RESEARCH
Chlorophyll analog structure determined Carnegie-Mellon work on vanadyl porphyrin indicates Ε ring imparts oxidation resistance to chlorophyll The synthesis and structural deter mination of a chlorophyll analog at Carnegie-Mellon University may aid scientists in relating chlorophyll's struc ture to its biological function. One question that the Carnegie-Mellon re search helps answer is: What fea tures of chlorophyll's structure influ ence its resistance to oxidation? Dr. Earl W. Baker of Carnegie-Mel lon, with an assist from three scientists at Johns Hopkins University, has synthesized a compound, va nadyl deoxophylloerythroetioporphyrin (VO-DPEP), that has several of the important structural features of chloro phyll. And Dr. Roger C. Pettersen and Dr. Leroy E. Alexander of Car negie-Mellon have determined the chlorophyll analog's geometrical struc ture by three-dimensional single-crys tal x-ray diffraction analysis. The Car negie-Mellon work indicates that the fused isocyclic ring E—common to both chlorophyll and VO-DPEP-plays an important role in chlorophyll's re sistance to oxidation. Because of chlorophyll's unique im portance to life, scientists in many lab oratories throughout the world have devoted a great deal of effort to de termining its structure. Up to now, however, these efforts have been thwarted by the scientists' failure to get chlorophyll, or a derivative, in a crystalline form. Because of this fail ure, the Carnegie-Mellon workers tried another approach. Their idea was to prepare and study a simple (model) compound that retains at least one of the important structural features of chlorophyll and that can be crystal lized. In VO-DPEP they have been successful. Work on the VO-DPEP synthesis was started when Dr. Baker was work ing in the laboratory of Dr. Alsoph H. Corwin at Johns Hopkins. Others in the laboratory besides Dr. Corwin who took part in the early stages of the work were Dr. Ernst Klesper and Dr. P. E. Wei. The synthesis will be de scribed next month in The Journal of Organic Chemistry. Dr. Pettersen and Dr. Alexander have crystallized VO-DPEP in a 1:1 ratio with ethylene chloride and have determined the crystal's molecular geometry by threed'mensional x-ray analysis [/. Am. Chem. Soc., 90, 3873 (1968)]. 34 C&EN JULY 22, 1968
Vanadyl porphyrin analog synthesized by Dr. E. W. Baker has the same ring system as chlorophyll, but differs in the side groups and central atom
The synthesis of VO-DPEP results from a long, tedious program. "We didn't have to develop any new reac tions to accomplish the 15-step synthe sis, but we had to refine some of the known reactions as we went along," Dr. Baker tells C&EN. In the synthetic scheme, VO-DPEP is prepared from the end product of a multistep degradation of pheophytin (chlorophyll without the magnesium). The overall yield of VO-DPEP is only about 0.25%, Dr. Baker points out. Thus large quantities of the pheophy tin starting material were needed. In the synthesis, pheophytin is first converted to pyropheophorbide by refluxing it in concentrated hydrochloric acid. Next comes a critical s t e p converting pyropheophorbide to deoxophylloerythrin. A crucial paper by Dr. E. J. Corey, Dr. W. L. Mock, and Dr. D. J. Pastro of Harvard Uni versity provided the key to the solu tion of this problem. The Harvard
group found that clean reduction of the vinyl group does not occur under Wolff-Kishner conditions in a sealed tube and that the effective reductant is not hydrazine, but its oxidation product, diimide. Using the informa tion obtained by the Harvard group, Dr. Baker has developed a scheme by which pyropheophorbide is con verted to deoxophylloerythrin in 60 to 68% yield in one composite reaction without isolation of the intermediates. In this scheme, three distinct reactions take place sequentially: reduction of the vinyl group to the ethyl group, re duction of the carbonyl functions to hydrogen, and dehydrogenation of ring D. Deoxophylloerythrin is then decarboxylated to yield deoxophylloerythroetioporphyrin by a seven-step reaction sequence. This sequence includes Curtius rearrangement, Hoffman deg radation, and catalytic hydrogénation. VO-DPEP is then prepared by react-
X-RAY. Dr. Ε. W. Baker (left) and Dr. R. C. Pettersen examine chlorophyll analog models constructed from single-crystal x-ray diffraction analysis results
ing deoxophylloerythroetioporphyrin with vanadyl sulfate in the presence of a small amount of trichloroacetic acid. Although no x-ray study has been made of chlorophyll's structure, much information on its molecular structure has been gathered. The correct gross structure of chlorophyll was pro posed in the early 1930's by Dr. Hans Fischer and his coworkers at the Technische Hochschule, Munich, Ger many, and confirmed about 25 years later by Dr. R. B. Woodward and his coworkers at Harvard University when they synthesized the compound. The absolute configuration of the side groups in chlorophyll has been worked out completely with the aid of recent work by Dr. Ian Fleming of the Uni versity of Cambridge, England. The structure of other porphyrins and porphines has been determined by x-ray methods by a number of earlier workers, including Dr. J. L. Hoard and his coworkers at Cornell Univer sity, Dr. Ε. Β. Fleischer and his co workers at the University of Chicago,
and Dr. Donald F. Koenig at Johns Hopkins. VO-DPEP is similar to these compounds except that a fifth, or E, ring has been introduced, making the molecule a closer analog of chloro phyll. Dr. Pettersen and Dr. Alexander have prepared a crystalline form of VO-DPEP using a technique devel oped by Dr. Gabrielle Donnay and Dr. C. B. Storm at Carnegie Institute of Washington. Crystals of the mate rial are grown by slow vapor-phase diffusion of methanol into a nearly saturated solution of VO-DPEP in ethylene chloride. In determining the molecular ge ometry of VO-DPEP by x-ray diffrac tion, the Carnegie-Mellon scientists use a single crystal of this material.
They have measured nearly 2000 in dependent reflections for the 42-atom structure. Calculations are done with the x-ray 63 computer program sys tem written by Dr. James Stewart of the University of Maryland. From the computer analysis an electron den sity map is constructed which gives information on the geometrical struc ture of the molecule. The x-ray analysis indicates that the VO-DPEP molecule is nearly pla nar. It has the shape of a very shal low saucer with the vanadium dis placed out of the plane defined by the four nitrogen atoms by about 0.5 A. Three of the four vanadium-nitrogen bonds measure about 2.12 A. But the vanadium-nitrogen bond attached to the C ring is 0.15 A. shorter. This difference is probably caused by the effect of the Ε ring in pushing the nitrogen atom in toward the vanadium. In VO-DPEP the presence of the Ε ring causes a strain in the molecule. The strain is not localized, but is trans mitted throughout the entire molecule, Dr. Pettersen explains. Bond dis tances and bond angles are markedly distorted compared to the structures of other porphyrins and porphines de termined by the x-ray method. It's likely that the Ε ring "freezes" the molecule into a more planar form. The isOcyclic Ε ring plays an im portant role in the chemistry of chloro phyll, the Carnegie-Mellon work shows. For example, porphyrins of this series are easily reduced to chlorins. And chlorins of this type, includ ing chlorophyll, resist oxidation ( dehydrogenation). This could result from the distortion caused by the Ε ring which may increase the electron den sity in the β-β bond of the D and Β rings. Also the in-plane crowding, which is probably enhanced by the Ε ring, is relieved by reduction.
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JULY 22, 1968 C&EN
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