I
I
John S. M e e k University of Colorado Boulder, 80302
The Determination of a Mechanism of bomerization of Maleic Acid to k m a r i t Acid
I n undergraduate organic laboratory work students are expected t o know t h e mechanism of one preparative reaction after another. They obtain this information by reading their text a n d rarely see t h a t alternative mechanisms can b e suggested for a reaction a n d seldom learn on what experimental evidence t h e mechanism is based. At present mechanistic experiments seem t o be confined t o obtaining d a t a which enable students t o determine whether a reaction is first- or second-order i n terms of reactants, b u t they d o not enable t h e m t o obtain d a t a on which t o exclude a plausible mechanism a s being inoperative a n d t o deduce one in accord with experimental facts which they obtain. I n seeking such a n experiment t h e isomerization of maleic acid t o fumaric acid by heating with hydrochloric acid h a s proven t o he almost ideal. T h e mechanism is not readily guessed nor is it t o be found i n current lecture texts. In fact for t h e past year we have been asking colleagues, visiting professors, and graduate students what was t h e mechanism of this reaction a n d obtained t h e correct answer only once, before we received late i n M a y t h e 5 t h Edition of "Laboratory Practice in Organic Chemistry" by T. L. Jacobs, W. E. Truce, a n d G. R. Robinson, Macmillan Publishing Co., Inc., New York, 1974. I n this laboratory text a procedure for isomerizing maleic acid t o fumaric acid is given and t h e mechanism of isomerization by hydrochloric acid is well delineated, b u t t h e laboratory exercise is still t h e typical preparative type of experiment rather t h a n one designed t o elucidate a mechanism. O u r handout, which has been successfully tested on u n dergraduate majors, was designed t o teach some history, some concepts of stereochemistry, a n d t o encourage deductive reasoning. O u r latest version reads a s follows. The Mechanism of the lsomerization ol Maleic t o Fumaric Acid by Hydrochloric Acid Historical Information Scheele in 1785 isolated an acid from unripe apples. This acid is still called malie aeid after the Latin ward malum meaning apple. The acid also occurs in grapes and rhubarb and is levorotatary. Structural studies have shown it to be L(-)hydraxysuccinic acid. The racemic form is manufactured today and is used as a food acidulant without restriction since the compound is easily metabolized. In 1817 dry distillation of malic acid by Braconnet and independently by Vauquelin led to the discovery of two acids which became known as maleic acid and fumaric acid. The first name is based on the French "maleique acide" which appears to he a variation of malic acid. The second acid derives its name from the fact that the acid is found in fumitory plants. These belong to the genus furnoria, a common European herb. Studies by Pelouze in 1836 indicated these acids were isomers, and Liebig in 1838 showed they had the same composition and he believed that fumaric acid (mp 300-30Z°C) was a polymer of maleic acid (mp 139-140°C d). This idea was mentioned by Erlenmeyer in 1870 and again in 1886. Kekule in 1861 reduced both substances to succinic acid (butanedioic acid) and wrote -CHCOOH
I -CHCOOH
for fumaric acid and
for maleic acid. Later work by Swarts in Kekule's laboratory led to a publication in which fumaric acid was depicted with a double bond CHCOOH
II
CHCOOH
In 1874 van't Hoff suggested that carbon atoms were tetrahedral and explained why malic aeid and other compounds with four different groups on one carbon atom could exist as optical isomers. In discussing the tetrahedral shape he wrote "Double linking is represented by two tetrahedrons with one edge in common" and he pointed out that when two tetrahedrons are so attached isomerism results if each tetrahedron has two different substituents at the two noncantiguous corners of each tetrahedron. These can be depicted thus HCCOOH
HOOCCH
II
HCCOOH
HCCOOH H
HOOC ma1eic acid
H 1umwic a d
The first of these structures was assigned to maleic acid by van't Hoff since maleic acid melts at 140°C and loses water to make an anhydride while fumaric acid does not do this at its higher melting point. Only the cis isomer could make a cyclic anhydride
maleic anhydt.ide
Kekule and Strecker in an 1884 publication observed that maleic acid, when warmed with hydrochloric acid, was easily converted to fumaric acid. Isomerization by halogens and hydrogen halides aided in establishing structures and relative stabilities of geometrical isomers. Once the cis-trans nature of maleie and fumaric aeid was established, advances in stereochemistry could take place. Wislecenus in 1881 correctly interpreted Kekule's 1863 conv;rsion of maleic acid to meso tartaric accd as being the result of a cis opening of the double bond. Kalbe attacked van't Hoff's stereochemical ideas as did Fittig, Lassen, and others, but Wislecenus became a leader in recognizing the value of the new theory. After Fittig, Erlenmeyer, Michael, Beilsteip, and Ansbutz had a succession of failures in solving structural problems without using vanst Hoff's new concepts, apposition gradually disappeared and acceptance emerged. However, a really satisfactory explanation of the mechanism of the hydrochloric acid isomerization of maleic aeid to fumaric acid was not advanced until almost 60 years after Kekule and Streeker discovered the reaction. Skraup studied the isomerization in great depth and published his results in 1891 without giving an adequate explanation, but did comment on the plausibility of Wislecenus' suggestion that hydrogen chloride added to give chlorosuccinic acid which upon loss of hydrogen chloride gave fumaric acid. Theoretical Section Mechanisms which can be considered for the isomerization are as follows: A . Thermal
One of the double bonds breaks, rotation occurs and then the double bond reforms. Volume 52, Number 8, August 1975 / 541
B. Eleetraphilic 1) Addition of a proton gives CMH
~OOH
Loss of a proton now givesfumsric acid. 2) The cation above reacts with water to give malic acid which in acid solution dehydrates and produces fumaric acid. 3) The cation above reacts with itself to form a ladone. This opens to give malic acid and then dehydrates tofumsric acid. 4) The cation above picks up a chloride ion and so forms chlarosuccinic acid. Loss of hydrogen chloride now occurs to form fumaric acid. 5) Protonation does not occur on the carbon atom hut on the carbonyl group of a carboxyl group. Due t o resonance the electrons in the double bond are delocalized so that the following can occur
2) Place your six filled test tubes in either a steam bath or a beaker of water a t its boiling point. Swirl the test tuhes in order to dissolve the solids. Once solution has occurred, they need no further swirling. Heat them for 15 min and record your observation of any changesnoted in the test tubes. 3) If s solid forms in a test tube by the end of the 15-min period of heating, coal the contents and remove the solid by filtration, using a Hirsch funnel. Wash the solid with a milliliter of water, dry the solid, and determine its weight and melting point. Pour the eontentsar filtrate from tube 66 into the jar provided. Melting points of the acidsdiscussed above are as follows: L(-)malic acid, 99-100°C DL-malic acid, 128-129°C maleic acid, 139-140"dC fumaric acid, 300-302°C L(-)chlorosuccinie acid, 176°C DL-chlorosuceinie acid, 153-154°C Generally the higher the melting point of a d i d the higher are the forces holding the molecules together in a crystalline solid. These forces have t o he overcome uoon solution: thus i t should not be surprising that the higher melting fumarie acid is much less soluble than any of the other acids listed above.
Theoretical Section
fummir neid
+
Hi
-
H,
C
,CiOHl,
11
/OH H\C/C\OH
-
11
n+
C. Nueleaphilie Addition of a chloride ion gives an anion which upon inversion of the carbanion or rotation around the C2-C3 bond and lossof chloride ion results in fumaric acid. This anion is C0,H I
Hk-
I
C0,H
D. Unsuggested It must he realized that mechanisms are proposed theories and that they can be tested. If not in accordance with known facts then the mechanism is incorrect. Even if a mechanism is in accord with all known facts this does not make it the correct mechanism since a n unconceived mechanism might be the true one. For example one can postulate that the isomerization of maleie aeid t o fumaric acid is due to light in the laboratory. It is known that ultraviolet light will convert fumaric acid to maleie acid. Another suggestion could be that it is due t o heavy metal catalysis due to impurities present in the hydrochloric acid. Skraup reported heavy metal catalyzed isomerization does indeed occur. A third explanation is that a free radical adds to the double bond to eive a radical intermediate similar t o the cation pictured in B1, rotation around the remaining single bond, CZ-C3, occurs and then loss of the radical restores the double bond. This mechanism has been postulated since under certain conditions bromine plus light converts maleic acid to fumarie acid.
Experimental Section 1) Label six medium sized test tubes and fill them first with the solids as shown below and then with the solvents. Test Tube rl
2 3 4 5 6
Solids 1g maleic acid 1e maleic acid 1 maleic acid and 1e NHICI ---1 maleic aeid and 1g NH&l 1g maleic acid 1.3 g chlorosuecinic acid
e
g
-
0
Solvents 3 ml hydrochloric acid 3 ml sulfuric acid 3~-~~~ ml water 3 ml sulfuric aeid 3 ml hydrochloric acid 3 ml hydrochloric acid ~
~~
The acid solutions are made up by pouring cautiously two volumes of the concentrated acid intoone volume of water. 542 / Journal of Chemical Education
If the isomerization of maleie acid to fumaric acid is merely a thermal reaction, which test tuhes should give rise to fumaric acid? If the mechanism of isomerization is B1, which test tuhes should give rise to fumaric acid" W h ~ shouldgive h positiw rerulrsior H2. HR. erc.? What mechanism dr,vot. feel is in accord with sour facts7 Questions 1) In simple esterifieations such as the conversion of benzoic acid and methanol to methyl benzoate small amounts of hydrogen chloride or sulfuric acid are equally satisfactory as catalysts. However, when a methanol solution of maleic acid is esterified using sulfuric acid a liquid ester is obtained, but if hydrogen ehloride isuseda solid ester is formed. Explain. 2) Maleic acid on treatment with thionyl chloride gives fumaryl chloride and maleyl chloride was unknown for many years after fumaryl chloride was first prepared. What conditions would be needed for preparing rnaleyl chloride? 3) Ultraviolet light can convert fumaric aeid to maleic aeid. Why is it obvious that visible light can not do this? 4) What is the melting point of D(+)malic acid? Why does DL malic acid melt higher than the L form? Why does DL chlorosuceinie acid melt lower than the L farm? 5) Fumaric acid is formed in the body in what is known as the Krebs cycle. Since the compound is easily metabolized it is allowed in foods as an acidulant. What property, however, makes fumaric acid less desirable in many cases than malic acid? 6) Skraup tried the isomerization of maleic acid using perchloric acid as the catalyst as well as hydriadic acid. Consider the polarizability of the perchlorate and iodide ions and the difference in charge delocalization in the ions as affecting their nueleophilicity. Now list in order of increasing efficiency how HCI, HI and HClO. solutions should rank as catalysts for the isomerization reaction. 7) Scheele has the mineral calcium tungstate named scheelite in his honor. Liebig condensers and Erlenmeyer flasks are still used today. Fittig, Kolbe, Strecker, Skraup, Swarts, and Michael have reactions named for them and Lossen has a rearrangement coupled with his name. Give an example of each of these organic reactions.
Experimental Results and Discussion Fumaric acid crystallizes only in tubes z l and 24. If the mechanism was a simple thermal isomerization not due to hydrochloric acid it is obvious the first four test tubes would have given fumaric acid. The yield is about 85% of practically pure fumaric acid melting very close to the value reported in a handbook. With no recrystallization involved the experimental and theoretical work are easily completed in less than a laboratory period. Since no fumaric acid was formed in tube ;2, the cation, proposed originally by Palanyi, in mechanism B1 is not correct nor is the mechanism B5 valid. Since the tuhes with malic b i d and chlorosuccinic aeid do not give fumaric acid, neither of these succinic acids can be intermediates in the real pathway and Wislecenus' suggestion is thereby eliminated, and mechanism B2, 83, and B4 must be discarded. The lack of fumaric acid formation with ammonium chloride in tube $4 shows the nueleophilic meeh-
anism C is unimportant and the student is left with D, a n unsuggested meehanism. The next suggestions in D can be ruled out. Light in the visible region is not absorbed by white maleic acid and ultraviolet light, if it had been involved, would have caused the first four tubes to give positive results. If one suggests that an unknown catalyst causes the isomerization, then test tube 22 shows the postulated material was not in the sulfuric acid or maleic aeid used and tube 23 shows that no such catalyst existed in the tap water or the ammonium chloride used. However, if one postulates sulfuric acid and ammonium chloride generate a "catalyst," then the results of tubes x 1 and -4 clearly indicate the same results in regard to rate and that the material generated in tube 24 is clearly hydrochloric aeid and nothing else. Thus heavy metal catalysis can be ruled out. Ruling out a free radical mechanism is almost as simple. All samples were exposed to the diradical oxygen and obviously that radical does not affect maleic acid. At this point i t becomes obvious that both the hydronium ion and the chloride ion are required and if the reader bas not yet deduced the meehanism, pause and do so. The reasoning required is quite simple. Protonation can occur an two sites as was pointed out in the mechanisms proposed. If it occurred on a carbon atom, then isomerization would bave occurred. If it occurred on oxygen, then it is obvious that the cation formed in mechanism B5 can not rotate around the C2-C3 bond or both sulfuric and hydrochloric acid would give fumaric acid. Now one only has to decide how this cation would react reversibly with a chloride ion to permit isomerization. The students usually come up with the statement that the isomerization is due to "a reversible conjugate addition." Better ones will point out that in the compound formed by conjugate addition there is free rotation around the C2-C3 band and that the bisulfate or sulfate ion is not as nucleophilic as the chloride ion and sulfuric acid does not add in a conjugate fashion. The major drawback to assigning this mechanistic exercise is the commercial unavailability of chlorosuccinic acid. One can purchase bromosuceinic acid and switch to bydrobromic acid and ammonium bromide but the cost of doing the experiment increases and does not follow the historical development with hydrochloric acid. The cast of maleic and racemic malic acid is very low and attractive in these days of inadequate budgets. One can omit test tube 6 if the students are told that Horrex found that when DC1 in heavy water was used to treat maleic anhydride, fumaric acid farmed. If the acid was crystallized from ordinary water i t was found to have no deuterium in it. Recrystallization of fumaric aeid in heavy water introduces only two deuterium atoms. These data can then be interpreted to rule out mechanisms, but we feel it is better to bave the students get all the data themselves. Thus we had t o seek a preparation df racemic chlorosuccinic acid, and found the syntheses reported were not amenable to adaptation by undergraduates, and had to devise the relatively quick simple method given below. Eight grams of DL-malic acid, 20 ml of redistilled reagent grade thionyl chloride, and four drops of dimethylformamide are heated on a steam bath with gentle refluxing in a good hood. The solid acid gradually dissolves and towards the end of the reaction the liquid in the flask is swirled to wash down particles of malic acid adhering to the upper portion of the flask. About 40 mi" of reflux is sufficient and the completion of the conversion to ehlorosuccinyl chloride is signalled by the cessation of bubbling. At this point
the flask is removed and the contents poured into a small beaker. Two milliliters of water are added and swirled with the acid chloride which almost immediately starts to hydrolyze. Evolution of hydrogen chloride becomes brisk but little heat is evolved. In approximately 10 min the material has formed a solid cake in the beaker. This is broken loose, crushed, and placed in a drying oven for a short time a t 100°C. This removes the odor of thionyl chloride and hydrogen chloride. The yield of cream colored solid is about 9 g and is suitable for use even without drying. The melting point is about 149-152°C and can be improved slightly by recrystallization. Solvents such as acetic acid, water, ether-benzene, acetane-benzene, ethyl acetate, benzene-hexane, etc., have been tried. Chlorosuceinic aeid is quite soluble in water, ether, acetic acid, ethanol, and other solvents and its solutions deposit solid cakes only after several hours of standing in a refrigerator. We recommend recrystallizing from concentrated hydrochloric acid. Cooling 9 g of product dissolved in about 8 ml of solvent gives a rapid deposition of solid, but again, well formed crystals are not observed. The method of preparation and this recrystallization show the student cblarosuccinie aeid does not yield fumaric acid under the conditions used far test tube c6. Thus we feel if the students do make the compound they should do i t after they have deduced the mechanism and their product should then be used for the classes next year. Since chlorosuccinic acid m n be extracted from aqueous solutions with ether and easily recovered far reuse, our directions call for saving the solutions from tube 16. Notes 1) Much of the historical data is based on the papr of Ihde (1) and the references therein. 2) The use of dimethylformamide to catalyze the formation of a n acid chloride is based on the work of H. H. Bosshard and caworkers (2). See also Fieser and Fieser (3). 3) The use of thionyl chloride to convert optically active malic aeid into the (+) rotatory chlorosuccinic acid in 30% yield by McKenzie and Barrow (41 was the starting point for our preparation of the lower melting racemic form of the acid. 4) C. Horrex published his work in 'IYansxtions of the Faraday Society (51. 5) Essentially the conjugate addition mechanism was deduced save for the rotation around the C2-C3 bond by Nozaki and Ogg (6). They gave a mechanism in terms of two Walden inversions of C-3 and one of C-2. Their isomerization using potassium thiocyanate is a good example of nucleophilic catalyhs and a student could be asked to deduce the intermediate in that reaction. The paper has much of interest in regards to energies of activation, rate constants, etc. 6) The author does not write textbooks and trusts any interested reader will feel free to adopt this experiment for his classes or laboratory textbook. The author hopes the mechanism of the isomerization will continue to be omitted in lecture texts and hopefully in future laboratory manuals so that the mystery of the mechanism will continue t o exist for all students.
Literature Ciled (1) Ihde.A..J.CHEM.EDUC..3L330l1959). 121 Rnsrhard. H. H.. H e l u Chim Acto. 42. 165311959). (31 Fieser. L. F., and Fiosor. M.. ''Reagents for Organic Synthesis." vol. I. Xew York, p.289, 141 McKenzie, A,, and Barrow, F.,J. Chem Sae., 99, 1919 119111. 15) Hones. C.. l h n s ForadqvSoc.. 33,57011937). 161 Uozaki. K.,and 0gg.R.. Jr.. J. A m m Chem Soe., 6% 2583 IIS411.
D.C.Heath,
Volume 52, Number 8. August 1975 / 543
