In the Laboratory edited by
The Microscale Laboratory
R. David Crouch Dickinson College Carlisle, PA 17013-2896
Kinetic Study of the Heck Reaction: An Interdisciplinary Experiment
Christel Gozzi* and Naoual Bouzidi Laboratoire de Chimie Organometallique de Surface (LCOMS), Ecole Supérieure de Chimie Physique Electronique de Lyon (CPE Lyon), Villeurbanne cedex, France; *
[email protected] Since the 1970s, the palladium-catalyzed C−C coupling between aryl halides or vinyl halides (iodides and bromides are preferred) and activated alkenes in the presence of a base has been referred to as the Heck reaction (1–4) or the Mizoroki– Heck reaction (5). The classical approach consists of aryl addition onto a terminal alkene bearing an electron-withdrawing group such as acrylate (Scheme I). The homogeneous catalytic system generally consists of palladium(0) stabilized by phosphines, such as Pd0(PPh3)4, in presence of a base. The Heck reaction is regio- and stereoselective and leads to the transarylated alkene. Different mechanisms have been proposed; however, the Heck reaction is still being studied. The main steps generally proposed are shown in Scheme II. The first step consists of catalyst generation, followed by oxidative addition of aryl halide onto the catalyst leading to the ArPdX species. This addition is commonly thought to be the rate-determining step of the catalytic
Ar–X
Pd0 ligand
+
COOR
base
Ar COOR
Scheme I. General Heck reaction.
cycle. In the next steps, the coordinated alkene undergoes synaddition to form an unstable σ-bonded complex. Then, after rotation around the C−C bond, β-hydride elimination leads to the arylated alkene and inactive HPdXL2 complex. Finally, the base regenerates the active Pd0L2 complex (6–8). The syn-addition on the alkene and the following β-hydride elimination can explain the observed stereoselectivity. Recent developments in the catalyst nature and reaction conditions
Pd0 or PdII
catalyst generation
PPh3
HX/base
ArX
ź
base
reductive elimination
PPh3 H COOR
PdII P
Pd0 PPh3
PPh3
oxidative addition
PdII
Ar
X
X
PPh3
PPh3
COOR
Ar PPh3
COOR Ar H Q complex
PdII
COOR
X
Ar
PPh3 C-hydride elimination
insertion
PPh3
ROOC
PdII H Ar
H
PdII PPh3
X Q complex
PPh3
X
PPh3
Pd T-bonded intermediate Scheme II. Main steps of commonly proposed mechanism for Heck reaction.
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Journal of Chemical Education • Vol. 85 No. 8 August 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Laboratory
have resulted in a broader range of reagents being amenable to the Heck reaction including intramolecular, asymmetric, or tandem reactions (9–13). We think that students should have a global view of chemistry. They need to realize that fields, such as organic chemistry, catalysis, kinetics, analytical chemistry, and chemical engineering, are interdependent and cannot always be studied separately. To make students work in a combination of different chemical disciplines, we organized this kinetics laboratory associating organic chemistry, catalysis, and analytical chemistry. The aim of this experiment is to study the kinetics of a Heck reaction. We chose the arylation of but-3-en-2-ol by iodobenzene catalyzed by palladium acetate in presence of triethylamine in DMF that led to a mixture of two ketones (Scheme III). This manipulation is based on a simple procedure described in this Journal (14). It was chosen because of the absence of phosphine, thereby avoiding the need to work in inert atmosphere. This allows us to use a simple procedure for taking samples during reaction without destabilization of the catalytic system. The students have to control the global order of the reaction and have to prove that the two reactions are parallel reactions. The ketones are produced by two different mechanisms having the same initial step that definitively determines isomer proportions. The other reaction steps proceed rapidly and the proportions are not changed. Therefore, for students, the initial work consists in understanding the mechanism. They have to determine that the rate-determining step is the syn-addition of ArPdX onto the alkene. The regioselectivity of ArPdX addition is determined by the polarization of the alkene. Depending on conditions (neutral or ionic), the aryl is usually bonded on the
terminal carbon when the alkene is electron deficient (such as acrylate), while it is bonded on the substituted carbon for an electron-rich alkene (Scheme IV) (6). In this study, we use neutral conditions and the alkene is not electron deficient. The addition of Ph-Pd-I is therefore not regiospecific. Students have to find the way to synthesize both ketones (Scheme V). The determining step is the addition of Ph-Pd-I onto the alkene, which determines the isomer ratio. Then, after β-hydride elimination, which is common to both mechanisms, all other steps are fast equilibrium and the ratio of isomers is no longer influenced. The experiment is carried out in pairs within a four-hour laboratory period. It offers students an opportunity to apply their knowledge and practical experience of quantitative gas chromatography for reaction kinetic measurements. The students become familiar with different notions: conversion, selectivity, yield, and TON (turn over number). For quantitative control of results, the reaction is performed with an internal standard, (−)-fenchone. This standard was chosen because it is soluble in the reaction mixture while classical alkanes are not. Hazards N,N-Dimethylformamide (DMF) is a teratogen. Triethylamine may cause severe burns. But-3-en-2-ol, (−)-fenchone and triethylamine are highly flammable. Iodobenzene is harmful if swallowed. Palladium acetate may cause irritation. Dichloromethane is suspected of being a carcinogen and is incompatible with strong oxidants and some metals (Groups IA, IIA, IIB).
Ph Ph
O
+ PhI OH
PdI
+ Ph–Pd–I Ph
Et3N, DMF
HO major
Ar
L
+
á
OBu
R
Ar
+
Pd X
R
OBu
COOMe
L Ar Ar
keto–enol tautomarization fast
O minor
Ph
Ph
+ HO
O major Ph
Ar
Ar L
COOMe
HO minor C-hydride elimination
Ph
Scheme III. Heck reaction of but-3-en-2-ol.
Pd
Ph
+
HO
O minor
L
IPd
major
Pd(OAc)2
keto–enol tautomarization fast
Ph
HO double bound migration fast
HO
Ar
Scheme IV. Regioselectivity of ArPdX addition onto alkene: (top) ionic conditions and (bottom) neutral conditions.
Scheme V. Mechanism of formation of the two ketones.
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 8 August 2008 • Journal of Chemical Education
1127
In the Laboratory
Experiment
version with the initial equation
The reaction is performed at 80 °C in DMF without special precautions. Inert atmosphere and solvent drying are not needed because we do not use phosphine as the palladium ligand. Samples are taken at t0 and after 5, 10, 15, 20, 25, 30, 50, 80, and 120 minutes. After 120 minutes there is no further conversion. All samples, diluted in dichloromethane, are analyzed by gas chromatography (GC). Analysis and calculations take place during the end of the four-hour laboratory period. For the second step, students calculate conversion of iodobenzene, selectivity and yield of each ketone using the GC peak area assuming all products have the same response factor. Without using the internal standard peak, they find the formulas using the GC area. For each chromatogram, we use Iodo as the area for iodobenzene, Majo for the area of major isomer, and Mino for the area of minor isomer. The formula for the iodobenzene conversion (CONV) is CONV = 100% × {1 − [Iodo/(Iodo + Mino + Majo)]} the selectivity of major product, SMajo, is SMajo = 100% × [Majo/(Mino + Majo)]
the selectivity of minor product, SMino, is SMino = 100% × [Mino/(Mino + Majo)]
the catalyst turn over number, TON, is TON = CONV × (amount of iodobenzene/amount of Pd) and finally, the minor product yield, YMino, is
YMino = CONV × SMino
These calculations are done for each sample and students can draw conversion, selectivity, and yield curves. Thus, they can prove that the two reactions are parallel reactions but not competitive because the selectivity curves are parallel lines. Typical results lead to a selectivity ratio between 9 and 10, and iodobenzene conversion can reach 75 to 85%. The global order of the reaction can be obtained using the curve ln[(A − X)/(B − X)] = f (t) where A is initial amount of iodobenzene, B is initial amount of but-3-en-2-ol, X is converted amount of iodobenzene, and t is time. For the initial kinetics, this curve has to be a straight line and corresponds to the general equation
y = ax + b
where a = (A − B)(k + k′) and k and k′ are the rate constants of the reactions to produce the major and minor products, respectively. Since students have proved in previous work that the two reactions are in parallel but not competitive, they know that partial orders are similar for both isomers. Hence
k/k′ = Srat
where Srat is SMino/SMajo. At the end of this work, students are able to calculate each rate constant. Typically k = 0.9 to 2.2 mol‒1 min‒1 and k′= 0.08 to 0.22 mol‒1 min‒1. Finally, students confirm their results using an internal standard. For each sample, they calculate the iodobenzene con1128
Miodo/Mfenchone = K × (Aiodo/Afenchone)
where Miodo is the iodobenzene mass in the sample, Mfenchone is the fenchone mass in the sample (constant), Aiodo is the iodobenzene peak area, Afenchone is the fenchone peak area, and K is the ratio of response factor of iodobenzene and fenchone. The author (CG) found K to be 1.9425 from previous experiments. For each sample, students calculate the iodobenzene mass and so they have access to conversion and turn over number. They should conclude that the results are more accurate with the internal standard but are still close to the initial calculations. Results show a typical difference from the precedent calculation by 10% for iodobenzene conversion and by 4 to 5 for TON. This will prove to the student that the internal standard is an efficient quantitative method. Conclusion This experiment works well in an integrated laboratory and illustrates the interdependence of chemical specialties. It has been run approximately 80 times each year since 2004. From a practical point of view, students have to do a synthesis with precision to obtain good quantitative results. Literature Cited 1. Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320– 2322. 2. Patel, B. A.; Ziegler, C. B.; Cortese, N. A.; Plevyak, J. E.; Zebovitz, T. C.; Terpko, M.; Heck, R. F. J. Org. Chem. 1977, 42, 3903–3907. 3. Cortese, N. A.; Ziegler, C. B., Jr.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem. 1978, 43, 2952–2958. 4. Heck, R. F. Organic React. 1982, 27, 345. 5. Mizoroki, T. T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn 1971, 44, 581. 6. Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427–436. 7. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066. 8. Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31–44. 9. Doyle, D. G.; Hallberg, A. Chem. Rev. 1989, 89, 1433–1445. 10. De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1995, 33, 2379–2411. 11. Negishi, E.-I.; Copéret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365–394. 12. Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371–7395. 13. Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959–5989. 14. Lauron, H.; Mallet, J.-M.; Mestdagh, H.; Ville, G. J. Chem. Educ. 1988, 65, 632.
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2008/Aug/abs1126.html Abstract and keywords Full text (PDF) with link to cited JCE article Supplement
Student handouts, in French and English
Instructor notes including the source of the reagents, chromatograms, ratio of the response factor, and typical results
Journal of Chemical Education • Vol. 85 No. 8 August 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
