LARKSPURS, DELPHINIUMS, AND CHEMISTRY ROBERT C. KVDER University of Dayton, Dayton, Ohio
autumn, and grow until frost. They are found chiefly TEAT THE old-fashioned garden larkspur and the stately delphinium contain many poisonous compounds, in forested ranges, usually a t altitudes of 8000 to 11,000 some with therapeutic value, may not be recognized feet (12). A few typical members of each of these subby some of our horticultural and chemical friends. Yet groups are: since the time of Pliny certain drugs derived from these Low Larkspurs Tall Larkspurs plants have been employed for the relief of numerous D. biolw Nutt. (Purple lark- D. Barbeui Huth (Tall larkailments. Furthermore, in the western United States spur) spur) the wild larkspurs are recognized as a major cause of D. Geyeri Greene (Plains Lark- D. califmicum T. & G. (Coast Poisonweed) larksour) cattle poisoning. Certain preparations from larkspurs D.spu;, Menziesii DC. (Menzies D. eu~llaiurnA. Nels. (Tall have been found also to have insecticidal properties. larkspur) larkspur) The chemical compounds responsible for all these D. trieone Miehx. (Dwarf D. occidentale S. Wats. (Tall larkspur, Staggerweed) larkspur) poisonous and therapeutic properties are alkaloids, over D. t~ollizfoliumGrav (Poison a score of which have been isolated from the various Larksp"r, Caw poiknj larkspur and delphinium species. Unfortunately, little is known concerning their chemical constitution. The cultivated varieties of delphiniums are likewise subdivided into the annuals and the perennials. To the TAXONOMY OF THE GENUS DELPHINIUM horticulturist, only the annuals are known as "larkIn order to understand fully the meanings of the spurs,t, while the perennials are known as the words ''larkspur" and "delphinium," we shall survey delphiniums:r ~h~ horticultural varieties are so highly briefly the botanical and horticultural classifications of developed by cross breeding that it is not possible to these plants. classify them botanically according to species, but cermay be recognized, Botanically speaking, all larkspurs and delphiniums tain ancestral are members of the genus Delphinium, itself a member ~ h garden , delphiniums may be briefly as of the crowfoot family, Ranunculaceae. This family in- follows cludes species of anemone, hepatica, buttercup, clematis, aconite, and many others. The genus Delphinium conCULTIVATED DELPHINIUMS sists of about 125 species of perennial (and occasionally I The annual larkspurs annual), erect, branching herbs of world-wide disA The Ajacis type 1 Tall Rocket Larkspurs tribution. The genus acquired its name from the 2 Dwarf Rocket Larkspurn Greek word delphis, because the shape of the flowers 3 Hyacinth-flowered Larkspurs , suggests the classical figure of the dolphin (18). B The consolido type The wild (or naturally-occurring) delphiniums are 1 Double Stock-Flowered Larkspurs commonly called larkspurs (a name also derived from 3 Emperor or Double Giant Imperisl Larkspurn C The grnndiflomm type the shape of the flowers) and may be divided into the 1 Bouquet Larkspurs annual and the perennial species (2). Of the annuals 2 Chinese Larkspurs the most important are two species known collectively I1 The perennial Delphiniums as the European consolida group: D. Ajmis L. (Annual A The elaturn type 1 Candle Larkspurs Larkspur) and D. consolida L. (Field or Branching 2 Bee Larkspurs Larkspur). They were introduced to the United States B The eheilanthum type as garden varieties but, having escaped somewhat from 1 Garland Larkspurs the gardens to uncultivated habitat, they may be con2 Belladonna type sidered as naturalized species of the east and eastC The nudicaule or Ruysii type Red Larkspurs central states. The two species are often confused. The wild perennial del&miums may be subdivided into the low larkspurs and the tall larkspurs. The low ALKALOIDS FROM DELPHINIUM SPECIES larkspurs attain a height of about one or two feet, Alkaloids have been detected in about two dozen blossom early in the spring, and die down soon after different species of Delphinium and it is probable that flowering. They are found in a variety of habitats from all of the species of this genus contain alkaloids. From sea level to foothills and sometimes as high as 10,000 only six definite species, however, have the alkaloids feet. The tall larkspurs, on the other hand, may reach been isolated and their empirical formulas and other a height of five feet or more, blossom in midsummer or in properties been determined. The alkaloids appear to 418
SEPTEMBER. 1947
be distributed throughout all the diierent parts of the delphinium plant, from which they may be isolated by extraction with organic solvents. The alkaloidal content of the various parts of the plant varies from about 0.2 per cent to 2 per cent; the greatest concentration usually occurs in the seeds. Considerable confusion concerning tieaidentity of many of the delphinium alkaloids exists in the literature. Their high molecular weight and complex structure make determination of empirical formulas difficult. The structural formulas have not yet been determined completely for any of the delphinium alkaloids, although some of the substituents on the nitrogen-containing kernel have been identified. A list of the crystalline alkaloids whose empirical formulas are known is given in Table 1. In addition to the crystalline compounds listed in this table, several amorphous alkaloids have also been isolated-notably methyl-lycaoonitine, C3,HilsN20~~, which was obtained from horticultural D. elatum by Goodson (14). It should be noted that alkaloids have been isolated from horticultufal varieties (D. elatum of Goodson, D. conjumm, etc.) as well as from the natural species. Further, it should be noted that some species (e. g., D. Ajacis, D. staphisagria) contain more than one kind of alkaloid. Certain similarities in the empirical formulas of the delohinium alkaloids can be noticed. Most of them contain one nitrogen atom per molecule and six or seven oxygen atoms. The functions of all the nitrogen and oxygen atoms have been determined for eight of the alkaloids. The partial structural formulas for these eight are shown in Table 2. It will be noted that in all except one of these alkaloids the nitrogen occurs as ethylimide; in the exception, delphinine, the nitrogen occurs as methyliide. The oxygens occur in hydroxyl groups, either free or alkylated or acylated. The
.
Figure 1. Ddphinivm d.tum L., a N.tur.lly Occu~ringSpecies-from L. H. Bailey, "Tha Qsrden of ~ l u k a p ~ dUSW, ' by permission of ~ h M*..
millam
company
alkylating group is always methyl, except in delpheline, in which a methylenedioxy group also occurs. The acylating groups are acetyl, benzoyl, acetylanthranoyl, or methylsuccinylanthranoyl. The carbon skeleton - -
-
Crystalline Delphinium Alklaoids
420
JOURNAL OF CHEMICAL EDUCATION
contains 19 carbon atoms (except in delphamine) and obviously has a highly condensed ring structure. Nothing concerning the actual structure of the carbon skeleton is known except that from the selenium dehydrogenation of staphisine several hydrocarbons were obtained which had absorption spectra resembling polymethylphenanthrenes (26). TABLE 2 Functional Grouua i n Deluhinium Alkaloids
Base C Base B
PHYSIOLOGICAL ACTION OF DELPHINIUM ALKALOIDS
In general the physiological action of the delphinium alkaloids is similar to the action of the aconite alkaloids, such as itconitine, C31H49NOll. This similarity is not surprising iaview of the chemical likeness noted above. Delphinine has also been compared to veratrine, C ~ B H ~ ~inNits O ~physiological , action. The chief difference between the action of delphinine and that of aconitine and veratrine is the direct depressing action of delphinine on the vasomotor and respiratory centers of the spinal cord, medulla oblongata, and afferent vagus fibers, resulting in death by asphyxiation rather than by paralysis of the heart muscles, as in the case of aconitine and veratrine poisoning. Because of the circulatory effect of delphinine, however, the heart action is weak and stops about as soon as respiration ceases (56). An amorphous mixture of alkaloids, obtained from the roots of D. bicolor, D. Menziesii, D. Nelsonii, and D. scopulorum, was named delphocurarine because of its curare-like action ($3). Curare, a South American arrow-poison, is nontoxic when taken orally, but on hypodermic injection it acts as a rapid and powerful poison, due to paralysis of the striped-muscle motor nerve endings, resulting in cessation of voluntary movements and finally death from respiratory failure (21). Delphocurarine in warm-blooded animals produces a temporary lowering of the blood pressure and destroys the normal action of peripheral vagus stimulus (7). The toxicity of some of the delphinium alkaloids is indicated in Table 3. DELPHINOSIS
Some of the delphinium alkaloids differ from each other only in the extent of acylation or methylation of the hydroxyl groups. Thus ajacine and methyllycaconitine are both acylated derivatives of the base CaH1PNEt(OH)3(0Me)4, lycoctonine. Ajacine can actually be hydrolyzed to give lycocotonine and acetylanthranilic acid, and methyl-lycaconitine can be hydrolyzed to give lycoctonine and methylsuccinylanthranilic acid. Lycocotonine is also a hydrolytic product of the alkaloid lycaconitine (succinylanthranoyllycoctonine), 'which is obtained from Aconitum lycoctonum. This relationship between the delphinium and the aconite alkaloids was first suspected by Manske (SZ) in 1938 and definitely established by Goodson (14) in 1943. Lycoctonine itself may be regarded as a monomethylated derivative of Goodson's Base C, whereas his Base B is a mono-acetylated derivative of the same Base C. Delphinine is an acetylbenzoyl derivative of a base quite similar to lycoctonine. Delpheline, condelphine, and delphamine are also closely related to lycoctonine.
In view of the toxic properties of the delphinium alkaloids described above, it is not surprising that the consumption of delphinium plants is harmful to animals. The poisoning of cattle resulting from eating delphinium plants is known as delphinosis and is a common cause of stock losses on the ranges of the western United States. Larkspurs cause more loss among cattle than any other poisonous plant except locoweeds (SO, 36,SQ). In addition to the annuals, D. Ajacis and D. eomolida, a t least 16 species of low larkspurs and 13 species of tall larkspurs have been found to be definitely toxic. The most widely distributed of the tall larkspurs is D. Barbeyi (Tall Larkspur). Found in open woods and grassy mountain parks a t altitudes of 8000-11,000 feet in Montana, Wyoming, Colorado, Utah, and farther south, it is responsible for greater losses of cattle than any other species of Delphinium. The most common low larkspur is D. Menziesii (Menzies Larkspur, Purple Larkspur, Low Larkspur). Found in hills, open ranges, and mountain meadows from California and New Mexico north to Alberta, British Columbia, and Alaska, i t is probably the most destructive low larkspur because of its occurrence in such enormous masses (55). In some states, such as California, Oregon, and Wyoming, and in the mountainous regions of Colorado, delphinosis is responsible for more cattle losses than any other plant poisoning, including that due to locoweed (IS,
SEPTEMBER, 1947
421
TABLE 3 Toxicity of Delphinium Alkaloids Lethal dose, Ton'c dose,
Source
Alkaloid
D. Ba~beyi D. Barbeyi D. bieolor D.bieolor D. cucullalum
Amorphous M. P. 124-5' Amorphous Delphawrarine* M . P . 178'
w./kg. 6 80 20
D. Nelsonii D. staphisagria D. slaphisagria D. slaphisagria D. slaphisagria
Amorphous ~el~hinine Delphinine Delphisine Delphinoidine
10 0.1 1.5 0.7 5
...
40
m9.h
Animal
Ref.
... ...
Rabbit Rabbit Rabbit Froe
(3, 6) (3. 6 )
15 1.0 33
ahh hit.
6
Rabbit Frog Cat, dog Cat, dog Cat, dog
... ...
... . ...
isj
'
(7. , , $3)
(7) ($3) ($8) ($8)
*Also obtained from D. Menziesii, D. Nelsmii, and D. scopulolum.
19, 31, 44). In fact, in Wyoming the one species D. Geya' (Geyer's Larkspur, Plains Larkspur, Poison Weed) is claimed to be responsible for more losses among cattle than are all the other poisonous plants of the state combmed (Pi, 4,6,88,31). The larkspurs are poisonous for horses and cattle, but usually not for sheep; horses, however, rarely eat enough of the plants for the harmful effects to be noticed, epecially on the open range. A quantity of plant material of about two to three per cent of the weight of the animal is necessary for serious poisoning or death. The general symptoms are apparently the same regardless of the species causing the poisoning: a staggering gait, abdominal pain, and finally convulsions, resulting in death due to respiratory failure (18, 36, 39, 45). Hence the common names-Poison' Weed, Staggerweed, etc.-are often applied to.severa1 species of delphiniums. THERAPEUTIC VALUE
Several therapeutic preparations from a few of the Delphinium species have been recognized officially. Here again the effect of the preparations is probably due to their alkaloidal content. From D. Ajaeis is obtained the dmg, Larkspur N.F. VI, consisting-of the dried ripe seeds of this species. Besides the alkaloids the seeds also contain volatile and 6xed oils, gums, resins, and gallic and aconitic acids (37). The official preparations are Tinctura Delphinii N.F. VI (Tincture of Larkspur) and Tinctura Delphinii Acetica N.F. VI (Acetic Tincture of Larkspur). The Tincture of Larkspur is used externally a s a parasiticide in pediculosis capitis et pubis (infestation with head and crab lice). The Acetic Tmcture of Larkspur (also known as Larkspur Lotion) is also used externally as a pediculicide (40). Preparations from D. consolida were a t one time used for a variety of ailments, but a t present are only used as a local application for the destruction of lice in the hair (46). The dmg or alkaloid, delphocurarine, which is obtained from D. scopulorum and other species, has
Figure 2. Candle L~.+ur.. Loft, As S w n in Old Garden.: R i ~ h tOn. . of thoAm.li.ratedDo"hl.Flovelvld K i n d h f r o m L. H.%ley. .'The G u d e n of Larkapun" (1839). by Pormivrion of The MacmiUan Company
been used hypodermically as an antidote for hydrophobia, tetanus, and strychnine (38). Perhaps the oldest Delphinium preparations are those obtained from D. staphisagria (Stavesacre, Lousewort). The ripe seeds of this species have been used since the time of Pliny as a louse preventive (87, 36). Known commonly as lice grains or Stephans grains, or technically as Staphisagria U.S.P. IX or Staphisagriae Semina B.P., these seeds contain malic
JOURNAL OF CHEMICAL EDUCATION
acid and fixed oil in addition to all the staphisagria alkaloids (delphinine, delphisinc, staphisine, staphisagroine, and others) (37). Official preparations are: Fluidextracturn Staphisagriari U.S.P. (Fluidextract of Staphisagria); Lotio Staphisagria B.P.C. (Stavesacre Lotion or Nursery Hair Lotion), employed as a lotion for children's hair, being used to kill pediculi and their ova; and U n ~ u e n t u mStaphisagria B.P. (Stavesacre Ointment), used as a parasiticide to kill pediculi capitis et pubis (8). The alkaloid delphinine itself was formerly employed for its antipasmodic and antineuralgic action, but at present it is only rarely used, being restricted to external application in pediculosis and occasionally in scabies (infestation with scab mites; mange) (37, 38). The use of larkspur tinctures to destroy lice is not without undesirable effects; it is often accompanied by acute dermatitis resembling eczema, evidenced by redness and vesicles. Delphinine itself is a mild vesicant, producing burning and inflammation when applied to the skin. Ointments containing delphinine, when rubbed on the skin, cause burning, prickling, and a transitory redness, such as veratrine produces (47). It is reported that even the herbage of larkspur causes a burning sensation (80). INSECTICIDAL ACTION
The oil and the alkaloid from D. Ajacis seeds possess insecticidal properties against insects, such as bedbugs (48). The alkaloid of D. Brownii has been found to be promising as an insecticide for mosquitoes and potato beetles. It is not expected to excel nicotine sulfate as a contact insecticide but it may prove to be a superior stomach poison and feeding repellant (44). The larkspur oil from the seeds of D. consolida, when used in the form of soap emulsions, is t o ~ oto red spiders and aphids. Delsoline and delcosine are highly toxic to aphids and thrips and of some value as stomach poisons against certain leaf-feeders, but are ineffective against red spiders (11). From D. slaphisagria, stavesacre oil (as a soap emulsion) is also toxic to red spiders and aphids. Delphinine is toxic to thrips but not to aphids, red spiders, etc.; it isalso effective as a stomach poison. Usually, delphinine is much less toxic than the consolida alkaloids (If). LITERATURE CITED (1) AHRENS.F. B., Ber., 32, 15814, 1669-70 (1899). (2) BAILEY,L. H., "Cyclopedia of American Horticulture," The MacmiUan Company, Inc., New York, 1900, pp. 4fie7. ... ..
BEATH,0. A., Ww.Agr. Ezp. Sta. Bull., 120 (1919). BEATH,0. A., ibid., 126.9-13 (1921). BEATH,0. A,, H. J. DRAIZE,AND C. S. GILBERT, ibid., 200, 12-20 (1934). BEATH,0. A., AND A. NELSON,ibid., 143, 51-70 (1925). BOEHM.R.. "Handbuch der Emen'mentelle Pharmakoloaie." " , volume 2 , pt. 1,283-319 (1920). "British Pharmaceutical Codex, 1923," The Phrtrmaceutical Press, London, 1923, pp. 10634. CIONGA, E., AND C. ILIESCU,Ber., 74B, 1031-4 (1941). COUCH, J . F., J . Am. Chem. Soe., 58, 684-5 (1936). DAVIDSON, W. M., J. Econ. Entomol., 22, 22634 (1929). DIIRRELL,L. W., AND I. E. NEWSON, Cola Em. Sta. Bull., 429,35-6 (1936).
(13) GLOVER,G. H., Cola. Aqr Ezp. Sta. Bull., 113, 10-19 (1906). J. A,, J. Chem.Soe., 13941 (1943). (14) GOODSON, J. A., ibid., 108-9 (19441. (15) GOODSON, J . A., ibid., 665 (1944). (16) GOODSON, J. A., ibid., 245-6 (1945). (17) GOODSON, (18) GRAY'S"New Manual of Botany," 7th ed., American Book Company, Inc., New York, 1908, pp. 405-6. (19) HALL,H. M., AN? H. S. YATES,Calif. APT.Ezp. Sta. Bull., 249 IlSI51. ~- --,, (20) HALSTEAD, B. H., iV. J. Agr. Ezp. Sta. Bull., 135,24 (1899). T. A., "The Plant Alkaloids," The Blakiston Com(21) HENRY, pany, Philadelphia, 1939. (22) HEYL,F. W., F. E. HEPXER,AND 8. K. LOT,J. Am. Chem. Soc., 35,881t5 (1913). (23) HEYL, G.,Siiddeut. Apoth. Zt., 43, Nos. 2&30 (1903); Chem. Zentr., I, 1187-8 (1903); J . Chem. Soe., 84, 650 (19031. . ~~~, (24) HUNTER,M. V., Chemist and Druggist, 139, 304 (1913); Phann. J., 150, 82, 95 (1943); Quad. J . Pharm., 17, 302 (1944). W. A., AND L. C. CRAIG,J. Biol. Chem., 127,361-6 (25) JACOBS, (1939); 128, 4 3 1 1 (1939); 136, 303-21 (1940). W. A., AND L. C. CRAIG,ibid., 141, 67-84 (1941). (26) JACOBS, R., AND H. JANECKE, Arch. Pharm., 278, 156-62 (27) JARETZKY, (1940); Chem. Abstracts, 35, 2271 (1911). C., Inaugural Dissertation, University of (28) KARL-~m~anow, Dorpet (1889); Schweiz. Woehschr., 28, 287-9; Pharm. Z. Russ., 29,628-30,641-8,657-64,673-8.689-92,705-8, 721-6 (1890); Chem. Zentr., 11,625-6 (1890); J. Pha~m., (5) 23, 302-6 (1891); J. Chem.Soc., 60, 842-3 (1891). . 263, 274-93 (1925). (29) KELLER,O., A ~ e h Pharm., W. E., Ore. Agr. Ezp. St. Bull., 187, 1 1 4 (30) LAWRENCE, (1922). . . (31) LOY, S. K., F. W. HEYL,AND F. E. HEPNER,Wuo. AT. Ezp. Sta. Brd A m . Repl., pp. 73-9 (1913). R. H. F., Can. J. Research, 16B, 57-60 (1938). (32) MANSKE, >, L. N., J. Am. Pharm. Assoc., 13, 696-702 (34) MARQUIS,Arch. ezp. Path. Pharmakol., 7, 55-80 (1877); Pharm. Z. Russ., 16, 449-59, 481-92, 513-22 (1877); Jahresber. Pha?., 89&7 (1877). (35) MARSH,C. D., U.S . Dept. Agr. Bull., 1245, 7-12 (1924). AND H. MARSH,ibid., 365 (36) MARSH,C. D., A. B. CLAWSON, (1916). ~-.-.,.
"The Merck Index," 5th ed., Merck & Company, Rahhway, N. J., 1940,pp. 1899,310,529. "Merck's 1907 Index." 3rd ed.. Merck & Com~anv. . .,New York, 1907, pp. 163, 166. MUENSCHER, W. C., "Poisonous Plants of the United States," The Macmillan Company, New York, 1939, pp. 79-8 L (40) "The National Formulary," 6th ed., Am. Pharm. Assoo., Washington, 1935, pp. 402-3. G. A,, "Delphiniums," The Miacmillan Company, (41) PHILLIPS, New York, 1933 (42) RABINovrca, M. S., AND R. A. KONOVALOYA, R. A,, J . Gm. Chem. U. S . S . R.. 12, 321-8, 329-36 (1942); Chem. Abst~acts,37,3097 (1943). (43) SIMPSON,A. W., AND H. E. MALMSTEN, Calif. Agr. Ezp. Sta. Bull., 593 (1935). H. T., AND N. A. PATTERSON, Sei. Agr., 21,776-82 (44) STULTZ, (1941); Chem. Abstracts, 35, 7634 (1941). R. B., AND H. G. SIFTON,"A Guide to the (45) TH~MSON, Poisonous Plants and Weed Seeds of Canada and the Northern United States," University of Toronto Press, 1922, pp. 5 6 9 . (46) "U. S. Dispensatory," 22nd ed., J. B. Lippinoott Company. Philadelphia, 1937, pp. 389-90. (47) WHITE,J. C., "Dermatitis Venenrtta," Cupples & Hurd, Boston, 1887, pp. 119-20. (48) WILLIAMS, J. B., Am. J. Pharm., 86,414-6 (1914).
