The Natural Production of Chlorinated Compounds - ACS Publications

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η 1968, F o w d e n wrote that "present information As s h o w n in Table 1, the n u m b e r of k n o w n natural suggests that organic c o m p o u n d s containing coorganohalogens has increased dramatically since 1968, valently b o u n d halogens are found only infre a n d t h e c u r r e n t n u m b e r of i d e n t i f i e d c o m p o u n d s quently in living organisms" (2). Although this stands at about 2000 (5). Consequently, this review pro observation was u n d e n i a b l e 25 years ago, it is vides a very limited glimpse of this fascinating field of nothing but a myth today. natural products. Some 2000 Occurrence chlorinated ES&T FEATURES a n d other haloSimple alkanes and genated chemi related compounds. cals are dis The simplest natural charged into organohalogen com our b i o s p h e r e by pounds—halogenated plants, marine organ alkanes—are a b u n d a n t isms, insects, bacte on our planet (Table 2). ria, fungi, a n d m a m C h l o r o m e t h a n e is pro m a l s , a n d by o t h e r d u c e d by marine algae natural processes. En (10), g i a n t k e l p (22), zymatic, thermal, a n d wood-rotting fungus other natural pro (12), the ice plant (20), cesses are constantly cultivated m u s h r o o m s occurring in the (23), the pencil cedar oceans, in the atmos (24), the evergreen cy phere, and in the soil press (24), several that lead to the forma Fomes fungi (25), a n d t i o n of c h l o r i n a t e d p h y t o p l a n k t o n (26). phenols and myriad C h l o r i d e i o n is n o r other chlorinated mally present in plants, chemicals, including w o o d , soil, a n d miner dioxins and CFCs, als (22, 14), a n d their that p r e v i o u s l y w e r e c o m b u s t i o n inevitably thought to result only leads to the formation from t h e a c t i o n s of of organochlorine com h u m a n s . It is c l e a r p o u n d s . Consequently, that these natural pro forest fires (2 7); brush cesses have been pro and vegetation burning ducing chlorinated (28); and volcanoes (24, c o m p o u n d s a n d have 19, 20), i n c l u d i n g t h e b e e n a vital c o m p o e r u p t i o n s of M t . St. nent of our ecosystem Helens (22) and for eons. K i l a u e a [22), all p r o duce significant and, in C h l o r i n e is in t h e some cases, massive political and environ q u a n t i t i e s of c h l o r o m e n t a l spotlight (2), m e t h a n e . This global and an aggressive emission rate of chloro campaign by the envi m e t h a n e from t h e ma ronmental organiza rine a n d terrestrial biotion G r e e n p e a c e to mass is 5 million tons ban s u m m a r i l y all per year [23), w h e r e a s production and uses a n t h r o p o g e n i c chloro of chlorine (and bro m e t h a n e emissions are mine) is u n d e r way. only 26,000 tons per The field of organoyear (22). Several other halogen natural prod simple haloalkanes ucts has blossomed, also have natural a n d the first "Interna sources (Table 2). tional Conference on G O R D O N W. GRIBBLE Naturally Produced In a d d i t i o n to t h e Organohalogens" was simple one- and twoDartmouth College, Hanover, NH 03755 held last year in The carbon halogens (Table N e t h e r l a n d s (3). Not 2), n u m e r o u s h a l o g e only are naturally oc nated alcohols, ketones, curring organohalogen c o m p o u n d s ubiquitous in our carboxylic acids a n d amides, aldehydes, epoxides, and e n v i r o n m e n t , b u t c o n c e n t r a t i o n s of s o m e of t h e s e alkenes have also been isolated a n d characterized from chemicals exceed their anthropogenic levels. Although marine algae [24-26). Indeed, nearly 100 different chlo myriad examples of chlorine-, bromine-, iodine-, and rinated, brominated, a n d i o d i n a t e d c o m p o u n d s have even several fluorine-containing natural products exist been found in Asparagopsis taxiformis, the favorite ed (4), the present review focuses principally on organoible seaweed of most Hawaiians [24). The following are chlorine c o m p o u n d s . samples of those chlorinated c o m p o u n d s (p. 312A):

The

Natural

Production of

Chlorinated Compounds

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Environ. Sci. Technol., Vol. 28, No. 7, 1994

0013-936X/94/0927-310A$04.50/0 © 1994 American Chemical Society

The simple marine haloalkanes, such as chloroform and bromoform, could arise from in vivo haloform reactions, a mechanism that may enable algae, for example, to secrete continuously these "antipredator" chemicals [24, 27). Volcanoes produce large quantities of both hydrogen chloride (up to 3 million tons per year) and hydrogen fluoride (up to 11 million

tons per year) [14, 28). It has been proposed that HC1 and HF can react with organic compounds to prod u c e o r g a n o h a l o g e n s [28). Although the quantities may be small compared with anthropogenic levels, several chlorofluorocarbons (CFCs) have been detected in volcanic gases from the Santiaguito volcano in Guatemala (29) and the Kamchatka volcanoes in Siberia [14). It is estimated that 75% of the world's 500—700 active volcanoes are capable of producing CFCs [14). The CFCs and compounds below show the organochlorines produced by these volcanoes. CFCI3 (Freonll) CF2C12 (Freon 12) CHF2C1 CHFC12

Crî2Cl2

CH3CCI3

F 2 C=CF 2 FC1C=CF2 CC12FCC1F2 (Freon 113) C12C=CC12

C12C=CHC1

The concentrations of these chemicals as measured in and around the solfataric vents of the Kamchatka volcanoes range from 0.4 ppb to 160 ppb of CFCs. Deep drill wells (one mile or deeper) are also a source of several organochlorine compounds and CFCs [14). Terpenes and related compounds. Terpenes are ubiquitous in terrestrial organisms and are essential for life, but marine terpenes were not discovered until 1955, and halogenated marine terpenes were

Naturally occurring organohalogen compounds (structures below are identified by number in the text)

312 A Environ. Sci. Technol., Vol. 28, No. 7, 1994

first isolated only in 1963 (29-31). Examples of chlorinated terrestrial terpenes were first reported in 1969 [32). Since then, there has been a veritable explosion of activity, and a legion of new chlorinated and brominated terpenes has been isolated and identified (30, 31, 33, 34). Notably, the red algae Laurencia and Plocamium have provided a rich and diverse assortment of chlorinated and brominated terpenes over the past 25 years (structures 1-6). Nearly 20 chlorinated diterpenes and one tetraterpene have been isolated from several soft corals (3539). An example of the structural complexity of these compounds is erythrolidé C (Structure 7) (38). Another very large group of halogenated organic compounds is the

"nonterpenes," compounds that do not arise from an obvious terpenoid pathway. The Guam "bubble shell" (Haminoea cymbalum) contains kumepaloxane (Structure 8) (40), a feeding-deterrent chemical that is discharged when this mollusk is disturbed by unwelcome carnivorous fishes. Marine red algae, especially Laurencia, are a source of fantastically complex nonterpenoid chemicals. Thus, L. implicata has yielded six new cyclic ethers, some of which are aliènes (e.g., Structure 9) (41, 42). Nostoc blue-green algae are recognized as a threat to human health when they infest drinkingwater sources (43, 44). Cultivation and extraction of Nostoc linckia have yielded four unusual chlorinated paracyclophanes, for exam-

ple, nostocyclophane D (Structure 10) (45). Amino acids and peptides. With the exception of the naturally occurring iodinated tyrosines such as thyroxine, there are relatively few examples of halogenated amino acids and simple peptides. The marine sponge Dysidea herbacea contains four novel trichloromethyl metabolites, i n c l u d i n g d y s i d i n ( S t r u c t u r e 11) a n d d y s i d e n i n (Structure 12) (46-50). Several Streptomyces and Pseudomonas spp. contain chlorinated amino acids and/or peptides, many of which have potent antibacterial activity. For example, Streptomyces griseosporeus produces γ-chloronorvaline (Structure 13) (51), a n d Streptomyces viridogenes


313 A

TABLE 1

The number of naturally occurring organohalogen compounds TABLE 1 Year Reviewer

Summary

Reference

1968

Fowden

30 organochlorine natural products and a few containing bromine, iodine, and fluorine

1

1971

Turner

70 fungal metabolites containing chlorine

6

1973

Siuda and DeBernardis

200 organohalogen compounds from all sources (150 organochlorine, 50 organobromine)

7

1983

Turner and Aldridge

80 new fungal metabolites containing chlorine

8

1986

Engvild

130 organochlorines from higher plants

9

1992

Gribble

611 new organohalogen compounds from all sources isolated between 1980 and 1991

3

yields Structure 14 (52). Alkaloids. Although terrestrial plant alkaloids have been scruti nized by chemists for more than a century, very few of these nitrogen compounds contain halogen of any kind. Recently, oxypterine (Struc ture 15), a dichlorinated pyrrolizidine derivative, was found to be present in the herb Lotononis oxyptera [53), and a Streptomyces sp. produces clazamycin A (Struc ture 16) and Β (54-56). Steroids. Steroids rarely contain halogen. However, a few examples of chlorinated steroids are found in the plants Withania somnifera, Acnistus breviflorus, Physalis peruvi ana, and Jaborosa magellanica, such as jaborochlorodiol (Structure 17) [57). The first three examples of chlorinated marine steroids—kiheisterones C, D, and Ε—were re cently characterized from the Maui sponge Strongylacidon sp. (58). Fatty acids, prostaglandins, and lipids. Although fluoroacetic acid and fluoro-fatty acids in certain ter restrial plants have been known for many years (59, 60), chloro-fatty ac ids were unknown until recently. The edible jellyfish and the white sea jellyfish (Auritia aurita) contain six fatty acid chlorohydrins (61). Mammalian prostaglandins are of paramount importance in the regu lation of physiological processes. Therefore, it was of enormous inter est when chlorinated prostaglan dins were discovered in the octocoral Telesto riisei (62) and in the stolonifer Clavularia viridis (63), a marine animal. A total of eight novel chlorinated prostaglandins have been identified [e.g., punaglandin 1 (Structure 18)] (62), some of which have potent antitumor ac tivity (63). The marine brown alga 314 A

Egregia menziesii produces three prostaglandin-like chlorinated oxylipins, for example, egregiachloride A (Structure 19) (64). Of some 22 freshwater algae species that were examined for chlorosulfolipids, all but one contained quantities of these novel lipids (65, 66). Pyrroles. The pronounced reac tivity of pyrroles in electrophilic substitution reactions endorses the observation that chlorinated and brominated pyrroles are found widely in nature. Following the iso lation in 1958 of pyoluteorin (Struc ture 20), a new antibiotic from Pseudomonas aeruginosa (67), nu merous additional natural chlori nated and brominated pyrroles have been discovered. The soil microbe Streptomyces sp. produces pyrrolomycin Β (Structure 21) (68), and a soil Streptomyces sp. produces the novel neopyrrolomycin (Structure 22), a metabolite that has biphenyltype optical activity (69). Many of the pyrrolomycins have strong anti biotic activity, and a clinical drug from this structural type seems to be a real possibility. Indoles. The indole ring system has the distinction of being embod ied in the indigo derivative Tyrian purple, the ancient Egyptian dye ex tracted from mollusk shells and the focus of a significant industry in Mediterranean countries (70). The marine acorn worm Ptychodera flava laysanica produces the unsta ble 3-chloroindole (Structure 23) and 3-chloro-6-bromoindole com pounds that are responsible for the peculiar "iodoform-like" odor of this animal (71). The 4-chloroindole ester (Structure 24) and the corre sponding carboxylic acid are found in Pisum sativum and several other terrestrial plants (lentil, sweet pea,


sea pea, vetch) (72, 73). Like 3-indoleacetic acid, these compounds function as very strong plant growth hormones. A blue-green alga, Hapalosiphon fontinalis, contains 12 c h l o r i n a t e d i s o n i t r i l e s , one of which is hapalindole A (Structure 25) (74). The deep water Bahamas sponge Batzella sp. produces six chlori nated indoles, e.g., batzelline A (Structure 26) (75), and nature's vir tuosity in organic synthesis is fur ther revealed by the marine bryozoan Chartella papyracea, which constructs a complement of five halogenated indoles, such as chartelline A (Structure 27) (76-78). Miscellaneous heterocycles. Some interesting halogenated thiophenes are found in certain plants. For ex ample, Pterocaulon virgatum con tains five chlorinated thiophenes (79), and six species of Echinops are found to contain Structure 28 (80). Only a few examples of nucleic acid bases are known to contain halogen. An Actinomyces sp. produces 2 ' chloropentostatin (Structure 29) (81, 82). The first example of a chlo rinated porphyrin was recently iso lated in trace quantities from cul tures of two Pseudomonas spp. (83), and 2-chloropyridine is embodied both in the potent enediyne antitu mor agent kedarcidin (84) and in the novel Ecuadoran poison frog metabolite (Structure 30), which is secreted by several species of Epipedobates and which has powerful analgesic activity (85). Aromatic compounds. Although most of nature's chlorinated aro matic rings are phenolic, a few ex amples of simple chlorinated aromatics are known. The Mississippi salt marsh "needlerush" (/uncus roemerianus) contains 1,2,3,4-tetrachlorobenzene (86). A careful study of the ash from the 1980 eruption of Mt. St. Helens has revealed the pres ence of chloroaromatics (Structures 31 and 32), and, more surprisingly, three previously unknown isomers of pentachlorobiphenyls (PCBs) (Structure 33). The nature of the PCB isomers is not what would be expected from industrial PCBs (87). This landmark observation repre sents the first (and only) discovery of natural PCBs. The authors sur mise that rapid, incomplete hightemperature combustion of chlo ride-containing plant material in the eruption zone led to these chlo rinated aromatics, as well as to chloromethane. Plants typically contain 200-10,000 ppm of chloride ion (12). Another unusual discovery is

TABLE 2

Biogenic sources of simple haloalkanes Compound

Sources

CH3CI

Marine algae, giant kelp, wood-rotting fungus, ice plant, cultivated mushrooms, white cedar, pencil cedar, evergreen cypress, fungi, phytoplankton, forest fires, bush burning, volcanoes, tobacco smoke Oceans, marine algae, giant kelp, volcanoes Oceans, marine algae, volcanoes Marine algae, white cedar, lemon, orange, moss, barley, volcanoes, drill wells Marine algae, oceans Marine algae, oceans, volcanoes, drill wells Volcanoes, barley Marine algae Marine algae Marine algae Marine algae, oceans Marine algae, oceans Marine algae Marine algae, oceans Marine algae Marine algae, oceans Marine algae Marine algae Marine algae Marine algae Marine algae Marine algae Oceans, volcanoes Oceans, volcanoes Oceans Volcanoes Volcanoes, drill wells Volcanoes Volcanoes Volcanoes Volcanoes Volcanoes Volcanoes

CH3Br CH3I CHCI3 CHBr3 CCI4 CH2CI2

CBr4 CH2CIBr CH2CII CHBrCI2 CHBr2CI CH2Br2l CH2I2

CHI3 Gr^Bf^ Ο Η3Ο rlgfcîr CH3OH2I

BrCH2CH2l CH2Brl CHBrlCI CHBrl2 CI 2 C=CHC CI 2 C=CCI 2 CH3CCI3

CHFCI2 CFCI3 CF2CI2 CHF2CI CHFCI2 F 2 C=CF 2 FCIC=CF 2 CCI2FCCIF2

that an unidentified deep-sea gorgonian, collected at a depth of 350 m, exudes haloazulenes (Structure 34) [88). Phenols and phenolic ethers. A number of chlorinated tyrosine derivatives have been isolated from marine sponges, seafans, and other gorgonians [89-90). These amino acids, w h e n i n c o r p o r a t e d into structural proteins, may stabilize the proteins in the organism by improving the adhesion between protein fibers and sheets [90). The mollusk Buccinum undatum utilizes 3-chloro-5-bromotyrosine (Structure 35) in its structural proteins [90). The isolation of 3,4-dichlorotyrosine, as well as Structure 35, from Limulus polyphemus [91), and of 3-chlorotyrosine from the cuticle of locusts [Schistocerca gregaria)

References 10-20

11, 16, 18,20 11, 14, 16, 18,20 14 24 14 14 24 3 3 3 24 24 3 24 24 3 3 24 24 24 24 19 14 3 14 14, 19 14 19 19 19 19 19

[92), have been reported. Chlorophenols are used industrially on a large scale and have been classified by EPA as Priority Pollutants [93). Surprisingly, several of these and other chlorophenols are produced naturally. The soil fungus Pénicillium sp. produces 2,4-dichlorophenol (Structure 36) [94), and grasshoppers secrete 2,5-dichlorophenol (Structure 37), which is repellent to ants [95). The sex pheromone of the female Lone Star tick [Amblyomma americanum) and several other hard ticks is 2,6dichlorophenol (Structure 38) [96, 97). Careful studies in the first and last of these investigations rule out the possibility that these compounds are artifacts. The blue-green alga Anacystis marina contains chlorophenol (Structure 39) [98),

and another Nostoc sp. blue-green alga secretes large quantities of two chlorinated phenolic furanones, nostoclides I and II, into the culture medium [99). The acorn worm Ptychodera bahamensis produces 13 halogenated phenols, including 3,4dichloro- and 3,5-dichlorophenol [100). The "mixed" bromochlorodiphenyl ether (Structure 40) is produced by a marine sponge and accounts for 1.3% of the dry weight [101). It is interesting to note that this compound is a "predioxin" intermediate. The red alga Rhabdonia verticillata produces six bromo/ chloro phloroglucinols [102). Dioxins and related compounds. "Dioxin," 2,3,7,8-tetrachlorodibenzo-p-dioxin (Structure 41), was once generally thought to be the most toxic man-made chemical known [103-105). However, extensive evaluations by epidemiologists of people exposed to dioxin, such as Vietnam veterans [106, 107), inhabitants of Seveso, Italy [the site of a major dioxin release in 1976 [108)], and industrial plant workers [109, 110), have revealed that dioxin is not the "doomsday chemical" once believed [110-112). Nevertheless, the extraordinary toxicity of some polychlorinated dioxins (PCDDs) and related compounds, such as the polychlorinated dibenzofurans (PCDFs) (e.g., Structure 42), in some animals is reason enough for the continued study of these compounds, especially because it is now recognized that PCDDs and PCDFs are, in fact, natural products and are ubiquitous in our environment. The production of chloromethane and other organochlorine compounds when organic material is burned, in association with the omnipresent chloride ion (see above), led to the belief, now supported by evidence, that PCDDs could form during combustion processes [113, 114). Laboratory studies have revealed that PCDDs, including "dioxin" (Structure 42), and PCDFs form in parts-per-billion amounts during the combustion of wood (treated or untreated) [115-118). The relatively poor efficiency and incomplete oxidation when damp vegetation and wood are burned in the presence of high chloride concentrations (70—2100 ppm in wood pulp) [14) are conditions conducive to PCDD formation, and two research groups have concluded that forest and brush fires are the major source of PCDDs and PCDFs in the environment [115, 119). It is estimated that some 130 lb [1 lb =


315 A

0.4536 kg] of PCDDs are produced in Canadian forest fires annually [119). This is 10 times more than the amount formed in the 1976 Seveso plant accident. Because most forest fires are lightning-caused, and there are 200,000 forest fires annually worldwide that burn 27,000 square miles [1 mi = 1.609 km] [14), it is logical to assume that PCDDs have been present in the environment for many centuries. An 1877 soil sample was found to contain PCDDs and PCDFs (220). Another milestone observation is the enzymatic conversion of chlorop h e n o l s into both PCDDs and PCDFs in the parts-per-million range by horse-radish peroxidase enzyme (HRP) (Equation 1) [121). This extraordinary revelation opens the door to the possibility that a source of environmental PCDDs and PCDFs may be their completely natural formation from (natural) chlorophenols by soil and water microbes.

(38 compounds identified; Cl 4 , Cl 5 , Cl 6 isomers dominate; ppm range)

Mechanisms of biogenic chlorination Marine organisms, terrestrial plants, fungi, microorganisms, and mammals all contain haloperoxidase enzymes that can chlorinate, brominate, and iodinate organic c o m p o u n d s in the presence of chloride, bromide, or iodide ions, respectively [122-124). Of 33 species of Phaeophyceae algae from the Atlantic Coast, 22 displayed 316 A

p e r o x i d a s e e n z y m a t i c activity [125), a n d c h l o r o p e r o x i d a s e , which occurs in the mold Caldariomyces fumago, has been extensively studied [126). Soil extracts have been shown to have chlorinating ability [122, 127), and more than 80 species of Death Valley fungi displayed chloroperoxidase activity [122). Peroxidases are present in the thyroid gland of mammals [128). The enzymes chloroperoxidase, HRP, and vanadium peroxidase are capable of chlorinating phenols and phenol ethers (anisole) in the presence of chloride [129, 130). Lactoperoxidase, an enzyme present in mammalian milk [131), is capable of chlorinating organic substrates [129, 131). An electrifying development is the utilization of the halide-peroxidase—hydrogen peroxide chemical system by humans and other mammals to generate active halogen (HOC1, HOBr) in order to destroy microorganisms. Thus, human white blood cells (eosinophils and neutrophils) contain myeloperoxidase, which, in the presence of chloride, bromide, or iodide, and hydrogen peroxide, rapidly forms active halogen, resulting in the death of bacteria and fungi by halogenation reactions [132, 133). It would appear that biohalogenation is an integral component of our immune system! Metabolism and biodégradation Contrary to common perception, organohalogen compounds, both natural and unnatural, are readily metabolized and biodegraded to halide ion by assorted microorganisms. The simple organochlorines CH2C12, CHCI3, CC14, C1 2 C=CC1 2 , and others can be degraded to C0 2 (or other simple organics) and chloride by soil bacteria [134). The soil bacterium Pseudomonas putida oxidizes chloro- and other halobenzenes to the cis-diol [135). This is a remarkably general reaction and succeeds even with fluorobenzene. The biodégradation of chlorophenols has been thoroughly studied. For example, 2,4-dichlorophenol is rapidly metabolized in soils (236), and an exhaustive mechanistic study of the degradation of this compound to chloride and C0 2 by the white-rot fungus Phanerochaete chrysosporium has been reported [137). This versatile and remarkable fungus is capable of degrading other chlorinated phenols (2 38), DDT (239), pentachlorophenol (240), and PCBs(242).


Natural versus anthropogenic organohalogen compounds Chloromethane is overwhelmingly biogenic in origin. But what about the relative quantities of the other natural organochlorines and organohalogens vis-à-vis the approximately 20 million tons per year of 150 industrial organohalogens currently in use worldwide (222, 242)? A detailed study of the acorn worm Ptychodera flava has revealed that a known population of these animals (64 million) excrete in their fecal matter 95 lb of organohalogens daily in a 1 km 2 habitat in Okinawa [143). Obviously, many more studies of a similar nature are needed in order to estimate the global quantities of natural organohalogens. Several researchers have reported the identification of halogenated phenolic compounds in ocean waters and in soil extracts (229, 244, 245). The major source of most of these compounds, such as 2,4,6trichlorophenol, is biogenic and from natural halogenation processes such as reactions between humic acid and soil microbes (chloride and chloroperoxidase). Humic acids are present not only in soil, but also in rivers, lakes, and the oceans [146). The yearly net production of environmental humic acid from the decomposition of organic material has been estimated at 63 billion tons (246). This can be added to the estimated existing global 1.0—1.5 trillion tons of soil humic acids and one trillion tons of ocean humic acid (246). Numerous studies have demonstrated the ease with which humic acid model compounds (phenolics) react with chlorine to produce chloroform and other simple organochlorines via chlorophenols [146-148). As we have seen, chloride is ubiquitous in soil, plants (200-10,000 ppm) (22), rivers (average 8 ppm) (2 49), lakes [149), and, of course, oceans [146, 149). These ingredients, in combination with natural chloroperoxidase and other enzymes, provide a plausible rationale for the natural formation of chlorinated phenols. Several studies have demonstrated that the natural production of chlorinated phenols and anisoles outweighs their anthropogenic sources (244, 245). Although a vast number of halogenated compounds have been isolated from natural sources (3), relatively few marine organisms have been examined for their chemical

content. For e x a m p l e , whereas some 12,000 natural products of all types have been isolated from terrestrial plants, only 500 h a d been isolated from marine plants (algae) up to 1987 (150). However, there are some 500,000 k n o w n species of marine a n i m a l s , plants, a n d bacteria (151). For example, there are 80,000 living s p e c i e s of m o l l u s k s (152), 5000 species of sponges (153), a n d 4000 species of bryozoans (moss animals) (154), but only six of the latter have been e x a m i n e d (155). Of m o r e t h a n 90 k n o w n s p e c i e s of deep-sea gorgonians in t h e Hawaiian Islands, only 20 have been investigated for their c h e m i c a l cont e n t (156), a n d , of 1 3 Mycale sponges living in the Mediterranean Sea, only one has been investigated (157). The list goes on. The enormous diversity of marine life and, hence, of potential new organochlorine c o m p o u n d s , is epitomized by t h e Great Barrier Reef. This 100,000-mi 2 area consists of 2500 separate small reefs. Around just o n e of t h e s e , of less t h a n 14 square miles, there have been identified 930 species offish; 107 corals; and 154 u r c h i n s , cone shells, a n d other mollusks (158). Given s u c h diversity a n d magnitude of biological species, it is indisputable that a large number of unique organochlorine c o m p o u n d s will be isolated and identified from ocean life, to say nothing about t h e novel chlorinated and other halogenated compounds waiting to be discovered in terrestrial plants, animals, bacteria, fungi, and perhaps even h u m a n s . Indications are that organohalogen c o m p o u n d s have been with us for centuries. For example, halogenated fulvic acids have been isolated from g r o u n d w a t e r s a m p l e s that date back 1300, 4600, and 5200 years (144)1 Organohalogen material was identified in sediments dating back to the 13th century (159). Microfossils in Precambrian rocks, which are a billion years old, are identical to the blue-green alga Nostoc, and other microfossils are morphologically indistinguishable from Oscillatoria, t w o present-day species rich in o r g a n o h a l o g e n compounds (160). Function of natural organohalogens Why does nature create organochlorine c o m p o u n d s ? Many marine a n d terrestrial o r g a n i s m s u s e organochlorine and other organohalogen c o m p o u n d s in c h e m i c a l d e fense—feeding deterrents, irritants,

or pesticides—or in food gathering (161-164). A recent, careful study of t h e sea hare Stylocheilus longicauda clearly indicates a feeding deterrent role for its organohalogen c o m p o u n d s (165). T h e sea hare Aplysio brasiliana is distasteful to fish a n d rejected by sharks in part because of its p a n a c e n e , a bromin a t e d a l i è n e (266). M a r i n e algae store organohalogen c o m p o u n d s in the vesicular cells for facile secretion to discourage predators (27, 167), a n d t h e terrestrial blue-green alga Fischerella ambigua secretes into t h e m e d i u m t w o c h l o r i n a t e d phenols that show antibacterial, antifungal, a n d molluscicidal activity (168). T h e marine algae metabolite telfairine (Structure 5) is 1 0 0 % lethal to mosquito larvae at 10 p p m (169), a n d t h e related chlorinated monoterpene plocamene Β is three times more effective than the com mercial pesticide Lindane against mosquito larvae (170). An organobromine c o m p o u n d with natural ins e c t i c i d a l p r o p e r t i e s (against t h e cotton boll weevil) was recently iso lated from the Thai plant Arundo donax (171), a n d t h e coral Tubastraea micrantha secretes t w o organobromine c o m p o u n d s that deter the destructive crown-of-thorns sea star from feeding (172). Recently, it was found that t h e German cock roach (Blattella germanica) utilizes two chlorinated steroid glycosides, blattellastanosides A a n d B, as ag gregation pheromones (173). One very attractive hypothesis is that n a t u r a l o r g a n o h a l o g e n com p o u n d s play an essential role in the survival of t h e organism, a n d t h e

ability of the organism to synthesize such c o m p o u n d s for chemical de f e n s e a n d food g a t h e r i n g h a s evolved over time under the stress of natural selection (174). Conclusion The continued improvements in isolation, purification, a n d spectro scopic techniques ensure that even the most structurally intricate orga nohalogen natural products will be identified. W i d e s p r e a d antibiotic, antitumor, antifungal, insecticidal, herbicidal, and other potentially valuable biological activities have been observed w i t h these natural chlorinated chemicals. As o u r u n d e r s t a n d i n g of b i o h a l o g e n a t i o n progresses, it will be possible to dif ferentiate and quantify more accu rately t h e n a t u r a l a n d a n t h r o p o g e n i c s o u r c e s of h a l o g e n a t e d chemicals. References (1) (2) (3)

(4) (5) (6) (7) (8)

(9) (10) (11) (12) (13) (14)

(15) (16)

Gordon W. dribbla is a professor and former chairman of the Department of Chemistry at Dartmouth College. He re ceived his B.S. degree from the Univer sity of California-Berkeley and his Ph.D. from the University of Oregon. After a year at UCLA as a National Cancer Insti tute Postdoctoral Fellow, he joined the faculty of Dartmouth College in 1968. His research interests include the syn thesis and isolation of biologically ac tive natural products, heterocyclic chemistry, and environmental organic chemistry.

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