Communication pubs.acs.org/Organometallics
Synthesis of Iron Hydride Complexes Relevant to Hydrogen Isotope Exchange in Pharmaceuticals Renyuan Pony Yu, Jonathan M. Darmon, Scott P. Semproni, Zoë R. Turner, and Paul J. Chirik* Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States S Supporting Information *
ABSTRACT: Addition of H2 gas to the bis(arylimidazolin-2-ylidene)pyridine iron bis(dinitrogen) complex (H4-iPrCNC)Fe(N2)2 resulted in facile oxidative addition of the H−H bond to yield a mixture of (H4-iPrCNC)FeH4 and trans-(H4-iPrCNC)FeH2(N2), depending on the partial pressures of H2 and N2. Both iron hydride complexes were characterized by X-ray diffraction and proved relevant to the catalytic hydrogen isotope exchange of arene C(sp2)−H bonds. Activation of the benzene-d6 solvent at ambient temperature produced deuterated isotologues of both compounds that exhibit large isotopic perturbation of resonances in the hydride signals.
T
dihydrides, and iron disilyl silane and dihydrogen complexes, depending on the identity of the silane reagent.12 Addition of 1 atm of H2 to a benzene-d6 solution of (H4-iPrCNC)Fe(N2)2 resulted in a gradual color change from dark purple to clear orange. Monitoring the addition by 1H NMR spectroscopy revealed gradual formation of a new C2vsymmetric product within minutes at 23 °C. Four well-resolved resonances were observed at −10.56, −10.82, −11.05, and −11.22 ppm (Figure 1). The relative intensities of these signals varied as a function of time and completely disappeared after approximately 36 h at 23 °C, while the resonances for the H4CNC ligand that had not undergone hydrogen isotope exchange remained (vide infra). Repeating the hydrogenation in p-xylene-d10 generated the same C2v-symmetric iron product, but with a single hydride resonance centered at −11.36 ppm that integrates to 4H (see Figure S3 in the Supporting Information). This solvent was selected to prevent H−D exchange and enable preparation of the pure natural-abundance isotopologue. The observations in benzene-d6 are consistent with formation of an iron tetrahydride, (H4-iPrCNC)FeH4, with the additional hydride signals arising from deuterated isotopologues generated from hydrogen isotope exchange with the benzene-d6 solvent (Scheme 1). Performing the hydrogenation in toluene, freezing the sample, and analyzing by Mössbauer spectroscopy at 80 K revealed an isomer shift of 0.01 mm/s and quadrupole splitting of 1.66 mm/s. The NMR chemical shift and multiplicity of each peak are reported in Table 1, and this information coupled with the relative rates of formation and disappearance establishes the most upfield (−11.22 ppm) resonance corresponding to (H4-iPrCNC)FeH4. Sequential
he radiolabeling of pharmaceutical lead compounds is a key component of drug discovery and registration,1 enabling applications ranging from preclinical adsorption, distribution, metabolism, and excretion (ADME) studies to late-stage clinical trials.2 Tritium, ideally introduced from T2 gas, is often the preferred radiolabel, given its relative availability and the presence of exchangeable C−H bonds in active pharmaceutical ingredients (APIs). Transition-metal catalysts that incorporate tritium at low pressure, in polar solvents compatible with APIs, and with predictable site selectivities are preferred.3 The bis(arylimidazolin-2-ylidene) iron dinitrogen complex (H4-iPrCNC)Fe(N2)24 exhibits many beneficial features for drug tritiation, including accelerated hydrogen isotope exchange at lower pressures of D2 or T2 gas, efficient catalysis in Nmethylpyrrolidone solvent with a range of pharmaceuticals, and site selectivity that is highly predictable and sterically driven, complementary to iridium-catalyzed methods that typically rely on directing groups.5−7 To understand the catalytic performance, particularly the inverse pressure dependence, as well as the fundamental role various pincers play in supporting oxidative addition to iron(0) compounds, the reactivity of (H4-iPrCNC)Fe(N2)2 with H2 was investigated. The interaction of dihydrogen and silanes with formally iron(0) complexes supported by tridentate pincer ligands varies as a function of chelate. With relatively electron withdrawing, redox-active bis(imino)pyridines,8 σ complexes are favored. Isolable iron(II) dihydride and silyl hydride derivatives supported by pyridine bis(phosphine) ligands are known; however, these compounds were prepared from hydride addition.9 With iron and cobalt, the [CNC] class of ligands has exhibited both redox-innocent10 and redox-active11 behavior. Most relevant to this study, Danopoulos and coworkers have reported the oxidative addition of primary silanes to (iPrCNC)Fe(N2)2 to yield iron(II) silyl, iron(IV) bis(silyl) © XXXX American Chemical Society
Received: May 28, 2017
A
DOI: 10.1021/acs.organomet.7b00398 Organometallics XXXX, XXX, XXX−XXX
Communication
Organometallics
reaction time, an additional C2v-symmetric iron product often accompanied formation of (H4-iPrCNC)FeH4 (Figure 1b). This compound exhibits a singlet in the hydride region centered at −8.08 ppm, which is accompanied by a second signal at −7.94 ppm (J = 5.7 Hz) upon standing in benzene-d6 at 23 °C. Evacuation of the H2 atmosphere following hydrogenation of (H4-iPrCNC)Fe(N2)2 and addition of 15N2 gas also generated this second product. Notably, the hydride signal appeared as a doublet (2JN−H = 6.1 Hz) centered at −8.08 ppm (Figure 1c). The combination of the labeling experiments and interconversions under mixtures of H2 and N2 gas supports formulation of the second product as trans-(H4-iPrCNC)FeH2(N2). In both complexes, isotopic exchange into the hydride, one of the methyl group environments of the isopropyl aryl, and 4pyridine positions was observed upon standing in benzene-d6 at 23 °C. However, the rate of hydrogen isotope exchange of the 4-pyridine position was significantly slower. Additional 1H NMR measurements were conducted to determine whether (H4-iPrCNC)FeH4 and (H4-iPrCNC)FeH2(N2) were classical or nonclassical hydride complexes.13 The JH−D values reported in Table 1 alone are insufficient to make this distinction.14 T1(min) values were measured at 400 MHz, and a value of 522 ms (−45 °C, THF-d8) was determined for (H4-iPrCNC)FeH2(N2), consistent with classical behavior and the trans disposition of the hydride ligands. At the same temperature, a value of 15 ms was determined for (H4-iPrCNC)FeH4, consistent with nonclassical behavior and rapid averaging between the Fe−H bonds. Because both iron hydrides rapidly revert to (H4-iPrCNC)Fe(N2)2 upon exposure to N2, single crystals suitable for X-ray diffraction were obtained from a saturated pentane solution under a H2 atmosphere. Orange cocrystals of (H4-iPrCNC)FeH4 and (H4-iPrCNC)FeH2(N2) were obtained (Figure 2).
Figure 1. Partial 1H NMR spectra of (a) mixtures of (H4-iPrCNC)FeH4 and (H4-iPrCNC)FeH2(N2) and their corresponding isotopologues in benzene-d6, (b) mixtures of the all-protio (H4-iPrCNC)FeH4 and (H4-iPrCNC)FeH2(N2) in protio benzene/10% cyclohexane-d12, and (c) a mixture of all-protio (H4-iPrCNC)FeH4 and (H4-iPrCNC)FeH2(N2) in protio benzene/10% cyclohexane-d12 after 30 min exposure to 1 atm of 15N2. Spectra were recorded at 25 °C.
Scheme 1. Hydrogenation of (H4-iPrCNC)Fe(N2)2 with H2 To Generate (H4-iPrCNC)FeH4 and (H4-iPrCNC)FeH2(N2)
Table 1. 1H NMR Data for (H4-iPrCNC)FeH4, trans(H4-iPrCNC)FeH2(N2), and Their Corresponding Deuterated Isotopologues in Benzene-d6 at 25 °C (H4-iPrCNC)FeH2(N2) region 3-pyridine hydride (all H) hydride (15N2 coupled) hydride-d1 hydride-d2 hydride-d3
δ (ppm)a
Jobs (Hz)
5.78 −8.08 −8.08 (d)
7.9
−7.94 (t)
5.7
Figure 2. Representations of the solid-state structures of (a) (H4-iPrCNC)FeH2(N2) and (b) (H4-iPrCNC)FeH4 with 30% probability ellipsoids. All hydrogen atoms except for the located iron hydrides are omitted for clarity.
(H4-iPrCNC)FeH4 δ (ppm)
Jobs (Hz)b
6.05 −11.22
7.8
−11.05 (t) −10.82 (p) −10.56 (sep)
6.3 (6.2) 5.1 (5.1) 4.1 (4.9)
The nitrogen atoms of the dinitrogen ligand were refined anisotropically with their own free variable to a final occupancy of 41% for both atoms. The X-ray data confirm the identity of (H4-iPrCNC)FeH2(N2) and the trans arrangement of the hydride ligands. Crystals of pure (H4-iPrCNC)FeH4 were obtained by performing the recrystallization under 4 atm of H2. Residual electron density likely due to trace contamination from the dinitrogen complex was detected, and the additional hydride ligands could not be reliably located. On the basis of the spectroscopic and structural data, and analogy to (H4-iPrCNC)FeH2(N2)2, (H4-iPrCNC)FeH4 is best formulated as an iron(II) complex with classical trans-hydride ligands and a formally L-type η2-H2 ligand completing the coordination sphere.15 The symmetry observed by NMR spectroscopy coupled with the T1(min) data suggests that this view is an
6.1
a Multiplicities are presented in parentheses. bCalculated JHD,obs values are presented in italics and were derived from analysis of the NMR spectroscopic data (see the Supporting Information for full details).
addition of deuterium atoms resulted in systematic and relatively large downfield resonance perturbations with the peak centered at −10.56 ppm corresponding to (H4-iPrCNC)FeD3H. Depending on the pressure of added hydrogen and the B
DOI: 10.1021/acs.organomet.7b00398 Organometallics XXXX, XXX, XXX−XXX
Communication
Organometallics
(8) (a) Chirik, P. J.; Wieghardt, K. Science 2010, 327, 794−795. (b) Bart, S. C.; Chłopek, K.; Bill, E.; Bouwkamp, M. W.; Lobkovsky, E.; Neese, F.; Wieghardt, K.; Chirik, P. J. J. Am. Chem. Soc. 2006, 128, 13901−13912. (c) Stieber, S. C. E.; Milsmann, C.; Hoyt, J. M.; Turner, Z. R.; Finkelstein, K. D.; Wieghardt, K.; DeBeer, S.; Chirik, P. J. Inorg. Chem. 2012, 51, 3770−3785. (d) Praneeth, V. K. K.; Ringenberg, M. R.; Ward, T. R. Angew. Chem., Int. Ed. 2012, 51, 10228−10234. (9) Trovitch, R. J.; Lobkovsky, E.; Chirik, P. J. Inorg. Chem. 2006, 45, 7252−7260. (10) Darmon, J. M.; Yu, R. P.; Semproni, S. P.; Turner, Z. R.; Steiber, S. C. E.; DeBeer, S.; Chirik, P. J. Organometallics 2014, 33, 5423−5433. (11) Yu, R. P.; Darmon, J. M.; Milsmann, C.; Margulieux, G. W.; Stieber, S. C. E.; DeBeer, S.; Chirik, P. J. J. Am. Chem. Soc. 2013, 135, 13168−13184. (12) Pugh, D.; Wells, N. J.; Evans, D. J.; Danopoulos, A. A. Dalton Trans. 2009, 7189−7195. (13) Crabtree, R. H. Chem. Rev. 2016, 116, 8750−8769. (14) Morris, R. H. Coord. Chem. Rev. 2008, 252, 2381−2394. (15) A similar complex with a PNP pincer ligand was recently reported by Kirchner: Gorgas, N.; Alves, L. G.; Stöger, B.; Martins, A. M.; Veiros, L. F.; Kirchner, K. J. Am. Chem. Soc. 2017, 139, 8130− 8133. (16) Aresta, M.; Giannoccaro, P.; Rossi, M.; Sacco, A. Inorg. Chim. Acta 1971, 5, 115−118. (17) (a) Maseras, F.; Duran, M.; Lledós, A.; Bertrán, J. J. Am. Chem. Soc. 1991, 113, 2879−2884. (b) Van Der Sluys, L. S.; Eckert, J.; Eisenstein, O.; Hall, J. H.; Huffman, J. C.; Jackson, S. A.; Koetzle, T. F.; Kubas, G. J.; Vergamini, P. J.; Caulton, K. G. J. Am. Chem. Soc. 1990, 112, 4831−4841. (c) Bianchini, C.; Masi, D.; Peruzzini, M.; Casarin, M.; Maccato, C.; Rizzi, G. A. Inorg. Chem. 1997, 36, 1061− 1069. (d) Riehl, J.-F.; Pélissier, M.; Eisenstein, O. Inorg. Chem. 1992, 31, 3344−3345. (e) Došlić, N.; Gomzi, V.; Mališ, M.; Matanović, I.; Eckert, J. Inorg. Chem. 2011, 50, 10740−10747.
oversimplification, as all four hydride ligands are rapidly exchanging in solution, a behavior similar to that reported for (EtPh2P)3FeH2(η2-H2)16 and consistent with the “cis-effect” in metal dihydride−dihydrogen complexes.17 In summary, introduction of a relatively electron donating pyridine bis(carbene) ligand enables oxidative addition of H2 to iron(0). The resulting iron hydride complexes promote facile C(sp2)−H activation of benzene and are likely relevant to catalytic hydrogen isotopic exchange of pharmaceuticals.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.7b00398. Experimental details, characterization data, and structural data for (H4-iPrCNC)Fe(N2)2, (H4-iPrCNC)FeH2(N2), and (H4-iPrCNC)FeH4 (PDF) Accession Codes
CCDC 1543345−1543346 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail for P.J.C.:
[email protected]. ORCID
Paul J. Chirik: 0000-0001-8473-2898 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Merck, the Intellectual Property Accelerator Fund, and NSF GOALI (CHE-1564379) are acknowledged for financial support. We also thank Máté Bezdek for assistance with Xray crystallography.
■
REFERENCES
(1) Lappin, G.; Temple, S. In Radiotracers in Drug Development; CRC Press: Boca Raton, FL, 2006. (2) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf, L. Chem. Res. Toxicol. 2012, 25, 532−542. (3) Voges, R.; Heys, J. R.; Moenius, T. Preparation of Compounds Labeled with Tritium and Carbon-14; Wiley: Hoboken, NJ, 2009. (4) A compound related to the unsaturated N-heterocyclic carbene variant (iPrCNC)Fe(N2)2 was first reported by Danopoulos and coworkers: Danopoulos, A. A.; Wright, J. A.; Motherwell, W. B. Chem. Commun. 2005, 784−786. (5) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Nature 2016, 529, 195−199. (6) (a) Zhou, J.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 5783−5787. (b) Crabtree, R.; Felkin, H.; Morris, G. J. Organomet. Chem. 1977, 141, 205−215. (c) Nilsson, G. N.; Kerr, W. J. J. Labelled Compd. Radiopharm. 2010, 53, 662−667. (d) Hesk, D.; Das, P. R.; Evans, B. J. Labelled Compd. Radiopharm. 1995, 36, 497−502. (e) Salter, R. J. Labelled Compd. Radiopharm. 2010, 53, 645−657. (7) (a) Lockley, W. J. S.; Heys, J. R. J. Labelled Compd. Radiopharm. 2010, 53, 635−644. (b) Brown, J. A.; Cochrane, A. R.; Irvine, S.; Kerr, W. J.; Mondal, J. A.; Parkinson, J. A.; Paterson, L.; Tuttle, M.; Andersson, S.; Göran, N. Adv. Synth. Catal. 2014, 356, 3551−3562. C
DOI: 10.1021/acs.organomet.7b00398 Organometallics XXXX, XXX, XXX−XXX
