SUPPORTING MATERIALS
Expeditious Horner-Wadsworth-Emmons Synthesis Of Methyl Cinnamate Esters Under
Aqueous Conditions
Lawrence L. W. Cheung, Rui Jun Lin, Jason W. McIntee and Andrew P. Dicks*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario,
Canada, M5S 3H6.
E-mail: adicks@chem.utoronto.ca
The information contained within this document is organized into three sections1.
Laboratory Notes For Students – background information, hazards and safety,
experimental procedures and post-lab questions (pages 2 - 5).
2.
Additional Notes For Instructors – equipment needs, synthetic notes, sample
preparation for UV analysis and required chemicals with CAS numbers (pages 6 - 8).
3.
Spectroscopic Information & Physical Data – methyl (E)-4-methoxycinnamate product
H NMR, 13C NMR, MS, IR and UV spectra and assignments, other ester product
physical data (pages 9 - 16).
1
1
Laboratory Notes For Students
Estimated Length Of Experiment:
90 – 120 minutes
Experimental Objectives
1.
2.
3.
4.
To synthesize a stereoisomer of methyl 3-(4-methoxyphenyl)-2-propenoate (methyl
4-methoxycinnamate) by a Horner-Wadsworth-Emmons reaction.
To characterize the reaction product by 1H NMR, IR and UV spectroscopy.
To deduce and rationalize the product geometry via 1H NMR spectroscopy.
To appreciate the advantages of using water as the solvent for this (and other) organic
reactions.
Background
The Horner-Wadsworth-Emmons (HWE) reaction is a widely used method for the
preparation of α,β-unsaturated esters (1,2). The procedure formally resembles the classical
Wittig reaction but utilizes phosphonate esters instead of phosphonium ions as the source of
phosphorus-stabilized carbanions. It is therefore possible to synthesize methyl
4-methoxycinnamate (a sunscreen analog (3)) and other methyl cinnamate esters by a one-step
reaction starting from a benzaldehyde derivative (below). The HWE reaction is usually
stereoselective, i.e. one stereoisomer ((Z) or (E)) of the product is formed at the exclusion of the
other.
OCH3
O
C
O
H
+
H3CO
P
OCH3
H3CO
OCH3
K2CO3
O
H2O, heat
O
(Z) or (E)?
OCH3
H
4-methoxybenzaldehyde
trimethyl
phosphonoacetate
methyl
4-methoxycinnamate
Horner-Wadsworth-Emmons Synthesis Of A Methyl Cinnamate Ester
There is currently tremendous interest in designing organic reactions that will take place
in an aqueous solvent (4). Today’s reaction is an example of one that has traditionally been
undertaken using strong bases in organic solvents (such as sodium methoxide in methanol, or
sodium hydride in 1,2-dimethoxyethane). With modification it is possible to use a much milder
2
base (potassium carbonate) and water as the reaction medium. Water is also used in the product
isolation step so that the use of organic solvents is completely eliminated (except during
recrystallization).
Safety Notes
Wear eye protection, a laboratory coat and protective gloves during this
experiment. 4-Methoxybenzaldehyde and trimethyl phosphonoacetate are irritating to the eyes,
respiratory system and skin. Potassium carbonate is a skin irritant and hygroscopic. 95% Ethanol
is flammable.
CAUTION – PERFORM ALL SYNTHETIC AND PURIFICATION OPERATIONS
IN A FUMEHOOD
Experimental Procedure
A table of the reactant/solvent physical properties is detailed below:
Compound
GMW
4-methoxybenzaldehyde
potassium carbonate
trimethyl phosphonoacetate
water
95% ethanol
136.15
138.21
182.11
18.02
46.07
Amount
Added
365 µL
1.10 g
1.40 mL
0.5 mL
mmol
mp (°C)
bp (°C)
3.00
7.96
8.65
-1
891
248
0
-114
118/0.85mm Hg
100
78
d
(g/mL)
1.119
2.43
1.125
1.00
0.789
1.
IN A FUMEHOOD, place the following in a 25 mL round bottomed flask:
4-methoxybenzaldehyde (365 µL, measured with an automatic delivery pipette);
potassium carbonate (1.10 g); trimethyl phosphonoacetate (1.40 mL – automatic delivery
pipette); and water (0.5 mL – automatic delivery pipette). Add a magnetic stir bar.
2.
Heat the mixture vigorously under reflux (water condenser) for 10 – 15 minutes, using a
sand bath as the heat source and maintaining rapid stirring.
3.
Remove the flask from the sand bath and allow to cool to room temperature. Perform
TLC on a small sample removed (stationary phase, silica gel; eluent, 5:1 hexanes:ethyl
acetate).
3
4.
Add water (10 ml) to the round bottomed flask to yield a white precipitate. Isolate the
precipitate by vacuum filtration using a Hirsch funnel and dry on the funnel for 5
minutes.
5.
Recrystallize the crude product by dissolving the solid in hot 95% ethanol, adding water
dropwise until a permanent cloudiness persists and then adding more 95% ethanol
dropwise to clarify the solution.
6.
Allow the solution to cool slowly to room temperature and then cool in an ice-bath.
7.
Collect the purified compound by vacuum filtration and dry thoroughly on the funnel.
Remove the solid from the funnel, weigh and calculate the percentage yield. Take
appropriate physical measurements (mp, UV, IR, 1H NMR spectra) and identify whether
you have synthesized the (Z)- or (E)-stereoisomer of methyl 4-methoxycinnamate.
SUBMIT A SAMPLE OF YOUR SYNTHESIZED PRODUCT WITH YOUR REPORT
Clean-Up
Dispose of all waste into the appropriately marked containers in the fumehoods.
Dismantle and clean all glassware with soap and water.
Laboratory Report
Your report should contain the following points:
1.
Discussion of the Horner-Wadsworth-Emmons reaction performed (5,6), including
(i)
a detailed “curved-arrow” reaction mechanism for formation of methyl
4-methoxycinnamate, focusing on
a)
b)
c)
the role of potassium carbonate
the first C–C bond forming reaction step
the formation of the alkene double bond
(ii)
the calculated percent yield
(iii)
identification of product alkene geometry, based on the 1H NMR spectrum (see
below) and operative reaction mechanism – explain why the HWE reaction is
stereoselective.
4
2.
3.
Discussion of spectral data obtained, including
(i)
an IR spectrum analysis (in terms of product absorbances and differences from the
IR spectrum of 4-methoxybenzaldehyde)
(ii)
an interpretation of the 1H NMR of methyl 4-methoxycinnamate (with respect to
chemical shifts, spin-spin splitting patterns and coupling constants (J values)).
Can you confirm the product alkene geometry from this spectrum? How?
(iii)
An explanation of why alkyl 4-methoxycinnamate esters are commonly used in
sunscreens, based on the measured UV spectrum of methyl 4-methoxycinnamate.
An outline of the benefits of performing the HWE reaction under aqueous conditions
(compare and contrast this reaction with the approach in reference (7) that you performed
earlier this semester). Why are HWE reactions are often experimentally preferred to
conventional Wittig reactions?
Useful References
1.
Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber., 1958, 91, 61-63.
2.
Wadsworth Jr., W. S.; Emmons, W. D. J. Am. Chem. Soc., 1961, 83, 1733-1738.
3.
Woodruff, J. Chem. Br., 2001, 37, 58-61.
4.
Li, C-J.; Chan, T-H. In Organic Reactions In Aqueous Media, Wiley, New York, NY,
1997, p. 2-3.
5.
Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford Jr., J. A. J. Org. Chem., 1965, 30,
680-685.
6.
Boutagy, J.; Thomas, R. Chem. Rev., 1974, 74, 87-99.
7.
Stabile, R. G.; Dicks, A. P. J. Chem. Educ., 2004, 81, 1488-1491.
5
Additional Notes For Instructors
Equipment Needs
1 x 25 mL round bottomed flask
2 x 25 mL Erlenmeyer flasks
1 x 25 mL measuring cylinder
Reflux condenser
Hirsch funnel and flask
Magnetic stirrer/hotplate
Magnetic stir bar
Ice bath
3 x Pasteur pipettes
Automatic delivery pipette (able to dispense 300 - 400 µL for the liquid aldehydes, can be
shared)
Automatic delivery pipette (set to 1.40 mL, can be shared)
Automatic delivery pipette (set to 0.5 mL, can be shared)
Silica gel TLC plates with fluorescent indicator (Sigma-Aldrich, product no. Z19,329-1)
UV lamp (254 nm)
Notes Regarding Synthesis Of Methyl (E)-4-methoxycinnamate
1.
The protocol outlined for synthesizing this compound assumes that the product alkene
geometry is unknown – this adds a useful investigative feature to the experiment.
2.
The synthesis outlined on pages 3 - 4 works successfully for thirteen other
benzaldehyde derivatives (see tables on pages 8 and 15). Average yields are usually
greater than 60% with the reaction appearing independent of electronic effects.
3.
The methyl (E)-4-methoxycinnamate product is easily visualized under a 254 nm UV
lamp with an Rf value of ∼ 0.5 – 0.6 (hexanes:ethyl acetate, 5:1).
4.
A recent reference (Touchard, F. P. Tet. Lett., 2004, 45, 5519-5523) outlines a
modification of the HEW reaction permitting the preparation of (Z)-unsaturated esters
rather than the usual (E)-unsaturated esters. We intend to inform our students in the
future about this approach so that they are aware of appropriate stereoselective synthetic
methodology.
6
Preparation Of Sample For UV Analysis
The UV absorption spectrum of methyl (E)-4-methoxycinnamate can be measured using the
following procedure.
A stock solution is firstly prepared by dissolving 15.5 mg of methyl (E)-4-methoxycinnamate in
10 mL 95% ethanol (volumetric flask).
50 µL of this stock solution is then dissolved in 10 mL 95% ethanol (volumetric flask). This
corresponds to a concentration of 4.04 × 10-5 M.
Typical λmax value and absorbance:
Methyl (E)-4-methoxycinnamate: λmax = 310 nm, absorbance ∼ 1.08, ε = 2.67 x 104 M-1 cm-1 (1)
Reference
1.
UV absorption literature values for methyl (E)-4-methoxycinnamate:
λmax = 311 nm, ε = 2.40 x 104 M-1 cm-1
Wiesler, W. T.; Nakanishi, K. J. Am. Chem. Soc. 1989, 111, 9205-9213 (using
acetonitrile as solvent for UV measurements).
7
Chemicals Required (Per Reaction) & CAS Numbers
*
**
Compound*
Quantity Required**
CAS Number
4-Methylbenzaldehyde
(4-Tolualdehyde)
354 µL
104-87-0
4-Nitrobenzaldehyde
453 mg
555-16-8
3-Nitrobenzaldehyde
453 mg
99-61-6
4-Chlorobenzaldehyde
422 mg
104-88-1
4-Bromobenzaldehyde
555 mg
1122-91-4
3-Bromobenzaldehyde
349 µL
3132-99-8
Benzaldehyde
305 µL
100-52-7
4-Cyanobenzaldehyde
393 mg
105-07-7
3-Cyanobenzaldehyde
393 mg
24964-64-5
4-Methoxybenzaldehyde
(4-Anisaldehyde)
365 µL
123-11-5
4-Fluorobenzaldehyde
322 µL
459-57-4
4-(Dimethylamino)benzaldehyde
447 mg
100-10-7
3,4-Dichlorobenzaldehyde
525 mg
6287-38-3
3,5-Dimethoxybenzaldehyde
498 mg
7311-34-4
Potassium carbonate
1.10 g
584-08-7
Trimethyl phosphonoacetate
1.40 mL
5927-18-4
Water
0.5 mL
107-83-5
95% Ethanol
variable
64-17-5
Hexanes
-------
7732-18-5
Ethyl acetate
-------
141-78-6
All chemicals are readily available and purchased from Sigma-Aldrich. The HWE
reagent trimethyl phosphonoacetate (catalogue no. T79758) costs $44.80 CDN for 25 g.
The corresponding Wittig precursor ((methoxycarbonylmethyl)triphenylphosphonium
bromide, catalogue no. 259063) costs $64.70 CDN for 50 g. The pre-formed Wittig
reagent (methyl(triphenylphosphoranylidene)acetate, catalogue no. 157929) costs
$110.50 CDN for 25 g.
Quantity of each aldehyde = 3.0 mmol.
8
Spectroscopic Information
1
H NMR assignments for methyl (E)-4-methoxycinnamate
O
5H
H
2
OCH3
6
3
H
H4
H3CO
H
3
1
H
13
Chemical Shift (ppm)
7.65
7.47
7.27
6.90
6.31
3.83
3.79
Assignment
4 (d, J = 15.9 Hz)
3 (d, J = 8.7 Hz)
CHCl3
2 (d, J = 8.7 Hz)
5 (d, J = 15.9 Hz)
1
6
2
C NMR assignments for methyl (E)-4-methoxycinnamate
O
8
7
Chemical Shift (ppm)
OCH3
9
4
3
H3CO
1
2
5
4
3
6
167.90
161.58
144.68
129.88
127.31
115.47
114.51
77.23
55.52
51.71
Assignment
8
2
6
4
5
7
3
CHCl3
1
9
9
1
H NMR (300 MHz) of methyl (E)-4-methoxycinnamate (CDCl3)
10
13
C NMR (300 MHz) of methyl (E)-4-methoxycinnamate (CDCl3)
11
Mass spectrum (electron impact) of methyl (E)-4-methoxycinnamate
12
Infra-red spectrum of methyl (E)-4-methoxycinnamate (thin film from CHCl3)
13
UV spectrum of methyl (E)-4-methoxycinnamate (95% C2H5OH, 4.04 x 10-5 M, 1 cm path
length)
1.2
Absorbance
O
O
0.8
O
0.4
0
200
250
300
350
400
Wavelength (nm)
14
Physical Data Pertaining To All Methyl Cinnamate Ester Products
Methyl cinnamate
derivative
Measured
Literature
mp (°C) mp (°C) (Ref.)
Yield
(%)
1
H-NMR (CDCl3, 400 MHz)
4-CH3
56
56 (1)
83
δ2.37 (3H, s), 3.79 (3H, s), 6.39 (1H, d, J=16.4 Hz),
7.18 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.0 Hz), 7.67
(1H, d, J=16.0 Hz)
4-NO2
157-160
160-161 (2)
72
δ3.84 (3H, s), 6.57 (1H, d, J=16.0 Hz), 7.68 (2H, d,
J=8.8 Hz), 7.72 (1H, d, J=16.0 Hz), 8.25 (2H, d,
J=8.25 Hz)
3-NO2
124-125
124-125 (3)
89
δ3.84 (3H, s), 6.57 (1H, d, J=16.0 Hz), 7.59 (1H, t,
J=7.8 Hz), 7.73 (1H, d, J=16.0 Hz), 7.83 (1H, d,
J=7.6 Hz), 8.24 (1H, d, J=8.0 Hz), 8.38 (1H, s)
4-Cl
75
75-76 (4)
86
δ3.81 (3H, s), 6.41 (1H, d, J=16.0 Hz), 7.36 (2H, d,
J=8.8 Hz), 7.45 (2H, d, J=8.8 Hz), 7.64 (1H, d,
J=16.0 Hz)
4-Br
86-87
89-90 (5)
90
δ3.81 (3H, s), 6.42 (1H, d, J=16.0 Hz), 7.38 (2H, d,
J=8.4 Hz), 7.52 (2H, d, J=8.4 Hz), 7.62 (1H, d,
J=16.0 Hz)
3-Br
53
47-51 (6)
70
δ3.75 (3H, s), 6.76 (1H, d, J=16.4 Hz), 7.40 (1H, t,
J=7.6 Hz), 7.64 (1H, d, J=7.2 Hz), 7.66 (1H, d,
J=16.0 Hz), 7.76 (1H, d, J=7.6Hz), 8.00 (1H, s)
H
34-35
34-35 (7)
67
δ3.81 (3H, s), 6.45 (1H, d, J=16.0 Hz), 7.38-7.40
(3H, m), 7.51-7.54 (2H, m), 7.70 (1H, d, J=16.0
Hz)
4-CN
119-120
120-122 (8)
84
δ3.83 (3H, s), 6.52 (1H, d, J=16.0 Hz), 7.60-7.70
(5H, m)
3-CN
95
-
84
δ3.83 (3H, s), 6.49 (1H, d, J=15.9 Hz), 7.52 (1H, t,
J=8.0 Hz), 7.61-7.80 (4H, m)
4-OCH3
88-89
89-90 (9)
75
δ3.79 (3H, s), 3.83 (3H, s), 6.31 (1H, d, J=15.9 Hz),
6.90 (2H, d, J=8.7 Hz), 7.47 (2H, d, J=8.7 Hz), 7.65
(1H, d, J=15.9 Hz)
4-F
43
40-42 (7)
83
δ3.80 (3H, s), 6.36 (1H, d, J=16.0 Hz), 7.07 (2H, d,
J=8.8 Hz), 7.50 (2H, d, J=8.8 Hz), 7.65 (1H, d,
J=16.0 Hz)
4-N(Me)2
138
134-136 (10)
62
δ3.02 (6H, s), 3.78 (3H, s), 6.22 (1H, d, J=16.0 Hz),
6.67 (2H, d, J=9.2 Hz), 7.42 (2H, d, J=8.8 Hz), 7.63
(1H, d, J=15.6 Hz)
3,4-di-Cl
110
-
77
δ3.81 (3H, s), 6.42 (1H, d, J=16.0 Hz), 7.34 (1H, d,
J=8.0 Hz), 7.46 (1H, d, J=8.4 Hz), 7.58 (1H, d,
J=16.4 Hz), 7.59 (1H, s)
3,5-di-OCH3
75
74.5-75.5 (11)
88
δ3.81 (9H, s), 6.41 (1H, d, J=15.6 Hz), 6.49 (1H, t,
J=2.2 Hz), 6.66 (2H, d, J=2.0 Hz), 7.61 (1H, d,
J=16.0 Hz)
15
References For Table On p. 15
1.
De la Mare, P. B. D.; Wilson, M. A.; Rosser, M. J. J. Chem. Soc. Perkin Trans. 2, 1973,
1480-1490.
2.
Dieck, H.A.; Heck, R.F. J. Am. Chem. Soc., 1974, 96, 1133-1136.
3.
Stecher, E. D.; Waldman, A.; Fabiny, D. J. Org. Chem., 1965, 30, 1800-1805.
4.
Scott, G. P. J. Org. Chem., 1955, 20, 736-746.
5.
Stone, M. J.; Van Dyk, M. S.; Booth, P. M.; Williams, D. H. J. Chem. Soc. Perkin Trans.
1, 1991, 1629-1635.
6.
Banwell, M. G.; Cameron, J. M.; Corbett, M.; Dupuche, J. R.; Hamel, E.; Lambert, J. N.;
Lin, C. M.; Mackay, M. F. Aust. J. Chem., 1992, 45, 1967-1982.
7.
Moyna, G.; Williams, H. J.; Scott, A. I. Synth. Commun., 1996, 26, 2235-2239.
8.
Brown-Wensley, K. A.; Mattes, S. L.; Farid, S. J. Am. Chem. Soc., 1978, 100, 4162-4172.
9.
Curtin, D. Y.; Dayagi, S. Can. J. Chem., 1964, 42, 867-877.
10.
Galat, A. J. Am. Chem. Soc., 1946, 68, 376-377.
11.
Klemm, L. H.; Klemm, R. A.; Santhanam, P. S.; White, D. V. J. Org. Chem., 1971, 36,
2169-2172.
16