John S. M e e k I The Determination of a Mechanism of University of Colorado

Boulder, 80302 I bomerization of Maleic Acid to kmar i t Acid

I n undergraduate organic laboratory work s tudents are expected t o know the mechanism of one preparative reac- tion after another. They obtain this information by read- ing 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 the mechanism is based. At present mechanistic experiments seem to be confined t o obtaining d a t a which enable s tudents t o determine whether a reac- tion is first- or second-order in terms of reactants, bu t they d o not enable them to obtain d a t a on which t o ex- clude 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 the isomerization of ma- leic acid to 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 to be found in current lecture texts. In fact for the past year we have been asking col- leagues, visiting professors, and graduate s tudents what was the mechanism of this reaction a n d obtained the cor- rect answer only once, before we received late i n May the 5 th Edition of "Laboratory Practice in Organic Chemis- try" 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 to fumaric acid is given and the mechanism of isomerization by hydrochloric acid is well delineated, b u t the laboratory exercise is still the typical preparative type of experiment rather than one designed t o elucidate a mechanism.

Our handout, which has been successfully tested on un- dergraduate majors, was designed t o teach some history, some concepts of stereochemistry, a n d to encourage de- ductive reasoning. Our latest version reads a s follows.

The Mechanism of the lsomerization ol Maleic to 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 levoro- tatary. Structural studies have shown it to be L(-)hydraxysuc- cinic acid. The racemic form is manufactured today and is used as a food acidulant without restriction since the compound is eas- ily metabolized.

In 1817 dry distillation of malic acid by Braconnet and inde- pendently 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 ma- leic acid (mp 139-140°C d). This idea was mentioned by Erlen- meyer in 1870 and again in 1886.

Kekule in 1861 reduced both substances to succinic acid (buta- nedioic 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 dou- ble bond

CHCOOH II CHCOOH

In 1874 van't Hoff suggested that carbon atoms were tetrahe- dral 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 com- mon" and he pointed out that when two tetrahedrons are so at- tached isomerism results if each tetrahedron has two different substituents at the two noncantiguous corners of each tetrahe- dron. These can be depicted thus

HCCOOH HOOCCH

HCCOOH II

HCCOOH

H HOOC H ma1eic acid 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 an- hydride

maleic anhydt.ide

Kekule and Strecker in an 1884 publication observed that ma- leic acid, when warmed with hydrochloric acid, was easily con- verted 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 fu- maric 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 recogniz- ing the value of the new theory. After Fittig, Erlenmeyer, Mi- chael, Beilsteip, and Ansbutz had a succession of failures in solv- ing 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 ade- quate explanation, but did comment on the plausibility of Wisle- cenus' suggestion that hydrogen chloride added to give chlorosuc- cinic 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.

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B. Eleetraphilic 1) Addition of a proton gives

C M H

~ O O H

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 chla- rosuccinic 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 to resonance the elec- trons in the double bond are delocalized so that the following can occur

H, ,CiOHl, /OH

C H\C/C\OH fummir neid + Hi - 11 - 11

n+

C. Nueleaphilie Addition of a chloride ion gives an anion which upon inver-

sion 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 cor- rect mechanism since an unconceived mechanism might be the true one. For example one can postulate that the isomerization of

maleie aeid to 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 to heavy metal catalysis due to impurities present in the hydrochloric acid. Skraup reported heavy metal catalyzed isomerization does in- deed occur. A third explanation is that a free radical adds to the double bond to eive a radical intermediate similar to 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 Solids Solvents rl 1 g maleic acid 3 ml hydrochloric acid

2 1 e maleic acid 3 ml sulfuric acid 3 1 e maleic acid and 1 e NHICI 3 ml water

- 0 - - - - ~-~~~ ~ ~~

4 1 g maleic aeid and 1 g NH&l 3 ml sulfuric aeid 5 1 g maleic acid 3 ml hydrochloric acid 6 1.3 g chlorosuecinic acid 3 ml hydrochloric acid

The acid solutions are made up by pouring cautiously two vol- umes of the concentrated acid intoone volume of water.

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 observa- tion of any changesnoted in the test tubes.

3) If s solid forms in a test tube by the end of the 15-min peri- od 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 to 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

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 ~ h shouldgive 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 hydro- gen 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 ehlo- ride isuseda solid ester is formed. Explain.

2) Maleic acid on treatment with thionyl chloride gives fumar- yl 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 chlorosuc- einie 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 al- lowed 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 perchlo- ric acid as the catalyst as well as hydriadic acid. Consider the po- larizability of the perchlorate and iodide ions and the difference in charge delocalization in the ions as affecting their nueleophili- city. 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 mecha- nism was a simple thermal isomerization not due to hydrochloric acid it is obvious the first four test tubes would have given fu- maric 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, pro- posed 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 suc- cinic acids can be intermediates in the real pathway and Wislec- enus' 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-

542 / Journal of Chemical Education

anism C is unimportant and the student is left with D, an un- suggested 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 isomeriza- tion, 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 de- duced 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 oc- curred. 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 in- creases and does not follow the historical development with hy- drochloric 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 an- hydride, fumaric acid farmed. If the acid was crystallized from ordinary water i t was found to have no deuterium in it. Recrys- tallization 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 to seek a preparation df racemic chlorosuccinic acid, and found the syntheses reported were not amenable to ad- aptation 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 ehlorosuccin- yl 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 chlo- ride which almost immediately starts to hydrolyze. Evolution of hydrogen chloride becomes brisk but little heat is evolved. In ap- proximately 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 at 100°C. This removes the odor of thionyl chlo- ride 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 recrys- tallization. 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 aque- ous solutions with ether and easily recovered far reuse, our direc- tions 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 an acid chloride is based on the work of H. H. Bosshard and ca- workers (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 prepara- tion of the lower melting racemic form of the acid.

4) C. Horrex published his work in 'IYansxtions of the Fara- day 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 thiocy- anate 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 inter- ested 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 to 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. D.C. Heath,

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.

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