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Acc. Chem. Res.

1998, 31, 141-152

Naturally Occurring Organohalogen Compounds†
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 Received August 12, 1997

Once considered to be rare chemical freaks of nature or artifacts formed during isolation, naturally occurring organohalogen compounds in recent years have assumed an important role both in the field of natural products per se and in the drama of global halogen burdens visa-vis their anthropogenic counterparts.1-3 The number ´ of natural organohalogen compounds has multiplied about 250 times in the past 40 yearssfrom a dozen in 19544 to more than 2900 as of December 1997.1,5 This explosion of information parallels the general resurgence of natural products discovery that is due to improved collection and isolation methods, the development of 2D NMR spectroscopy, advances in mass spectrometry, new and more sensitive bioassays, and the perpetual need to find new medicinal leads. Since it is obviously impractical to describe all natural organohalogens in this Account, only the most interesting and biologically important compounds will be presented, with emphasis on recent examples. Most of the compounds chosen herein have not appeared in our comprehensive review,1 and the few exceptions can be found in ref 1. Halogen-containing examples from nearly every organic chemical class are known; equally diverse are the organisms that biosynthesize these structurally and biologically extraordinary chemicals.

aureomycin, caldariomycin, sporidesmin, ochratoxin A, and others. The fungus Mollisia ventosa produces several organochlorine calmodulin inhibitors such as KS-504d (1), which contains 70% chlorine by weight! The lichen Nephroma laevigatum has yielded 2,6 and falconensin E (3) from the Venezuelan soil fungus Emericella falconensis is one of several chlorinated azaphilones that have potent inhibitory activity against diacylglycerol acyltransferase and acyl-CoA: cholesterol acyltransferase.7 The fungal pathogen Periconia circinata, which causes “milo disease” of grain, produces periconin B (4) as one of four chlorinated metabolites.8 The mushroom Russula subnigricans contains a number of chlorohydroquinones (e.g., russuphelol (5)),9 and the wood-rotting forest fungus Lepista nuda produces 14 organohalogens including several brominated phenols (e.g., 6).10

Sources and Structures
Fungi and Lichen. Fungi and lichen, the latter of which are symbionts consisting of a fungus and an alga living together in a united structure, are a bountiful source of novel organochlorine metabolites, and the earliest examples of natural chlorine-containing metabolites include fungal metabolites such as griseofulvin, chloramphenicol,
Gordon W. Gribble was born in San Francisco, CA, and attended San Francisco City College and the University of California, Berkeley, for his undergraduate training. Early exposure to organic chemistry from John E. Booher and Andrew Streitwieser, Jr., continued at the University of Oregon with Lloyd J. Dolby, under whose guidance he received a Ph.D. in indole alkaloid chemistry in 1967. He was a National Cancer Institute postdoctoral fellow at UCLA with Frank A. L. Anet and has been at Dartmouth since 1968. Apart from his scholarly interest in naturally occurring organohalogen compounds, his research program focuses on heterocyclic chemistry and the synthesis of biologically active natural products, and he has published more than 150 papers in these areas. As an amateur winemaker, he also has a strong interest in the chemistry of wine and winemaking.
S0001-4842(97)00177-5 CCC: $15.00 © 1998 American Chemical Society Published on Web 02/18/1998

Bacteria. Streptomyces sp. bacteria produce an incredible array of complex metabolites, many of which contain halogens. Chloropeptin I (7), which inhibits HIV replication, is produced by Streptomyces sp. WK-349,11 and Streptomyces rugosporus has furnished the antibiotic pyrroindomycin B (8), which is active against both penicillin-resistant Staphylococcus aureus and vancomycinresistant Enterococci.12 The glycopeptide antibiotic vancomycin (9), which is produced by Amycolatopsis orientalis, has been used for 40 years to treat life-threatening infections. More than 40 Streptomyces species have
† Offered in memory of Professor Karen E. Wetterhahn, 1948-1997, revered colleague, respected teacher and administrator, and eminent researcher, who left us too soon. * E-mail: Fax: (603) 646-3946.



marine algae and giant kelp. Relatively few plant metabolites contain halogens. joining nicotine. is not converted to 15 under the isolation conditions. CH3CH2I. the Thai plant Arundo donax produces 16. from Physostegia virginiana ssp. and others. This red alga has yielded nearly 100 organohalogen compounds. potato tubers.1 In the latter instance. CH2ClI. 142 ACCOUNTS OF CHEMICAL RESEARCH / VOL. and the pyrethrins. CHI3. and wood-rotting fungi. and one of the more interesting is the enediyne C-1027. including many lachrymatory haloacetones and related metabolites. CH3CH2Br. and fava bean. the epoxide corresponding to 15. CBr4. CHClBr2. CHCl2Br. CHClBrI. which repels weevils. virginiana.” It seems likely that the “smell of the ocean” is due to this potpourri of volatile halocarbons. vetch. CH2Br2. 1998 Remarkably. CH2ClBr. Plants. A myriad of a simple haloalkanes have been isolated from marine algae: CH2Cl2. CHBrI2.17 and. sweet pea. 3. . CHBr2I. the chromophore of which is shown in 10. both macro and micro. NO. chloromethane appears to play a key role in the degradation of wood lignin by acting as a methyl donor in the biosynthesis of anisoles.16 Although organobromines are rare in terrestrial life. the ice plant. Such compounds probably number more than 1000. both of which were isolated from the Brazilian plant Vellozia bicolor. are truly astounding. as shown either by direct sampling of the plant material or by subjecting the corresponding epoxide to the isolation protocol.1 Bromoform (CHBr3) is the major (80%) constituent. a bryozoan. CCl4. CHBr3. CH3I. CH3CH2CH2Br. The array and diversity of organohalogen compounds that are produced by marine algae.20 The authors of this latter study conclude that “the measured rates suggest that emission of trichloroethylene and perchloroethylene from the oceans to the atmosphere may be of such a magnitude that it cannot be neglected in the global atmospheric chlorine budget. For example.14 and stegioside I (14).Naturally Occurring Organohalogen Compounds Gribble yielded organohalogen metabolites. BrCH2CH2I. Parsley and other plants contain the psoralen saxalin (12). CH2BrI.15 Chlorohydrins such as 13 and 14 are usually not artifacts of the isolation process. The favorite edible seaweed of native Hawaiians is “limu kohu” (Asparagopsis taxiformis).18. CHCl3. lentil. CH3Br.13 Chlorochrymorin (13) is found in Chrysanthemum morifolium. 16 appears to be another natural plantproduced insecticide. is one of 15 chlorine-containing iridoids. Marine Plants. CH2I2. 31. A notable exception is the plant growth hormone 4-chloroindole-3-acetic acid (11) and its methyl ester which are produced by green peas. chloromethane is produced by evergreen trees. mushrooms.19 and the dry-cleaning solvents trichloroethylene and tetrachloroethylene are produced by at least 27 species of marine algae.1 The commercial fumigant BrCH2CH2Br is made by antarctic macroalgae. grass pea. cocaine.

30 Blue-green algae (cyanobacteria) yield organohalogen compounds. are produced by the blue-green alga Nostoc linckia. 27.g.25 one of a large number of nonterpene-C15 acetogenins found in Laurencia red algae. 31. and a drug candidate seems highly probable. is a potent insecticide resembling the commercial pesticide lindane in toxicity and structure. e.Naturally Occurring Organohalogen Compounds Gribble Numerous halogenated monoterpenes are produced by marine algae.31 Marine Sponges.g.22 Telfairine (19). A series of nostocyclophanes. and Fischerella ambigua contains the HIV reverse transcriptase inhibitor ambigol A (30). Monoterpene 20 from Portieria hornemannii has very pronounced anticancer activity against human cancer cell lines and was started in preclinical development. which was identified in Plocamium telfairiae. and Laurencia viridis from the Canary Islands has yielded five such brominated triterpenoids such as 15.26 The terrestrial blue-green alga Fischerella muscicola and other cyanobacteria produce more than 20 indole isonitriles. These prolific and versatile algae are the source of several squalene-derived organohalogen metabolites. 3. 28. Aplysia californica. which feeds on the algae containing these monoterpenes. which were actually isolated in 1973 from a sea hare. one of which is the highly toxic brominecontaining aplysiatoxin believed to be the cause of “swimmer’s itch” in Hawaii. which is a potent fish toxin. such as hapalindole A (29).27 as was barbamide (26)28 from the Curacao species.1 The nucleoside kumusine (32) is found in both Theonella sp. majapolene (21).16-dehydrovenustatriol (23). Several such metabolites are produced by Lyngbya majuscula.33 The unusual trichloromethyl herbamide A (33) is found in VOL. and the first such compounds were 17 and 18.24 and the Vietnamese Laurencia pannosa has yielded pannosallene (22).g.32 and Trachycladus laevispirulifer. NO. are found in cultures of a Nostoc sp. More than 40 species of red algae of genus Laurencia have yielded hundreds of halogenated terpenes. An Australian Lyngbya sp. majuscula. The Philippine Laurencia majuscula contains 13 novel halogenated sesquiterpenes. The phylum Porifera contains those animals commonly called sponges. e. and malyngamide I (25) was isolated from L.21 Such a “procured” chemical defense is apparently common in marine life. e.23 containing cryptophycins.29 Some of these latter compounds have unprecedented anticancer activity against solid tumors. which frequently have potent biological activity. and at least 18 chlorine- The red tide alga Prymnesium parvum produces the incredibly complex prymnesin-2 (31). contains 24. and a mind-boggling collection of diverse halogen-containing sponge metabolites is known. 1998 / ACCOUNTS OF CHEMICAL RESEARCH 143 .

and 144 ACCOUNTS OF CHEMICAL RESEARCH / VOL.37 Brominated pyrroles are plentiful in sponges. is one of three such metabolites produced by the lithistid sponge Callipelta sp. 3.43 Dysidea herbacea. one of two bromine-containing antazirines from the Pohnpei sponge Dysidea fragilis.41 and psammaplysin F (40) from Aplysinella sp. which contains a chlorocyclopropane. is one of many transformed brominated tyrosines found in sponges.36 and the highly congested palau’amine (36).38 The cytotoxic macrolide callipeltoside A (38).39. such as bastadin 20 (41).45 The . organoiodine is rarely found in nature and fewer than 100 examples are known.1. is found in Stylotella agminata.5 The sponge Cymbastela sp.44 and the Senegalese sponge Ptilocaulis spiculifer contains dakaramine (43). recently isolated from Ianthella basta.35 The latter compound might be viewed as a “pre-dioxin” since such in vitro enzymatic transformations are known (vide infra). has afforded geodiamolide G (42). The quinolizidine halichlorine (35) has been characterized from Halichondria okadai.34 a sponge genus known to produce both trichloromethyl metabolites and polybrominated diphenyl ethers such as 34.42 Another group are the bastadins. which is cytotoxic and immunosuppressive.Naturally Occurring Organohalogen Compounds Gribble mauritiamine (37) is an antifouling compound produced by Agelas mauitiana that prevents the overgrowth of the barnacle Balanus amphitrite. NO. 1998 Apart from the iodine-containing thyroid hormones.40 Another unusual metabolite is 39. 31.

Nudibranchs. are among the most potent substances screened in the National Cancer Institute panel of 60 human cell lines. are active at the nanograms per milliliter level against both P388 and KB cancer cells.52 The macrolide spongistatins. e. which is a potent feeding deterrent. Ironically.49 These compounds. 31. can apparently “steal” their chemical arsenal by feeding on sponges.46 Lissoclinum voeltzkowi. e. 3. which are the first organochlorines to be isolated from Urochordata. vinyl chloride itself is a well-known human liver carcinogen. The Caribbean mangrove ascidian Didemnum conchyliatum produces four didemnimides.54 The venomous cone snail Conus imperialis produces two toxic peptides which contain a 6-bromotryptophan amino acid.56 Ascidians. VOL.53 and Diaulula sandiegensis secretes nine chloroacetylenes as chemical defensive agents.51 and the novel nucleoside 50 is produced by Didemnum voeltzkowi. are closer evolutionary to humans. These brightly colored marine animals. e. one of which (49) contains the rare amino acid enduracididine.47 The chlorine atom seems to be important for activity. and the African sponge Spirastrella spinispirulifera. These filter feeders may be solitary or colonial but. are in the phyllum Mollusca (class Gastropoda) and.g. spongistatin 9 (45). of which the most abundant is 52. five of which contain a chlorovinyl moiety. belong to the subphyllum Urochordata (or Tunicata) of the phyllum Chordata and.g. These marine animals.48 The novel chlorine-containing lissoclimides (47 and 48) are produced by the New Caledonian ascidian Bryozoans. like sea hares. 1998 / ACCOUNTS OF CHEMICAL RESEARCH 145 . often called sea slugs. thus. two of which contain bromine. D (46). These macrolides are found in the Indian Ocean sponge Spongia sp.Naturally Occurring Organohalogen Compounds Gribble Maui sponge Strongylacidon sp. NO. kiheisterone C (44).55 The grazing predatory nudibranchs Tambje eliora and Tambje abdere prey upon and confiscate from the bryozoan Sessibugula translucens the chemical defensive and fish antifeedant tambjamine B (53) (and others). often called tunicates or sea squirts. has yielded three chlorosteroids. like sponges.50 The ascidian Leptoclinides dubuis has afforded three novel brominated indoles.g. This gives new meaning to the phrase “lazy slug”! The African nudibranch Chromodoris hamiltoni contains four chlorinated homo-diterpenes such as hamiltonin C (51). apparently rely heavily on chemical defense for survival. These “moss animals” (phylum Bryozoa ) Ectoprocta) have produced some of the most novel and elaborate organohalogen metabolites from any source.

The Florida Ptychodera bahamensis has furnished 12 different halogenated phenols and hydroquinones. Azulenes 63-65 are found in a deep-sea gorgonian. Corals. and this phenol and 2. 54).g. The German cockroach (Blattella germanica) employs the chlorinated stigmastane steroids blattellastanoside A (68) and B as aggregation pheromones. 3-chloro-.1 The acorn worm Balanoglossus biminiensis produces up to 15 mg of 2. and 3. which synthesizes a stunning array of halogen metabolites. Several bromine-containing benzoquinones are found in Ptychodera flava laysanica. 3-bromo-. Although some hard corals have afforded halogen-containing metabolites. 3.6-dibromophenol per animal.g.57 and Securiflustra securifrons produces seven chlorinated and brominated securamines of great complexity (e. and both 3-bromobenzoic acid and tubastraine (66) are produced by the stony coral Tubastraea micrantha. The beautiful octocoral Telesto riisei. which was featured on the cover of a journal in 1994.6-dibromo-4-chlorophenol and 2-bromo6-chlorohydroquinone.63 is the source of 19 chlorine-containing punaglandins (e. Related chlorine-.g. one of which is chartellamide B (56). and 3-chlorotyrosine occurs in the cuticle of locusts.g.6-tribromophenol are secreted by Phoronopsis viridis. 31... 6-bromo-3-chloro-. some of which have promising anticancer activity. which display differentiation of HL-60 cells. NO. 62). 3.59 Four halogenated convolutamydines (e. Halogenated indoles are also manufactured (or acquired) by acorn worms. Although insect pheromones have long provided a fertile and active arena for natural products research...6-dibromo-.Naturally Occurring Organohalogen Compounds Gribble Several bromine-containing tambjamines similar to 53 have been isolated from the bryozoan Bugula dentata. Thus. such as 2. such as 57. Several different insects contain 2-(or 4-)iodohistidine and mono.6′-dibromoindigotins. The major metabolite of P.64 Acorn Worms. flava laysanica pro146 ACCOUNTS OF CHEMICAL RESEARCH / VOL. 60). Many chlorine-containing briarane diterpenes have been isolated from gorgonians such as juncin H (67) from the Indian Ocean Junceella juncea.62 duces not only seven chlorinated/brominated indoles (e. bromine-. This coral is avoided by the coraldestroying Crown-of-Thorns seastar (Acanthaster planci). only a few of these compounds contain halogens.4. 1998 Insects. and this animal has also yielded two other brominated diphenyl ethers (e..7-tribromoindole) but also Tyrian Purple (61) and two other 6. 55).5. and is highly cytotoxic against P-388 cells in vitro (IC50 ) 10 ng/mL).61 The Atlantic Amathia convoluta has yielded five brominated volutamides. and epoxide 58 is found in a Maui Ptychodera sp.60 The maestro of organic synthesis in the Bryozoa is clearly Chartella papyracea. which have antifeedant properties. are found in Amathia convoluta. P.58. and iodine-containing vulones are produced by Clavularia viridis.and dibromotyrosines. These halogenated tyrosine residues . octocorals (gorgonians and soft corals) have furnished most of these chemicals. These marine worms in phylum Hemichordata are a rich and prolific source of novel halogenated phenols and indoles. flava is the octabrominated ether 59.g.

The Ecuadorian tree frog Epipedobates tricolor secretes epibatidine (70). including diazepam (76) (valium) have been isolated from the brains of humans and other animals. 1998 / ACCOUNTS OF CHEMICAL RESEARCH 147 . The transformation of arachidonic acid and docosahexaenoic acid with lactoperoxidase. Remarkably. which is a potent monoamine oxidase inhibitor. The isomeric 2..5-dichlorophenol has been isolated from the common grasshopper and is an ant repellent. which had been isolated from the cerebrospinal fluid of normal humans.69 Higher Animals. and with the exception of the thyroid hormones. This remarkable compound.Naturally Occurring Organohalogen Compounds Gribble are believed to improve adhesion between protein fibers and sheets.72 3-Chlorotyrosine has been detected in human atherosclerotic lesions73 and also in the reaction of human serum albumin with MPO. 31. and chloride in neutrophils. healthy donors. the precursor to the common herbicide “2. and in the mound of one species.75 and the active oxidants produced by human neutrophils might be long-lived VOL.68 Some of these benzodiazepines may be synthesized by neural cells. wheat. only recently has free chlorine been demonstrated to be involved in this process. 76-78). is a very effective inducer of REM (rapid-eye-movement) sleep and may play an An unimaginable discovery is the finding of free chlorine and organochlorine compounds in humans! A review of this topic has appeared.05 ppb.4-dichlorophenol. A surprising source of chloroform are Australian termites in the outback.1 including three human brains that were preserved years before diazepam was synthesized in the laboratory!65 These naturally occurring chlorine-containing benzodiazepines are synthesized in plants (corn. Thus.4-D”.005-0. Until recently. rice.74 In the former study the highest concentration of 3-chlorotyrosine was observed in two patients with coronary artery disease. such as thyroxine (74). and they may have a biological role.1 Twenty eight percent of the oxygen consumed by stimulated human neutrophils is used to oxidize chloride ion to chlorine or hypochlorite. a compound which is a potent analgesic. Coptotermes lacteus. is produced by a Penicillium sp. soybeans) and thus enter the food chain in this manner. mushrooms. is found in bovine urine and is believed to have a natural origin.66 Levels in plants are 0. NO. 3. the only organohalogen to be found in humans was bromoester 75. Humans.1 Seven chlorine-containing benzodiazepines (e. important role in inducing the sleep phenomenon. although it was previously found in the cuticle protein of locusts and in Limulus polyphemus. and 2. Radiolabeled chloride feeding studies prove that 69 is biosynthesized within the female tick. H2O2. iodide. Iodolactones 72 and 73 have been identified in the thyroid gland of dogs. which is also present in cats and rodents. 3-Chlorocarbazole (71). 2.6-dichlorophenol (69) is the sex pheromone of a dozen species of ticks. The authors conclude that chloroform produced from termites accounts for up to 15% (100 000 tons/year) of the global emissions. soil fungus.65 Six termite species produce chloroform within their mounds. Benzodiazepine biosynthesis in Penicillium cyclopium is well-known. and this compound was generally undetectable in the LDL isolated from young. potatoes. and hydrogen peroxide into 72 and 73 in vitro suggests that this pathway may operate in vivo with thyroid peroxidase.g. The concentration of 75 is 100-200 times higher in the retina.67 as it is in bovine rumen. the chloroform concentration was 1000 times higher within the mound than the ambient concentration.71 Chlorine is also involved in the in vitro conversion of low-density lipoprotein (LDL) cholesterol by myeloperoxidase (MPO) into several chlorinated sterols 79-81. hypophysis.70 Although it has long been known that halides are oxidized to free halogens (or hypohalites) in neutrophils (white blood cells) as part of the immune system. 3-chlorotyrosine is a bona fide human organochlorine compound. lentils. and cerebral cortex than in the blood.

and other microfossils are morphologically indistinguishable from Oscillatoria. Microfossils in billion-year-old Precambrian rocks are identical with the blue-green alga Nostoc. Natural biomass burning. which reflect different stages of coalification. CCl3CHCl2. and the authors conclude that this compound results from the burning of pollutants already present in the biomass since “CF2Cl2 cannot be produced by fires. CHCl3.81 Likewise. CHBr2CHBr2. CF3CFdCF2. The total global annual production of CH3Cl is (5-6) × 106 tons from all natural sources. 2-chloro-. Although volcanoes emit large quantities of HCl and HF.96. CFCs are also found in the gases from hydrothermal vents and thermal springs in the Kamchatka. 1998 ancient sediments reveals the presence of unidentified organohalogens in peat. 1922. Ashkhabad. CHFCl2.labeling experiments. Trichloroacetic acid is present in bog water. Halogenated fulvic acids have been isolated from groundwater samples that date back 1300. NO. the concentration of a CFC was 400 times that of the background. 3. 2. studied with regard to environmental concerns. CH2ClCH2Cl.91 and the possibility that organochlorine and organofluorine compounds will be counted among the more than 100 organic chemicals found in deep space is quite real. The gases from a fumarole on the Santiaguito volcano in Guatemala contain CF2dCF2. the formation of CH3Cl and other organochlorines is not surprising.87 Following the identification of chlorobenzene. lignite. All of these data demonstrate that organochlorine compounds predate the arrival of man on earth! The organochlorines found in pristine forests and lakes appear to form from the in situ chlorination of humic acid by the ubiquitous soil enzyme chloroperoxidase. CHF2Cl. produce large quantities of CH3Cl. bituminous coal.1 Since all biomass contains carbon and chloride.6-dichlorobenzoic acids could be detected in the Cold Bokkeveld meteorite. CCl4. CClFdCF2. CH3Cl. dichlorobenzene. CH3I.82 Their formation probably originates from the high-temperature and -pressure reactions of organic-rich sediments or fossil soils and HCl and HF during the eruption event. 1-chloronaphthalene. and 2-bromomesitylene.81.89 another examination of four meteorites discovered adsorbable organic halogens in levels up to 200 ppm.83-85 Minerals and Meteorites. 31. the biogeneration of which was confirmed by 37Cl. two present-day species rich in organohalogen compounds.78 the emissions of organohalogen compounds is less well known. dwarfing the 26 000 tons per year from anthropogenic sources.76 The aqueous chlorination of purines and pyrimidines. CCl2dCHCl. Volcanoes and Other Geophysical Phenomena. 1938.99 Sediments and Soil Production. and soil samples from pristine locations. CFCl3. the 1980 eruption of Mt. From one solfataric vent of a Kamchatka volcano.86. Helens released CH3Cl. in two lignite samples that date from the Tertiary era. or about 30% of the stratospheric bromine budget. of which some 200 000 occur annually worldwide. CFCl3.88. such as lightning-triggered forest and brush fires. 15 million years ago. The Siberian Kamchatka volcanoes produce CF2Cl2. and CCl2FCClF2 among other organic compounds.92 Forest Fires. CF3CF2CF2H. These natural organochlorines in sediments either result from the deposition of biogenic materials from plants already containing organochlorines or arise by the formation of organochlorines within the sediments. 1906.94 Several North American biomass fires were found to contain high amounts of CF2Cl2 (60 000 tons/ year). CHCl3. St. CFCl3. and organoiodine compounds. When certain rocks. Preindustrial glacial ice from Antarctica and northern Sweden contains organohalogen levels of 1-3 ppb.4-. Both hydrogen chloride and hydrogen fluoride have been detected in interstellar space.1 Methyl bromide is also formed in biomass burning to the extent of 10 000-50 000 tons/year.97 but the amounts are difficult to quantify.93. and Tskhaltubo regions of the former Soviet Union. CHFCl2. Organochlorines have also been found in 1000year-old peat. CCl3CCl3.Naturally Occurring Organohalogen Compounds Gribble N-chloramines. An examination of 148 ACCOUNTS OF CHEMICAL RESEARCH / VOL. CF2Cl2.90 For example. and minerals are crushed in mining operations. and they are found in 8000-year-old deep sediments in Japan.80. and other (unidentified) organohalogens. and 2. and later.” 95 Dioxins are produced in forest fires. CH3Br. rain.1.98 Dioxins and the related polychlorinated dibenzofurans are present “in small but significant levels during the period 1882-1962” in sediment samples from 1882. Natural fires have occurred on earth since terrestrial vegetation evolved 350-400 million years ago. including trichloroacetic acid. 4600. CCl2dCCl2. and anthracite. CCl4. CH2Cl2. the gases released contain CH3Cl. and in a 300 million year old bituminous coal sample from the Upper Carboniferous period. in 4000-year-old marine clay. and 5200 years. shales. CHF3. chloride . organobromine. The latter and chloroform are found to be ubiquitous in soil. CH3CHCl2. and it must be true that CH3Cl has been a natural component of our atmosphere for eons.100 The analysis of 35 000-year-old organic matter (14C-dating) reveals the presence of organochlorine. and (CH3)2SiF2.77 may be relevant to the aqueous chlorination of pathogens by human neutrophils. and several chloroalkanes in carbonaceous chondrites (meteorites). snow.79 Other organohalogens were unidentified because of the complexity of the mass spectra. CH3CH2Br.

The exploration of marine bacteria and fungi is only beginning.113 and the gene for this enzyme has been cloned and sequenced. which produces 7-chlorotetracycline. The extraordinary bromo ester 75 found in human cerebrospinal fluid may play an important role in inducing the sleep phenomenon. and 3. the atmosphere. green. Moreover. and brown algae.102-105 Dioxins (82) and polychlorodibenzofurans (83) are produced from chlorophenols in the presence of horseradish peroxidase and hydrogen peroxide. NO. and 80 000 molluscs each represent a fantastically rich and largely untapped source of new chemical structures. and the related plocamene B is three times more effective than lindane against mosquito larvae. Of the 4000 species of bryozoans fewer than 20 have been examined for their chemical content.117 Future Outlook Not counting terrestrial organisms. The 3000 species of opisthobranchs. and CH2BrI by marine phytoplankton has been isolated. the mechanism for their formation initially involves the oxidation of halide by a peroxidase enzyme and hydrogen peroxide. 9000 sponges.Naturally Occurring Organohalogen Compounds Gribble ion.114 The CPO gene from the fungus Caldariomyces fumago. such as Phellinus pomaceus and Phanerochaete chrysosporium. 3. which is produced by Dictyostelum discoideum. But not all organohalogen compounds have a defensive role.101 High molecular weight organochlorines have been identified in the soil collected from a coniferous forest.5-dichlorohexanophenone.109 The BPO responsible for the production of CHBr3. the 500 000 species of marine animals. The German cockroach (Blattella germanica) utilizes blattellastanosides A (68) and B as aggregation pheromones. 4-Chloroindole-3-acetic acid (11) is a natural plant growth hormone. CH2ClI.112 The BPO from Streptomyces aureofaciens. has been isolated and sequenced. and land. The exploitation of chlorine by white blood cells in the immune process may account for the higher concentraVOL. The chlorine atoms in the clinical antibiotic vancomycin (9) are crucial in enforcing the requisite conformation for receptor binding. or as regulatory hormones.106. is a signal molecule that triggers the transformation of undifferentiated cells of this slime mold into fruiting bodies.116 and the biosynthetic conversion of (Z)-prelaureatin (86) to laurallene (87) has been demonstrated. has been characterized by X-ray crystallography. Chloroperoxidase (CPO).111 An X-ray crystal structure has been reported for a vanadiumcontaining CPO from the fungus Curvularia inaequalis. Other peroxidases such as myeloperoxidase generate halogens in white blood cells to fight infection.1 For many of these compounds. which produces the dichloro caldariomycin. and hydrogen peroxide.115 Several in vitro reactions with peroxidases support the proposed biosynthetic pathways for some organohalogens. Telfairine (19) is 100% lethal to mosquito larvae at 10 ppm. and one iodoperoxidase enzyme have been characterized. Chloromethane serves a key role in the degradation of lignin by wood-rotting fungi. CH2Br2. bromoperoxidase (BPO). in food gathering. CH2I2. 31.97 This reaction occurs under true in vivo conditions in fresh garden compost piles and sewage sludge. Laurediol 84 cyclizes to the Laurencia metabolite (E)prelaureatin (85).107 Function Many organisms use organohalogens (and nonhalogenated compounds) in chemical defense. plants. these enzymes are becoming valuable catalysts in organic synthesis. see ref 108. and bacteria guarantees that thousands of new organohalogen compounds are awaiting discovery. many of which are certain to contain halogens. 1998 / ACCOUNTS OF CHEMICAL RESEARCH 149 . Biohalogenation The formation of natural organohalogens in living organisms is well established. and this will be an important area for future research. For a recent review of the natural production of organohalogens in water and sediments. 4000 segmented worms. The role of simple halomethanes may be to recycle halogens/halides between oceans. which is part of the natural decay and recycling of organic matter in the forest soil.110 BPO activity has been detected in 94 species of red.

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