Room-Temperature C–H Functionalization ... - ACS Publications

Laboratory Experiment Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

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Room-Temperature C−H Functionalization Sequence under Benchtop Conditions for the Undergraduate Chemistry Laboratory Shuming Chen* Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States S Supporting Information *

ABSTRACT: An iridium(III)-mediated C−H functionalization sequence involving a concerted cyclometalation−deprotonation/migratory insertion pathway is reported for the undergraduate chemistry laboratory. The air- and water-stable iridacycle intermediates are readily isolated and characterized by NMR spectroscopy. Both steps of the experiment are performed at room temperature under benchtop conditions, rendering the protocol suitable for a wide range of student skill levels.

KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Inorganic Chemistry, Interdisciplinary/Multidisciplinary, Laboratory Instruction, Hands-On Learning/Manipulatives, Coordination Compounds, Organometallics

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INTRODUCTION Carbon−hydrogen bonds are the most ubiquitous type of chemical bonds found in organic molecules. Transition-metalmediated activation of C−H bonds is an increasingly powerful and versatile reaction in the arsenal of modern synthetic organic chemistry.1 Despite the enormous advances that have been made in the field of C−H functionalization, there have been few published examples of C−H activation reactions being performed in undergraduate teaching laboratories.2 While transition-metal-catalyzed functionalizations of unactivated aromatic C−H bonds are excellent for showcasing the power and utility of C−H functionalization, various factors limit their incorporation into undergraduate laboratory courses. A vast majority of aromatic C−H functionalizations require forcing conditions, such as prolonged heating. Many C−H activation catalysts and organometallic intermediates are also air- and water-sensitive, requiring them to be handled under an inert atmosphere, which can be difficult to implement in an undergraduate teaching laboratory. More practical and forgiving experimental protocols would therefore be desirable for the incorporation of these synthetically useful and atom-economical reactions into undergraduate chemistry curricula. The two-step sequence presented herein allows the functionalization of an aromatic C−H bond under room temperature and benchtop conditions (Scheme 1).3,4 The reaction proceeds through a concerted cyclometalation− deprotonation to yield the 5-membered iridacycle A, which undergoes a migratory insertion with dimethyl acetylenedicarboxylate (DMAD) in the second step of the sequence to furnish the 7-membered iridacycle B. The sequence is © XXXX American Chemical Society and Division of Chemical Education, Inc.

Scheme 1. Concerted Cyclometalation−Deprotonation/ Migratory Insertion Sequence Performed in This Experiment

performed with a stoichiometric amount of the transition metal complex, which enables students to isolate the organometallic intermediate A and product B involved in the reaction pathway. The air- and water-stable coordination complexes A and B are characterized using 1H NMR spectroscopy. Received: September 10, 2017 Revised: April 21, 2018

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DOI: 10.1021/acs.jchemed.7b00694 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

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PEDAGOGICAL GOALS Students complete a sequence of organometallic reactions that includes the isolation and analysis of two transition metal complexes. After completing this experiment, students should be able to (1) use NMR spectroscopy data to determine the identity of organometallic intermediates, and (2) predict structures of intermediates after elementary mechanistic steps in organometallic chemistry. These pedagogical goals were evaluated from written answers to pre- and postlab assignments.

complexes A and B, may be harmful if swallowed. All hazardous chemicals must be handled inside a fume hood (>4 in. distance from hood opening) to minimize risk of inhalation.

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RESULTS AND DISCUSSION In this experiment design, a cyclometalation−deprotonation/ migratory insertion sequence mediated by [Cp*IrCl2]2 was chosen to showcase the use of transition metal complexes in C−H functionalization. Among the commercially available C− H activation catalysts, [Cp*IrCl2]2 is relatively inexpensive (current price $207/g; compare to $408/g for [Cp*RhCl2]2) and easy to manipulate due to its benchtop stability. Remarkably, for a functionalization of unactivated C−H bonds, both steps of this sequence proceed readily at room temperature and under mild conditions. More significantly from a pedagogical perspective, both reaction steps yield readily isolable coordination complexes that are stable to air and water. Both complexes also provide clear, diagnostic 1H NMR chemical shifts. The imine NCH proton in the cyclometalated complex A gives rise to a peak at 8.26 ppm, which is shifted downfield relative to that of the reactant imine (8.14 ppm) due to coordination to the iridium center (see representative student spectra in Supporting Information). In the alkyne-inserted complex B, the imine proton is shifted further downfield to 8.62 ppm. The two ester methyl groups in complex B give a pair of distinct and well-resolved singlets that do not overlap with the ester methyl signal of residual DMAD, allowing straightforward identification of the product from the starting material. The cyclopentadienyl methyl groups on both A and B show up as a singlet, indicating rapid rotation of the Cp* ring on the 1H NMR time scale. The currently described experimental protocol was implemented during two terms (Winter Quarters 2017 and 2018) of an organic chemistry laboratory course intended for secondyear undergraduates and beyond. All 56 students that have carried out this experiment were third- or fourth-year undergraduates. All students had completed a minimum of 66% of the introductory organic chemistry course sequence, and had been previously introduced to organometallic chemistry. Students were required to read a detailed laboratory handout, which consisted of the requisite theoretical background and the experimental protocol. Students also attended a lecture which provided them with an introduction to basic organometallic mechanisms involved, as well as the opportunities and challenges associated with the field of C−H functionalization in general. Before performing the experiment, students completed a prelaboratory worksheet, which was also designed to ensure that students understand the relevant concepts, the experimental procedure, and the necessary safety precautions. Students carried out the experimental protocol individually, although the experiment can also be performed in teams of two. NMR samples of products were submitted at the end of the laboratory periods. Spectroscopic data acquisition was performed by a teaching assistant, although it could also be performed by the students if desired. After the laboratory period, students completed a postlaboratory worksheet that included a detailed analysis of the experimental results as well as further applications of concepts learned. All of the students who performed the experiment were able to successfully obtain characterization data for coordination complexes A and B, indicating high reproducibility and robustness of the currently described protocol. Self-reported student yields ranged from 34% to 87% (20.5−52.5 mg) for the

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OVERVIEW OF LABORATORY EXPERIMENT This laboratory experiment is designed for an upper-division undergraduate organic or inorganic chemistry laboratory. The experimental protocol is performed over 3 laboratory periods, each lasting 3 h. Before the experiment, students complete a prelaboratory assignment, which ensures that students familiarize themselves with the protocol and the safety requirements. After the laboratory period, students complete a postlaboratory assignment to reflect deeper on the concepts and apply the skills that have been learned.

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EXPERIMENT Students conduct the experiment individually. During the first lab period, 50.0 mg (62.8 mmol) of [Cp*IrCl2]2, 32.0 mg (390 mmol) of sodium acetate, and 17.0 mg (143 mmol) of Nbenzylidenemethylamine are added to a round-bottomed flask. Dichloromethane (20 mL) containing a drop of benzaldehyde is subsequently transferred to the flask. The reaction vessel is sealed with a rubber septum and stirred at room temperature overnight, or until the next lab period. At the beginning of the second lab period, solvent is removed from the reaction mixture, and the crude product is filtered through a plug of Celite and reconcentrated in vacuo. Excess Nbenzylidenemethylamine is removed by rinsing with a small amount of hexanes. Students use part of the solid residue to prepare a sample for 1H NMR characterization, and store the rest for use in the next lab period. In the third lab period, students dissolve the solid residue in methanol and add 20.0 μL (163 mmol) dimethyl acetylenedicarboxylate (DMAD) to the flask. The reaction is stirred at room temperature for 1 h. Solvent is evaporated from the reaction mixture under reduced pressure, and the residue is rinsed with hexanes to remove excess DMAD. After drying the product, students prepare samples for 1H NMR characterization. A more detailed description of the experiment is included in the Supporting Information.

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HAZARDS Closed-toed shoes, long pants/skirts covering the ankles, safety glasses, gloves, and flame-resistant laboratory coats should be worn at all times in the laboratory. Handle and dispose of all hazardous materials in accordance with the recommendations of their Material Safety Data Sheets (MSDSs). Dichloromethane (methylene chloride) is a proven carcinogen and very hazardous in the case of eye or skin contact. Benzaldehyde is an irritant. Dimethyl acetylenedicarboxylate is corrosive and very hazardous in case of eye or skin contact. Hexanes are flammable. The n-hexane in hexanes is a neurotoxin. Methanol is a mutagen and possible teratogen. Chloroform-d (CDCl3) is toxic and a cancer suspect agent. [Cp*IrCl2]2, as well as iridium B

DOI: 10.1021/acs.jchemed.7b00694 J. Chem. Educ. XXXX, XXX, XXX−XXX

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Laboratory Experiment

opportunity to bridge an important and oft-neglected gap in the development of chemical thinking. Students contemplate the chemoselectivity question further by imagining the reaction sequence being performed on imines with substituted benzene rings (in which case more than one regioisomer could occur). In the concerted cyclometalation−deprotonation step, the addition of benzaldehyde to suppress imine hydrolysis is worth noting because it constitutes an application of Le Chatelier’s principle in a relevant experimental context.11 With the requisite background in carbonyl chemistry, students readily comprehend the significance of this detail. A substantial amount of instruction time was also dedicated to interpreting the NMR spectra of organometallic species, which is challenging for undergraduate students. Students appreciated that, depending on the nature of the metal and its ligands, metal coordination can have complex effects on the chemical shifts of protons in the vicinity of the metal.12

concerted cyclometalation−deprotonation step, and from 46% to 89% (11.7−56.4 mg) for the migratory insertion step. On the basis of graded pre- and postlaboratory assignments collected from a 28 student class, the following results were noted with regard to the accomplishment of the stated pedagogical goals: (a) On a prelaboratory assignment question, students were asked to provide structures of organometallic intermediates after mechanistic steps like oxidative addition, migratory insertion, and reductive elimination. The average grade on this question was 5.1 out of 6 possible points. (b) On a postlaboratory assignment question, students were asked to identify the imine NCH and NCH3 protons in the NMR spectrum of intermediate A, compare their chemical shifts to those of the corresponding protons in the imine starting material, and explain why these protons show up more downfield in intermediate A. The average grade on this question was 3.7 out of 4 possible points. Students noted the operational straightforwardness of the experimental procedure, and the ease with which the intermediates could be manipulated and characterized. Additional student comments regarding the experimental design are given in the Supporting Information.

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SUMMARY An operationally simple experimental protocol was developed for the undergraduate chemistry laboratory to introduce students to the application of C−H functionalization in organic synthesis. Throughout the course of the protocol, experiments are performed under benchtop conditions at room temperature, rendering the reaction sequence suitable to a wide range of laboratory skill levels. Intermediates and products are air- and water-stable coordination compounds that give rise to clear, diagnostic NMR spectra, which facilitate the analysis of the experimental outcome. Through performing the experimental protocol, students gain valuable experience in interpreting NMR data of organometallic species, as well as develop an appreciation for the remarkable utility and potential of transition-metal-mediated C−H activation reactions.

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DISCUSSION TOPICS This laboratory experiment offers the opportunity to introduce to students a rich array of topics in organometallic chemistry. The many applications of C−H functionalization reactions, particularly with regard to hydrocarbon conversion and natural product syntheses,5,6 are highlighted in class discussions. Students are made aware of both the enormous potential and challenges associated with the development of industrially useful C−H functionalization reactions. The metal-assisted nature of the reaction is another focal point for class discussions. To illustrate the pivotal role of the iridium metal in the concerted cyclometalation−deprotonation in a straightforward manner, students can be asked to calculate the equilibrium constant of a metal-free acid−base reaction between benzene and the acetate anion, which serves to communicate the idea that metal coordination is essential to the cleavage of unreactive C−H bonds. In a prelab assignment question, 27 of 28 students were able to correctly calculate the equilibrium constant to be 10−38 based on the pKa values of benzene (43) and acetic acid (5). For advanced students, more contextual background on metallocycle formation can be provided as part of class discussions or as extended reading.7,8 Examples of C−H functionalization enzymes like cytochrome P4509 and methane monooxygenase,10 which also rely on metal coordination spheres to activate C−H bonds, can also be discussed. Another prominent feature of the reaction sequence is the ortho regioselectivity of the C−H activation step. Selectivity is known to be a nontrivial challenge associated with C−H functionalizations, leading to the widespread use of directing groups, such as imines, in these reactions. While students will typically have been exposed to examples of innate chemoselectivity in introductory organic chemistry courses, they tend to be much less familiar with guided (directed) chemoselectivity such as the ortho selectivity observed in arene C−H functionalizations. This experiment, therefore, offers an

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00694. Detailed student handout, a prelaboratory assignment sheet, a postlaboratory assignment sheet, notes for instructors, and representative spectroscopic data from students (PDF, DOCX)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shuming Chen: 0000-0003-1897-2249 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS Students and teaching assistants of the Chemistry 30CL organic chemistry laboratory course are gratefully acknowledged for their feedback on this experiment. S.C. thanks the University of California, Los Angeles, for financial support. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the National Center for Research Resources (S10RR025631). C

DOI: 10.1021/acs.jchemed.7b00694 J. Chem. Educ. XXXX, XXX, XXX−XXX

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REFERENCES

(1) For recent perspectives and reviews on C−H activations, see: (a) Crabtree, R. H.; Lei, A. Introduction: CH Activation. Chem. Rev. 2017, 117, 8481−8482. (b) Davies, H. M.; Morton, D. Recent Advances in C−H Functionalization. J. Org. Chem. 2016, 81, 343−350. (c) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Mild Metal-Catalyzed C−H Activation: Examples and Concepts. Chem. Soc. Rev. 2016, 45, 2900−2936. (2) Chetcuti, M. J.; Ritleng, V. Formation of a Ruthenium−Arene Complex, Cyclometallation with a Substituted Benzylamine, and Insertion of an Alkyne. J. Chem. Educ. 2007, 84, 1014−1016. (3) Li, L.; Brennessel, W. M.; Jones, W. D. C−H Activation of Phenyl Imines and 2-Phenylpyridines with [Cp*MCl2]2 (M = Ir, Rh): Regioselectivity, Kinetics, and Mechanism. Organometallics 2009, 28, 3492−3500. (4) Li, L.; Brennessel, W. M.; Jones, W. D. An Efficient LowTemperature Route to Polycyclic Isoquinoline Salt Synthesis via C-H Activation with [Cp*MCl2]2 (M = Rh, Ir). J. Am. Chem. Soc. 2008, 130, 12414−12419. (5) Bergman, R. G. Organometallic Chemistry: C−H Activation. Nature 2007, 446, 391−393. (6) Periana, R. A.; Taube, D. J.; Gamble, S.; Taube, H.; Satoh, T.; Fujii, H. Platinum Catalysts for the High-Yield Oxidation of Methane to a Methanol Derivative. Science 1998, 280, 560−564. (7) For more in-depth treatment of iridacycle and rhodacycle formation, see: (a) Bleeke, J. R. Aromatic Iridacycles. Acc. Chem. Res. 2007, 40, 1035−1047. (b) Li, J.; Hu, W.; Peng, Y.; Zhang, Y.; Li, J.; Zheng, W. Theoretical Study on Iridacycle and Rhodacycle Formation via C−H Activation of Phenyl Imines. Organometallics 2014, 33, 2150−2159. (c) Albrecht, M. Cyclometalation Using d-Block Transition Metals: Fundamental Aspects and Recent Trends. Chem. Rev. 2010, 110, 576−623. (8) For other examples of undergraduate laboratory experiments incorporating cyclometalation, see: (a) Herrmann, W. A.; Böhm, V. P. W.; Reisinger, C.-P. Introduction to Homogeneous Catalysis: CarbonCarbon Bond Formation Catalyzed by a Defined Palladium. J. Chem. Educ. 2000, 77, 92−95. (b) Albert, J.; Cadena, M.; Granell, J. Cyclopalladation of Phenyl-(2,4,6-trimethylbenzylidene)-amine: An Undergraduate Organometallic Laboratory Experiment. J. Chem. Educ. 2003, 80, 801−802. (9) Rittle, J.; Green, M. T. Cytochrome P450 Compound I: Capture, Characterization, and C−H Bond Activation Kinetics. Science 2010, 330, 933−937. (10) Lieberman, R. L.; Rosenzweig, A. C. Crystal Structure of a Membrane-Bound Metalloenzyme That Catalyses the Biological Oxidation of Methane. Nature 2005, 434, 177−182. (11) Le Chatelier, H.; Boudouard, O. Limits of Flammability of Gaseous Mixtures. Bull. Soc. Chim. Fr. 1898, 19, 483−488. (12) For a more striking example of metal coordination shifting imine protons downfield, see: Fernández, A.; López-Torres, M.; Fernández, J. J.; Vázquez-García, D.; Vila, J. M. A One-Pot SelfAssembly Reaction To Prepare a Supramolecular Palladium(II) Cyclometalated Complex: An Undergraduate Organometallic Laboratory Experiment. J. Chem. Educ. 2012, 89, 156−158.

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DOI: 10.1021/acs.jchemed.7b00694 J. Chem. Educ. XXXX, XXX, XXX−XXX