a limitation to the scope of biologically relevant substrates with which PHIP is compatible, methods such as PHIP-SAH (PHIP via the Side Arm Hydrogenation), which incorporate unsaturated sites up to five chemical bonds away from the long-lived nuclear spin states, have expanded the number of substrates amenable © XXXX American Chemical Society

toward hyperpolarization using PHIP through the application of magnetic field cycling (MFC).20−25 PHIP-SAH has been applied for the hyperpolarization of metabolically relevant molecules.20,22,26,27 Currently, one major limitation of generating hyperpolarized compounds via PHIP for in vivo biomedical applications or translation into clinical trials is the presence of the toxic hydrogenation catalyst in the solution of the hyperpolarized product.28,29 The removal of the hydrogenation catalyst remaining in solution via filtration on ionic resins or phase extraction is promising and has been met with limited polarization loss to the substrate.21,26,30 Heterogeneous catalysts have also been considered as a tool to address this shortcoming, and continued work to increase the polarization levels is ongoing.29,31−47 An alternative strategy to alleviate this limitation involves developing more benign hydrogenation catalytic systems which incorporate bioavailable transition metals in place of the currently employed homogeneous rhodium catalysts. This presents late first-row transition metal catalysts as attractive alternatives;47 however, due to the requirements of PHIP,48,49 few first-row transition metal complexes have been studied using PHIP, and none have been reported to hyperpolarize 13C NMR signals using pH2.50−56 Our group has previously described the cobalt-based hydrogenation catalysts, (MesCCC)Co-(N2)(PPh3)52,53 and (MesCCC)Co-py51 (MesCCC = bis(mesityl-benzimidazol-2ylidene)phenyl; py = pyridine), which are active for the hydrogenation of carbon−carbon multiple bonds and nitriles to primary amines, respectively. Mechanistic studies of the Received: August 10, 2018

A

DOI: 10.1021/jacs.8b08614 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Article

Journal of the American Chemical Society

mechanistic tool.7,51−62 To this end, 1H and 13C NMR spectroscopic studies based on PHIP demonstrated that the mechanistic pathway of the cobalt system is distinct from that of the cationic diphosphine rhodium catalyst. Namely, the reversible coordination of both the olefin and H2 transpires throughout the hydrogenation catalysis of (MesCCC)Co-py to yield the hyperpolarized products.

hydrogenation catalysis using PHIP and multinuclear NMR spectroscopic studies established that a two-electron redox process, Co(I)/Co(III), was operative. Furthermore, given the robust functional group tolerance of these catalytic systems and hyperpolarization of 1H NMR signals of the hydrogenated products via PHIP, the ability of the low-valent cobalt complexes to effectively enhance the 13C NMR signals was postulated. Herein the hydrogenation of ethyl acrylate using (MesCCC)Co-py and p-H2 was carried out. Comparisons between a commonly employed rhodium(I) PHIP catalyst, [(dppb)Rh(COD)]BF4 (dppb = 1,4-bis(diphenylphosphino)butane; COD = 1,5- cyclooctadiene), and (MesCCC)Co-py for the carboxylate 13C NMR signal enhancement of ethyl propionate, demonstrates that the cobalt system is a comparable PHIP catalyst alternative (Figure 1), providing an efficient level of

■

RESULTS AND DISCUSSION To probe the viability of 13C NMR signal enhancement with the (MesCCC)Co system, PHIP studies were commenced following similar conditions previously reported by Reineri and co-workers.23 Ethyl acrylate was chosen as the substrate because the added parahydrogen protons would be positioned two to three chemical bonds away from the carboxylate carbon. In this scenario, MFC was not required for the observation of the hyperpolarized carboxylate 13C NMR signal.23 (MesCCC)Co-py was chosen as the hydrogenation catalyst instead of (MesCCC)Co(N2)(PPh3) because the presence of triphenyl phosphine was previously demonstrated to inhibit catalysis.52,53 Acetone-d6 was chosen as the solvent so that direct comparisons with the cationic diphosphine rhodium catalyst could be carried out. The hydrogenation of ethyl acrylate using the cobalt catalyst was first examined to ensure the successful hydrogenation of this class of substrate could be achieved in acetone-d6. Following ALTADENA conditions,63 the addition of 4 atm of p-H2 to a solution of ethyl acrylate (64 mM) and (MesCCC)Co-py (9 mol %) resulted in the hyperpolarization of the 1H NMR signals of ethyl propionate in the 1H NMR spectrum (Figure S4). This demonstrates that the pairwise addition of p-H2 in the hydrogenation of ethyl acrylate by the cobalt catalyst is not inhibited by acetone or the ester functionality of the substrate.

Figure 1. Hydrogenation catalysts, [(dppb)Rh(COD)]BF4 (left) and (MesCCC)Co-py (right), examined in these studies.

substrate conversion while maintaining pairwise transfer of pH2. However, differences in the signal enhancement factors for the alpha- and beta-carbon positions of ethyl propionate (vide infra) suggest that the two catalytic systems undergo unique mechanistic pathways. Extensive utilization of PHIP NMR spectroscopy to study hydrogen transfer pathways in hydrogenation reactions also established PHIP as an effective

Figure 2. 13C NMR spectrum (1 scan, displayed in absolute mode) of the hydrogenation of ethyl acrylate (64 mM) using (MesCCC)Co-py (top, orange) and [(dppb)Rh(COD)]BF4 (middle, blue) in acetone-d6 using p-H2. 13C NMR spectrum (1 scan, displayed in absolute mode) of ethyl propionate (500 mM) in acetone-d6 (black, bottom) (*denotes acetone-d6). Inset (top-right) showing 13C NMR signal enhancement values using the cobalt and rhodium catalytic systems. B


Article


occurs first, followed by the irreversible addition of H2, yielding the hyperpolarized product upon reductive elimination.69−73 Mechanistic studies probing the catalytic intermediates of (MesCCC)Co-py linked to the observed hyperpolarized 13C NMR signals have not been examined. Such studies may offer insights into the observed differences in the 13C NMR signal enhancement and provide a foundation for catalyst design improvements. Mechanistic Studies. Reasoning that under catalytic conditions, the dissociation of pyridine and the coordination of the olefin transpires, mechanistic studies were undertaken by first examining the coordination of the olefin with the cobalt center. The addition of 10 equiv of ethyl acrylate to (MesCCC)Co-py resulted in the formation of a yellow solution within 2 h, and following workup, (MesCCC)Co(η2-H2C CHCOOCH2CH3)2 was isolated as a yellow solid in 81% yield (Scheme 1).

Encouraged by the ability of the cobalt catalyst to hydrogenate ethyl acrylate in a pairwise manner, 13C NMR data were collected to determine if the 13C nuclei could be effectively hyperpolarized, as the low -field hydrogenation of ethyl acrylate should lead to enhanced 13C resonances in the hydrogenation product as described by Bargon and coworkers.64 The transfer of polarization from 1H to 13C nuclei occurs through the scalar coupling system at a low magnetic field such as Earth’s magnetic field,65 and can be further enhanced when the reaction is carried out at a near zero magnetic field (using mu metal) through application of MFC.24,27 The basis for the transfer of polarization to 13C and other heteronuclei has been described in further detail elsewhere.28,66,67 In the initial hydrogenation experiments, ethyl acrylate was hydrogenated under ALTADENA conditions63 using (MesCCC)Co-py and p-H2 (4 atm) at Earth’s magnetic field, and a proton-coupled 13C NMR spectrum was quickly collected after shaking the sample at room temperature (see the Supporting Information for details). The 13C NMR spectrum shows the enhancement of 13C NMR signals of the carboxylate, Cα, and Cβ carbon positions of ethyl propionate (Figure S5) with signal enhancement factors of at least 17, 82, and 530, respectively. A recent study using a rhodium catalyst for PHIP of amino acid derivatives demonstrated that the efficiency of hyperpolarization arising from p-H2 addition is affected by temperature of the catalytic reaction.68 Considering (MesCCC)Co-py was demonstrated to operate at 115 °C for the hydrogenation of nitriles,51 the temperature of the hydrogenation reaction was increased to determine if increased polarization levels of the 13C NMR signals would result. To this end, the catalytic reaction was increased to 37 °C, considering the possible use of this catalytic system for biomedical applications. Following a similar procedure as described above, the reaction was heated to 37 °C and shaken at Earth’s magnetic field, and a 13C NMR spectrum was collected (Figure 2, top). The 13C NMR spectrum shows the hyperpolarized carboxylate, Cα, and Cβ carbon positions of ethyl propionate (Figure 2) with signal enhancement factors of at least 23, 81, and 1131, respectively. Encouraged by the enhancement of 1H and 13C NMR signals of ethyl propionate, (MesCCC)Co-py was compared with a widely employed rhodium catalyst to further elucidate the potential of the cobalt system as an alternative PHIP catalyst. Under identical reaction conditions using [(dppb)Rh(COD)]BF4 (Figure 2, middle) and (MesCCC)Co-py (Figure 2, top) as the catalyst, the parahydrogenation of ethyl acrylate at 37 °C was carried out. The 13C NMR spectrum shows a similar signal enhancement factor for the carboxylate carbon between the cobalt and rhodium system (Figure 2). This demonstrates that the cobalt system is equally effective for generation of the hyperpolarized 13C NMR signal of the carboxylate carbon in ethyl propionate by the parahydrogenation of ethyl acrylate. Interestingly, an examination of the signal enhancement factor for the Cα carbon is larger for rhodium, while the same is true for the Cβ carbon with the cobalt catalyst (Figure 2). The 13C NMR signal enhancement differences may arise from variations in the catalytic pathway that each metal complex undergoes during the hydrogenation process. Extensive mechanistic studies regarding the operative mechanism of chelating cationic diphosphine rhodium hydrogenation catalysts have elucidated that the coordination of the olefin

Scheme 1. Synthesis of (MesCCC)Co(η2-H2C CHCOOCH2CH3)2

Characterization of (MesCCC)Co(η2-H2C CHCOOCH2CH3)2 by 1H NMR spectroscopy revealed a diamagnetic spectrum with 15 resonances (Figure S1). Three singlets in the upfield region integrating to 6H each corresponded to the mesityl methyl groups on the ligand periphery and the downfield resonances, integrating to 15H, were assigned to the aryl backbone of the pincer ligand. The remaining 1H NMR resonances were assigned to the coordinated olefin, which were shifted upfield from free ethyl acrylate. Based on the integration of the olefinic resonances, the cobalt center accommodates two ethyl acrylate molecules, yielding an 18-electron cobalt(I) complex. Further characterization of (MesCCC)Co(η2-H2CCHCOOCH2CH3)2 by single-crystal X-ray diffraction studies confirmed the formulation of this complex (Figure 3). The coordination of the ethyl acrylate molecules with the cobalt center occurs through the carbon−carbon double bond and resembles the first step of cationic rhodium hydrogenation catalysis, where substrate coordination to rhodium occurs first. Following the isolation of ( Mes CCC)Co(η 2 -H 2 C CHCOOCH2CH3)2, the hydrogenation catalysis was examined using the coordinatively saturated species. Under catalytic conditions, with (MesCCC)Co(η2-H2CCHCOOCH2CH3)2 as the catalyst, hyperpolarized carboxylate, Cα, and Cβ carbon 13 C NMR resonances of the hydrogenation product, ethyl propionate, were observed (Figure S9). This demonstrates that olefin coordination is reversible. In this case, olefin dissociation from the bis(olefin) complex, ( Mes CCC)Co(η 2 -H 2 C CHCOOCH2CH3)2, must occur for H2 oxidative addition to take place and shows that pyridine is not necessary for catalysis to occur. Given that PHIP NMR studies can also be used as a mechanistic tool,7,51−62 there is the potential that we can use this to detect not only the hyperpolarized products but also C


Article


Ha to the Cα carbon occurs at low field, and hyperpolarized ethyl acrylate is released from the metal center upon β-hydride elimination (Figure 4, intermediate I-1). To further examine the possibility of a 1,2-insertion product as a catalytic intermediate, the 1H NMR spectrum of a catalytic run using the cobalt catalyst and parahydrogen was examined. The 1H NMR spectrum shows the expected hyperpolarized signals of ethyl propionate. Further examination of the hydridic region shows one antiphase signal at −4.84 ppm in acetone-d6 (Figure S10). Based on the chemical shift and the observed reactivity, the antiphase resonance was assigned as a transient cobalt hydride (Figure S13). However, the expected additional resonance from the pairwise addition of p-H2 was not resolved in the hydridic region of the 1H NMR spectrum (Figure S10). Furthermore, based on the magnitude of the resonance at −4.84 ppm, a similar antiphase resonance in the aliphatic region corresponding to a cobalt−alkyl fragment in the 1H NMR spectrum would naturally be difficult to characterize because of the presence of hyperpolarized ethyl propionate and additional ligand resonances. Changing the solvent of reaction to THF-d8 or benzene-d6 did not resolve the additional peak in the 1H NMR spectrum (Figures S11 and S12, respectively). Examining the 1H-OPSY (only parahydrogen spectroscopy)74 NMR spectrum of the same reaction displayed the expected hyperpolarized resonances of ethyl propionate; however, signals corresponding to the proposed cobalt-hydride resonance were not resolved (Figure S14). Surprisingly, the signal integration of the proton (Ha) on Cα is greater than the proton on the Cβ position of ethyl propionate (Figure S14). These differences may arise due to the quadrupolar relaxation by the cobalt nucleus (I = 7/2). In this case, the relaxation of the hydride (Hb) in the proposed intermediate (Figure 4, intermediate I-1) is shortened by the cobalt nucleus, contributing to an overall weaker 1H NMR signal intensity for the proton attached to Cβ carbon. In addition, the

Figure 3. Molecular structure of ( Mes CCC)Co(η 2 -H 2 C CHCOOCH2CH3)2 shown with 50% probability ellipsoids. Solvent molecules and H atoms have been omitted for clarity. Selected bond lengths and angles can be found in the Supporting Information (Table S2).

hyperpolarized intermediates. Here the key mechanistic steps would be expected to involve a cobalt-dihydride or a cobaltdihydrogen olefin complex. A close examination of the 13C NMR spectrum revealed an antiphase doublet at 129.84 ppm (1JCH = 164.4 H) which was assigned as the Cα carbon of ethyl acrylate. The formation of a transient 1,2-insertion intermediate is proposed in Figure 4 for this observed hyperpolarized olefinic carbon (Figure 4, pathway 1, and Figure S9). In the proposed intermediate, the symmetry of p-H2 is broken following oxidative addition onto the metal center. Upon insertion of olefin into the Co−H bond and the formation of a Co−alkyl and Co−H fragment, the two H atoms originating from p-H2 molecule remain mutually coupled, which is consistent with the formulation of the 1,2-insertion product, intermediate I-1 (Figure 4). The transfer of polarization from

Figure 4. Proposed hydrogenation pathways of the cobalt catalyst for the observed hyperpolarized products in the 1H and 13C NMR spectra. D


Article


catalysis is proposed to transpire through a cobalt−alkyl hydride intermediate. Lastly, the success of a bench-stable cobalt precursor, (MesCCC)CoCl2py, activated in situ by NaHBEt3, demonstrated that this cobalt bis(carbene) pincer system is a viable alternative to the widely employed rhodium PHIP catalyst.

hyperpolarization of the olefinic protons of ethyl acrylate were also observed in the 1H NMR spectrum (Figure S15), which is consistent with the hyperpolarized olefinic Cα carbon of ethyl acrylate in the 13C NMR spectrum (Figure S9). When the same reaction was monitored using [(dppb)Rh(COD)]BF4 as the catalyst, each proton of ethyl propionate was equally hyperpolarized, as determined by the integration of the signal, and the olefinic protons of ethyl acrylate were not observed in the 1H-OPSY NMR spectrum (Figure S16). Unlike in the rhodium-catalyzed hydrogenation, β-hydride elimination and reversible coordination of H2 ensue in the cobalt system.53 These studies demonstrate that a 1,2-insertion product is transiently formed during the hydrogenation of ethyl acrylate. However, since the signal enhancement factor of the Cβ carbon is greater than that of the Cα carbon in the 13C NMR spectrum during the hydrogenation of ethyl acrylate using the cobalt catalyst (Figure 2), a 2,1-insertion intermediate is also proposed (Figure 4, pathway 2). The 13C NMR signal enhancement differences (Figure 1) are likely due to the quadrupolar effect of the cobalt nucleus (I = 7/2) on the hydride during the formation of the transient intermediate (Figure 4, intermediate I-2), resulting in weaker polarization transfer to the 13C nuclei in the hyperpolarized product. The 1,2- and 2,1-insertion of alkyl acrylates into a metal-hydride bond is well precedented with cobalt.75 Furthermore, the chelation of the carbonyl oxygen during the (MesCCC)Co-pycatalyzed hydrogenation likely also results, as this would stabilize an 18-electron cobalt(III) intermediate for which the cobalt-hydride signal was observed in the 1H NMR spectrum (Figure 4, intermediates I-1 and I-2). The capacity of (MesCCC)Co-py to mediate the hyperpolarized 13C NMR signals of the hydrogenation product of ethyl acrylate with p-H2 offers a potential alternative to the cationic chelating diphosphine rhodium complexes currently employed, despite the reversible coordination of H2 and apparent long-lived cobalt intermediates. The 16-electron cobalt(I) complex remains active in acetone; however, the sensitivity of the catalyst to air limits the capacity of this system. The bench-stable 18-electron cobalt(III) precursor, (MesCCC)CoCl2py, was demonstrated to selectively hydrogenate nitriles to primary amines upon in situ activation with NaHBEt3.51 A similar approach was envisioned to determine if starting with the cobalt(III) precursor was a feasible route toward the generation of hyperpolarized 13C NMR signals. To this end, the hydrogenation of ethyl acrylate was carried out in acetone-d6 using (MesCCC)CoCl2py with 2 equiv of NaHBEt3 and p-H2. The 13C NMR spectrum (Figure S9) shows the hyperpolarization of the carboxylate, Cα, and Cβ carbon resonances of ethyl propionate and the Cα carbon resonance of ethyl acrylate. This signifies that the bench-stable cobalt(III) precursor can serve as a starting complex for the generation of hyperpolarized 13C NMR signals using PHIP.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b08614. Experimental procedure; tables and figures of experimental results (PDF) Experimental data (TXT)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Alison R. Fout: 0000-0002-4669-5835 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors thank the NSF for financial support with a CAREER award (1351961) to A.R.F. The authors also thank Safiyah Muhammad for her help in collecting the spectra and Charles R. Markus and Prof. Benjamin J. McCall for use of the p-H2 generator; Charles R. Markus has been supported in part by an NSF award (CHE 12-13811) and a NASA award (NNX13AE62G) to PI Prof. Benjamin J. McCall.

■

REFERENCES

(1) Halse, M. E. Perspectives for hyperpolarization in compact NMR. TrAC, Trends Anal. Chem. 2016, 83, 76−83. (2) Kovtunov, K. V.; Pokochueva, E. V.; Salnikov, O. G.; Cousin, S. F.; Kurzbach, D.; Vuichoud, B.; Jannin, S.; Chekmenev, E. Y.; Goodson, B. M.; Barskiy, D. A.; Koptyug, I. V. Hyperpolarized NMR Spectroscopy: d-DNP, PHIP, and SABRE Techniques. Chem. - Asian J. 2018, 13, 1857−1871. (3) Rizi, R. R. A new direction for polarized carbon-13 MRI. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 5453−5454. (4) Wilson, D. M.; Hurd, R. E.; Keshari, K.; Van Criekinge, M.; Chen, A. P.; Nelson, S. J.; Vigneron, D. B.; Kurhanewicz, J. Generation of hyperpolarized substrates by secondary labeling with [1,1-13C] acetic anhydride. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 5503−5507. (5) Day, S. E.; Kettunen, M. I.; Gallagher, F. A.; Hu, D.; Lerche, M.; Wolber, J.; Golman, K.; Ardenkjaer-Larsen, J. H.; Brindle, K. M. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat. Med. 2007, 13, 1382−1387. (6) Nelson, S. J.; Kurhanewicz, J.; Vigneron, D. B.; Larson, P. E. Z.; Harzstark, A. L.; Ferrone, M.; van Criekinge, M.; Chang, J. W.; Bok, R.; Park, I.; Reed, G.; Carvajal, L.; Small, E. J.; Munster, P.; Weinberg, V. K.; Ardenkjaer-Larsen, J. H.; Chen, A. P.; Hurd, R. E.; Odegardstuen, L.; Robb, F. J.; Tropp, J.; Murray, J. A. Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate. Sci. Transl. Med. 2013, 5, 198ra108. (7) Duckett, S. B.; Mewis, R. E. Application of Parahydrogen Induced Polarization Techniques in NMR Spectroscopy and Imaging. Acc. Chem. Res. 2012, 45, 1247−1257 and references therein. . (8) Eisenschmid, T. C.; Kirss, R. U.; Deutsch, P. P.; Hommeltoft, S. I.; Eisenberg, R.; Bargon, J.; Lawler, R. G.; Balch, A. L. Para hydrogen

■

CONCLUSION In conclusion, (MesCCC)Co-py was demonstrated to effectively enable the hyperpolarization of the carboxylate 13C NMR signal of ethyl propionate by the parahydrogenation of ethyl acrylate. Comparisons of the carboxylate 13C NMR signal enhancement using [(dppb)Rh(COD)]BF4 and (MesCCC)Copy demonstrated that the cobalt system hyperpolarization efficiency is comparable with that of the rhodium system. Based on the 1H and 13C NMR studies presented the binding of olefin and H2 to the metal center is reversible and the E


Article


hydrogen with 15N-Propargylcholine. J. Am. Chem. Soc. 2012, 134, 11146−11152. (26) Cavallari, E.; Carrera, C.; Sorge, M.; Bonne, G.; Muchir, A.; Aime, S.; Reineri, F. The 13C hyperpolarized pyruvate generated by ParaHydrogen detects the response of the heart to altered metabolism in real time. Sci. Rep. 2018, 8, 8366. (27) Chukanov, N. V.; Salnikov, O. G.; Shchepin, R. V.; Kovtunov, K. V.; Koptyug, I. V.; Chekmenev, E. Y. Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-13C-Acetates and 1-13C-Pyruvates via Side Arm Hydrogenation. ACS Omega 2018, 3, 6673−6683. (28) Cavallari, E.; Carrera, C.; Reineri, F. ParaHydrogen Hyperpolarized Substrates for Molecular Imaging Studies. Isr. J. Chem. 2017, 57, 833−842 and references therein . (29) Hövener, J.; Pravdivtsev, A. N.; Kidd, B.; Bowers, R.; Glöggler, S.; Kovtunov, K. V.; Plaumann, M.; Katz-Brull, R.; Buckenmaier, K.; Jerschow, A.; Reineri, F.; Theis, T.; Shchepin, R. V.; Wagner, S.; Bhattacharya, P.; Zacharias, N. M.; Chekmenev, E. Y. ParahydrogenBased Hyperpolarization for Biomedicine. Angew. Chem., Int. Ed. 2018, 57, 11140−11162. (30) Chan, H. R.; Bhattacharya, P.; Imam, A.; Freundlich, A.; Tran, T.; Perman, W. H.; Lin, A. P.; Harris, K.; Chekmenv, E. Y.; Ingram, M.; Ross, B. D. No clinical toxicity is seen in vivo from hyperpolarized PASADENA MR reagents or catalyst. Prc. Int. Soc. Mag. Reson. Med. 2009, 17, 2448. (31) McCormick, J.; Korchak, S.; Mamone, S.; Ertas, Y. N.; Liu, Z.; Verlinsky, L.; Wagner, S.; Glöggler, S.; Bouchard, L. S. More Than 12% Polarization and 20 minute Lifetime of 15N on Choline Derivative Utilizing Parahydrogen and a Rhodium Nanocatalyst in Water. Angew. Chem. 2018, 130, 10852. (32) Salnikov, O. G.; Kovtunova, L. M.; Skovpin, I. V.; Bukhtiyarov, V. I.; Kovtunov, K. V.; Koptyug, I. V. Mechanistic Insight into the Heterogeneous Hydrogenation of Furan Derivatives with the use of Parahydrogen. ChemCatChem 2018, 10, 1178−1183. (33) Bales, L. B.; Kovtunov, K. V.; Barskiy, D. A.; Shchepin, R. V.; Coffey, A. M.; Kovtunova, L. M.; Bukhtiyarov, A. V.; Feldman, M. A.; Bukhtiyarov, V. I.; Chekmenev, E. Y.; Koptyug, I. V.; Goodson, B. M. Aqueous, Heterogeneous para-Hydrogen-Induced 15N Polarization. J. Phys. Chem. C 2017, 121, 15304−15309. (34) Kovtunov, K. V.; Barskiy, D. A.; Shchepin, R. V.; Salnikov, O. G.; Prosvirin, I. P.; Bukhtiyarov, A. V.; Kovtunova, L. M.; Bukhtiyarov, V. I.; Koptyug, I. V.; Chekmenev, E. Y. Production of Pure Aqueous 13 C-Hyperpolarized Acetate Via Heterogeneous ParahydrogenInduced Polarization. Chem. - Eur. J. 2016, 22, 16446−16449. (35) Zhivonitko, V. V.; Skovpin, I. V.; Crespo-Quesada, M.; KiwiMinsker, L.; Koptyug, I. V. Acetylene Oligomerization over Pd Nanoparticles with Controlled Shape: A Parahydrogen-Induced Polarization Study. J. Phys. Chem. C 2016, 120, 4945−4953. (36) Zhao, E. W.; Xin, Y.; Hagelin-Weaver, H. E.; Bowers, C. R. Semihydrogenation of Propyne over Cerium Oxide Nanorods, Nanocubes, and Nano-Octahedra: Facet-Dependent ParahydrogenInduced Polarization. ChemCatChem 2016, 8, 2197−2201. (37) Burueva, D. B.; Salnikov, O. G.; Kovtunov, K. V.; Romanov, A. S.; Kovtunova, L. M.; Khudorozhkov, A. K.; Bukhtiyarov, A. V.; Prosvirin, I. P.; Bukhtiyarov, V. I.; Koptyug, I. V. Hydrogenation of Unsaturated Six-Membered Cyclic Hydrocarbons Studied by the Parahydrogen-Induced Polarization Technique. J. Phys. Chem. C 2016, 120, 13541−13548. (38) Zhao, E. W.; Zheng, H.; Zhou, R.; Hagelin-Weaver, H. E.; Bowers, C. R. Shaped Ceria Nanocrystals Catalyze Efficient and Selective Para-Hydrogen-Enhanced Polarization. Angew. Chem., Int. Ed. 2015, 54, 14270−14275. (39) Salnikov, O. G.; Burueva, D. B.; Barskiy, D. A.; Bukhtiyarova, G. A.; Kovtunov, K. V.; Koptyug, I. V. A Mechanistic Study of Thiophene Hydrodesulfurization by the Parahydrogen-Induced Polarization Technique. ChemCatChem 2015, 7, 3508−3512. (40) Salnikov, O. G.; Kovtunov, K. V.; Barskiy, D. A.; Khudorozhkov, A. K.; Inozemtseva, E. A.; Prosvirin, I. P.; Bukhtiyarov, V. I.; Koptyug, I. V. Evaluation of the Mechanism of

induced polarization in hydrogenation reactions. J. Am. Chem. Soc. 1987, 109, 8089−8091. (9) Adams, R. W.; Aguilar, J. A.; Atkinson, K. D.; Cowley, M. J.; Elliott, P. I. P.; Duckett, S. B.; et al. Reversible Interactions with paraHydrogen Enhance NMR Sensitivity by Polarization Transfer. Science 2009, 323, 1708−1711. (10) Schmidt, A. D.; Berner, S.; Schimpf, W.; Müller, S.; Lickert, T.; Schwaderlapp, N.; Knecht, S.; Skinner, J. G.; Dost, A.; Rovedo, R.; Hennig, J.; von Elverfeldt, D.; Hövener, J.-B. Liquid-state carbon-13 hyperpolarization generated in an MRI system for fast imaging. Nat. Commun. 2017, 8, 14535. (11) Coffey, A. M.; Shchepin, R. V.; Truong, M. L.; Wilkens, K.; Pham, W.; Chekmenev, E. Y. Open-Source Automated Parahydrogen Hyperpolarizer for Molecular Imaging Using 13C Metabolic Contrast Agents. Anal. Chem. 2016, 88, 8279−8288. (12) Shchepin, R. V.; Coffey, A. M.; Waddell, K. W.; Chekmenev, E. Y. Parahydrogen Induced Polarization of 1-13C-Phospholactate-d2 for Biomedical Imaging with > 30,000-fold NMR Signal Enhancement in Water. Anal. Chem. 2014, 86, 5601−5605. (13) Zacharias, N. M.; Chan, H. R.; Sailasuta, N.; Ross, B. D.; Bhattacharya, P. Real-Time Molecular Imaging of Tricarboxylic Acid Cycle Metabolism in Vivo by Hyperpolarized 1-13C Diethyl Succinate. J. Am. Chem. Soc. 2012, 134, 934−943. (14) Bhattacharya, P.; Chekmenev, E. Y.; Reynolds, W. F.; Wagner, S. R.; Zacharias, N.; Chan, H. R.; Bünger, R.; Ross, B. D. PHIP Hyperpolarized MR Receptor Imaging In VivoA Pilot Study of 13C Imaging of Atheroma in Mice. NMR Biomed. 2011, 24, 1023−1028. (15) Reineri, F.; Viale, A.; Dastrù, W.; Gobetto, R.; Aime, S. How to design 13C para-hydrogen-induced polarization experiments for MRI applications. Contrast Media Mol. Imaging 2011, 6, 77−84. (16) Reineri, F.; Santelia, D.; Viale, A.; Cerutti, E.; Tichy, T.; Premkumar, S.S. D.; Gobetto, R.; Aime, S.; Poggi, L. Parahydrogenated Glucose Derivatives as Potential 13C-Hyperpolarized Probes for Magnetic Resonance Imaging. J. Am. Chem. Soc. 2010, 132, 7286−7193. (17) Chekmenev, E. Y.; Hövener, J.; Norton, V. A.; Harris, K.; Batchelder, L. S.; Bhattacharya, P.; Ross, B. D.; Weitekamp, D. P. PASADENA Hyperpolarization of Succinic Acid for MRI and NMR Spectroscopy. J. Am. Chem. Soc. 2008, 130, 4212−4213. (18) Bhattacharya, P.; Chekmenev, E. Y.; Perman, W. H.; Harris, K. C.; Lin, A. P.; Norton, V. A.; Tan, C. T.; Ross, B. D.; Weitekamp, D. P. Towards hyperpolarized 13C-succinate imaging of brain cancer. J. Magn. Reson. 2007, 186, 150−155. (19) Golman, K.; Axelsson, O.; Jóhannesson, H.; Månsson, S.; Olofsson, C.; Petersson, J. S. Pararhydrogen-Induced Polarization in Imaging: Subsecond 13C Angiography. Magn. Reson. Med. 2001, 46, 1−5. (20) Cavallari, E.; Carrera, C.; Aime, S.; Reineri, F. 13C MR Hyperpolarization of Lactate by Using ParaHydrogen and Metabolic Transformation in Vitro. Chem. - Eur. J. 2017, 23, 1200−1204. (21) Kovtunov, K. V.; Barskiy, D. A.; Salnikov, O. G.; Shchepin, R. V.; Coffey, A. M.; Kovtunova, L. M.; Bukhtiyarov, V. I.; Koptyug, I. V.; Chekmenev, E. Y. Toward production of pure 13C hyperpolarized metabolites using heterogeneous parahydorgen-induced polarization of ethyl[1-13C]acetate. RSC Adv. 2016, 6, 69728−69732. (22) Shchepin, R. V.; Barskiy, D. A.; Coffey, A. M.; Manzanera Esteve, I. V.; Chekmenev, E. Y. Efficient Synthesis of Molecular Precursors for Parahydrogen-Induced Polarization of Ethyl Acetate1-13C and Beyond. Angew. Chem., Int. Ed. 2016, 55, 6071−6074. (23) Cavallari, E.; Carrera, C.; Boi, T.; Aime, S.; Reineri, F. Effects of Magnetic Field Cycle on the Polarization Transfer from Parahydrogen to Heteronuclei through Long-Range J-Couplings. J. Phys. Chem. B 2015, 119, 10035−10041. (24) Reineri, F.; Boi, T.; Aime, S. ParaHydrogen Induced Polarization of 13C carboxylate resonance in acetate and pyruvate. Nat. Commun. 2015, 6, 5858. (25) Reineri, F.; Viale, A.; Ellena, S.; Alberti, D.; Boi, T.; Giovenzana, G. B.; Gobetto, R.; Premkumar, S. S. D.; Aime, S. 15N Magnetic Resonance Hyperpolarization via the Reaction of ParaF


Article

Journal of the American Chemical Society Heterogeneous Hydrogenation of α,β-Unsaturated Carbonyl Compounds via Pairwise Hydrogen. ACS Catal. 2014, 4, 2022−2028. (41) Kovtunov, K. V.; Barskiy, D. A.; Salnikov, O. G.; Khudorozhkov, A. K.; Bukhtiyarov, V. I.; Prosvirin, I. P.; Koptyug, I. V. Para hydrogen-induced polarization (PHIP) in heterogeneous hydrogenation over bulk metals and metal oxides. Chem. Commun. 2014, 50, 875−878. (42) Zhivonitko, V. V.; Kovtunov, K. V.; Chapovsky, P. L.; Koptyug, I. V. Nuclear Spin Isomers by Chemical Synthesis and Application for NMR Signal Enhancement. Angew. Chem., Int. Ed. 2013, 52, 13251− 13255. (43) Zhivonitko, V. V.; Kovtunov, K. V.; Beck, I. E.; Ayupov, A. B.; Bukhtiyarov, V. I.; Koptyug, I. V. Role of Different Active Sites in Heterogenous Alkene Hydrogenation on Platinum Catalysts Revealed by Means of Parahydrogen-Induced Polarization. J. Phys. Chem. C 2011, 115, 13386−13391. (44) Koptyug, I. V.; Zhivonitko, V. V.; Kovtunov, K. V. New Perspectives for Parahydrogen-Induced Polarization in Liquid Phase Heterogeneous Hydrogenation−An Aqueous Phase and ALTADENA Study. ChemPhysChem 2010, 11, 3086−3088. (45) Balu, A. M.; Duckett, S. B.; Luque, R. Para-hydrogen induced polarisation effects in liquid phase hydrogenations catalysed by supported metal nanoparticles. Dalton Trans. 2009, 5074−5076. (46) Kovtunov, K. V.; Beck, I. E.; Bukhtiyarov, V. I.; Koptyug, I. V. Observation of Parahydrogen-Induced Polarization in Heterogenous Hydrogenation on Supported Metal Catalysts. Angew. Chem. 2008, 120, 1514−1517. (47) Egorova, K. S.; Ananikov, V. P. Toxicity of Metal Compounds: Knowledge and Myths. Organometallics 2017, 36, 4071−40490. (48) Duckett, S. B.; Sleigh, C. J. Applications of the parahydrogen phenomenon: A chemical perspective. Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 71−92. (49) Natterer, J.; Bargon, J. Parahydrogen induced polarization. Prog. Nucl. Magn. Reson. Spectrosc. 1997, 31, 293−315. (50) Salnikov, O. G.; Liu, H.; Fedorov, A.; Burueva, D. B.; Kovtunov, K. V.; Copéret, C.; Koptyug, I. V. Pairwise hydrogen addition in the selective semihydrogenation of alkynes on silicasupported Cu catalysts. Chem. Sci. 2017, 8, 2426−2430. (51) Tokmic, K.; Jackson, B. J.; Salazar, A.; Woods, T. J.; Fout, A. R. Cobalt-Catalyzed and Lewis Acid-Assisted Nitrile Hydrogenation to Primary Amines: A Combined Effort. J. Am. Chem. Soc. 2017, 139, 13554−13561. (52) Tokmic, K.; Fout, A. R. Alkyne Semihydrogenation with a WellDefined Nonclassical Co-H2 Catalyst: A H2 Spin on Isomerization and E-Selectivity. J. Am. Chem. Soc. 2016, 138, 13700−13705. (53) Tokmic, K.; Markus, C. R.; Zhu, L.; Fout, A. R. Well-Defined Cobalt(I) Dihydrogen Catalyst: Experimental Evidence for a Co(I)/ Co(III) Redox Process in Olefin Hydrogenation. J. Am. Chem. Soc. 2016, 138, 11907−11913. (54) Godard, C.; Duckett, S. B.; Polas, S.; Tooze, R.; Whitwood, A. C. An NMR study of cobalt-catalyzed hydroformylation using parahydrogen induced polarization. Dalton Trans. 2009, 2496−2509. (55) Godard, C.; Duckett, S. B.; Polas, S.; Tooze, R.; Whitwood, A. C. Detection of Intermediates in Cobalt-Catalyzed Hydroformylation Using para-Hydrogen-Induced Polarization. J. Am. Chem. Soc. 2005, 127, 4994−4995. (56) Schott, D.; Callaghan, P.; Dunne, J.; Duckett, S. B.; Godard, C.; Goicoechea, J. M.; Harvey, J. N.; Lowe, J. P.; Mawby, R. J.; Müller, G.; Perutz, R. N.; Poli, R.; Whittlesey, M. K. The reaction of M(CO)3(Ph2PCH2CH2PPh2) (M = Fe, Ru) with para hydrogen: probing the electronic structure of reaction intermediates and the internal rearrangement mechanism for the dihydride products. Dalton Trans. 2004, 3218−3224. (57) Permin, A. B.; Eisenberg, R. One-Hydrogen Polarization in Hydroformylation Promoted by Platinum-Tin and Iridium Carbonyl Complexes: A New Types of Parahydrogen-Induced Effect. J. Am. Chem. Soc. 2002, 124, 12406−12407.

(58) Godard, C.; Duckett, S. B.; Henry, C.; Polas, S.; Toose, R.; Whitwood, A. C. New perspectives in hydroformylation: a parahydrogen study. Chem. Commun. 2004, 1826−1827. (59) López-Serrano, J.; Duckett, S. B.; Lledos, A. PalladiumCatalyzed Hydrogenation: Detection of Palladium Hydrides. A Joint Study Using Para-Hydrogen-Enhanced NMR Spectroscopy and Density Functional Theory. J. Am. Chem. Soc. 2006, 128, 9596−9597. (60) López-Serrano, J.; Duckett, S. B.; Aiken, S.; Lenero, K. Q. A.; Drent, E.; Dunne, J. P.; Konya, D.; Whitwood, A. C. A para-Hydrogen Investigation of Palladium-Catalyzed Alkyne Hydrogenation. J. Am. Chem. Soc. 2007, 129, 6513−6527. (61) Boutain, M.; Duckett, S. B.; Dunne, J. P.; Godard, C.; Hernández, J. M.; Holmes, A. J.; Khazal, I. G.; López-Serrano, J. A para hydrogen based NMR study of Pt catalyzed alkyne hydrogenation. Dalton Trans. 2010, 39, 3495−3500. (62) Guan, D.; Holmes, A. J.; López-Serrano, J.; Duckett, S. D. Following palladium catalyzed methoxycarbonylation by hyperpolarized NMR spectroscopy: a para hydrogen based investigation. Catal. Sci. Technol. 2017, 7, 2101−2109. (63) Pravica, M. G.; Weitekamp, D. P. Net NMR alignment by adiabatic transport of parahydrogen addition products to high magnetic field. Chem. Phys. Lett. 1988, 145, 255−258. (64) Barkemeyer, J.; Haake, M.; Bargon, J. Hetero-NMR Enhancement via Parahydrogen Labeling. J. Am. Chem. Soc. 1995, 117, 2927− 2928. (65) Kuhn, L. T.; Bommerich, U.; Bargon, J. Transfer of Parahydrogen-Induced Hyperpolarization to 19F. J. Phys. Chem. A 2006, 110, 3521−3526. (66) Adams, R. W.; Duckett, S. B.; Green, R. A.; Williamson, D. C.; Green, G. R. G. A theoretical basis for spontaneous polarization transfer in non-hydrogenative parahydrogen-induced polarization. J. Chem. Phys. 2009, 131, 194505. (67) Colell, J. F. P.; Logan, A. W. J.; Zhou, Z.; Shchepin, R. V.; Barskiy, D. A.; Ortiz, G. X.; Wang, Q.; Malcolmson, S. J.; Chekmenev, E. Y.; Warren, W. S.; Theis, T. Generalizing, Extending, and Maximizing Nitrogen-15 Hyperpolarization Induced by Parahydrogen in Reversible Exchange. J. Phys. Chem. C 2017, 121, 6626−6634. (68) Glöggler, S.; Wagner, S.; Bouchard, L. S. Hyperpolarization of amino acid derivatives in water for biological applications. Chem. Sci. 2015, 6, 4261−4266. (69) Reineri, F.; Aime, S.; Gobetto, R.; Nervi, C. Role of the reaction intermediates in determining PHIP (parahydrogen induced polarization) effect in the hydrogenation of acetylene dicarboxylic acid with the complex [Rh(dppb)]+ (dppb: 1,4(diphenylphosphino)butane). J. Chem. Phys. 2014, 140, 094307. (70) Giernoth, R.; Heinrich, H.; Adams, N. J.; Deeth, R. J.; Bargon, J.; Brown, J. M. PHIP Detection of a Transient Rhodium Dihydride Intermediate in the Homogeneous Hydrogenation of Dehydroamino Acids. J. Am. Chem. Soc. 2000, 122, 12381−12382. (71) Sánchez-Delgado, R. A.; Rosales, M. Kinetic studies as a tool for the elucidation of the mechanisms of metal complex-catalyzed homogeneous hydrogenation reactions. Coord. Chem. Rev. 2000, 196, 249−280. (72) Kirss, R. U.; Eisenberg, R. Para-hydrogen-induced polarization in rhodium complex-catalyzed hydrogenation reactions. J. Organomet. Chem. 1989, 359, C22−C26. (73) Natterer, J.; Schedletzky, O.; Barkemeyer, J.; Bargon, J.; Glaser, S. J. Investigating Catalytic Processes with Parahydrogen: Evolution of Zero-Quantum Coherence in AA’X Spin Systems. J. Magn. Reson. 1998, 133, 92−97. (74) Aguilar, J. A.; Elliott, P. I. P.; López-Serrano, J.; Adams, R. W.; Duckett, S. D. Only para-hydrogen spectroscopy (OPSY), a technique for the selective observation of para-hydrogen enhanced NMR signals. Chem. Commun. 2007, 1183−1185. (75) Doherty, M. D.; Grant, B.; White, P. S.; Brookhart, M. Reactions of H2 and R3SiH with Electrophilic Cobalt(III) Alkyl Complexes: Spectroscopic Characterization, Dynamics, and Chemistry of [Cp*Co(L)(H)(η2-H2)][B(ArF)4] and [Cp*Co(L)(H)(η2HSiR3)][B(ArF)4]. Organometallics 2007, 26, 5950−5960. G


13C NMR Signal Enhancement Using Parahydrogen-Induced

Recommend Documents