John Leo Abernelhy
The H'istorical and Current
California State Polytechnic College Pomona, 91766
Interest in Coumarin
A b o u t a century and one-half ago coumarin was first isolated from both the Tonka bean and sweet clover. It has taken on new significance in recent years through research in biochemistry and bioorganic chemistry. For example, i t was discovered that dicoumarol is the causative agent for the hemorrhagic sweet clover disease, deadly to cattle. Coumarin is converted into this compound during haying and ensiling. The organic synthesis of dicoumarol is effected by condensing formaldehyde with two molecules of 4-hydroxycoumariu ( I ) , thus bridging the reactive &positions with a methylene group. Development of varieties of clover with a minimal content of coumarin has been a practical consequence of this discovery. Biochemical pathways (3)are currently being elucidated for plants and microorganisms that incorporate coumarin and its many derivatives in metabolism or biosynthesis. Coumarin was the first compound prepared in the series of carbon to Carbon condensations that became known as the Perkin reaction (3). However, it involves considerably more chemistry than the structurally simplest of that series, namely the formation of cinnamic acid in the base-catalyzed reaction between heuzaldehyde and acetic anhydride. These additional facets have been glossed over in the past, but with increased understanding of bio-organic mechanisms on an orbital basis, coumarin can be used to greater advantage. From a theoretical point of view, coumarin, I, is obtained by fusion of benzene with non-existent or-pyrone to form this well known 5,6benao-a-pyrone. If treated with sodium hydroxide, the lactone ring opens. Since the cis configuration is retained, this salt, which is stable in excess alkali, is named sodium coumarinate. Coumarinic acid, 11, has not been isolated, nor have sufficiently sophisticated methods of chemistry been used to reveal directly its transient existence when coumarin is formed on addition of acids to sodium coumarinate. Coumarin is usually dissolved in excess sodium hydroxide. Careful neutralization (4), to leave only the equivalent amount of added base, and therefore sodium coumarinate, permits this sodium salt to undergo sufficient hydrolysis to form a precipitate of coumarin. When coumarin is removed by ether extraction, the equilibrium is disturbed and more coumarin deposits due to further hydrolysis. Also, progressive addition of small amounts of strong acid to the sodium salt gives increasing amounts of deposited coumarin. Contribution from the California Association Teachers.
of
Chemistry
o-Coumaric acid, 111, can be formed from sodium coumarinate in ways that will be discussed later. Reduction of o-coumaric acid with sodium amalgam (6) and water yields melilotic acid, IV, which occurs in Melilotus, of which sweet clover is the best known species. All four of these compounds and the 8-Dglucopyranosides of three of them are important to several plant and microbiological systems under bioorganic examination. The 8-D-glucopyranoside of coumarinic acid is commonly called bound coumarin and it occurs in substantial quantity with coumarin in the cotyledons of mature and immature Tonka beans (6). Free o-coumaric acid is essentially absent, while its 8-~glucopyranosideis present in small amount.
--
Coumarin, I m.p. 69%
o.CoumaricAcid,III m.p. 207-8%
Coumarinic Acid, I1 Unstable
Melilotic Acid, N
m.p. 14I0C
The Historic Isolation of ~oumdrin
Isolation of coumarin was first reported in 1820 by A. Vogel (7), who was a regular member of the Royal Academy of Science in Munich. He used the term "benzoic acid" in a general manner to include the acid, itself, coumarin, benzoin resins, resins from vanilla and cinnamon and residues from the urine of horses, cows, camels, elephants, rhinoseroses, and also children. The question had arisen as to whether these benzoiclike resins from animal urine were due to strongly disruptive digestion of edible plants from grazing meadows and low grade feed, or if these resins were existent more or less as such in the plank or feed and therefore passed intact or through moderate digestion into the urine. Hence, Vogel turned his attention to plant sources themselves. He associated the heavily scented odor of clover blossoms of new-mown hay, Melilotus oficinalis, with that of the Tonka beau, which had been named Dipteryx odorata by Wildenow. These beans had been imported from the 60-ft trees of Guiana. While he Volume
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did not obtain rigorous proof that these two sources yielded the same compound, the experimental procedures of his day showed that certain properties were in common and it is now known that the compound from both sources is coumarin. He sliced the leathery shell of the bean with a knife and found a long, white crystal among the contents. This dissolved with ease in ethanol. The solution was diluted with a little water until turbidity was shown. The solvent was then allowed to evaporate in a cool location with resultant formation of long, glistening, white necdles which had the coumarin odor. Gentle heating melted the needles to a transparent liquid, while more vigorous heating caused rapid vaporization. He called this sublimation because the vapors condensed on a cool surface to a white solid, with the same coumarin odor. He found that by slowly warming the Tonka bean kernels in a flask vaporization also occurred, also with formation of crystals of coumarin from the cooled vapor. The beans also contained a yellow-colored fat with the constituency of cocoa butter. Next, he extracted an ounce of fresh clover blossoms with 24 oz of warm alcohol. The greenish yellow solution he suggested would be yellow if freed from plant pigment. This solution was diluted with an ounce of water, and a large portion of the solvent was removed by heating in a retort. The remnant was poured into a porcelain dish and set aside in a cold room for several days. First, a fatty residue settled out. Then, long, fine needles slowly crystallized on top of this residue. After separation of these crystals, they were shown to melt, vaporize, and condense in a similar manner to those from the Tonka bean. The yield was much lower, but Vogel was convinced that they were the same compound. The Curing Process for Tonka Beons
Cured Tonka beans are used in tonnage quantities (8) each year for perfumery and flavoring. Natural forests of trees exist in Venezuela, Colombia, the Guianas, and Brazil, with particular abundance along tributaries of the Orinco River in Venezuela, where they reach a height of 100-150 ft. Groves of trees are cultivated in Trinidad for export of beans. At the ageof 7-10 yr they yield the best crops. Yellowish green to brownish yellow fallen fruit with a mango appearance are harvested from February through April in Venezuela and from March through May in Trinidad. Drying softens thc fruit and shrinks the outer skin. The 5-cm long, elliptical pod, inside, is tapped with a hammer and the single, wrinkled, dull-mahogany colored bean is removed. Average measurements of 19 mixed bean samples from Trinidad (17 beans) and Venezuela (2 beans) gave a length of 16 cm, a breadth of 1.2 cm and a thickness of 0.7 cm. They have a crystalline deposit of coumarin on the outside. The coumarin contcnt was 2.3% and moisture was 7.80j0; hence, the moisture-free coumarin content was 2.5%. During thc drying process of the fruit, a natural (3-glucosidssc iricreases the amount of coumsrin by hydrolysis of thc (3-r-glucopyranoside also present. 011the average, 1-2 lb of beans are obt,ained per trce, although singlc trees can produce as much as 50 Ib. Curing involves soul&ig the beans for several days in rum, which is thc cheapest source of alcohol, arid con562
/ Journal of Chemicol Education
tains 4&G50j0 alcohol. This is reduced somewhat by extraction of moisture from the beans. Some coumarin dissolves but the water content in the alcohol is regulated so as to reduce substantially this solubility. The drained rum, with some dissolved coumarin, is reused by addition of alcohol or new rum with high alcohol content. This reduces loss of coumarin in curing other dried beans. When the alcohol is draincd, the beans are left tightly packed in the barrel. Further decomposition or spoilage is prevented due t,o the alcohol absorbed by the beans. Soon, a fine, white, very thin crystalline deposit forms on the bean surfaces and they are ready for export. Natural coumarin, lilie natural vanilla, contains certain impurities that enhance the flavor when compared wit.h pure, synthetic material. Extraction of coumarin from Tonka beans can follow several procedures, or a combination of thcm. By heating the ground beans, directly, followed by condensation of the volatile components, a product can be obtained with coumarin as the predominant component. The use of volatile solvents like alcohol, chloroform, ethylene chloride, or certain hydrocarbons can be followed by distillation of the solvent from the extract. Steam distillation can be employed with ground cotyledons, or through the use of boiling water covering them. The particular processes utilized would depend on the specifications required for use of the coumarin concentrate. As groves of Tonka bean trees were developed, there was a rapid increase (8) in exports from 10,015 lh in 1927 to 92,719 Ib in 1936. Also, beans imported mainly from Venezuela and cured in Trinidad for transshipment increased from 72,183 lb in 1927 to 838,700 lb in 1936. I n recent years the trend has reversed (9). The total export of cured beans from Trinidad was 552,000 lb in 1960 and 137,863 lb in 1967. It is anticipated that the decline will continue. Uses of Coumorin
Pure coumarin has a bitter, stinging, taste, with an odor and flavor suitable for mixing with vanillill or vanilla. Natural and synthetic coumarin have been used extensively for flavoring and perfumery (10). Coumarin is reported to have three times the flavoring strength of vanillin on a weight basis. Formulations for such usage are often carefully guarded trade secrets. Tonka bean extracts are sometimes employed as additives for artificial vanilla. Coumarin is used with vanilla in the carbonated beverage Cream Soda. I t imparts a vanilla-butter flavor to bakery products lilie hiscuits and cakes, for which its somewhat low volatility has proven advantageous. For men's toiletries, it imparts a woody type of fragrance. I t has found usage as a neutralizer of disagreeable odors of rubber, plastics, and paints, and is occasionally used in sprays. Premium bar soap formulas contain coumarin as a constituent, particularly for synthetic lavender, lilac, and rose perfumes. The First Synthesis of a Vegetable Perfume
William Henry Perkin (11) synthesized coumarin in 1868, when organic chemistry was in its early period of development,. Various priuciples of a basic scientific
mct,hod were being slowly evolved. Dalton's atomic theory 11:i.d given clarity t,o the application of deductivc and inductive logic to science, since first stated in 1808. Nevertheless, molecular formulas of compounds were in a condit~ionof chaos until Stanislao Cannizzaro (12) in his Suuto in 1858 properly applied G:L~-Lussac's law of combining volun~es,which was strictly based on principles of inductive logic, with Avogmdo's law, which was essentially a statement of sheer intuition. With corrections for deviations from the gas laws, such as associatiori and dissociation and other factors we readily accept as causing deviations, plus recognition that gaseous elements can be polyatomic, he clearly distinguished between combining and atomic weights. After acceptance of his ideas, the atomic theory was once more regarded, with confidence, as a set of scientific truths in the correct sense of suggesting that such truths may need alteration with further factual information. Properly developed molecular formulas could now be internationally identical. I'or Perlcin and the chemists of his day, coumarin was C9H602, hut it had been written as CaaH140sby Delalande (13) in 1842. Some of Perkin's reasoning would seem naive or fallacious today, when taken out of the historical setting. Actually, it was no different than a modern, intuitive approach, based on the best evidence accumulated by a given chemist, and the sort of response his mental processes could provide in associating stored information. This we call logic, or perhaps more cautiously, thinking. The chemical and physical aspects of thought, we can have confidence, will he revealed by current and future research concerning functions of the brain. There should be a remarkable similarity in the thought processes of chemists through the whole history of scientific inquiry, when this more penetrating analysis is made. Processes of mental stimulation, retardation, recall, information storage, association, and intuition of course are involved. At the age of twelve, Perkin was subjected to the influence of Robert Hall, who was a student of August W. Hofmann. Perlrin attended noon lectures by Hall on Natural Philosophy. Hofmann had been brought to England from Germany to head the new Royal College of Chemistry in London, shortly after an influential visit by Justus Liebig to England. Hall persuaded Perkin's father to allow Perkin to pursue chemistry as a career. At the age of 18, Perkin published his first work on dinaphthylguanidine in the Journal of the Chemical Society in 1856. Under Hofmann, Perkin became interested in quinine and its synthesis. Additive and subtractive processes seemed reasonable because of the newly established, correct, molecular formulas, in converting toluidine, CHaCeH4NH2,into quinine, CZ0H2,02N2. Substitution of one hydrogen of toluidine with an ally1 group was to be followed by subtraction of two atoms of hydrogen from two molecules of allyltoluidine, and then addition of two atoms of oxygen. Leaving this unsuccessful attempt, he explored aniline as a starting basc. He obtained the renowned anilinc purple, with a lilac color which the French technologist,scalled mauve, meaning mallow. This became the starting point for an industrial era of synthetic organic chemicals, particularly coal tar dyes. Many industrial chemicals became commonly available for mow academic work. A few years after he left aca-
demic work to launch industrial chemistry, he began investigations with salicylaldehydc, sodium acetate, and acetic anhydride. He knew from Delalande's research (IS) that potassium hydroxide a t high temperatures caused fission of coumarin to give saIt,sof salicylic and acet,ic acids. For synthesis, he tried various combinations which resulted in t,he first synt,hesis of a vegetable perfumc. The procedure of mixed melting points was linown at that time, so t,hat, coupled wit,h analytical data the product was shown t.o be identical with coumarin from Tonka beans. It should be pointed out that the structure Perkin suggested for coumarin, CHaCO-CcH3=C=0, in 1868, was incorrect. Other incorrect structures were also proposed (14) by Baseclre (1870), Salkowslci (1877), Morgan (1906), Alucklethwait (1906), and Clayton (1908). Stecker (1867), Fittig (18G8), and Tiemann (1877) all gave the structure that has been found to agree with the chemical properties of coumarin (11) when modern electron delocalization is incorporated. The mechanism of simple Perliin condensations was not settled until many reactions leading to the Lewis Acid-Base generalizations were organized in the 1930's. Coumarin is more intriguing because the original trans condensation product must be followed by trans to cis geometrical isomerism, and ring closure. Modern organic chemistry emphasizes that aromatic aldehydes condense with the conjugate base of an acid anhydride (15).
Experimental work of I'ialnin (16) decisively proved that Fittig had been wrong in considering the Perkin condensation to occur between sodium acetate and the Volume 46, Number 9, September 1969
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aromatic aldehyde. Kalnin used the aldehyde with acetic anhydride and sodium or potassium acetate, and then for comparison he successfully replaced these salts with others such as sodium carbonate and sodium phosphate. Far more interesting was the use of triethylamine, pyridine and diethylbenzylamine. The reaction mechanism he proposed was still considerably in error, as pointed out by Hurd and Thomas (17). It was customary a t that time to use enolization with certain compounds that contained hydrogen bonded to a carbon in an alpha position to a carbonyl group
rather than complete removal of the labile proton in forming the conjugate reactive base
Kaluin considered his basic catalysts to cause enolization, hut he did not discern the more satisfactory electronic interpretation that was about to appear. His experiments became a vital part of the deluge of contributions from organic chemists that emerged under the even greater coverage provided by the Lewis theory of Acids and Bases. Interconversions of Coumorinic and o-Coumaric Contlgurations
Appropriate treatment of a-coumaric acid, its esters or salts, or salts of coumarinic acid in excess alkali to prevent lactonization, can bring about cis-trans interconversions. There must be either removal of the a olefinic boud or substantial weakening of it a t the moment of isomerization. The remnant o bond permits rotation for proper adjustment to the isomeric form. The common methods used for such interchanges employ: (1) ultraviolet light with exclusion of other light or essentially so by appropriate filtration, or sometimes nearly monochromatic light, or else light from an unfiltered source or direct sunlight; (2) protic acids such as hydrochloric or sulfuric acids or a Lewis acid like the mercuric ion; (3) strongly basic reagents like sodium methoxide or heated potassium hydroxide solutions; and (4) sodium bisulfite addition products. While many details of the mechanisms are not clearly elaborated, advantageous usage for educational purposes can stimulate interest in the known and in alternate, potential routes for situations where further investigation is needed. Two adjacent, similarly spaced, ultraviolet absorption peaks are:hown for coumarin (18) (cis) in ethanol, X ,. = 2740 A and h = 3120 A; for sodium cou; 2250 A marinate (19) (cis) i2 0.1 N IYaOH,, , . A, and, , . ,A = 3300 A; and for s o d i q a-coumarate (trans) in 0.1 N NaOH,, . ;A, = 2800 A and, , . ,A = 3600 A. For coumarinate (I$), A,. is less clearly defined because the absorption band overlaps a broad hand whose peak is a t a still lower wave length with a much greater extinction coefficient. l'cr coumarinate an absorption minimum occurs a t 2895 A. Coplanarity of the substituted phenoxidc and
,.,
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A
B
Figure 1. A, o-Coumarate exhibits rvbrtontid coplonwity. marinate exhibits steric hindrance toward coplanority.
8, Cou-
carboxylate with the ethylenic atoms is greater for a-coumarate than for coumarinate, shown in Figure 1, as a consequence of steric hindrance in the latter case. Efficient a + a* excitation to an antibonding orbital requires less energy, and longer wave length, for a-coumarate than for coumarinate because there is greater conjugate electron delocalization with less inhibition of coplanarity. Single bond character is considerably increased between the olefinic carbons by electron delocalization, especially with resonance through the conjugate system from phenoxide oxygen to carboxylate. The change of a singlet electron, So,in a ground state to a singlet, S,, excited state conserves electron multiplicity (SO), and therefore retains pairing of spins with opposite signs by no change in total positive and total negative electron spins. Hund's rule (81) states that the system with highest multiplicity has the lowest energy. The S1 antibonding electron then changes its sign of spin to a triplet, T I , excited state of lower energy, since it is no longer in the same orbital with the paired electron of opposite sign. There is a corresponding increase in multiplicity by this unpairing of spin signs. The & -+ T1 change occurs mainly through a combination of decay processes involving a transition of electronic excited energy to atomic vibrationally excited energy, and then to translational kinetic energy by collisions with surrounding molecules. Activation of the So to an Sl or a T 1 state further reduces the double bond character of the olefinic bond. A certain amount of intersystem crossing, which is an intramolecular S1 to T1 spin reversal, may be enhanced by inclusion of a carhonyl (22) within the ultraviolet chromophore of coumarinate or a-coumarate. Although either excited state can cause a cis-trans isomerism, the triplet state possesses a lower barrier to isomerization. The lowering of double bond character a t the olefinic bond is responsible for the ease of isomerism. For some olefins, there may be a phantom triplet (22, 2.9) intermediate that results from a perpendicular twist a t the essentially non-olefinic bond. The usual mechanism proposes only Franck-Condon (80) excitation, which means a perpendicular rise in energy (Y-axis) on electron excitation with no change in bond distances (X-axis). Isomerism is then promoted by the associated non-uniform intramolecular energetic forces that also cause a + a* absorption to he a spectral band rather than a single line. This consists of vibration, rocking, and rotation;constantly altered by intermolecular collisions. Figure 2 partially indicates this by taking the liberty of omitting conjugate electron delocalization through the olefinic system for the ground and excited orbital states. Activation of the ground
Figure 3.
Figure 2.
Inversion of trans b cis Ihmugh excited ringlet and triplet states.
state cis form, higher energy a t shorter wave length than for the trans form, can then result in a reversal or a return of configuration in a procedure similar to the one in Figure 2. It can readily be seen that regardless of how detailed a current mechanism may be, there are still unrevealed details that may become important to more intricate problems of chemistry. Separate solutions of sodium coumarinate and sodium o-coumarate in excess alkali were irradiated with a filtered source of ultraviolet light whose maximum intensity was near to 3600 A. It took less than 2 hr to reach a photostationary state with 76% trans and 29% cis in both mixture% When wave lengths were controlled to above 4500 A, no interconversion of either salt was noticed. If the range of light from the source was mainly between 4100 A and 4900 A, with essentially none a t 3600 A, the photostationary state was reached in about 4-6 hr with 32% trans and 68% cis. The percentages depend upon the differences in extinction coefficients of the isomers for given wave lengths, with sufficient time for reaching a photostationary condition. A convenient means for converting o-cournaric acid to coumarin is to expose a solution of the acid to snnlight ($4). I n 6 'hr the yield of coumarin was 48% and in 24 hr it was 65%. I n the same study, i t was shown that either methyl or ethyl o-coumarate, after similar exposure to sunlight, produced an even greater percentage of coumarin. More recently (25), 1.01 g of ethyl coumarate in 30 ml of benzene was irradiated for 72.5 hr with ulfiltered light. Only coumarin was isolated from the reaction mixture. When the trans configuration is changed to cis, the ortho phenolic hydroxyl has proper juxtaposition for rapid lactone formation by elimination of water from coumarinic acid or ethanol from ethyl coumarinate. This is typical of neighboring group effects, and the substrate activation by some enzymes or model systems used for studying enzyme-like mechanisms. Methyl or ethyl c-coumarate can be prepared (34) by refluxing c-coumaric acid with absolute methanol or ethanol containing 2% of dry hydrogen chloride for 4 hr. If solutions are saturated with dry hydrogen chloride, refluxing causes trans to cis isomerism, followed by the formation of coumarin. Similarly, treatment of c-coumaric acid with concentrated sulfuric acid (36) on a hot water bath causes trans to cis isomerism and immediate formation of coumarin. These isomerisms
Formation of mumarin fmm o-coumwic acid.
involve an addition of a proton to the olefinic s electrons, then the equivalent of a hydride shift toward the carbonyl group, with an increase in spa character a t the carbon where the hydrogen becomes bonded, and s p e character a t the carbonium carbon. Rotation about the u bond, then a shift of the hydride back into the position of protonated s electrons of the cis configuration, is followed by lactonization with removal of the proton from the s electrons. This is outlined in Figure 3. Divalent mercury from mercuric oxide or mercuric salts also gives preliminary addition of mercury to the olefinic a electrons. Sodium coumarinate-l-CL4 has been changed to sodium o-coumarate-l-C1' by a cis to trans isomerism (27),when coumarin-2-C14 was refluxed with 10% sodium hydroxide and mercuric oxide. Passage of hydrogen sulfide into the cooled reaction mixture, followed by acidification, gave a 62% yield of o-coumaric acid. Bonded mercury was removed by sulfide, leaving the trans isomer. Mercuric salts often give a concurrent mercuration of the aromatic ring, due to ortho or para activation by the oxygen bonded to the ring. This is not the case when coumarin is heated with mercuric chloride in acetone. I n the absence of a base, which would open the ring, crystalline 3-chloromercuri-4-chloromelilotolactone (933, m.p. 165"C, is formed, as displayed in Figure 4.
Figure 4. morin.
Formation of 3-chlommercuri-4-chlommelilotoI~ctonofrom cow
When strongly basic reagents are used to open the lactone ring of coumarin, and then heated, a cis to trans inversion occurs from coumarinate to o-coumarate. Strong sodium hydroxide has been heated (g8) with coumarin to form sodium o-coumarate. The mechanism is not absolutely certain, but it is possible that the hydroxide weakly bonds to the carbon in a beta position Volume 46, Number 9, September 1969
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cis
1
no other special reagents such as nitrite ion are incorporated in the aqueous pha3e, a free radical sulfite or bisulfite has been used to explain the abnormal mode of addition (Sf). This type of abnormality is more familiar in the peroxide effect for addition of HBr to olefins. Free radical bisulfite might also operate in these somewhat more complex, conjugate, olefinic situations related to coumarin. The mechanisms should be similar to the following steps. 1) Formation of the sulfite or bisulfite radical by means of oxygen, which has triplet ground state electrons.
trans Figure 5.
Cis to trans inversion of o-coumaric mid.
to the carboxylate of coumarinate. Rotation about the single bond could precede elimination of hydroxide. Figure 5 shows this. If dry sodium ethoxide in ethanol is reflnxed with coumarin, the lactone ring is opened to give ethyl coumarinate. Then a similar sequence of events takes place to yield ethyl o-coumarate. Subsequent treatment with water causes the ester to be saponified and acidification produces a-coumaric acid (29) in 82% yield. A thermal reversal of configuration, trans to cis, occurs (24) when methyl or ethyl o-coumarate is heated for 5 min to form coumarin in 45% yield. Controlled geometric inversions can be brought about by proper use of sodium bisulfite (4, 14, 50). Heating coumarin with a 20% sodium bisulfite solution and then cooling produces a precipitate of the monohydrate of the bisulfite addition product. Whether the sulfur is bonded at the .3- or 4-position has not been established. If it is bonded a t the 4-position, then sodium 3,4-dihydro-4-coumarinsulfonate, V, results (Fig. 6). The salt V is essentially neutral and the lactone ring can be opened by titrating to the end point with an equivalent of sodium hydroxide to form sodium melilotate-3-sulfonate, VI. Since atmospheric oxygen has been shown to be necessary for bisulfite addition to ordinary olefins, when
I
6-S-0: .. .
..
+
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Formation of bisulflto addition produes of mumarin.
Journal o f Chemical Education
I
+
:ij-s-~-H ..
-OH
2) Free radical cycle.
The HOz radical could then be removed by the usual means familiar to radiation chemistry. However, a more complete study would be required to provide assurance of a definitive mechanism in these bisulfite additions. Structures of the addition products have not been proven. A degree of uncertainty is created by electron delocalization for conjugate olefins. Equations (4) and (5) of the free radical cycle may involve inversion of configuration a t the free radical carbon. If the solid monohydrate of the sodium bisulfite addition product V is heated for 2 hr a t 150-160°C, it is converted quant,itatively into coumarin, with concurrent formation of sulfur dioxide, water and sodium sulfite. 2C4H,02SOnONa.H80(V)
Figure 6.
-
HOH
-
+ + + NsnSOs
ZCoumarin f 2H10 [2NaHSOa]-SO% Hz0
Addition of excess HCL t o sodium melilotate-3-sulfonate, VI, contrasts the weak carboxylic and strong sulfonic acidities because sodium melilotic acid-3-sulfonate, VII, precipitates from solution. The product redissolves in sodium hydroxide to form VI. On heating sodium melilotate-3-sulfonate, VI, with 20-50% KOH followed by acidification, o-coumaric acid is formed in excellent yield, Figure 7. This is a frequently used route to a-coumaric acid (trans) from coumarin (cis).
ax6Na+ ,H
,SO&
'.J
~ a '
HotKOH, Then HCl
N Excess ~HSOI
H
VI
Figure 7. fonate.
Formation of 0-coumaric acid fmm sodium m e l i b t a t e - 3 4 -
Figure 8. Use of sodium melilotote-3-rvlfon.k an intermediate in the route from o-soumoric ocid Itran4 to coumarin Icirl.
The strong hydroxide could remove a proton, while heat expels the sulfonate group in the form of sulfite, Figure 8. Bisuifite, of course, adds to sodium o-coumarate from 111 to produce VI. If cold, dilute, sodium hydroxide is added at once, in small proportions to VI, conmarin is precipitated. Rapid removal of bisullitc yields N:hSOS and sodium coumarinate. Hydrolysis of sodium coumarinate in the weakly basic solution precedes instant lactonization to coumarin. This is not a stable situation because stirring the mixture converts coumarin back to soluble VI. Many reactions in this detailed series of cis and trans interconversions have iuvolved intermediate saturation a t the olefiuic doubldbond and then a return to olefinic bonding. I n genedd, control of the cis or trans configuratiou incofj&tes effects of temperature, pH, concentrations, wave length of light and extinction coefficients, and the t,ime allowed for reactions to proceed.
are not quite given directly. Two chief phenolic compounds emphasized for large scale syntheses of coumarin are phenol and c-cresol. An intermediate, salicylaldehyde, has historically been synthesized from phenol, chloroform, and strong alkali in the ReimerTiemann reaction. The Perkin reaction, which then yielded coumarin, has been reported to have been later abandoned as a principal synthetic route. However, the patent literature (55) shows that it is still given consideration. An alternative preparation of salicylaldehyde has been the reaction between phenol and formaldehyde, with dry HC1 as the condensing agent to form o-(hydroxymethy1)phenol. Then, p-nitroso-N,Ndimethylaniline (54) is used as a patented method for oxidation to salicylaldehyde with concurrent formation of p-(dimethy1amino)aniline. o-Cresol has commonly been converted to o-cresyl carbonate by means of phosgene in the presence of a base. The product was chlorinated to o-(dichloromethy1)phenyl carbonate and then converted to o-(diacetoxymethyl)phenyl carbonate with sodium acetate and cobalt chloride. Several steps followed treatment with acetic anhydride, that terminated in the emergence of coumarin (36). One process (36) for purification of coumarin uses polyhydric alcohols that form azeotropes. 1''or example, coumarin of about 949" purity is mixed with 4 times its weight of trimethylene glycol and distilled under 11 mm pressure. It is then passed into 5 times its weight of hot water and cooled, with a resultant 92% yield. Sometimes impurities are removed (57) by heating coumarin with 10-20% sulfuric acid. Neutralization with NaCOa, then washing with warm water and distilling under reduced pressure, yields high grade coumarin. Another purification procedure converts coumarin to its sodium bisulfite addition product (38). Extraction with a solvent like ethylene chloride, carbon tetrachloride, or benzene removed the main organic contaminants. The bisulfite addition product was then converted to coumariu by addition of sulfuric acid.
Synthetic Industrial Coumarin
The annual commercial sales (52) of synthetic coumarin in recent years have been 0.713 million lb in 1961, 0.696 in 19G2, 0.901 in 1963, 1.000 in 1964, 0.963 in 1965 and 1.192 in 1966. The synthetic compound must ofteu be subjected to special purification procedures for flavors and perfumcs because of highly repulsive effects of small amounts of by-product impurities. While the patent literature does not always contain the actual procedures for preparing industrial coumarin, much chemistry is revealed that has importance to chemistry in general. Details of industrial processes
Acknowledgment
Indebtedness is expressed to several persons who have generously provided information toward the organization of this paper. Professor Charles D. Hurd of Northwestern University was consulted on some of the portions of nomenclature and other features. Any nomenclature errors will be in those portions where his advice was not sought. Dr. Christopher Foote of UCLA provided advice concerning phases of organic photochemistry and other mechanisms. Dr. Bruce Monroe and Dr. Jack Leonard, post-doctorate fellows in the Gates and Crellin Laboratories of Chemistry at Volume 46, Number 9, September 1969
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Caltech, gave important information with respect to photochemical mcchnnisms. Dr. Richard Ii. Long, The Dow Chemical Company, Rlidland, hlichigan, supplied aspects of coumarin of a practical nature. Dr. F. B. Zienty, Ifonsanto Chemical Company, St. Louis, Missouri, gave important details of the uses of coumarin. Mr. Donn N. Bent, Secretary, U. S. Tariff Commission, Washington, D. C., gave the sales information for synthctic coumarin. Mr. W. L. Phillipsen, Agricultural Attache, American Embassy, Port of Spain, Trinidad, furnished details of the export of Tonka beans. Dr. J. Spector, Head, Central Lahoratories, University of the West Indies, sought out some of the features concerning the Tonka beans. Dr. A. L. Houk of the California State Polytechnic College, Sau Luis Obispo, made helpful suggestions with respect to the use of diagrams. Literature Cited
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Journol of
,.-"",. ,."C"3
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