RESEARCH
New Type of Octahedral Anion Complex Found Pentafluorotitanate complex contains molecule of solvent or base, axial fluorine, and four equatorial fluorines coordinated to titanium Mechanism Involves Formation of Fluorine Bridge 144TH
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Inorganic Chemistry
A unique type of octahedral anion complex has been found by Dr. Ronald O. Ragsdale and Dr. Burch B. Stewart of Allied Chemical Corp., Morristown, N.J. The species, a pentafluorotitanate complex, consists of one molecule of solvent (or base), one axial fluorine, and four equatorial fluorines coordinated to the titanium. This type of anion has the general formula [TiF n ROH](R represents an alkyl group). The new pentafluorotitanate complexes were first discovered and characterized in the reaction of titanium tetrafluoride with di-?i-propylammonium hexafluorotitanate in absolute ethanol. Nuclear magnetic resonance spectra and a conductivity study established the structure of the complex. A plot of conductivity vs. mole fraction shows a maximum corresponding to the empirical formula T i F . - - , the two chemists say. NMR confirms presence of a T i R - - species and indicates that a solvent molecule occupiey the octahedron's sixth position. NMR spectra obtained at - 3 0 ° C. show a quintuplet for the axial fluorine and a doublet for the equatorial fluorines, with a quintuplet-to-doublet intensity ratio of 1:4. Dr. Ragsdale and Dr. Stewart note that this is an AX4type spectrum, and they conclude that a molecule of solvent must occupy the sixth position in the octahedron. For all the molar ratios studied, titanium tetrafluoride, the hexafluorotitanate anion, and the pentafluorotitanate complex were seen in the spectra. Other pentafluorotitanate complexes, [ T i F - R ] - , where B represents solvent or added base, can be made from an e t h a n o l - [ T i F - C 2 H r , O H ] solution by displacing ethanol from the coordination sphere with a stronger base. Water, amines, and ether have been added as bases. Ad40
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Mechanism proposed by Dr. R. 0. Ragsdale and Dr. B. B. Stewart for the formation of [TiFr/ROH] - involves an initial displacement of a molecule of solvent by the formation of a fluorine bridge. Subsequent re-entry of solvent into the second octahedron breaks the bridge and gives the pentafluorotitanate complex
SPECTROMETER. Dr. Ragsdale (standing) and Dr. Stewart study the structure of a pentafluorotitanate complex with a nuclear magnetic resonance spectrometer
dition of excess strong base destroys the anion complex and gives hexafluorotitanate as one of the products. The [ T i F 5 a m i n e ] ~ complex can also be prepared by adding a primary, secondary, or tertiary amine to alcoholic solutions of titanium tetrafluoride, the two chemists say. Here again, the addition of excess amine destroys the complex. The F 1 9 NMR spectra of the [TiF 5 ROH]complexes are temperature
dependent, the Allied team says. Above —10° C , rapid exchange causes a loss of fine structure, resulting in a broad, single-line resonance at room temperature. Exchange. Dr. Ragsdale believes that the temperature dependence of the spectrum is due to the exchange:
resulting in an environmental exchange
of fluorines between two nonequivalent sites. This is based on the fact that very fast intermolecular fluorine exchange in octahedral MF G , MF6~~, and MF f i ~ 2 complexes hasn't generally been observed near room temperature, and that the pentafluorotitanate complex is in excess base. Dr. Ragsdale and Dr. Stewart believe that a better understanding of cis and trans effects in octahedral complexes can be obtained from studying the F 1 9 chemical shifts of the [TiF. r B]~ complex. In [TiF r> -C 2 H 5 O H ] ~ , the fluorine trans to ethanol appeared at —182 p.p.m. (relative to CFCI3) and the cis fluorine at - 9 9 p.p.m. The trans fluorine is unshielded to a much greater extent than the basal fluorines. This deshielding probably results from two effects: a change in charge distribution, which is considerably greater in the d-2 orbital than in the dA.2_?y2 orbital of the metal ion; and an increase in the pi character of the bond between the metal and the fluorine trans to ethanol. Upon displacement of ethanol by a stronger base (amines, water, or ether), the trans fluorine shifts up field (becomes more shielded) to a greater degree than the cis fluorines. Two Effects. Thus two effects must be operating, Dr. Ragsdale says. The first is one in which the ligands have no tendency to form double bonds and in which the inductive forces are of prime importance. The second effect would be due to the ligands which are capable of 7r-bonding. In the second effect, mesomeric effects causing deshielding of the trans fluorine relative to the degree to which the fluorine donates TT-electron density would be expected, Dr. Ragsdale points out. In all cases, the inductive effect would increase the shielding of the highly electronegative fluorine atom trans to the ligand, he adds. Mechanism proposed for formation of the complexes involves the initial displacement of a molecule of solvent from TiF 4 • 2ROH by the formation of a fluorine bridge. Subsequent re-entry of solvent into the second octahedron then breaks the bridge and yields the anion complex. The Allied workers believe that this type of octahedral complex isn't unique to titanium. It may be possible to make a large number of anionic metal halide complexes of the generic formula [MX.-, • B] v , where y represents the charge of the complex and B the base, they say.
Nonaqueous Exchange Rates Studied Study uses N15 to show exchange of ammonia between [Cr(NH3)6]+3 and solvent 144TH ACS NATIONAL
MEETING
Inorganic Chemistry
The exchange rate of N 1 5 H 3 between hexammine c h r o m i u m ( I I I ) , [C r ( N H 3 ) G ] + 3 , and liquid ammonia solvent at 20° C. has been studied by Dr. John P. Hunt, L. F. Coleman (now at General Electric Co., Richland, Wash.), and Dr. T. W. Swaddle (now at the University of Wisconsin, Madison) at Washington State University, Pullman. The system was found to be very complex. Most of the runs carried out by the Washington State group were made using liquid ammonia solutions of Cr (NH 3 ) 6 ( N 0 3 ) 3 with ammonium nitrate or potassium nitrate added. Some were done using C r ( N H 3 ) 6 ( C 1 0 4 ) 3 with ammonium perchlorate or sodium perchlorate added. Although the addition of water had no detectable effect on the exchange rate, anhydrous conditions were maintained during the runs. The runs were carried out in the dark, and care was taken to ensure that no sodium metal was present in the reaction mixtures. Sodium metal appreciably accelerates the exchange rate. The exchange is homogeneous. Under comparable conditions, the perchlorate salt shows an exchange
rate 10 to 30 times faster than that of the nitrate salt. The addition of either ammonium nitrate or ammonium perchlorate reduces the exchange rate, as does the addition of potassium nitrate or sodium perchlorate. Activation Energy. The apparent activation energy for the C r ( N H 3 ) ( r ( N 0 3 ) 3 system with no added salts was found to be about 33 kilocalories per mole, Dr. Hunt says. Since the dielectric constant of the liquid solvent at 20° C. is about 15, extensive ion-pairing must occur, he adds. The apparent activation energy for the analogous water exchange is 28 kilocalories per mole. Although guesses may be made concerning what species are present, a detailed explanation of the kinetic data must await more definite information about the species, Dr. Hunt says. Attempts are being made to fit the kinetic data to various rate laws using a computer program. In any event, Dr. Hunt adds, the kinetic results show that even a "simple" reaction in liquid ammonia can be very complex and that naive comparisons of rate data in this medium can't be made. The study is representative of a relatively new area of interest: measurements of exchange rates of ligand molecules that also make up the solvent. Most of the work in this area so far has dealt with aqueous solutions.
[Cr(NH 3 ) 6 ] +3 —Liquid Ammonia System Is Complex
These equilibria are suggested as being important with nitrate solutions in the hexamminechromium(lll) system by Dr. John P. Hunt and co-workers. Consideration of possible ion-pair formation leads them to propose these equilibria. Ions having a charge greater than -j-1 are unlikely, they say APRIL
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New Clue Found to Snail Fever Control Naphthylazo compounds are among the most active schistosomicides known 144TH
ACS
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Medicinal C h e m i s t r y Some naphthylazo compounds are active against worms which cause schistosomiasis (also known as bilharziasis or snail fever). Studies show that many [4- (aminoalkylamino) -1-naphthylazo]-heterocyclic compounds can eradicate schistosomes in experimental animals. Several of them are the most active schistosomicides found to date (aside from antimonials), say Dr. E. F. Elslager, Dr. D. B. Capps, Dr. L. M. WerbeL and D. F. Worth of Parke, Davis & Co., Detroit, Mich. One promising compound of the series studied is 5-[4-(2-diethylaminoethylamino) - 1-naphthy 1 azo ] -ur a c i l (called CI-407 by P-D). CI-407 is
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very effective in 'mice and monkeys, says Dr. P. E. Thompson, director of P-D's parasitology laboratory. Although moderately active against schistosomes in people, CI-407 produces severe gastrointestinal side effects, according to Dr. K. O. Courtney of P-D's department of clinical investigations. Still, naphthylazo compounds have promise as a good lead to finding a cure for one of the world's biggest medical problems, Dr. Elslager believes. Schistosomiasis ranks close to malaria in importance as a tropical and semitropical disease. Some 200 million people plus countless animals in many parts of the world are afflicted. The disease is showing up in a growing number of countries. Medical authorities say it could easily become the number one tropical
health problem of this century. To date, there is no drug available which is considered adequate in combating schistosomiasis. Snails Involved. The culprit in schistosomiasis is a parasite which is a member of the flatworm family. The worm passes through a growth cycle in three types of fresh water snails. One type is found in Asia, one in Africa, and the other in Africa, Puerto Rico, and South America. Free-living forms, called cercariae, are produced in snails and pass into bodies of water frequented by people. The cercariae easily penetrate the skin of people coming in contact with the water, mature into worms, and lay eggs Vvhich are carried by the blood stream to vital organs. The many eggs laid damage these organs and produce chronic disease. Poor sanitary habits put some of the eggs back into streams and the cycle starts over again. Efforts to eliminate the snails and thus break the life cycle have failed— a single snail can theoretically be the ancestor of 3 million new snails a year. The water pollution problem also is a major one. The most widely used drug against the worms in man is potassium or sodium antimony tartrate, given by injection. This treatment is often described as "almost as bad as the disease." Related organic antimonials work, but they are very toxic. Other chemicals showing some effect in man or animals include lucanthone hydrochloride, tris(p-aminophenyl) carboninm salts, 4,4 / -(heptamethylenedioxy) dianiline dihydrochloride, N-[5(p-aminophenox y ) p e n t y 1 ] - p ht h a 1 i mide, and 3-[4-(3-chloro-p-tolyl)-lpiperazinylcarbonyl]-acrylic acid. Several of these compounds suffer from a limited spectrum of activity or are too toxic. At P-D, an intensive research program on schistosomiasis was started in 1951. So far, P-D scientists have tested more than 8000 chemicals', found activity in only about 15 types. At one point, P-D scientists went through 3000 compounds without finding a new type active against the worms. Azo Dyes Offer Lead. Included in the many compounds studied were several hundred azo dyes. Dyes have shown antiparasitic and antibacterial activity. Today, they are enjoying something of a renaissance in medicine. Promising activity has been
COLLECT. Dr. P. E. Thompson (left) and Dr. E. F. Elslager of Parke-Davis collect specimens of Australorbis glabratus, the intermediate snail host for Schistosoma mansoni
found in 5-(4-amino-l-naphthylazo)uracil. But other heterocyclic derivatives of this compound are inactive, the P-D workers say. Using this as a lead, Dr. Elslager and co-workers synthesized many substituted heterocyclic naphthylazo compounds. Tests showed that basically substituted 5- (4-amino-l -naphthylazo) -uracils were mora active than the compound without the side chain. Surprisingly, many heterocyclic varieties with basic substitution were also active, Dr. Elslager says. Most active compound of this series is 5-[4-(2-diethylaminoethylamino) -1-naphthylazo] -uracil—CI-407. This is synthesized by diazotizing 5aminouracil and adding it to l-(2-diethylaminoethylamino) -naphthalene in ethanol and hydrochloric acid. The green hydrochloride which precipitates is made slightly alkaline with sodium hydroxide and the desired red dye precipitates and is crystallized. An alternate route to CI-407 involves diazotizing iV-(4-amino-lnaphthyl) -N- (2-diethylaminoethyl)2,2,2-trifluoroacetamide monohydrochloride. This is coupled with uracil, and the desired compound precipitates
from alkaline solution after hydrolysis. Dr. Elslager predicts that the trifluoroacetyl group may find widespread use as a protecting group in the synthesis of «azo dyes from 1,4-naphthalenediamines and other easily oxidized systems. Studies Continue. Structure-activity studies indicate a 4-amino-lnaphthylazo orientation is necessary for antischistosome activity, Dr. Elslager says. Activity is either abolished or greatly reduced when hydrogen is substituted for one or both of the alkyls of the terminal aliphatic amines of CI-407. The same thing happens if the secondary amine at C-l is alkylated, or if a carbonyl group is substituted for the methylene group adjacent to the terminal aliphatic amine. Also inactive are 4-azo-l-(dialkylaminoalkyl) -aniline derivatives. The research effort with naphthylazo compounds is being continued. Directions of further study could include varying side chains at C-l of the naphthyl structure and varying the heterocyclic radical. P-D scientists are also studying other types of compounds, Dr. Elslager says. Currently, they are testing chemicals for antischistosome activity at the rate of 1500 a year.
Enzymic Browning Substrate Identified 144TH
ACS NATIONAL
MEETING
Carbohydrate Chemistry
A crystalline compound, the main enzymic browning substrate in dates, has been identified as a caffeoylshikimic acid by Dr. V. P. Maier and D. M. Metzler of the U.S. Department of Agriculture's Fruit and Vegetable Chemistry Laboratory, Pasadena, Calif. This appears to be the first isolation of a crystalline caffeoylshikimic acid from a natural material, Dr. Maier says. It is also the first demonstration that such acids will undergo enzymic browning, he notes. The isolation of a crystalline caffeoylshikimic acid firmly establishes the existence of a new group of substituted cinnamic acid esters based on shikimic acid, Dr. Maier says. It seems likely that members of this series will prove to be widely distributed in plants. But they may not ac-
cumulate as much as chlorogenic acids, possibly because of greater metabolic activity. Earlier work by other workers has provided chromatographic evidence (as* well as identification of hydrolysis products) showing that p-coumaryl-, caffeoyl-, and feruloylshikimic acids are present in Western hemlock cambium. But it hasn't yet been established whether either of the date isomers is identical with that found in Western hemlock, Dr. Maier says. Caffeoylshikimic acids' chromatographic properties are similar to those of the chlorogenic acids (or caffeoylquinic acids); and they have almost identical ultraviolet spectra. Dr. Maier points out that many chlorogenic acid identifications based only on Rf data or UV spectra must be considered doubtful. The identification of caffeic and quinic acids following hydrolysis is essential for a dependable identification, he emphasizes. Isolation. Caffeoylshikimic acid was isolated from date fruit extracts (Phoenix dactylifera) by adsorption chromatography on silicic acid using a chloroform-methanol gradient. It was further purified by recrystallization from water. The spectral evidence shows that a free ortho-dihydroxy group is present. Enzymic hydrolysis gives caffeic and shikimic acids, thus establishing that the compound is a caffeoylshikimic acid. This was further confirmed by elemental analysis and neutralization and hydrogenation data. The caffeic acid was identified by mixed melting point, ultraviolet and infrared spectra, Rf values, and migration on a paper electrophoretogram. The shikimic acid was identified by Rf values, color reactions, and migration on a paper electrophoretogram. Preliminary evidence based on formation of an isopropylidene derivative indicates that the compound is 3-caffeoylshikimic acid. Dr. Maier suggests the name dactylifric acid for this compound. More recent work has indicated that a second caffeoylshikimic acid, isomeric with dactylifric acid, is present. Dr. Maier believes this to be either 4- or 5-caffeoylshikimic acid. Both dactylifric acid and its isomer are readily oxidized by a crude enzyme extract from dates and by tyrosinase to brown pigments. Since there are three position isomers possible, there might also be a third isomer present in smaller amounts, he suggests. APRIL
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