lsomerization of Dimethyl Maleate to Dimethyl Fumarate
An Undergraduate Experiment Utilizing High-Performance Liquid Chromatography
David B. Ledlie, Thomas J. Wenzel, and Susan M. Hendrickson
Bates College. Lewiston, ME 04240
~ ~ -~
It is eenerallv recomized that most routine chromato-
graphic techniq;es sh&ld he introduced to students within
the context of the undereraduate ornanic laboratorv. While a
substantial number of undergraduate organic experiments
utilizing gas chromatography or thin-layer chromatography
have been published, there is a deficiency of those involving
high-performance liquid chromatography (HPLC). Herein
we describe an experiment utilizing HPLC that we have
successfully used for several years in our introductory organ-
ic laboratory. The experiment involves the isomerization of
dimethyl maleate (DMM) to dimethyl fumarate (DMF) (eq
1)and was adapted from a procedure described by Roberts,
Gilbert, Rodewald, and Wingrove in their laboratory text.'
The proposed mechanism for the reaction is illustrated in
Figure
Figwe 1. Reaction machanlsm tor me isomeriratim of dimethyl maleate to
dimethyl fumarate.
The liquid chromatographic analyses required of each stu-
dent, which involve ohtaininc a chromatomam on the pure
starting material, the crude reaction mixture, and the pure
product, can be carried out in less than 5 min. The experi-
ment not onlv offers students "hands-on" exoerience with
liquid chromatographic instrumentation, it 'also demon-
strates the sensitivity and efficiency of the method. We
devote a substantial amount of our prelaboratory session for
this exoeriment to the discussion of the theoretical asvects
of liquid chromatography. In addition to introducing our
- . .. the experiment provides
students t o liquid chromatoeravhv,
an introduction to stereoisomerization of hkenes, to certain
a p e & of free radical chemistry, and to thermodynamics
(see Discussion). ~ u r t h e r m o r e the
, procedure described
could easily he adapted to microacale experimentation.
Experimental Procedure
Isomerization Procedure
Toa 10- X 15-mmtesttuhe wasadded 1.5 n L of dimethyl maleate
(DMM) and six drops of 0.60 M bromine in carbon tetrachloride.
This operation should be carried out in a hood. The test tuhe was
corked and placed in direct sunlight (a south-facingwindow sill is
ideal for this purpose; alternatively a sun lamp may be used as an
ultraviolet source) for 45 min. Crvstals of dimethvl fumarate (DMF)
hegan to form almost immediatily. After the 45:min reaction pcri-
MI. s small amount of the crude pruduct wad removed7from t h lest
~ required-just enough to cover the tip of the spatula.
I
I IDMF DMF
-
Fioure 2. LhuM chmmatwram of ial - materiall.. ibl
. .dlmemvl maleate (startino
crude reactlor mixture. and (c) dimethyl tumaram aner reqstalliration horn
..
smsnal. Mobile phase: msmanoi-waler (6040 ulv), 1.5 mumin. See ExpaC
mental Senion fw mlmn and other details.
... .-in
tnhe. dissolved - 15
- mL ~~ ~~~~ ~
" .~
-- of the Liauid ehromatomaohic
~ mobile
~~~ ~ ~ ~ ~.
phase, and analyzed using HPLC. The crude reaction mixture was
recrystallized from ethanol to afford pure dimethyl fumarate (mp
101-102 OC). The product as well as stating material were analyzed
using lrquid chmmatography and infrared spectroscopy. In the case
of DMF, several cryawls were dissolved in 16 mL of the mobile
phase. Fur DMM, adropwapdiasolved in 1SmLafthemobilephase.
Liquid Chromatographic Analysis
The liquid chromatographic analysis was performed using either
a Beckman Model 332 Gradient System equipped with a Beckman
Model 153 ultraviolet detector (fixed wavelength, 254 nm) or a
Perkin-Elmer 3-D liquid chromatograph. The ultraviolet detector
(fixed wavelength, 254 nm) of the 3-D chromatograph was used. A
Pecosphere 3 X 3 C-18 column (3.3 cm packed with 3-rm particles)
provided by Perkin-Elmer was employed. Samples were injected
using a 10-pLinjection Loop. The mobile phase was methanol-water
(60:40 vlv) at a flow rate of 1.5 nLImin. The methanol was HPLC
grade; water was obtained from a Milli Q filtration device.
Typical chromatograms are illustrated in Figure 2. The
chromatogram in Figure 2a is that of the starting material,
dimethyl maleate. A small peak a t 29 s, due to a slight
impurity of dimethyl fumarate, is observed in the chromato-
e r k . A twical chromatoeram obtained for the crude reac-
;ion mix&e is shown in Figure 2b. Substantial amounts of
both of the isomers are observed in this mixture. The peak
areas can be used to determine the percentage of each isomer
in the mixture. Figure 2c is the chromatogram obtained for
'Roberts, R. M.; Gilbert. J. C.; Radewald, L. 6.; Wingove. A. S.;
Modem Experimental Organic Chemistry, 4th ed.; Saunders: New
York, 1985; p 168.
Kkasch, M. S.; Mansileld. J. V.; Mayo, F. R. J. Am. Chem. Soc.
lS37.59.1155. A more elaboratemechanism for this type of reaction
has been suasested. See Back. M. H.; Cvetanovic. R. J. Can. J. Chem
l963,4L 1566.
A microspatual was used for this purpose. Only a small amount is
Volume 66 Number 9 September 1989 781
the product, dimethyl fumarate, after recrystallization from
ethanol.
As part of the laboratory report, students are required to
answer several ouestions. Given the heats of combustion of
the isomers (DMM, -669.2 kcallm; DMF, -664.3 kcal/m4)
students are able to calculate that DMF is more stable than
DMM by 4.9 kcallm. If thermodynamic conditions are ap-
proached or prevail, the more stable isomer should predomi-
nate in the reaction. First, students are asked to comment on
why dimethyl fumarate is the more stable isomer. Ab initio
calculations (STO-3G level) of the energies of the various
conformational isomers of the (El- and (Z)-2-butenedials
indicate that the ( E ) isomer (planar, Czh symmetry) is more
stable than the (Z) isomer (nonplanar, either CZor Cssym-
metry) due primarily to an electronic (conjunction) effect.5
Students are apprised of the details of this study in the
'Weast, R. C., Ed. Handbwk of Chemistryand Physics, 66th ed.;
CRC: Boca Raton. FL. 1985.
We are indebted to James Diamond and Diane Ellis of Bates
College for canylng out these calculations.For calculations on DMM
and DMF and related material, see Vsetecka, V.; Pecka. J.; Pro-
charka, M. Coliect. Czech. Chem. Comm. 1982.47.277,
' Both ~lanarC,A DMF and nomlanar C9hDMM have Identical
symmet&numbers%eir entropy difference isthus zero, and both of
these isomers differin entropy from nonplanar C, DMM by only 1.37
cal. The energy difference(AH) between nonplanar C2hDMM and
nonplanar C, DMM b -0.4 kcailm (by calculation);therefore, AG =
AH. In our prelaboratory session wegivea brief discussion of symme-
try as it relates to entropy.
Several options are available here: Students can be ask& to
determine a response factor;the response factor can be given; or the
response of both isomers can be assumed to be Identical. In the
Interest of time, we have opted for the last option.
782 Journal of Chemical Education
prelaboratory session. I t is assumed that they will conclude
that DMF is more stable than DMM for an analogous rea-
son.
Second, students are asked to compute the percentage of
DMF and DMM present under equilibrium conditions at 25
OC. Since the entropy difference between the isomers is
negligible, the equilibrium constant is thus calculated using
eq 2."
Third. students are asked to comvare their calculated
percentages to the observed percentages, as measured via
HPLC,and to account for the difference between these two
sets ofvalues. The resonse of the instrument to both isomers
is assumed to be identical. (This is not quite correct; for
identical weights, the area ratio of DMMIDMF = 0.7).' In
the example included (Fig. 2) the percentages of DMF add
DMM are annroximatelv 66% and 33%. resnectivelv. This
correspondsltb a differeice in energy of 0.4 dcal/m. klearly,
the reaction was ~erformedunder conditions such that eoui-
librium was not achieved. Reasons for this include noniso-
thermal reaction conditions. a heteroeeneous
" reaction medi-
urn, possible competing side reactions, and insufficient reac-
tion time. Finallv, students are asked to calculate the heats
of formation foreach of the isomers and to draw an energy
diamam that shows the relationship between the heats of
formation and heats of combustion of these compounds.
Acknowledgment
We are grateful to the National Science Foundation (Col-
lege Science Instrumentation Program) for a grant to pur-
chase a gradient liquid chromatograph, and to the Perkin-
Elmer Corporation for the gift of a 3-D liquid chromato-
graph.