RESEARCH
Steroids Show Stereoelectronic Effect Photo-oxygenations of 2-methyl- and 3-methyl-/\2-cholestenes show importance of steric hindrance and steric alignment Two aspects of the catch-all phrase, steric effects, are a little clearer be cause of the work of Dr. Alex Nickon and co-workers at Johns Hopkins Uni versity, Baltimore, Md. These as pects are just plain physical crowding and the importance of a bond having a precise position in space. The first is steric hindrance, the second is called a stereoelectronic effect. The photosensitized oxygenation of olefins serves as the test reaction. The compounds that the Johns Hopkins chemists use are all cholesterol deriva tives that differ only in rings A and B. The angular methyl groups at C-10 and C-13 provide the hindrance, and the steroid's rigidity prescribes the geometry of the bonds. Steric hindrance favors attack from
the under (or alpha) side of the ring. The stereoelectronic effect predicts that axial (perpendicular to the ring) allylic bonds will be more reactive than equatorial ones because they over lap more readily with the orbitals of the double bond. This overlap may be important in the photoreaction. Such effects can either augment or oppose each other. Oxygen, a diradical, usually reacts by a free radical chain mechanism. There is very little selectivity, and hy droperoxides often react further. By contrast, photochemical reaction of oxygen with a dilute olefin solution in presence of a sensitizing agent fre quently gives a specific hydroperoxide without going through a chain mecha nism [JACS, 83, 1498 (1961)].
CONFERENCE. Dr. Alex Nickon (center) discusses some olefin oxygenation possi bilities with Dr. Joseph DiGiorgio (right) as Norman Schwartz looks on 50
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The current theory is that the sen sitizing agent—usually a fluorescent dye—absorbs light, is activated, and complexes with oxygen. Then either this complex reacts with an olefin, or the complex dissociates to give acti vated oxygen which, in turn, reacts with the olefin. While their experiments do not ex pose either of these paths, Dr. Nickon and Dr. Jehanbux F. Bagli, who is now with Ayerst, McKenna & Harrison Re search Laboratories, Montreal, are in clined to favor attack by the complex. Some support is given by the steric hindrance that they observe. In the photoreaction, the oxygen at tacks one end of the double bond. An allylic hydrogen is removed and the double bond moves over one carbon to form an allyl hydroperoxide. Pre vious work on open chain compounds reveals little about the steric require ments for the loss of this hydrogen be cause the bonds are free to rotate to favorable positions, the chemists say. Dr. Nickon points out, though, that steroids provide a rigid system. A°-Cholestene has two hydrogens allylic to the double bond ( 5 a and
8/?). Both of these hydrogens have bonds that are in good position to over lap with the orbitals from the double bond during the reaction. The prod uct is the 7a-hydiOperoxide. It results from loss of the 5a-hydrogen. No 6-hydroxy-A 7 -steroid (from loss of the 8/?-hydrogen) is observed. This could be due to hindrance by the angular methyl groups. To test the inertness of the 8/?-hydrogen, the 5 position was blocked with an α-hydroxy group. Prolonged reaction left the molecule unchanged. To define the specificity of the re action a little further, Dr. Nickon and Dr. Bagli oxygenated 7a-deutero and
The Stereoelectronic Effect,.. In THEORY
and In PRACTICE
Axial bond to X can overlap with the orbitals from the double bond better than the equatorial bond to Y can and will react more easily.
7/?-deutero cholestérols. In both cases, the 7a-substituent was lost, indicating a possible cyclic mechanism.
The 5a-hydroperoxide was formed in each case. The allylic hydrogens that have been shown to react in these steroids are all axial. Their bonds parallel the orbitals of the double bond rather than the rings. A G -Coprostene differs from AG-cholestene (cholesterol without the 3βhydroxyl and with the double bond at C-6) by having a 5β- rather than
a 5a-hydrogen. This gives the mole cule a cis A/B ring juncture. The 5/?-hydrogen is more parallel to ring Β than it is to the orbitals of the double bond. This compound is also inert to extended treatment. The case is still not clear-cut, however. It could be argued, the Johns Hopkins group says, that the oxygen must at tack from above the ring since the allylic hydrogen involved is above the
No evidence was found for reac tion at C-6 from above. The 10βmethyl hinders approach of the complex; bond alignment aids attack at C-5 and C-7 from below.
ring. This would be hindered by the same ΙΟβ-methyl that screens the 8/?-hydrogen. A critical system was needed that would show the relative importance of crowding and bond alignment. Dr. Nickon and Dr. Joseph DiGiorgio found 2-methyl- and 3-methyl-A 2 cholestenes to be such a system. In both compounds, the allylic hy drogen involved comes from the methyl group. The hydrogen can al ways get into a favored position by rotation, so its effect is the same in either case. In the 2-methyl com
pound, attack from above is not fav ored since the ΙΟβ-methyl blocks it, and because the bond to the hydroperoxy group in the product will not be parallel to the orbitals of the orig inal double bond. Attack from be low is favored for the opposite rea sons. This prediction is borne out by a six-to-one ratio of attack from below. Approach from above will be hin dered again by the 10#-methyl in 3-
methyl-A 2 -cholestene. But, in this case, the forming hydroperoxy bond is parallel to the orbitals of the double bond and should be favored. Attack from below gives an equatorial hydro peroxy group and will not be favored. Although final purification is not complete, enough evidence is in to show about a fifty-fifty ratio of prod ucts. This shows the importance of both steric hindrance and the stereoelectronic effect. When they operate together, the ratio is six to one; when they oppose, it's a standoff. Implications. The use of oxygen, light, fluorescent dye, and olefins is a striking parallel to the processes in living systems. This reaction, using enzymes rather than light, could be one of the ways that oxygen is used in animals. The parallel is even more pointed with plants: the use of light, the quantity and variety of olefins avail able, and the variety of oxygenated materials that plants make. Hydro peroxy groups are energy rich and can decompose in many ways. They are easily converted to alcohols, ketones, aldehydes, and epoxides; almost any oxygenated material could have a hy droperoxy percursor. This makes them attractive as possible oxidation intermediates in living systems. The reaction also has many possi bilities as a synthetic tool, particularly when other functional groups are near. JUNE
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D-Luciferin Synthesis Confirms Structure COLONIAL SE SURFACTANTS
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L-Luciferin also made; it reacts biologically at the same rate as the natural but does not produce light Lightning bugs can breathe easier now that the structure and synthesis of luciferin have been settled by Dr. Emil White and co-workers at Johns Hopkins University, Baltimore, Md. Degradative evidence did not lead to a unique structure. However, their suc cessful synthesis does complete the structure proof [JACS, 83, 2402 (1961)]. Luciferin (part of the firefly's light ing system) is difficult to isolate and purify. No good solvent was found, the material oxidizes readily, and much of the early work was plagued by racemization. It was difficult to get any quantity of luciferin. Most of what was obtained was being used in biological studies by Dr. William D. McElroy of the university's biology department. About 5 mg. was the most that the chemists had at any one time. An early series of analyses indicated that the material probably was a C1:> compound. But recent analyses of a PHOTO. Dr. William McElroy (seated) and Dr. Emil White ponder a 100 χ photograph (inset) of the first crystal line natural luciferin that they were able to obtain
luciferin derivative show that it really is a C n compound. These related dif ficulties (purification and analysis) were partly offset by an early recogni tion of the similarity of the ultraviolet spectrum to those of benzothiazoles. Clues. The carboxyl was recog nized; D-cysteine and an aminophenol were found in the degradation prod ucts. The ready oxidizability of the molecule suggested that it might be a dihydro derivative of some aromatic system. On this evidence, Dr. White and Dr. Frank McCapra proposed a structure. Luciferin's intractability and the small quantity available drove Dr. White and Dr. George F. Field to synthesize the postulated structure. Synthesis. First, p-anisidine and ethyl oxalate are condensed. Sulfur is introduced with phosphorus pentasulfide. Ferricyanide oxidation closes the benzothiazole ring. The acid is converted to a nitrile via the ester and amide. The methyl is removed from
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NH., and H, are Keys to I New Chemical Process For Refining Copper Ore
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Ether to Meet New, Tighter ACS Specs Being Produced by New U.S.I. Refining Unit
A low-capacity (42 t o n s / d a y ) , low-in vestment plant for refining copper ore by chemical means is now under construction New Unit at Tuscola, 111. Increases Versatility of U.S.I. Ether Facilities in the Philippine Islands. The plant will employ a new. all-chemical process to A new ethyl ether unit h a s just gone on s t r e a m at U.S.I.'s alcohol-ether plant convert low-grade ores to high-grade in Tuscola. Illinois. E t h e r processed t h r o u g h the refining unit meets the new. (99.95% pure) metal. It will eliminate m o r e s t r i n g e n t specifications recently p u b l i s h e d by the A m e r i c a n Chemical expensive smelting and refining proce Society. In addition to requiring freedom dures. Air and stream pollution is ex from foreign odor, the new specifications pected to be negligible. I for ethyl ether. ACS absolute, contain Cesium Is Propellant \ In the process, the ore—concentrated by these tighter requirements: the usual crushing and flotation m e t h o d s In Prototype Ion Engine I • lower peroxide content (asHL>0L>) from is subjected to an ammonia leach under 0.001% maximum to 0.0001% maxi 125 psi pressure. Copper and zinc dissolve. mum. A small model of an ion propulsion ι Sulfur and iron are removed as a residue. • specifies aldehyde content (as H_»CO ) engine employing cesium as the propel The copper-zinc solution is distilled, and as 0.0005% maximum, rather than "to excess ammonia recovered in this step is lant is nearly ready to fly, according to a ! pass test". recent article on electrical propulsion en recycled. The solution of metals goes • lower water content from 0.05% maxi through oxydrolysis to reduction with hy gines for spaceships. The prototype, de-1 mum to 0.01% maximum. veloped for the Air Force, produces a ' drogen. Pure copper powder results, All other specifications for absolute which is compacted into wire or sheet. AH thrust in the range of several ten-thou ether have remained unchanged. These sandths of a pound. sulfur is converted to ammonium sulfate The ion propulsion, or electrostatic include density, acidity, non-volatile mat for use as fertilizer. • • • • • ^ ter, alcohol content, and substances dark The process is said to be easy to con engine accelerates a beam ened by sulfuric acid. trol, to require little electric power, and of positive cesium ions by ^ ^ ^ ^ ^ ^ ^ ! means of an electrostatic ^ ^ ^ ^ ^ ^ to be low in operating cost. Copies of the complete "Reagent Chemicals'* which contains these spe DIMAZINE® (UDMH) Plant Expanded cifications and test procedures are To Supply More Fuel for Titan II available from the American Chemical Society, 1155 Sixteenth St., N.W.. Washington, D.C. The new refining unit is designed to pro duce ether that is superior for Grignard and lithium aluminum hydride reactions. Greater Production Versatility The new unit is another step by U.S.I. in its program to increase the versatility of its alcohol-ether production facilities. In April 1960, it was reported ^ ^ ^ ^ ^ _ in the U.S.I. Chemical News ^ ^ ^ ^ ^ that the company had added ^ ^ ^ ^ ^ ^ ^
Polyethylene Pipe Gets OK from New York City for Chemical Waste Systems For the first time, the New York City Artist's cutaway conception of a typical TITAN underground launch site. Use of storable liquid Board of Standards and Appeals has ap propellants permits missile to be kept fully fueled—ready for launch directly from silo. New facilities to produce unsymmetrical dimethylhydrazine ( U D M H ) for the Titan II missile have just been completed. This high-energy, storable liquid rocket fuel will help reduce the Titan I P s launching time to seconds and give the U.S. an added deterrent in its defense arsenal.
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No. 1724 8 5 % copper, or to copper-plated metals, strong fields from very small quantities of is reported to give bond strengths of 20 electric power. Because the wire is super Portable gas detector now on market is claime to 40 l b . / i n . of width. Previously-used conductive, power is required only to start accurate, sensitive. Consists of volumetric pumj: methods are said to have given strengths detector tubes hermetically sealed in lead cylinthe flow and operate the refrigeration ders, remote sampling device. Detector tubes of only 5 to 10 lb./in. of width. available for 36 different gases. No. 1725 equipment needed. In the new process, developed by Bell Telephone Laboratories, the metal surface Silicone uses in aerospace industry is subject of new brochure. Relates value of silicones in variis treated with a special oxidizing agent to • j ^ ^ ^ ^ ^ ^ ^ ^ Cesium ous applications to properties such as extreme form a cupric oxide layer. 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the phenol group with pyridine hydrochloride. Finally, this product is condensed at room temperature (in aqueous methanol) with D-cysteine to produce authentic luciferin. No Light. An unusual feature appeared when L-cysteine was used in the synthesis. The L-luciferin behaved just like the D-isomer, even in biological reactions. Dr. McElroy believes that this is the first example where D and L isomers react at the same rate in biological systems. Even more peculiar, the reaction of L-luciferin with the enzyme luciferase, ATP, and oxygen doesn't produce light. How the D-isomer produces light is still a mystery. The broad band emission centering around 565 millimicrons corresponds to an average energy of 50 kilocalories with some of the emission as high as 60 kilocalories. Analytical Tool. D-Luciferin (with enzyme) is very useful in analyzing adenosine t r i p h o s p h a t e (ATP). When a substance containing ATP is added to an aqueous extract of firefly lanterns (which contains D-luciferin), typical firefly light is emitted. The quantum yield is 100% (one luciferin molecule gives one quantum). Measuring the light that's emitted then gives the amount of ATP present. Solutions down to 10 - 1 1 molar can be analyzed. One microgram of ATP per milliliter is analyzed routinely. ATP's involvement in most living material makes the D-luciferin-enzyme system a potent tool for biochemists. This analysis also has severely taxed the firefly population. About 2000 fireflies are needed to produce 1 milligram of D-luciferin. Dr. McElroy has been buying them from school age groups for 25 cents a hundred since 1948. Contests were organized and bonuses given to the winning teams. The average yearly take was about 700,000 fireflies. The synthesis of D-luciferin will reduce the need for the summer collections because fewer fireflies will be needed to supply the demand for the enzyme, luciferase.
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