Optimized Syntheses of Cyclopentadienyl Nickel Chloride

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In the Laboratory

Optimized Syntheses of Cyclopentadienyl Nickel Chloride Compounds Containing N-Heterocyclic Carbene Ligands for Short Laboratory Periods Jason Cooke* and Owen C. Lightbody Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada *[email protected]

The ubiquitous phosphine (PR3) has long been used as a supporting ligand in transition-metal catalysis. Although highly successful, phosphine-based metal catalysts can suffer from thermal degradation, ultimately leading to a loss in catalytic activity over time. In recent years, a new class of “phosphine-mimic” ligands has been developed that offer more robust compounds, often with the added benefit of greater catalytic activity. N-Heterocyclic carbenes, abbreviated NHC, are rapidly establishing themselves as valuable supporting ligands in homogeneous catalysis and a wide range of organometallic compounds containing NHCs have been reported in the chemical literature (1). Recently, two excellent publications in this Journal provided a thorough discussion of the chemical community's interest in this new ligand class, and presented experiments in which organometallic compounds containing the 1,3-bis(2,4,6-trimethylphenyl)imidazol2-ylidene (IMes) ligand could be prepared in the undergraduate laboratory (2). NHC ligands can be prepared in a variety of ways (1c, 1d). One method is to prepare a suitably substituted diazabutadiene precursor 1 that is cyclized to form the imidazolium salt 2 (Scheme 1); subsequent deprotonation forms the free N-heterocyclic carbene. This approach was used by students of Canal and co-workers to prepare 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (IMes 3 HCl, 2a), which was then combined with the internal base Ag2O to produce the organometallic compound (IMes)AgCl (2a). This elegant method has the advantage of generating the carbene in situ and thereby producing the desired product from air-stable precursors under fairly mild conditions. In the context of the undergraduate laboratory, this type of approach is preferable to the alternative of generating the free carbene in solution, which typically involves the use of strong bases such as KOtBu or NaH and requires rigorously anhydrous and oxygen-free environments (1e). During the preparation of this article, we learned that Ritleng et al. had their students use nickelocene in a similar manner to deprotonate IMes 3 HCl and generate (η5-C5H5)Ni(IMes)Cl (3a) (Scheme 2) (2b). Coincidentally, we first introduced the synthesis of compounds 1a, 2a, and 3a to a third-year inorganic chemistry lab in 2003 and shared a microscale version of the synthesis in an education symposium in 2005 (3). We have progressively refined our approach to minimize the time required and to determine an optimum scale for the syntheses. More recently, the methodology has been expanded to include the preparation of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr 3 HCl, 2b) and the corresponding half-sandwich nickel compound (η5-C5H5)Ni(IPr)Cl (3b) (Scheme 2). 88

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Adaptation of the Syntheses to Shorter Laboratory Periods A major challenge in many educational laboratory settings is designing experiments that can be completed within a fixed time frame for students on a constrained schedule. This often means that interesting syntheses of modern, relevant compounds are not possible because of time demands. To illustrate the problem, consider that Ritleng's established procedure for the preparation of (η5-C5H5)Ni(IMes)Cl (3a) requires four consecutive 8 h laboratory periods to complete and, as such, is better suited for a fourth-year undergraduate or graduate-level course with maximum scheduling flexibility (2b). Instead, we have developed complete syntheses of (η5-C5H5)Ni(IMes)Cl (3a) and (η5-C5H5)Ni(IPr)Cl (3b) that can be carried out in as little as three or four 3 h lab periods that are held once per week; the overall duration of the experiment depends on whether nickelocene is purchased or prepared (4).1 The experiments have been carried out in second- and third-year undergraduate laboratories with class sizes ranging from 18 to 58 students and individual lab section sizes varying from 4 to 12 students. From a pedagogic perspective, our hope is that the optimized syntheses will appeal to a wide range of chemical educators who prefer to include modern organometallic compounds in their experiments but face the challenge of restricted laboratory time frames when designing their curricula. Preparation of Diazabutadienes (1) The preparation of the diazabutadiene precursors 1 from the substituted aniline and glyoxal is straightforward (Scheme 1). We found that yields approaching 80% (1a) or 90% (1b) could be achieved if the reaction mixtures were stirred briefly and then stored in corked flasks until the next lab period. In fact, the suggested formic acid catalyst (2a) can be omitted without affecting yield or compound purity, and a wait time of 1-7 days can be used. This approach is adaptable to a variety of lab schedules as the flasks can simply be left to stand in the back corner of a fume hood until the next lab session. For example, if the experiment is conducted midway through a term, two short “filler” steps of 20-30 min can be included in earlier lab sessions, one to set up the reaction and the next to isolate the product. Alternately, if the complete synthesis of compound 1a or 1b is desired within a single lab period, a short duration reflux of the reaction mixtures in ethanol (1a, 20 min) or methanol (1b, 45 min) produces quicker results with similar product purity but slightly lower yields. Although a catalyst must be used in this case, an additional benefit for the undergraduate laboratory is that the less toxic acetic acid can be used in place of formic acid (5).

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In the Laboratory Scheme 1. Synthetic Sequence for the Preparation of the N-Heterocyclic Carbene Precursors IMes 3 HCl (2a) and IPr 3 HCl (2b)

approximately 2 h. The time savings for 2b is mainly due to a shorter stir period and the fact that the entire reaction is run at room temperature. Student yields for recrystallized 2a usually fall between 30 and 40%, compared with 30 and 50% for 2b. For the latter compound, combination of the filtrates from the recrystallization step and further workup yields significant additional material. This usually boosts the yield of 2b to between 60 and 65% for the class as a whole, which compares favorably with the 70% yield reported for the large scale literature method (6). Unfortunately, the corresponding procedure for 2a is less successful. Taking into account all of the above, the synthesis of IPr 3 HCl (2b) is arguably more straightforward than that of IMes 3 HCl (2a) in the hands of undergraduate students. Reaction of Imidazolium Chlorides (2) with Nickelocene

Scheme 2. Reaction of NHC 3 HCl (2) with Nickelocene To Form HalfSandwich Compounds CpNi(NHC)Cl (3)

Synthesis of Imidazolium Chlorides (2) For the preparation of 2a,b (Scheme 1), we have adapted Nolan's approach (6) by optimizing the syntheses to smaller scales and shorter time frames that easily fit within one 3 h lab period. Formation of the imidazolium ring is accomplished by adding a mixture of paraformaldehyde and 4 M HCl in dioxane to a rapidly stirred ethyl acetate solution of either 1a at 0 °C or 1b at room temperature. The crude products are then dissolved in acetone (2a) or methanol (2b) and are crystallized by adding diethyl ether. Full details of the optimization and reaction conditions are provided in the supporting information. By comparison, the previously reported syntheses of 2a involve either a short reflux followed by a 3-7 day stir period (2a) or a one-pot sequence with two reflux steps (2b). An additional convenient feature of our approach is that less equipment is used and no heating is required. The time required for the entire synthesis of 2a from 1a rarely exceeds 2.5 h in the hands of second- or third-year undergraduates, with the analogous synthesis of 2b being complete in

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The preparation of (η5-C5H5)Ni(NHC)Cl (3) (Scheme 2) is an adaptation of the previously reported methods (2b, 7, 8) with the inclusion of a significant time-saving step. Following reflux in dry, oxygen-free THF, the published methods advocate evaporating the THF and extracting the crude product with hot toluene before filtering, concentrating, and crystallizing. Although this method works, we have found that up to half of our students obtained product containing paramagnetic impurities that caused broad peaks in the 1H NMR spectra. Instead, we discovered that suction filtering the THF reaction mixture directly through a bed of Celite before evaporating the THF leads to a crude product that is generally free of paramagnetic material. Furthermore, the revised approach saves the average student approximately 30 min and has turned a synthesis that some students were pressed to fit within 3 h into one that almost all are finished within 2.5 h. Typical student yields for 3a,b ranged from 40 to 70% after recrystallizaton from hot toluene/hexane. The workup procedures are all readily carried out in air, which we feel nicely illustrates the additional stability that is often imparted when a NHC ligand replaces a phosphine within a compound (1b, 9). Additionally, a class of 58 students (11-12 students per lab section) successfully carried out the synthesis of 3a when rigorous Schlenk techniques were not possible; in this case, the students added a chunk of dry ice to degas the THF, which was then immediately poured into a nitrogen-purged reaction vessel containing the solid reactants. In contrast, we have discovered that (η5-C5H5)Ni(PPh3)Cl, prepared by the metathesis reaction between NiCl2(PPh3)2 and (η5-C5H5)2Ni (4), is moderately air-sensitive in solution.1 Our students have found that paramagnetic impurities from the decomposition of (η5-C5H5)Ni(PPh3)Cl are immediately evident in the 1H NMR spectrum unless the full synthesis and preparation of the NMR sample are carried out under an inert atmosphere. Preparing (η5-C5H5)Ni(PPh3)Cl and contrasting its stability with (η5-C5H5)Ni(NHC)Cl (3) is therefore a worthy exercise if time permits. Characterization of the 2,6-Diisopropylphenyl Substituted Compounds by NMR Spectroscopy As was noted by Canal and Ritleng, compounds 2a and 3a are readily studied by 1H and 13C NMR spectroscopy. If 1H NMR is the only form of spectroscopy that is available, the spectra are straightforward, with all signals appearing as singlets (2). A greater challenge is presented by the 2,6-diisopropylphenyl group in compounds 2b and 3b. For the imidazolium salt 2b,

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Figure 1. 1H NMR spectrum of IPr 3 HCl (2b) in CDCl3. Expansions with common integration and frequency scales have been provided above each peak; those labeled A and B have been translated vertically for clarity. The peak labeled with the asterisk (*) is the residual CHCl3 in the NMR solvent.

the aromatic protons of the phenyl group are first order in the 1 H NMR spectrum and appear as a triplet and doublet in the anticipated 2:4 ratio (3JHH = 8 Hz). The protons within the imidazolium ring have a similar triplet:doublet pattern in a 1:2 ratio, with a much smaller 4JHH coupling constant of 1.5 Hz; the latter feature becomes visible in samples that have been dried under high vacuum and dissolved in dry CDCl3 or CD2Cl2 (Figure 1). The appearance of the aliphatic region usually presents a puzzle for undergraduates. The four hydrogen septet for the CH(CH3)2 resonance is as expected, but the presence of two doublets for the methyl groups, each with a 12 hydrogen integration ratio, is not usually predicted by most students. Many initially assume that this means the isopropyl groups themselves are chemically inequivalent, until it is realized that this possibility is negated by the symmetry of the protons of the phenyl ring and the presence of only one aliphatic CH resonance. These observations are consistent with rotation about the Cipso-N bond being hindered so that the diisopropylphenyl rings adopt an orthogonal orientation relative to the imidazolium ring. Students are asked to consider the molecule in the aforementioned orientation and determine whether free rotation around the Cortho-Cisopropyl bond brings each methyl group exactly into the same position the other had occupied. This question is intended to aid the students in rationalizing the chemical inequivalence of the methyl groups within the chemically equivalent isopropyl groups. The 1H NMR spectrum of 3b (provided in the supporting information) is analogous to that of 2b with the exception that the acidic proton in the imidazolium ring is now absent (with concomitant loss of coupling to the olefinic proton resonance) and that a five-hydrogen singlet appears for the cyclopentadienyl ring. Coordination of the IPr ligand to nickel additionally results in a significant upfield shift of the CH protons within the imidazole ring relative to protonated 2b. 90

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Full assignment of the 13C{1H} NMR spectra present a greater, but reasonable, challenge. The more expensive solvent CD2Cl2 must be used for the 13C{1H} NMR spectra of compound 2b, as its limited solubility in CDCl3 makes observing all resonances difficult. If proton-decoupled APT NMR spectra2 are recorded, most signals can be assigned on the basis of resonance phase and chemical shift. However, rigorous assignment of the CH carbons within the aromatic region is only possible by 2D gHMQC 1 H-13C correlation NMR spectroscopy.3 Given the potential complexity involved in having the full range of 13C{1H} NMR spectra recorded by undergraduates, sample spectra are provided in the supporting information and may be presented as handouts if desired. As in the case of the 1H NMR spectra, the 13C{1H} NMR spectrum of 3b is quite similar to 2b, excepting the change of phase in the APT spectrum and the loss of 13C-1H correlation in the 2D NMR for the now deprotonated carbeneic carbon and the appearance of a signal for the cyclopentadienyl ring carbons. Thus, the spectroscopic characteristics of compounds 2b and 3b provide a good challenge for undergraduate students, and the ultimate level of difficulty can be tailored by choosing whether to study only the 1H NMR spectra or also the 13C{1H} and 1 H-13C correlation NMR spectra in the laboratory assignment. Hazards The syntheses of 1, 2, and 3 should be carried out within a fume hood and students should wear protective gloves and safety glasses. Acetone, diethyl ether, ethanol, hexane, methanol, tetrahydrofuran, and toluene are all flammable solvents whose vapors should not be inhaled. Diethyl ether and tetrahydrofuran also have the potential to form explosive peroxides upon prolonged storage. Glyoxal is an irritant. Glacial acetic acid is corrosive and has a strong, penetrating odor. Paraformaldehyde and 4 M HCl in 1,4-dioxane are potential carcinogens that are also corrosive and should be handled with additional care to avoid exposure. Nickelocene is a suspected carcinogen and, as with all volatile organometallic compounds, it should only be handled in a wellventilated fume hood or preferably within a nitrogen-purged glove bag or glove box. Dichloromethane, chloroform, 2,4,6trimethylaniline, and 2,6-diisopropylaniline are toxic liquids. Celite is an inhalation hazard owing to its small particle size. To the best of our knowledge, the properties of compounds 1-3 have not been thoroughly studied and should therefore be handled with appropriate caution. In particular, compounds 2 are fine powders that tend to become dispersed into the air upon scraping, and should therefore be manipulated only within a fume hood. Summary Chemical educators often face the challenge of designing experiments for a restricted time frame dictated by class scheduling. Perhaps the most demanding scenario is a weekly 3 h laboratory where it is not practical to have students return to the lab before the next scheduled session. We have described modified syntheses for the preparation of imidazolium chloride precursors to N-heterocyclic carbenes and half-sandwich cyclopentadienyl nickel chloride compounds that are appropriate for second- and thirdyear undergraduate laboratories with a maximum programmed length of 3 h per week. The additional challenges presented by the NMR spectroscopy of the 2,6-diisopropylphenyl substituted imidazole ring have been illustrated, and the arguably more straightforward procedure makes the synthesis of IPr 3 HCl (2b)

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and CpNi(IPr)Cl (3b) an interesting complementary or alternative experiment to the preparation of IMes 3 HCl (2a) and CpNi(IMes)Cl (3a). It is our hope that the above features will serve as additional encouragement for educators to incorporate experiments involving an N-heterocyclic carbene into their organometallic undergraduate laboratories. Acknowledgment The Department of Chemistry at the University of Alberta is thanked for funding the above project. The efforts of the undergraduate students who have successfully completed various iterations of the experiment in Chem 243 and Chem 341 at the University of Alberta are gratefully acknowledged, as are the helpful suggestions of the graduate teaching assistants in the courses. Jennifer Hendry is thanked for her early work on various aspects of adapting the syntheses of IMes 3 HCl and CpNi(IMes)Cl to the undergraduate laboratory. Assistance from the staff of the department's NMR Spectroscopy Laboratory was greatly appreciated, especially Mark “NMark” Miskolzie for his optimization of the APT parameters for the 13C NMR spectrum of IPr 3 HCl. Notes 1. The preparation of nickelocene followed “Route B” from ref 4 at 25% the suggested scale and the preparation of CpNi(PPh3)Cl was carried out at 20% the suggested scale with toluene replacing benzene in the workup. 2. APT stands for “Attached Proton Test” and is a pulse sequence that causes the C/CH2 carbons to appear in a different phase than the CH/CH3 carbons. 3. gHMQC stands for “gradient heteronuclear multiple quantum coherence”, which is a two-dimensional inverse 1H,13C correlation technique that is selective for direct C-H coupling.

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Literature Cited 1. For example, see (a) Boeda, F.; Nolan, S. P. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2008, 104, 184–210. (b) Crudden, C. M.; Allen, D. P. Coord. Chem. Rev. 2004, 248, 2247–2273. (c) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290–1309. (d) Herrmann, W. A.; Weskamp, T.; Bohm, V. P. W. Adv. Organomet. Chem. 2002, 48, 1–69. (e) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162–2187. 2. (a) Canal, J. P.; Ramnial, T.; Langlois, L. D.; Abernethy, C. D.; Clyburne, J. A. C. J. Chem. Educ. 2008, 85, 416–419. (b) Ritleng, V.; Brenner, E.; Chetcuti, M. J. J. Chem. Educ. 2008, 85, 1646–1648. 3. Cooke, J. Several Microscale Experiments in Organometallic Chemistry. Presented at the 2005 International Chemical Congress of Pacific Basin Societies, December 15-20, 2005, Honolulu, HI. 4. Barnett, K. W. J. Chem. Educ. 1974, 51, 422–423. 5. Weber, D.; Jones, C. Personal communication, 2008. 6. (a) Nolan, S. P. U.S. Patent No. 7109348, 2006. (b) Nolan, S. P. Personal communication, 2002. 7. Abernethy, C. D.; Cowley, A. H.; Jones, R. A. J. Organomet. Chem. 2000, 596, 3–5. 8. Kelly, R. A., III; Scott, N. M.; Díez-Gonzalez, S.; Stevens, E. D.; Nolan, S. P. Organometallics 2005, 24, 3442–3447. 9. (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674–2678. (b) Huang, J.; Schanz, H. J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5375–5380. (c) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543– 6554.

Supporting Information Available Instructions for the students; notes for the instructor; sample NMR spectra; full details of the optimization and reaction conditions. This material is available via the Internet at http://pubs.acs.org.

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