In the Laboratory
Synthesis of an Epoxide Carbonylation Catalyst: Exploration of Contemporary Chemistry for Advanced Undergraduates
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Yutan D. Y. L. Getzler,*† Joseph A. R. Schmidt,‡ and Geoffrey W. Coates Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301; *
[email protected] Motivation for the development of this experiment was twofold. One aspect was the desire, affirmed by the ACS (1), for undergraduate chemistry majors to encounter air-free synthetic techniques during the course of their studies. The other was a need to engage students’ interest by involving them in current chemistry, giving them access to reactions whose stories are still developing. We have recently introduced a class of highly active, well-defined compounds for the catalytic carbonylation of epoxides and aziridines to β-lactones and β-lactams, respectively (2, 3). The synthesis of one of these catalysts involves a simple imine condensation to form the ligand followed by air-sensitive metalation and salt metathesis steps. The modular nature of the ligand allowed each student in one section of a second-semester organic lab course to synthesize a unique and previously unknown catalyst while following nearly identical procedures. Of the seven students involved in this project, five were able to isolate semicrystalline material, one of which was X-ray quality. These crystalline products, tested in our research labs, all showed catalytic activity for the carbonylation of 1,2-epoxybutane.
O
OH
R⬙2 N
O
R R⬘
O
R
R⬘
+ CO2
R
R⬙
R⬘
NHR⬙2
∆
1. LDA 2. R⬙I
O O
(R = CH2R⬙)
R⬘
O
O
R
O
R⬙
R⬘
O O
•
n
N3 R⬘
Scheme I. β-Lactone reactivity.
R⬙ (CO)4Coⴚ
O
ⴙ
ML n
O R⬙
R⬘
B
R⬘
A
R⬙
[Ln Mⴙ][ⴚCo(CO)4 ]
O (CO)3Co
O
R⬙
D R⬘
C
R⬙
(CO)4Co
O O
MLn
R⬘
CO
O
†
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R⬘
R
HO
Current address: Department of Chemistry, Kenyon College, Gambier, OH 43022. ‡ Current address: Department of Chemistry, The University of Toledo, Toledo, OH 43606.
R
NaN3
Introduction β-Lactones are four-membered cyclic esters with considerable ring strain: ∼80 kJ兾mol. This contributes to their versatility as starting materials and intermediates for organic and polymer synthesis (Scheme I) (4). For example, when β-lactones are cleaved at the acyl position, by amines or other nucleophiles, their aldol equivalence is unmasked. Ring-opening polymerization by metal alkoxides results in poly(hydroxyalkanoate)s, a class of naturally occurring polyesters. These polymers are attractive synthetic targets owing to their excellent mechanical properties and biodegradability (5, 6). Recently, we have shown that discrete, well-defined complexes composed of a Lewis acidic cation and a cobalt tetracarbonyl anion are highly efficient in catalyzing the carbonylation of epoxides to β-lactones (Scheme II) (2, 3). The mechanism is thought to proceed by Lewis acid activation of the epoxide (A) followed by nucleophilic attack (B), and migratory insertion (C). Intramolecular ring closure (D) yields the product lactone and regenerates the free catalyst. This reaction proceeds without racemization and is regioselective with carbonylation occurring between the less substituted carbon and the oxygen. A vast selection of epoxides is commercially available, many in their enantiomerically pure
Ln M–OR
MgBr2
CO
MLn
R⬘
Scheme II. Proposed catalytic cycle for the carbonylation of epoxides.
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In the Laboratory
forms, and many more may be made via the oxidation of olefins. This widespread availability of epoxides, in conjunction with recent advances in catalysis mentioned here, broadens the range of β-lactones in the synthetic chemist’s toolbox.
tals will often appear within a day. The final oxygen-sensitive product, [LnAl(THF)2][Co(CO)4], may be characterized by IR, 1H-NMR, X-ray crystallography, and may be applied to the carbonylation of epoxides to β-lactones (2, 3).
Epoxide Carbonylation Chemistry
Hazards
Nucleophilic ring-opening and carbonylation of epoxides by the cobalt tetracarbonyl anion has been known for some time (7). The carbonylation of epoxides to β-lactones first appeared in 1994 in a patent (8). As claimed by Drent and Kragtwijk, a mixture of 3-hydroxypyridine and dicobalt octacarbonyl [Co2(CO)8] catalyze the reaction. In the past two years a number of reports have begun to investigate this catalysis in greater detail (2, 3, 9, 10). Alper and coworkers use a mixture of neutral Lewis acids and [Co(CO)4]− salts to achieve good yields over long reaction times. Work in our lab has shown that discrete complexes of [Co(CO)4]− and Lewis acidic cations are highly active epoxide carbonylation catalysts, as has been confirmed by others (10). We have proposed that carbonylation in all of these systems proceeds through a unifying mechanism (Scheme II). Initial coordination and activation of the epoxide by the Lewis acid is followed by nucleophilic attack on the less substituted carbon, leading to inversion of configuration. Migratory insertion yields a cobalt acyl that is susceptible to intramolecular nucleophilic attack by the alkoxide, yielding the product lactone and regenerating the catalyst.
This is an experiment for advanced students. All of the organic solvents are flammable. Diethyl aluminum chloride is pyrophoric and must be handled properly to avoid exposure to oxygen and water. However, as noted, the danger of this reagent is attenuated by using a dilute (1.0 M) solution. Amines are typically corrosive, phenylenediamine derivatives are commonly toxic and cancer-suspect agents and salicylaldehydes are often irritants. Whenever vacuum con-
O R⬘n
+ 2 NH2
salicylaldehyde
MeOH, ∆
2H 2O
R⬘n
Synthesis of the epoxide carbonylation catalyst starts with the condensation of two equivalents of a salicylaldehyde with one equivalent of a diamine to form the Schiff base ligand (Scheme III). In a typical reaction, a 1,2-phenylenediamine is added to a solution of a salicylaldehyde in methanol, which immediately turns yellow. The solution is refluxed overnight to give the ligand as a yellow-to-orange precipitate in high yield. The insoluble material is isolated by filtration and dried overnight in vacuo. 1H NMR analysis1 of the product shows loss of resonances due to the aldehyde proton at ∼9 ppm and appearance of resonances due to the imine proton at ∼8 ppm. Other signals shift significantly as well. The ligand is dissolved in dry, degassed CH2Cl2 under nitrogen. Dropwise addition of a 1 M solution of Et2AlCl in heptane is performed at room temperature. Evolution of ethane will be apparent owing to the formation of bubbles. The solution should stir for a minimum of three hours but extended reaction times are not detrimental. Solvent is removed in vacuo to leave behind an air-stable product that is approximately the same color as the ligand. 1H-NMR analysis of the product shows loss of the resonances due to the phenolic protons at ∼14 ppm. Other signals also shift significantly. Under nitrogen, sodium cobalt tetracarbonyl 2 [NaCo(CO)4] and LnAlCl are dissolved in dry, degassed THF. The solution changes color from yellow to red almost instantaneously and should be left to stir for at least 24 hours. The flask is covered in foil owing to the mild light sensitivity of [Co(CO)4]−. The solvent is concentrated and layered with a large excess of dry, degassed hexanes using a small gauge cannula. The reaction is left to crystallize covered in foil; crysJournal of Chemical Education
Rn
o-phenylenediamine
Catalyst Synthesis
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OH
NH2
•
Rn
N
Rn
N
OH
HO
Schiff base ligand Et 2 AlCl CH2Cl2 2EtH(g)
R⬘n Rn
N O
Rn
N
Al
O
Cl Ln AlCl
NaCo(CO)4 THF NaCl(s) −
Co(CO)4 Rn
R⬘n
THF N O
Al+ THF
N O
[Ln Al(THF)2][Co(CO)4] Scheme III. Three-step catalyst synthesis.
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Rn
In the Laboratory Table 1. Salicylaldehydes Used and Properties of the Resultant Catalysts O
CO
−
Co(CO)4
THF
Rn
N O
Al+ THF
N
Rn
ditions are used, glassware should be checked for flaws to avoid failure. Sodium cobalt carbonyl is a metal carbonyl and can yield carbon monoxide as a decomposition product. Appropriate disposal of solvent waste, some of which is chlorinated and some of which will contain residual ligand or salts of aluminum or cobalt, is required. Anyone choosing to apply these compounds in carbonylation should be familiar with the use of autoclaves, as well as toxic compounds like epoxides and compressed poisonous gases such as carbon monoxide.
O
Discussion O O
Student
Salicylaldehyde
1 O
Crystallinity
Activity
X-ray
Yes
Amorphous
Not Tested
Micro
Yes
Micro
Yes
Micro
Yes
Not Determined
Not Tested
Micro
Yes
OH
Br
2 O
OH Cl
3 Cl O
OH
4 O
OH
O
OH
5
t-Bu
6 O
OH
t-Bu
7 t-Bu O
OH
NOTE: 4,5-Dimethylphenylene-1,2-diamine was used in this experiment.
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The prime motivators for this project are to provide students with a hands-on, air-free project, while simultaneously involving them in exciting new chemistry. The initial step of the lab, synthesis of the ligand via imine condensation, is a useful review of techniques students approaching this lab should already know. The mechanism of this reaction is of the family of nucleophilic additions to carbonyls and an advanced undergraduate could be asked to push the arrows. Furthermore, the appearance of copious quantities of a colored solid in this step helps get students excited and confident about the rest of the lab. The second step, synthesis of LnAlCl, is an excellent introduction to Schlenk chemistry including the glassware, use of a vacuum manifold, and cannula techniques. The use of a relatively dilute solution of Et2AlCl minimizes the risks associated with this pyrophoric reagent, while still providing a clear indicator for when technique is subpar; the introduction of even minute quantities of ambient atmosphere will be readily apparent owing to the appearance of the white smoke of alkyl alumoxanes. After students perform the salt metathesis in the final step, they attempt to crystallize the catalyst. One of the gentlest and most powerful techniques of crystal formation is layering of a nonsolvent on a solution of desired product. This is a valuable skill for students to gain. Throughout the lab there are multiple opportunities to teach spectroscopic technique and interpretation. 1H NMR is useful at every step, including air-free usage for analysis of the final product. Each time students may be asked to predict the spectra they should see, including which resonances should disappear and which should shift most significantly in a given reaction. If IR is used in characterization of the final product, this is an opportunity to teach basic IR facts, such as relative stretches of metal-bound carbonyls versus free CO, as well as more advanced topics such as predicting the spectrum based on the Td symmetry of [Co(CO)4]−. Of the seven students involved in this project, five were able to isolate semicrystalline material, one of which was Xray quality. Of the two products that were not crystalline, one may simply be an oil and the other was not isolable owing to errors in air-free technique. Small quantities of each crystalline compound were tested in the carbonylation of 1,2epoxybutane to β-valerolactone and each showed significant catalytic activity (Table 1). We extend the invitation to those who plan to implement this laboratory exercise to contact us prior to implementation regarding advances in the catalysis and the possibility of testing pure, crystalline products as catalysts for the carbonylation of epoxides.
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In the Laboratory
Acknowledgments The authors would like to thank Rhiannon K. Iha and the students of CHEM 301; Lyn Chao, John Hamm, Wan Ying Ho, Jeff Rinehart, Rahul Singh, Marta Szymanski, and Margaret Yacabozzi. Your enthusiasm and excitement are inspirational. GWC gratefully acknowledges a Packard Foundation Fellowship in Science and Engineering and an Arnold and Mabel Beckman Foundation Young Investigator Award, as well as funding from the NSF (CHE-0243605) and Metabolix, Inc. This material is based upon work supported, in part, by the U.S. Army Research Laboratory and the U.S. Army Research Office under grant number DAAD19-02-10275 Macromolecular Architecture for Performance (MAP) MURI. W
Supplemental Material
Instructions for the students, notes for the instructor, and relevant NMR spectra are available in this issue of JCE Online. Notes 1. All NMR spectra were taken in benzene-d6 and referenced to residual protio solvent. Representative spectra for starting materials, ligand, and an aluminum complex are included in the Supplemental Material.W
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2. Due to time constraints, NaCo(CO)4 was prepared by the instructor but the synthesis is simple enough for undergraduates to undertake (see experimental section in the Supplemental MaterialW ).
Literature Cited 1. ACS Committee on Professional Training. http:// w w w. c h e m i s t r y. o r g / p o r t a l / a / c / s / 1 / a c s d i s p l a y. h t m l ?DOC=education\cpt\ts_inochem.html (accessed Nov 2004). 2. Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1174–1175. 3. Mahadevan, V.; Getzler, Y. D. Y. L.; Coates, G. W. Angew. Chem., Int. Ed. Engl. 2002, 41, 2781–2784. 4. Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403–6434. 5. Rieth, L. R.; Moore, D. R.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 15239–15248. 6. Müller, H.-M.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1993, 32, 477–502. 7. Heck, R. F. J. Am. Chem. Soc. 1963, 85, 1460–1463. 8. Drent, E.; Kragtwijk, E. (Shell Internationale Research Maatschappij B.V., Neth.). Eur. Pat. Appl. EP 577206; Chem. Abstr. 1994, 120, 191517c. 9. Lee, J. T.; Thomas, P. J.; Alper, H. J. Org. Chem. 2001, 66, 5424–5426. 10. Molnar, F.; Luinstra, G. A.; Allmendinger, M.; Rieger, B. Chem.-Eur. J. 2003, 9, 1273–1280.
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