N-Heterocyclic Carbene-Catalyzed Alcohol Acetylation: An Organic

Apr 2, 2014 - ... despite the high water sensitivity of uncomplexed (“free”) NHCs. ... A Cooperative Learning Activity in a Project-Based Laborato...
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Laboratory Experiment pubs.acs.org/jchemeduc

N‑Heterocyclic Carbene-Catalyzed Alcohol Acetylation: An Organic Experiment Using Organocatalysis John P. Morgan* and Jonathan H. Shrimp Department of Chemistry and Biochemistry, Hartline Science Center, Bloomsburg University of Pennsylvania, Bloomsburg, Pennsylvania 17815, United States S Supporting Information *

ABSTRACT: Undergraduate students in the teaching laboratory have successfully used N-heterocyclic carbenes (NHCs) as organocatalysts for the acetylation of primary alcohols, despite the high water sensitivity of uncomplexed (“free”) NHCs. The free NHC readily reacted with chloroform, resulting in an air- and moisture-stable adduct that liberates the free NHC when heated to temperatures above 45 °C in solution. The free NHC is a kinetically competent catalyst for the acetylation of benzyl, n-amyl, and isoamyl alcohols, a process that was monitored by gas chromatography (GC) and nuclear magnetic resonance (NMR) spectroscopy. Using the method of initial rates, students have calculated the relative rates for the three alcohol substrates, noting the trend: rate of benzyl > rate of n-amyl > rate of isoamyl alcohol. In their reports, students used these rates to demonstrate how NHC catalysts are sensitive to the steric bulk of the alcohol substrates. Overall, students were exposed to all aspects of chemical catalysis: synthesis of a catalyst, collection of initial rate data, development of a steric model to explain the data, and postulation of catalyst modification for increased activity based on their model. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Inquiry-Based/Discovery Learning, Problem Solving/Decision Making, Alcohols, Catalysis, Gas Chromatography, Kinetics, NMR Spectroscopy

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catalyst preparation to the measurement of reaction kinetics. This procedure is intended for a project-based laboratory exercise at the introductory organic level (such as a second semester “Organic 2” course). A hallmark of NHCs is their extreme susceptibility to decomposition in the presence of moisture from the air.5 This limitation has prevented their widespread use in the teaching laboratory, although three articles in this Journal have suggested ways to circumvent this reactivity to make organometallic complexes.6 An alternative procedure employs NHC “adducts” (Scheme 2), in which the carbene has inserted into an H−X bond to give a stable species.7 In particular, the adduct 3 of the dimesitylimidazolinylidene carbene 1 (abbreviated “H2IMes”) and chloroform (CHCl3) is catalytically useful: at temperatures of 45 °C and higher, compound 3 eliminates chloroform and forms the uncomplexed, catalytically active NHC 1. In the following procedure, the adduct 3 is prepared in a single step from its precursor, the imidazolinium salt 2. Both 2 and 3 are air-stable and can be readily handled by introductory students in the organic laboratory. Due to its high nucleophilicity, the active NHC catalyst 1 may attack the product ester in Scheme 1, resulting in sequestration of the catalyst in a nonproductive side reaction. In order to avoid this possibility, the method of initial rates is used for the kinetics

ndustrially relevant chemical catalysis has traditionally been the realm of metal-based catalysts.1 Recently, renewed interest in using nonmetallic species, including small organic molecules, has emerged due to their improved toxicity profiles over their metal-based counterparts.2 These “organocatalysts” are often nucleophilic Lewis bases such as amines and phosphines, familiar to the introductory organic chemistry student. Even more nucleophilic than phosphines are the N-heterocyclic carbenes, or NHCs (e.g., Figure 1), which have been particularly useful in

Figure 1. N,N′-Dimesitylimidazolinylidene, “H2IMes” (1), the NHC of interest.

acetylation reactions of weaker nucleophiles (such as alcohols).3 In this process, an NHC reacts with an acyl donor (e.g., acetic anhydride) to make an activated, “superelectrophilic” cationic intermediate species (Scheme 1).4 In the second (ratedetermining) step, the alcohol can then easily displace the NHC from the acyl donor, resulting in overall rate acceleration. The following experiment uses NHC-catalyzed alcohol acetylation reactions to highlight the “catalysis process” from © 2014 American Chemical Society and Division of Chemical Education, Inc.

Published: April 2, 2014 911

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significantly “greened” by minimizing the amount of environmentally harmful chloroform needed. In particular, excess powdered KOH, the imidizolinium salt 2, only 3 equiv of CHCl3, and toluene solvent were added to a capped vial equipped with a stirbar. Stirring for 2 h at room temperature produced a yellowish solution that was filtered to remove particulate solids. The toluene was then removed by vacuum distillation at room temperature or below. The toluene can be recycled to produce additional 3. The distillation residue must be purified at room temperature or below to avoid product decomposition. The residue was next passed through a silica gel plug eluting with 9:1 heptane/ethyl acetate, which is then removed by vacuum distillation. The final product 3 was nearly colorless and brittle. Compound 3, which is not hydroscopic, may be stored at room temperature indefinitely in a sealed bottle. Average student yield was approximately 70% overall. Alternatively, lab personnel can prepare 3 using the above methods, thereby shortening the overall class time to a single lab session and ensuring consistently high catalyst quality. The 1H NMR spectra of 2 and 3 are provided in the Supporting Information. A number of features distinguish the spectrum of 3 from that of the salt 2. First, the 2,6-methyl groups on the mesityl rings in 3 are not equivalent (unlike in 2); the same is true for the backbone hydrogen atoms (3−4 ppm) on the imidazolinyl ring. This nonequivalence is fully consistent with the formation of the chloroform adduct, in which the top and the bottom of the imidazolinyl ring are differentiated by a trichloromethyl group and a hydrogen atom, respectively (a three-dimensional model is recommended to f ully appreciate the inequivalence). Most importantly, this latter hydrogen atom (on the carbon between the two nitrogens) is notably present at 5.57 ppm in CDCl3. This resonance is the most definitive evidence that compound 3 has been successfully produced.

Scheme 1. Accepted Mechanism for NHC-Catalyzed Alcohol Acetylation

Scheme 2. The Chloroform Adduct (H2IMes·CHCl3, 3) Is Prepared Directly from 2 and Extrudes CHCl3 To Form 1 upon Heating (Mes = 2,4,6-Trimethylphenyl)

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GC KINETICS ANALYSIS Students began by preparing an external standard of their chosen primary alcohol in acetone. Care must be taken here to obtain the most accurate concentration possible: microsyringes or micropipetters and volumetric glassware are required for high accuracy. Typical GC conditions are detailed in the Supporting Information. Students prepared a “control” solution of acetic anhydride in an oven-dried, septum-capped vial, which was then equilibrated for 15 min in a 45 °C oil bath. Next, the alcohol was added via syringe and the timer was started. Every 4 min (up to 32 min) students removed an aliquot using a microsyringe and diluted it to appropriate GC concentrations. Each diluted aliquot was analyzed by GC, and the collected results were then adjusted using the GC response factors calculated from their external standard. The dilution and exposure to air are sufficient to halt the catalytic activity, so students collected their entire set of eight samples in separate vials while they waited for an open gas chromatograph. A typical laboratory section of 18−20 students therefore used two GC instruments to record all of their data during an average 3−4 h session.10 This latter exercise is particularly instructive in that students were required to calculate the amount of material injected in the GC, and then they used that number along with their dilution information to calculate how much product was present in their undiluted reaction mixture. Finally, students graphed amount of product formed versus time elapsed (e.g., Figure 2). The slope of this graph, measured during the first 20−30 min, was thus equal to the initial rate of the reaction.

analysis. An excess of acyl donor (acetic anhydride) and alcohol allows the ester production reaction to dominate over any possible side reactions. With student-prepared compound 3, the alcohol acetylation was thus performed, based on the equipment on hand. An introductory-level organic laboratory may have access to a standard gas chromatograph (GC) or an FT-NMR. Both methods are adequate for monitoring the progression of the reaction: both gave clear results for the catalytic rate acceleration. It is advisable to have the students work in pairs for the kinetics work, as they can then quickly run multiple trials. Collectively, students’ initial rate data were used to formulate a steric model for the N-heterocyclic carbene catalyst under study. Students were therefore encouraged to “close the loop” by suggesting how they would modify the NHC to be a more effective organocatalyst in future studies.

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SYNTHESIS OF THE NHC CATALYST The NHC salt (1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium tetrafluoroborate) can be purchased directly from Strem Chemicals or Aldrich Chemical Company.8 This option is practical for those wishing to perform the organocatalysis experiment in the second semester organic (sophomore-level) laboratory. Because the salt can be stored indefinitely under a dry atmosphere at room temperature, excess salt is never wasted from one laboratory section to the next. Formation of the chloroform adduct H2IMes·CHCl3 3 was readily achieved in a single 4 h laboratory period using a simplified procedure.9 Notably, the following preparation has been 912

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reasons: first, to ensure that the reaction rates are sufficiently fast, so that the reactions can be readily monitored over short reaction times (runs are approximately 20 min). Second, a typical NHC organocatalyst loading is 20 mol % for preparative reactions in which the goal is isolate the acylated product.3 Although this loading is high, the catalyst may be reisolated as salt 2 from the NMR sample by distilling away the solvent and the product esters, thereby allowing for catalyst recycling. This NMR kinetics method typically gives more satisfactory data sets than the above GC method, for the following reasons. First, VT NMR often results in better temperature control than an oil bath (the temperature in VT NMR is typically held within 0.2 °C of the target). Second NMR software macros can ensure that the time between spectra is consistent to the second, which leads to higher precision in the data. Finally, the entire reaction may be run in a sealed NMR tube, without the need to remove samples for analysis. Students may be asked to enumerate these reasons by carefully considering the GC and NMR methods. Typical initial rate results for a selection of primary alcohols are shown in Table 2. Again, collecting student data for all

Figure 2. Typical student plot for NHC-catalyzed acetylation of benzyl alcohol. Raw data were obtained on a Hewlett-Packard GC equipped with a HP5 phenylmethylsilicone column run at 180 °C isothermal and 18 mL/min column He flow. R2 values for the noncatalyzed and catalyzed fits are 0.95 and 0.9, respectively. Typical error in measured amounts is ±0.2 mmol for all data.

Students then prepared their “catalyzed” solution as described in the “control” section above, with the following exception: they heated compound 3 and acetic anhydride together for 15 min in the 45 °C bath prior to alcohol injection. All other conditions were identical to the above. Typical results for these experiments are listed in Table 1. Conditions are carefully

Table 2. Student-Measured NMR Results for the NHC-Catalyzed Alcohol Acetylation Substrate Alcohol

Uncatalyzed Rate/ μmol min−1, (uncat)a

NHC-Catalyzed Rate/ μmol min−1, (cat)a

(cat)/(uncat)

Benzyl n-Amyl Isoamyl

0.50 1.0 2.8

17 17 9.8

33 17 3.5

Table 1. Student-Measured GC Results for the NHC-Catalyzed Alcohol Acetylation Substrate Alcohol

Uncatalyzed Rate/ μmol min−1, (uncat)a

NHC-Catalyzed Rate/ μmol min−1, (cat)a

(cat)/(uncat)

Benzyl n-Amyl Isoamyl

34 ± 12 6±1 ≈4

73 ± 7 14 ± 3 ≈9 ± 3

2.1 2.3 2.2

a

With 20 mol % NHC, 1 mmol acetic anhydride, and 1 mmol alcohol. Data measured in acetone-d6 on a JEOL 400 MHz NMR at 45 °C for 35 min. Error in all data is approximately 0.1−0.2 μmol/min.

alcohols allows the laboratory class to observe how alterations in alcohol structure result in differential initial rates.

a

With 0.5 mol % NHC, 11 mmol acetic anhydride and 10 mmol alcohol. Data measured on a Hewlett-Packard GC equipped with a HP5 column at 180 °C isothermal and 18 mL/min total He flow.

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HAZARDS Toluene, heptane, ethyl acetate, and acetone are readily flammable. Chloroform and toluene are harmful in case of inhalation. Chloroform is a potential carcinogen and contact with skin should be avoided. Acetone is irritating to the eyes. Potassium hydroxide causes skin burns and eye irritation. Compounds 2 and 3 have not been fully tested for toxicity and should be handled with care. The tetrafluoroborate salt derivative of 2 is harmful if inhaled and it may cause burns to skin or the respiratory tract. Acetic anhydride may cause burns to skin or mucous membranes and causes eye irritation. Benzyl, n-amyl, and isoamyl alcohol are readily flammable and may cause skin irritation. n-Amyl and isoamyl alcohol may cause severe eye irritation.

chosen so that the alcohol and acetic anhydride were both in large excess relative to the loading of 3 used (typically 0.5 mol % catalyst loading). Under these conditions, side reactions are minimized and the observed initial rate will correspond solely to the desired ester-producing reaction.

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NMR KINETICS ANALYSIS The ready availability of software macros to record the kinetics of a sealed NMR tube reaction makes this method ideal for smaller class sizes with ready access to NMR facilities. Students prepare a NMR tube containing 3, acetic anhydride, and acetone-d6 which is then sealed with a septum under a nitrogen atmosphere. The tube is reacted for 15 min at 45 °C in the NMR instrument (if variable temperature, VT, control is available) or in an oil bath (without VT control). After this time, the alcohol is injected via microsyringe and 1H NMR data is obtained every 3−4 min (up to 32 min), typically with the aid of the NMR software macros. For primary alcohols such as benzyl, n-amyl, and isoamyl alcohols, the product O−CH2 resonances (4.0−5.1 ppm) are well separated from their alcohol counterparts (1.6−2.4 ppm), allowing integration to measure reaction progress. After graphing amount of product versus time, the initial reaction rate can be determined (vide supra). Overall, a high catalyst loading is used in these NMR experiments for two

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SUMMARY OF RESULTS Using either the GC or the NMR method, students should observe that the initial rate ordering for alcohol acetylation is benzyl > n-amyl > isoamyl.11 If the students obtain NMR kinetics data, the observed initial rate ratios also follow this trend (benzyl alcohol shows the highest overall increase in initial rate between catalyzed and uncatalyzed reactions, followed by n-amyl and then isoamyl). Grubbs et al. have noticed that solvent plays a unique role in the formation of the catalytically active NHC, possibly explaining why the difference in initial rate ratios is only observable in the NMR results.12 For the GC results, no solvent is 913

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2002, 4 (21), 3587−3590. (b) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. N-Heterocyclic Carbenes as Versatile Nucleophilic Catalysts for Transesterification/Acylation Reactions. Org. Lett. 2002, 4 (21), 3583−3586. (c) Grasa, G. A.; Güveli, T.; Singh, R.; Nolan, S. P. Efficient Transesterification/acylation Reactions Mediated by NHeterocyclic Carbenes. J. Org. Chem. 2003, 68 (7), 2812−2819. (4) Connor, E. F.; Nyce, G. W.; Myers, M.; Mock, A.; Hedrick, J. L. First Example of N-Heterocyclic Carbenes as Catalysts for Living Polymerization: Organocatalytic Ring-Opening Polymerization of Cyclic Esters. J. Am. Chem. Soc. 2002, 124 (6), 914−916. (5) Arduengo, A. J., III; Goerlich, J. R.; Marshall, W. J. A Stable Diaminocarbene. J. Am. Chem. Soc. 1995, 117 (44), 11027−11028. (6) (a) Canal, J. P.; Ramnial, T.; Langlois, L. D.; Abernethy, C. D.; Clyburne, J. A. C. A Three-Step Laboratory Sequence to Prepare a Carbene Complex of Silver(I) Chloride. J. Chem. Educ. 2008, 85 (3), 416−419. (b) Ritleng, V.; Brenner, E.; Chetcuti, M. J. Preparation of a N-Heterocyclic Carbene Nickel(II) Complex. J. Chem. Educ. 2008, 85 (12), 1646−1648. (c) Cooke, J.; Lightbody, O. C. Optimized Syntheses of Cyclopentadienyl Nickel Chloride Compounds Containing N-Heterocyclic Carbene Ligands for Short Laboratory Periods. J. Chem. Educ. 2011, 88 (1), 88−91. (7) (a) Arduengo, A. J., III; Calabrese, J. C.; Davidson, F.; Dias, H. V. R.; Goerlich, J. R.; Krafczyk, R.; Marshall, W. J.; Tamm, M.; Schmutzler, R. C-H Insertion Reactions of Nucleophilic Carbenes. Helv. Chim. Acta 1999, 82 (12), 2348−2364. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl, M.; Choi, T. L.; Ding, S.; Day, M. W.; Grubbs, R. H. Synthesis and Activity of Ruthenium Alkylidene Complexes Coordinated with Phosphine and N-Heterocyclic Carbene Ligands. J. Am. Chem. Soc. 2003, 125 (9), 2546−2558. (c) Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. A General and Versatile Approach to Thermally Generated NHeterocyclic Carbenes. Chem.Eur. J. 2004, 10 (16), 4073−4079. (d) Coulembier, O.; Lohmeijer, B. G. G.; Dove, A. P.; Pratt, R. C.; Mespouille, L.; Culkin, D. A.; Benight, S. J.; Dubois, P.; Waymouth, R. M.; Hedrick, J. L. Alcohol Adducts of N-Heterocyclic Carbenes: Latent Catalysts for the Thermally-controlled Living Polymerization of Cyclic Esters. Macromolecules 2006, 39 (17), 5617−5628. (8) Compound 2 can be purchased from Strem Chemicals: 1 g, $56.00. Each group of two students uses approximately 100 mg, so a typical laboratory section of 18−20 will use 1 g. Alternatively, the procedure in ref 9 can be used to prepare 2 in >20 g quantities, costing ∼$145 (or $7.25/gram plus ∼1 day of preparation time total). (9) The preparation of compound 3 in the Supporting Information is a modification of Grubbs, R. H.; Morgan, J. P.; Benitez, D.; Louie, J. U.S. Patent No. 6,613,910, 2003. (10) As a less expensive alternative, students may use Vernier MiniGC instruments ($1,989 each, Seacoast Science, Inc.) to obtain their rate data. Two MiniGC instruments are sufficient for a typical laboratory section size of 18−20 students. Data is comparable to the Hewlett-Packard results in Figure 2. Appropriate GC conditions are reported in the esterification experiment (“Experiment 2: Verification of Esterification”) in Mlsna, D.; Randall, J.; Mlsna, T.; Tolley, B. Gas Chromatography, Investigations with the Mini GC; Vernier Software and Technology: Beaverton, OH, 2009. (11) Similar kinetics trends have been previously observed in alcohol acylation with anhydride donors. See: Fischer, C. B.; Xu, S.; Zipse, H. Steric Effects in the Uncatalyzed and DMAP-catalyzed Acylation of Alcohols-Quantifying the Window of Opportunity in Kinetic Resolution Experiments. Chem.Eur. J. 2006, 12 (22), 5779−5784. (12) Blum, A. P.; Ritter, T.; Grubbs, R. H. Synthesis of N-Heterocyclic Carbene-Containing Metal Complexes from 2-(Pentafluorophenyl)imidazolidines. Organometallics 2007, 26 (8), 2122−2124. (13) Electronic reasons for the differences in initial rate between benzyl and n-amyl alcohols are less clear. Calculation of the potential energy surfaces using the semiempirical methods of Spartan Student Edition V3.0.2 (2004, Wavefunction, Inc.) reveals similar overall charges/potentials on the oxygen atoms of the alcohols. The oxygen atom in benzyl alcohol has a −0.569 charge and a −56.09 potential; in n-amyl alcohol, the oxygen has a −0.592 charge and a −56.83 potential.

used (the reaction mixture consists only of acetic anhydride and substrate alcohol). In particular, the alcohol is a nucleophilic solvent that may inhibit the catalytic activity of the NHC.2 Importantly, students may appreciate the “solventless” nature of the GC reactions as being minimally wasteful and overall highly “green.” Overall, the benzyl group is more conformationally constrained (i.e., “smaller”) than the alkyl groups, suggesting that the former should acylate the fastest.13 Clearly, n-amyl is “smaller” than isoamyl, resulting in a faster acetylation rate for the unbranched alcohol. With accompanying literature research, students may also propose other NHC catalysts that would be less susceptible to the steric bulk in the alcohols. In their final laboratory reports, students should also discuss how they would use their initial rate data to optimize reaction times for large-scale industrial use of these NHC catalysts in alcohol acetylation reactions. Many skills were practiced in this organocatalytic experiment: analytical preparation of standards, consistency in sampling the reaction, and quantitative result analysis. Unlike similar organometallic reactions, the NHC catalysts are more user-friendly, freeing the students to concentrate on the analytical aspects of the experiment rather than to focus on Schlenk technique. Plus, rate data from various alcohols were collected by different groups in the same lab section, allowing the students to appreciate and discuss any observable trends.

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ASSOCIATED CONTENT

S Supporting Information *

1 H NMR spectra of 2 and 3; student handout/lab manual; instructor notes. This material is available via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was in part sponsored by the Bloomsburg University Foundation Margin of Excellence Grant (to J.P.M.), the Bloomsburg University Research and Disciplinary Grant (to J.P.M.), the Bloomsburg University Department of Chemistry and Biochemistry, and a Summer Research Stipend (to J.H.S.). The authors sincerely thank Geneive Henry and the Susquehanna University Department of Chemistry for their generous use of NMR facilities. The authors also thank Christopher Endress, Kaitlyn Sanders, and Andrew Sibley for assistance in preparation of compounds 2 and 3.

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REFERENCES

(1) Hagen, J. Industrial Catalysis: A Practical Approach; Wiley-VCH: Berlin, 2006. (2) (a) Denmark, S. E.; Beutner, G. L. Lewis Base Catalysis in Organic Synthesis. Angew. Chem., Int. Ed. 2008, 47 (35), 1560−1638. (b) Marion, N.; Díez-González, S.; Nolan, S. P. N-Heterocyclic Carbenes as Organocatalysts. Angew. Chem., Int. Ed. 2007, 46 (17), 2988−3000. (c) Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-Heterocyclic Carbenes. Chem. Rev. 2007, 107 (12), 5606−5655. (d) Jacobsen, E. N.; MacMillan, D. W. C. Organocatalysis. Proc. Natl. Acad. Sci. U.S.A. 2010, 107 (48), 20618−20619. (3) (a) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.; Hedrick, J. L. Expanding the Catalytic Activity of Nucleophilic NHeterocyclic Carbenes for Transesterification Reactions. Org. Lett. 914

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