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The crystal and molecular structures of some inorganic, organic, and biological compounds Camerman, Norman 1964

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THE CRYSTAL .AND MOLECULAR STRUCTURES OF'SOME INORGANIC, ORGANIC, AND BIOLOGICAL COMPOUNDS by .NORMAN CAMERMAN B.Sc.(Hon.)j University of British Columbia, 1961 A THESIS SUBMITTED IN.PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of CHEMISTRY We accept this thesis, as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September, I 9 6 U . In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of • B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study* I f u r t h e r agree that per-m i s s i o n f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . I t i s understood t h a t . c o p y i n g or p u b l i -c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n permissions, Department of The U n i v e r s i t y of B r i t i s h Columbia, Vancouver 8, Canada The Uni v e r s i t y of B r i t i s h Columbia FACULTY OF GRADUATE STUDIES PROGRAMME OF THE FINAL ORAL EXAMINATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY of NORMAN CAMERMAN B.Sc, The University of B r i t i s h Columbia, 1961 WEDNESDAY, AUGUST 19th, 1964, AT 10:00 A.M. IN ROOM 261, CHEMISTRY BUILDING COMMITTEE IN CHARGE Chairman: I. McT. Cowan W.R. Cullen J.P. Kutney C A . McDowell S.A. Melzak E. Teghtsoonian J . T r o t t e r External Examiner: Dr. D.G. Watson University of Washington THE CRYSTAL AND MOLECULAR STRUCTURES OF SOME INORGANIC, ORGANIC, AND BIOLOGICAL COMPOUNDS ABSTRACT The c r y s t a l and molecular structures of cyanodi-methylarsine (cacodyl cyanide), diiodomethylarsine, and "cacodyl disulphide" (dimethylarsi.no dimethylditbioar-sinate) have been determined by x-ray d i f f r a c t i o n of singl e c r y s t a l s , i n order to investigate the stereo-chemistry of arsenic. The structure of cyanodimethylarsine was determined from projections along the three c r y s t a l l o g r a p h i c axes. The ce n t r a l arsenic bond angle of 105" agrees well with that found i n the halogendiphenylarsines, and i s con-siderably larger than the value assumed i n an electron-d i f f r a c t i o n i n v e s t i g a t i o n of the corresponding dimethyl d e r i v a t i v e s . There i s an unusually short A s , . . J i n t e r -molecular separation, which i s i n d i c a t i v e of charge -—~ transf e r bonding involving donation of nitrogen lone pair electrons to vacant arsenic 4d-orbitals, which probably accounts for the s o l i d i t y of the compound whereas the halogendimethylarsines are a l l l i q u i d at room temperature.. Diiodomethylarsine, one of the few simple arsenic de r i v a t i v e s which are s o l i d at room temperature, was s t r u c t u r a l l y determined from p a r t i a l three-dimensional data i n normal and generalized projections. Though severe absorption corrections had to be applied., values of the bond distances, valency angles, and intermolecular separations were obtained. The molecular structure of "cacodyl disulphide" was determined p r e c i s e l y , u t i l i z i n g the f u l l three-dimen-sional data, and the analysis revealed the compound to be dimethylarsino dimethyldithioarsinate, an unusual structure, having one t r i v a l e n t and one pentavalent arsenic atom i n the molecule. The former atom has a t r i -gonal-pyramidal configuration, while the l a t t e r i s roughly t e t r a h e d r a l . There i s an unusually short i n t e r -molecular As^*^.. .As-t^ separation which suggests charge-transfer bonding involving donation of lone p a i r electrons on each As-'-*-*- to vacant 4d-orbitals on the other A s ^ H . The structure of the a l k a l o i d cleavamine, a product of the a c i d i f i c a t i o n of the Vinca rosea Linn a l k a l o i d catha-ranthine, was determined from a three-dimensional x-ray analysis of cleavamine methiodide. The indole system i s retained i n cleavamine but the rest of the molecule undergoes rearrangement v i a bond f i s s i o n , the result: being a t e t r a c y c l i c a l k a l o i d s t r u c t u r a l l y resembling the known a l k a l o i d quebrachamine. The presence of the iodide ion prevented accurate measurements of the bond distances and angles, but, the measurements were s u f f i c i e n t l y pre-c i s e to d i f f e r e n t i a t e between the d i f f e r e n t types of bonds and angles. The absolute configuration of cleavamine was also established. The c r y s t a l and molecular structure of 5-iodo-2'-deoxy-uridine, the f i r s t a n t i - v i r a l agent to have proven c l i n i c a l chemotherapeutic value, was elucidated by a three-dimensional x-ray i n v e s t i g a t i o n . The bond lengths and angles i n the nucleoside were determined accurately, and indicated that, the pyrimidine base i s i n the di~k.et:o form. The deoxyribose r i n g i s puckered with, C2 ! displaced 0.59 A frcm the plane of the other four atoms; the distan-ces and angles i n the sugar r i n g are a l l normal. The most s i g n i f i c a n t intermolecular distance i s an I....0 (carbonyl) separation of 2.96 A; t h i s i s considerably shorter than the usual van der Waals contact (3.55 A) and suggests charge-transfer bonding involving donation of oxygen lone pair electrons to vacant- Sd-orbitals of the iodine atom-. A strong intermolecular a t t r a c t i o n of t h i s type may be the cause of the increase i n "melting temperature" observed when 5-iodo-2'-deoxyuridine i s substituted for thymidine i n DNA, and hence may be the molecular basis for the compound's a n t i - v i r a l a c t i v i t y . A preliminary x-ray i n v e s t i g a t i o n was c a r r i e d out: on c r y s t a l s of sodium t h y m i d y l y l - ( 5 3 ' ) - t h y m i d y l a t e - ( 5 1 ) . The c e l l constants and space group of the dinucleotide were determined, and the i n t e n s i t i e s of the three-dimen-sional d i f f r a c t i o n maxima were recorded, but the absence of a r e l a t i v e l y heavy atom made attempts at: a complete s t r u c t u r a l e l u c i d a t i o n unsuccessful. A number of c r y s t a l l o g r a p h i c computer programmes have been written f o r the IBM 1620 and 7040 computers; a l i s t , of these i s given i n an appendix. GRADUATE STUDIES F i e l d of Study: Chemistry Topics i n Physical Chemistry Topics i n Inorganic Chemistry Topics i n Organic Chemistry Cr y s t a l Structures Related Studies: Calculus & D i f f e r e n t i a l Equations D i g i t a l Computer Programming Linear Algebra Quantum Mechanics J..A. R. . Coope R.F. Snider A. Bree N. B a r t l e t t W.R. Cullen D.E. McGreer J.P. Kutney R.E.I. Pincock J . T r o t t e r W.H. Gage C. Froese R. Cleveland W. Opechowski PUBLICATIONS 1. N. Camerman and J . Trotter, "Crystal!ographic Data for Ethyl-3,5-dinitrobenzoate", Can.J.Chem. J9_t 2133 (1961) 2. N. Camerman and J . Tro t t e r , " C r y s t a l and Molecular Structure of Cyanodimethylarsine", Can .-J. Chem. 41, 460 (1963) 3. N. Camerman and J . Tr o t t e r . "The Structure of Ditodomethylarsine", Acta Cryst:, JL6, 922 (1963) 4. No Camerman and J . Trotter, "Structure of "Cacodyl Disulphide", Dimethylarsino Ditnethyldi-thioarsinate", J.Chem.Soc. 219 (1964) 5. N. Camerman and J . Trotter, "The Structure of Cleavamines X-ray Analysis of Cleavamine Methiodide", Acta Cryst. 17, 384 (1964) 6. J . Kutney, J . Trotter, T. Tabata, A. Kerigan and N. Camerman, "Chemistry of Catharanthine; Evidence for a Novel Acid Rearrangement," Chem. and Ind., 648 (1963) 7. No Camerman and J . Trotter, "Crystal and Molecu-l a r Structure of .5-Iddo-2'- deoxyuridine",• Acta Cryst. In Press 8. N. Camerman and J . Trotter, "5-Iodo-2 8-deoxyuri-dines Relation of Structure to i t s Ant:i-viral A c t i v i t y " , Science, 144, 1348 (1964) i i < ABSTRACT The crystal'and molecular structures of cyanadimethylarsine (cacodyl cyanide), diiodomethylarsine, .and.""cacodyl disulphide" (dimethylarsino dimethyldithioarsinate) have been determined by x-ray d i f f r a c t i o n of single c r y s t a l s , i n order to .investigate the stereochemistry of-arsenic. The structure of cyanodimethylarsine was determined from projections along the three c r y s t a l l o g r a p h i c -axes. The c e n t r a l arsenic bond angle of 105° agrees w e l l with that found i n the halogendiphenylarsines, ..and i s considerably l a r g e r than the value assumed i n an e l e c t r o n - d i f f r a c t i o n i n v e s t i g a t i o n of the corresponding dimethyl d e r i v a t i v e s . There is-an unusually.short"As...:N, intermolecular. separation, which i s . i n d i e a t i v e of charge-transfer bonding•involving donation of nitrogen "lone p a i r electrons to vacant .arsenic Ud-orbitals,.which probably.accounts f o r the s o l i d i t y of the compound whereas the halogendimethylarsines. are a l l l i q u i d at room temperature. Diiodomethylarsine, one of the few simple arsenic d e r i v a t i v e s which are s o l i d at room temperature, was structurally.determined from p a r t i a l three-dimensional data i n normal and generalized projections. Though severe absorption corrections had to be_.applied, values of the bond, distances, valency angles, and intermolecular separations were obtained. The molecular structure of "cacodyr.disulphide" was. determined p r e c i s e l y , u t i l i z i n g the f u l l three-dimensional data, and the analysis revealed the compound to'be dimethylarsino dimethyldithioarsinate,.an unusual structure, having one t r i v a l e n t and one pentavalent arsenic atom i n the molecule. The former atom has -a trigonal-pyramidal configuration, while the l a t t e r i s roughly tetrahedral. There i s an unusually. short intermolecular ••As"'""'"'''. . .As"'""'"''" separation which suggests charge-transfer bonding i n v o l v i n g donation of lone p a i r electrons on each As"^ "*" to -vacant Ud-orbitals on the other •As^'*'. i i i The s t r u c t u r e of the a l k a l o i d cleavamine, a product of the a c i d i f i c a t i o n of the V i n c a rosea L i n n a l k a l o i d catharanthine, was determined from-a three-dimensional x-ray-.analysis of cleavamine methiodide. The i n d o l e system i s r e t a i n e d i n cleavamine but the r e s t of the molecule undergoes.rearrangement v i a bond f i s s i o n , the r e s u l t being a t e t r a c y c l i c a l k a l o i d s t r u c t u r a l l y resembling the known a l k a l o i d quebrachamine- The :presence of the i o d i d e i o n prevented accurate measurements of the bond dist a n c e s and angles, but the measurements were s u f f i c i e n t l y p r e c i s e to d i f f e r e n t i a t e between the d i f f e r e n t types of bonds and angles. The absolute c o n f i g u r a t i o n ..of cleavamine was •also e s t a b l i s h e d . ' The c r y s t a l and molecular s t r u c t u r e of ^-±odo-2,-deoxyuridine,.the f i r s t a n t i - v i r a l - agent to have proven . c l i n i c a l chemotherapeut.ic value, was e l u c i d a t e d by a three-dimensional:X-ray i n v e s t i g a t i o n . The bond-lengths and angles i n the nucleoside were determined a c c u r a t e l y , and i n d i c a t e d t h a t the p y r i m i d i n e base i s i n the d i - k e t o form. The deoxyribose r i n g i s puckered with, C2' d i s p l a c e d 0-59 A" from the plane of the other f o u r atoms; the d i s t a n c e s and angles i n the s u g a r . r i n g are a l l normal. The most s i g n i f i c a n t i n t e r m o l e c u l a r distance i s an I....0 (carbonyl) s e p a r a t i o n of 2.96 1; t h i s i s c o n s i d e r a b l y shorter than the u s u a l van der Waals contact (3.55-A) and suggests charge t r a n s f e r bonding i n v o l v i n g donation of oxygen lone p a i r e l e c t r o n s to vacant 5 d - o r b i t a l s of the i o d i n e atom. .-A strong i n t e r m o l e c u l a r a t t r a c t i o n of t h i s type may be the-cause of the i n c r e a s e • i n - " m e l t i n g temperature" observed when 5-iodo - 2 '-deoxyuridine i s s u b s t i t u t e d f o r thymidine i n DNA, and hence may be the molecular b a s i s f o r the compound's a n t i - v i r a l a c t i v i t y . A p r e l i m i n a r y x-ray i n v e s t i g a t i o n - w a s c a r r i e d out on c r y s t a l s of sodium t h y m i d y l y l - ( 5 ' — * " 3 r ) - t h y m i d y l a t e - ( 5 ' )• The c e l l constants and space group of the dinuc-leotide were determined, and the i n t e n s i t i e s of the three-dimensional d i f f r a c t i o n maxima were recorded, but the absence of a r e l a t i v e l y heavy atom made attempts at a complete s t r u c t u r a l e l u c i d a t i o n u n s u c c e s s f u l . . A number of c r y s t ' a l l o g r a p h i c computer programs have been w r i t t e n f o r the IBM 1620 and 'JOkO computers; a l i s t of. these i s given i n an appendix. To MY MOTHER for a lifetime, of labor f o r her c h i l d r e n V , ACKNOWLEDGEMENTS I am greatly.indebted to Dr. J. T r o t t e r f o r h i s invaluable assistance, advice, and f r i e n d s h i p during the course of my graduate studies. I would also l i k e to express, my thanks, to Dr. W;R.-Cullen for.samples of the three arsenic-containing compounds,.to Dr. J . Kutney f o r the sample of cleavamine methiodide, ;and to Dr. G.M. Tener for the dinucleotide sample and f o r much h e l p f u l discussion and. advice on. the dinucleotide.and:5~iodo-2'-deoxyuridine. 'My thanks are also due to Dr.'F;R.•Ahmed forki n d l y . m a k i n g a v a i l a b l e h i s structure f a c t o r -and Fourier.programs, and to Dr. G-A. Mair f o r h i s anisotropic l e a s t squares program,.for the IBM 1620 computer. I a l s o thank Dr. J . T r o t t e r f o r his.assistance dn w r i t i n g s e v e r a l . c r y s t a l l o g r a p h i c computer programs. For many.of the i l l u s t r a t i o n s . i n t h i s thesis I am indebted to Mr. W. Griba. F i n a l l y , I g r a t e f u l l y acknowledge the generous support of the National Research Council of Canada Which•awarded me a bursary f o r 1961-62, and a studentship f o r the period 1962-64. v i TABLE OF CONTENTS • Page TITLE"PAGE . (i) ABSTRACT ( i i ) , ACKNOWLEDGEMENTS (v) TABLE OF CONTENTS (vi) LIST OF FIGURES . . ( v i i i ) LIST OF TABLES (x) GENERAL INTRODUCTION 1 PART I. SOME.ASPECTS OF THE THEORY OF "CRYSTAL STRUCTURE DETERMINATION 4 I. Elementary Crystallography . . 5 A. External Geometry and Symmetry 5 B. Internal Structure - Lattice Theory 6 C. Spac e Group s • 7 TI. X-Ray Diffraction by.-a Crystal . . . 9 ,A. Scattering by the-Atoms • • • 9 B.. von' Laijie's Equations and'Bragg's Law 10 ;C. Diffraction in Reciprocal Space ' 11 D. The Structure Factor 13 E. Intensities of Diffraction Maxima 14 F. Fourier Series and the"Phase Problem l 6 III. Structure Analysis. Procedures 17 . ;A. Determination of Structures . ; . . 17 B. Refinement of Structures 19 . C. Assessment of Accuracy 23 PART II. THE STRUCTURES OF CYANODIMETHYLARSINE, DIIODOMETHYLARSINE, A^ND' DIMETHYLARSINO DIMETHYLDITHIOARSINATE (^CACODYL DISULPHIDE"). 24 I. CYANODIMETHYLARSINE 25 A. Introduction 25 B. Experimental 25 C Structure Analysis 26 D. Discussion . . . . 29 v i i • Page II. DIIODOMETHYLARSINE . . . , 33 . A. • Introduction 33 B. ' Experimental .... . .... 33 C. • Structure Analysis . 3^ D. Discussion 35 II I . DIMETHYLARSINO DIMETHYLDITHIOARSINATE•("GACODYL DISULPHIDE") . kO A. Introduction • • kO B. Experimental. 41 C. Structure 'Analysis ... . . - . . 42 D. Discussion . . . . . . . . . ...... -hk PART.Til. THE "STRUCTURES. OF CLEAVAMINE METHIODIDE•. AND 5-Lt)DO-2'-DEOXYURIDINE, AND CRYSTAL DATA FOR SODIUM THYMIDYLYL - (5' —*~ 3' ) -THYMIDYLATE- (5' ) 53 I. CLEAVAMINE" METHIODIDE . 5^  A. Introduction . . . ....... 5^  B. Experimental 55 C. Structure Analysis ........ . ..... . . .... . . . . . ,56 ' D. Discussion .. . . . . ... 65 II. 5-IODO-2'-DEOXYURIDINE . . . • • 69 • •: A. Introduction 69 B. Experimental 70 C. Structured-Analysis . . 7°. D. Discussion .... . • • . . . 77 II I . • SODIUM THYMIDYLYL-(51 -*- 3* )-THYMIDYLATE-(51 ) 8 1 + .A. Introduction . .... . • • 84 B. Experimental 86 C. Attempts at Structure E l u c i d a t i o n 87 APPENDIX. A BRIEF' DESCRIPTION- OF SOME CRYSTALLOGRAPHIC. PROGRAMS FOR THE IBM l620 AND 7040 COMPUTERS 90 REFERENCES 94 v i i i LIST OF FIGURES Figure Page 1. The Ik- Bravais l a t t i c e s . . . 8 2. Scattering from a row of l a t t i c e points . 10 3- Relationship between S and c r y s t a l plane 10 k. Relationship between vectors s Q , s, and iS 11 5- Construction of a r e c i p r o c a l ' l a t t i c e ..... . . ..... . 12 6. D i f f r a c t i o n ,in' r e c i p r o c a l space . 13 CYANODIMETHYLARSINE ' 7- Electron-density p r o j e c t i o n and view of the structure along c '.27 8. Electron-density projections along a and b 28 9- Measured bond lengths and valency angles . . . . . . . . . . . 30 10. Packing of the molecules, projected-along Q)0lj . 32 DIIODOMETHYLARSINE 11. Electron-density p r o j e c t i o n and view of the structure along b 36 12. Cosine and sine h l i generalized projections . . . . . . . . . 37 13- Measured bond lengths and valency angles 38 lU. Packing-of the molecules, projected....onto (010) . . . . . . . 39 ,DIMETHYLARSINO DIMETHYTT1THI0ARSINATE ("CACODYL DISULPHIDE") 15. Superimposed sections of the three-dimensional electron-density d i s t r i b u t i o n , through the atomic centres perpendicular to b, .and perspective view-of the-molecule 45 16. Packing of the molecules, projected along '[lOo} • hQ 17. View of the molecule along the S^-Asj bond 49 i x Figure Page CLEAVAMINE METHIODIDE 18. Superimposed s e c t i o n s of the three-dimensional e l e c t r o n -d e n s i t y d i s t r i b u t i o n , through the atomic centres p a r a l l e l to (OlO),.and p e r s p e c t i v e view o f the molecule . . . . . . . 59 19- Bond dist a n c e s and valency angles 62 20. Packing of the molecules, p r o j e c t e d onto (100) 63 5-I0D0-2'-DEOXYURIDINE 21. Superimposed s e c t i o n s of the t h r e e - d i m e n s i o n a l . e l e c t r o n -d e n s i t y d i s t r i b u t i o n , through the atomic centres p a r a l l e l to (lOO), .and p e r s p e c t i v e view of the molecule 73 22. Bond lengths and valency angles 76 23. Isometric p r o j e c t i o n showing the molecular packing . . . . . . 82 LIST OF TABLES Table Page I. The '32 Point Groups or C r y s t a l Symmetry Classes 6 CYANODIMETHYLARSINE II. P o s i t i o n a l Parameters . 29 DIIODOMETHYLARSINE. I I I . P o s i t i o n a l Parameters . . . . . . . . . . 35 ' DIMETHYLARSINO -DlTVBTRYIigTHIOARSINATE ("CACODYL DISULPHIDE"). IV. P o s i t i o n a l and Thermal'Parameters with Standard- Deviations k6 V. Bond Distances and Valency/Angles with Standard Deviations kS VI. Shorter Intermolecular "Distances kj VII. Progress of Refinement kf • CLEAVAMINE METHIODIDE VIII. P o s i t i o n a l and Thermal!Parameters-with Standard Deviations, and-Peak Electron-Densities . . . . . . . . . . . . . . . . 60 IX. Shorter Intermolecular Distances 6l X. Deviations from Mean Planes 6k XI.' Determination of the Absolute Configuration 66 5-IODO-2'-DEOXYURIDINE XII. C r y s t a l Data 71 XIII. Positional•and Thermal Parameters with Standard Deviations. 75 XIV. Deviations from Mean .Planes 78 XV. Shorter Intermolecular Distances . 79 GENERAL INTRODUCTION 2. This t h e s i s i s concerned with the s t r u c t u r a l e l u c i d a t i o n of a number of inorganic,.organic,.and b i o l o g i c a l l y - a c t i v e compounds, by s i n g l e - c r y s t a l x-ray d i f f r a c t i o n . The contents are divided into three p a r t s : Part I i s a d e s c r i p t i o n of some of the theory of c r y s t a l symmetry, x-ray d i f f r a c t i o n by.single c r y s t a l s , and•methods presently.employed i n the e l u c i d a t i o n of c r y s t a l structures. I t .is by no means a thorough or comprehensive exposition,.and'is intended only..as an .introduction f o r the reader to some of the methods employed.in determining the . s t r u c t u r e s ' W h i c h follow i n parts II and I I I . Part II c o n s i s t s of the determination of the crystal.and molecular structures of.three -arsenic-containing compounds,-undertaken as.part of a project to .investigate the stereochemistry of a r s e n i c At the commencement •of my graduate studies there were no computing f a c i l i t i e s a v a i l a b l e , and structure factor, and Fourier c a l c u l a t i o n s had to be done manually on a desk c a l c u l a t o r ; t h i s severely l i m i t e d the size of the molecules, whose s t r u c t u r a l determination could be attempted, as w e l l as l i m i t i n g the methods which could.be used. Thus the f i r s t two compounds, discussed, cyanodimethylarsine and diiodomethylarsine, are r e l a t i v e l y small molecules and were investigated by,essentially,two-dimensional p r o j e c t i o n s . Toward the end of 1961 the UBC Computing Centre acquired.an IBM T620 computer and shortly thereafter "Dr. F.R. • Ahmed's-structure-factor-and Fourier programs were made. a v a i l a b l e to us. Larger molecules could now be investigated,,and the structure of '"cacodyl.disulphide" was determined, u t i l i z i n g the f u l l three-dimensional data. Part I I I describes the complete structural, determination by three-dimensional means of two -large, organic and b i o l o g i c a l molecules - the a l k a l o i d cleavamine and a nucleoside, ^-iod.o-2' -deoxyuridine. • In. addition, preliminary-data i s given f o r - a dinucleotide,,sodium thymidylyl-(5'—»•3')-thymidylate-(5'). A b r i e f appendix follows part T i l . •In. i t are short descriptions -of several c r y s t a l l o g r a p h i c computer programs, written and repeatedly u t i l i z e d i n the course of the s t r u c t u r a l investigations which are described i n t h i s t h e s i s . PART I SOME ASPECTS OF THE THEORY OF CRYSTAL STRUCTURE DETERMINATION 5-I. ELEMENTARY CRYSTALLOGRAPHY •A. External Geometry and Symmetry I t was recognized-in the'17th century that while c r y s t a l s of the same substance might appear i n many shapes and forms, the angles between the p r i n c i p a l faces remained constant. I t i s thus the o r i e n t a t i o n of the faces which i s a property of the c r y s t a l . I f three non-coplanar vectors are chosen as a reference system and we a r b i t r a r i l y choose a plane of the c r y s t a l ( c a l l e d the standard or parametral face), with a x i a l intercepts of a, b,.andc, then-any face of the c r y s t a l has a x i a l intercepts of a/^, b/^, c/£,; h,k,X are termed the M i l l e r indices of the plane. Hauy recognized i n 1784 that the r a t i o s of the indices of any face of any c r y s t a l are small integers (law-of r a t i o n a l i n d i c e s ) . When we say a geometrical f i g u r e has symmetry,.we mean that i f some operation (e.g. r o t a t i o n about an axis) ,is performed.on the f i g u r e i t w i l l produce an o r i e n t a t i o n which i s i n d i s t i n g u i s h a b l e from the o r i g i n a l f i g u r e . Though a geometrical f i g u r e can be -constructed to display any desired degree of symmetry, the law of r a t i o n a l indices l i m i t s the symmetry elements possible i n a c r y s t a l to 1-fold, 2-fold, 3-fold, 4-fold, or 6-fold r o t a t i o n or. rotatory inversion axes. It was f i r s t shown by Hessel i n I83O that there were only 32 ways -of combining the above symmetry, operations into s e l f - c o n s i s t e n t sets, and these sets are known as the 32 c r y s t a l classes or point groups (Table i ) . 6. Table I. The 32 C r y s t a l Classes (The eleven classes of d i s t i n c t Laue-symmetry are separated by v e r t i c a l ' l i n e s ) .System . Axes and angles C r y s t a l classes (point groups) T r i c l i n i c a b . c f> y 1 1 C l C i Monoclinic • a b „ c 90° ft 90° 2 m or 2 - 2/m c 2 C s c2h -Orthorhombic •a b c 90° 90° 90° . 222 mm2 mmm D2 c2v D 2 h Tetragonal a a c 90° 90° 90° 4 4 k/m Ck $k %h 422 4mm 42m 4/mmm D 4 C 4 v D 2 d D 4 h Trigonal (rhom-bohedral) aaa a a c or <**x 90° ' 9 0 ° 120° •3 3 c 3 c 3 i 32 3m 3m D 3 C 3 v D 3 d Hexagonal a a c 90° 90° 120° 6 Z 6/m c 6 c 3 h c 6 h 622 6mm 6m2 6/mmm D 6 c 6 v ' D 3 h B 6 h Cubic a a a 90° 90° 90° 23 m3 T T h 432 '4~3m m3m 0 T d 0 h B. Internal Structure - L a t t i c e Theory The idea that the regular external geometry and symmetry of c r y s t a l s r e f l e c t e d some ordered.arrangement of the ultimate matter of which the c r y s t a l i s composed, that i s that c r y s t a l s must be based on some sort of l a t t i c e s t r u c t u r e , ; a l s o .arose i n the 17th century. By l a t t i c e i s meant some regular geometrical r e p e t i t i o n i n space of i d e n t i c a l u n i t s , and i t may be represented by an orderly three-dimensional array of points. Connecting these points r e s u l t s i n an i n d e f i n i t e l y extended regular s e r i e s of par a l l e l o p i p e d s or unit c e l l s , defined by the three non-coplanar edge vectors and the contained 7-angles. Since there are usu a l l y many ways of connecting the l a t t i c e points the choice of a u n i t c e l l . i s d i c t a t e d "by size,, s i m p l i c i t y , and ease of v i s u a l i z i n g the symmetry and carr y i n g out mathematical c a l c u l a t i o n s . There -are seven possible u n i t cell-shapes, characterized by the symmetry elements contained, i n t h e i r l a t t i c e s , and these make up the seven c r y s t a l systems ( T a b l e ' l ) . When the p o s s i b i l i t y of centering i n the l a t t i c e i s considered, only fourteen d i f f e r e n t B r a v a i s ( l ) l a t t i c e s belonging to the seven systems can be distinguished ( F i g . l ) . C. •Spac e Group s Since l a t t i c e s c o n sist of regular arrays of i d e n t i c a l u n i t s , t y p i f i e d by l a t t i c e points, the structure -can be brought into self-coincidence i n . a new.way,- namely by t r a n s l a t i o n s along-any of the l a t t i c e - d i r e c t i o n s . This means that a new c l a s s of symmetry operations i s - a p p l i c a b l e to l a t t i c e structures,.obtained by combining r e f l e c t i o n s and rotations with t r a n s l a t i o n s , the former combination g i v i n g r i s e to gl i d e planes, and t h e 1 l a t t e r to. screw .axes. The s e l f - c o n s i s t e n t sets-of symmetry elements, i n c l u d i n g those having t r a n s l a t i o n a l p r o p e r t i e s , . c o n s t i t u t e groups of movements which are i n f i n i t e but discontinuous,.and these .are c a l l e d space groups. Federow (2), Schoenflies (3),, and Barlow •' (k) . showed independently that "230 d i f f e r e n t space groups are possi b l e . These are tabulated e x t e n s i v e l y . i n the International Tables for'X-Ray Crystallography, V o l . 1 (5). The basis f o r space group determination by x-ray d i f f r a c t i o n ,is that the presence of g l i d e planes and screw.axes produce-systematic absences i n the x-ray spectra. 'Because non-translational symmetry elements cause no • such.systematic absences-and because F r i e d e l ' s Taw-asserts that x-ray d i f f r a c t i o n .patterns have an inherent center of symmetry, i t i s not always poss i b l e to pinpoint the space group from the d i f f r a c t i o n pattern alone. 8 . 1. TRICLINIC KJ £7 2 S I M P L E M O N O C L I N I C 3. SIDE-CENTERED MONOCLINIC / T Z 7 1 ATy] Y-zy kCD7 ^t!2j 1\ 4 SIMPLE ORTHORHOMBIC S END-CENTERED ORTHORHOMBIC FACE-CENTERED ORTHORHOMBIC 7 BODY-CENTERED ORTHORHOMBIC 8 HtKAGONAL 9 H H O M B O M E D R A L io SIMPLE TETRAGONAL 11 BODY-CENTERED TETRAGONAL l i S I M P L E C U B I C 13 BOOY-CENTEUED COBIC 14 FACE-CENTERED CUBIC F i g . l . The - l U B r a v a i s l a t t i c e s . 9-I I . X-RAY DIFFRACTION BY A CRYSTAL : A. Scattering by the Atoms I f an .electron i s located i n the path of an x-ray beam i t i s forced into o s c i l l a t i o n by the .electromagnetic f i e l d of the x-rays impinging upon i t . Due to t h i s a c c e l e r a t i o n the electron i n turn becomes a source-of r a d i a t i o n of the same frequency, and wavelength,,and i n t h i s way i s said to • scatter the impinging r a d i a t i o n . The s c a t t e r i n g power of an atom,.designated f 0 (form f a c t o r ) , i s expressed i n term's of the s c a t t e r i n g power of a single free electron, . and therefore the maximum sc a t t e r i n g by an atom i s equal to i t s atomic number. Since-the •electrons are d i s t r i b u t e d throughout the volume-of the•atom,,destructive interference of the.wavelets scattered from d i f f e r e n t parts of the-electron cloud sets in, :and f G decreases with increasing Bragg.angle,8. Values of f Q have been computed for. most common atoms and ions by t h e o r e t i c a l methods,.and are tabulated-as-a function of s i n 6/X i n the International Tables, V o l . I l l (5)-In .calculating f Q values. the ; atoms are assumed to be at r e s t , but i n .actuality thermal o s c i l l a t i o n s of the atoms, r e s u l t i n a spreading of the •electron.distribution,.and so decrease the. i n t e n s i t i e s , of the spectra. The •temperature corrected s c a t t e r i n g f a c t o r , f, i s given, by '2_ ,.. 2 f = f G e -B. s i n 0 / X (l) B, the Debye-Waller temperature f a c t o r ( 6 , 7 ) , i s r e l a t e d to the mean square displacement of the atom normal to the r e f l e c t i n g .plane, ^X^t B,= 8 TC 2 JUL 2 (2) In c r y s t a l - s t r u c t u r e - a n a l y s i s , B.is usually, treated as an empirical parameter. • 10. B. von Laue's Equations and Bragg's Lav Consider a p a r a l l e l "beam of x-rays f a l l i n g upon a space l a t t i c e i n a d i r e c t i o n defined by the u n i t vector "SQ (Fig.2).• For constructive i n t e r -ference to occur i n the d i r e c t i o n of the u n i t vector ~s, . the path difference between-waves scattered from successive points separated by the basis vector •a must equal an.integral number of wavelengths, nA . Thus a ( c o s c < 0 - c o s o < ) ,= n A (3) or i n three dimensions, a ' A n , Fig.2 S c a t t e r i n g from a row of l a t t i c e points Fig.3 Relationship between £3 -and c r y s t a l plane n^r^n^ • ij_(cosc< 0j;- cos c< ^) = n^A i = 1,2,3 (3a) This set of equations .was. derived by von Laue•as the conditions f o r d i f f r a c t i o n from a c r y s t a l l a t t i c e , . a n d may be put into vector form: s-s^ •= 1 or n,-•1 n i S = 1 A 00 S i s known as the d i f f r a c t i o n vector, and i s i n the d i r e c t i o n of t h e b i s e c t o r of the i n c i d e n t and d i f f r a c t e d beams,,since the magnitudes, of s and s Q are equal. Subtraction of any two of equations (k) shows 11. = o i # (5) which means, that S i s perpendicular to the vectors — —si- ;•since these vectors are • i n the plane njn2n3> S i s perpendicular to t h i s plane (Fig. 3 ) . Thus the b i s e c t o r of the incident and d i f f r a c t e d beams, i s i d e n t i f i e d with the normal to the n^^n^, . ( o r h k i ) .plane - the f i r s t step i n the proof of Bragg's law, and the j u s t i f i c a t i o n f o r the concept of each d i f f r a c t i o n as a r e f l e c t i o n of the rays from l a t t i c e planes. The magnitude of the vector S.is obviously 2 s i n 8 (Fig.h) .and the •distance of the plane n-^ngn^ from. the o r i g i n i s a = ! i . s n-,n„n. 1 2 3 n i 2 s i n 0 f>la.ne. n,ntn& jsf -(6) or • 2dj 12_j 12n3 s : i- n ® ! = ^ Fig.h Relationship between the vectors s Q , s, and which i s Bragg's Taw, with the order n S. absorbed i n the integers n^j^n^. Indices of d i f f r a c t i o n , unlike M i l l e r indices, can have common factors; i f n i s t h i s common fa c t o r the spacing corresponding to indices, nh, nk, nX , i s regarded-as l / n t h the spacing corresponding to -indices, hki, , and the nth order r e f l e c t i o n from the hki. plane can be regarded as a 1st order r e f l e c t i o n from t h i s f i c t i t i o u s nh, nk, • ni.,plane. C. D i f f r a c t i o n i n Reciprocal Space To attempt to v i s u a l i z e a large number of planes of varying o r i e n t a t i o n i n a c r y s t a l i s very d i f f i c u l t ; a great s i m p l i f i c a t i o n occurs i f we construct a r e c i p r o c a l l a t t i c e . This i s done by drawing the normal to each.plane i n d i r e c t space from a chosen o r i g i n point, and representing each plane by a 12 . p o i n t on the normal at a distance |Q from the o r i g i n such that d = Kc (1) where K i s a constant. The i n f i n i t e number of f i c t i t i o u s planes of sub-multiple spacings which correspond to second.and higher order r e f l e c t i o n s , from a given ..crystal plane have a common, normal from the origin,.but the corresponding r e c i p r o c a l l a t t i c e points, are r e g u l a r l y spaced out,-.along each- normal i n accordance with (7.)- Extending F i g . 5 to three dimensions r e a d i l y shows, that the indices (hki, ) of any general plane i n r e a l space are simply.the coordinates of the corresponding point i n reciprocal,space. • I t i s convenient to make the constant i n (j_) equal to the x^ray. wave-length X , , so that Fig.5 Construction of a r e c i p r o c a l l a t t i c e /Q - A = 2 s i n 6 / cT ( 8 ) From ( 8 ) i t i s c l e a r that-a sphere described about the center of the r e c i p r o c a l l a t t i c e of radius ^ 0 = 2 contains a l l the reflections-which may be observed with r a d i a t i o n of wave-length X . This i s termed the l i m i t i n g sphere ( F i g . 6 ) . The r e c i p r o c a l l a t t i c e - a f f o r d s a .simple geometrical i n t e r p r e t a t i o n of d i f f r a c t i o n on the basi s of Bragg'sTaw. ( F i g . 6 ) . From ( 8 ) , s i n 0 .= />(P) ^ 2 (2) incident b e a m A si n OAP = — OA for any point P'at a distance from the o r i g i n , a condition s a t i s f i e d f o r Thus any point on the surface o f . t h i s any point on the sphere OAP, as 2 (10) 13-"sphere of r e f l e c t i o n " , and no other Fig.6 D i f f r a c t i o n i n re c i p r o c a l space p o i n t , . i s capable of r e f l e c t i n g r a d i a t i o n incident i n the d i r e c t i o n of i t s diameter AO. The basis of most.single-crystal d i f f r a c t i o n methods i s to rotate or o s c i l l a t e the crystals, so that i n e f f e c t , the d i r e c t i o n of incidence of the x-rays i s changed, and many r e c i p r o c a l l a t t i c e points w i l l be caused to in t e r s e c t the sphere of r e f l e c t i o n . In the derivation of Bragg's'law we assumed the sca t t e r i n g centers (atoms) to l i e on the r e f l e c t i n g crystal.planes, so that-each scattered '-wavelet was i n phase with those scattered from successive p a r a l l e l planes to b u i l d up a strong d i f f r a c t e d beam. .•• In. general, however, . the atoms are n o t - a l l situated on the various c r y s t a l planes, but are d i s t r i b u t e d through the c e l l , so that the waves scattered i n any order hk£ by the atoms i n a un i t c e l l d i f f e r i n phase and must be compounded v e c t o r i a l l y . For a set of planes hkjt , . the spacings a/h, b/k, c / i , correspond to pos i t i o n s from which s c a t t e r i n g d i f f e r s i n phase by 27t • The phase difference P x f o r displacement x i n the a d i r e c t i o n i s given by D. • The'Structure Factor x/a/, = Px/2Tt or P Y = 2TIh( x/ a) ( i i ) Ik. Extending to three dimensions,•the t o t a l phase change that•an-atom-at (xyz) contributes to the plane ( h k X ) i s P.= 27l(hx/ a + ky/ b +Xz/ C) (12) Adding v e c t o r i a l l y the contributions from a l l N atoms i n the u n i t c e l l , , „. J l , 12TC (hx./ .+ky./-+!z./ ) (,^ \ F(hki) = 2-J f.e j'-a j'b * j ' c ' v i i ) The resultant F(hk£. ) i s termed the structure factor. •It is.-a complex quantity, .with amplitude )F(hkjO| and phase cK(hkZ). I t can be evaluated by means of the expressions: .|F(hkJL)| = \ / A 2 + B 2 ( i i ) c X ( h k i ) = t a n " 1 | w h e r e A = i f j cos 2 7C ( h X j / a +k y j/ b+i.z./ c) W B = jS. f j s i n 211 ( h xj/a + kyj/b + i zj/c) I f the summations are c a r r i e d over the coordinates of the equivalent p o s i t i o n s of the space group, s i m p l i f i e d expressions often r e s u l t . In p a r t i c u l a r i f a center of symmetry i s present,.and chosen as the o r i g i n , every vector of phase angle 2TT. Xj/a i s accompanied by'another of phase angle -2TCXj/a. The B part of the structure f a c t o r therefore cancels to zero, and the p o s s i b l e phase angles of F(hk£) are l i m i t e d to 0 or % depending on whether the expression for/A i s p o s i t i v e or negative. E. I n t e n s i t i e s of D i f f r a c t i o n Maxima Most single c r y s t a l s behave as. i f they were not perfect c r y s t a l s , but made up sub-microscopically, of a conglomerate or mosaic of.small blocks,.each block-a p e r f e c t c r y s t a l , but the adjacent blocks not accurately f i t t e d together (8). The c r y s t a l thus r e f l e c t s , x-rays over a small range about the 15-Bragg angle. I f the c r y s t a l i s rotated through the r e f l e c t i n g p o s i t i o n with angular v e l o c i t y w, and I Q i s t h e - i n t e n s i t y of the incident beam and E the t o t a l r e f l e c t e d energy, the r a t i o Ew/l 0 i s . c a l l e d the integrated r e f l e c t i o n , and i s c h a r a c t e r i s t i c of a given c r y s t a l plane. For a mosaic c r y s t a l block of volume dV, small enough that no absorption occurs, Darwin (8) has given .the following r e l a t i o n ,= (N e f _ ) 2 X3 l+cos 22e |F| 2 dV (l5_) o mc 2 2sin2.6 In equation. 15, N i s the number of u n i t c e l l s per u n i t volume,': and e 2/mc 2.arises from the C l a s s i c a l formula f o r s c a t t e r i n g by an electron. The p o l a r i z a t i o n term, (l+cos 226)/2, a r i s e s because the r e f l e c t e d beam is. p a r t i a l l y p o l a r i z e d while the-incident beam i s unpolarized. The Lorentz factor, l/sin,26, takes into account the d i f f e r i n g speeds at which d i f f e r e n t r e c i p r o c a l ' l a t t i c e points move through the • sphere of r e f l e c t i o n . The expression f o r the Lorentz f a c t o r v a r i e s with the experimental conditions, , and. so equation ljp_ must be modified i n use. I f i n t e n s i t i e s are c o l l e c t e d by.the e q u i - i n c l i n a t i o n Weissenberg method,. f o r example, (l_5_) becomes l i c o s f ^ | F | 2 ( i 6 ) ° f cos e — where f i s the c y l i n d r i c a l coordinate of the r e c i p r o c a l ' l a t t i c e point. Other factors- may also a f f e c t the i n t e n s i t i e s . X-rays are absorbed i n c r y s t a l s i n accordance with the Beer-Lambert law,•resulting i n diminution of the various r e f l e c t i o n s , i n a complicated manner depending on the c r y s t a l size .and shape. Absorption corrections are d i f f i c u l t to c a l c u l a t e , but values f o r c r y s t a l specimens, of simple shapes are given i n the International Tables (5)' E x t i n c t i o n e f f e c t s also occur i n c r y s t a l s which are not i d e a l mosaics; primary,extinction r e f e r s to the r e - r e f l e c t i o n of the x-rays from p a r a l l e l 16. planes,,while secondary extenction r e f e r s to the weakening of the.incident beam as i t progresses through the c r y s t a l due to r e f l e c t i o n s from planes i n i t s path. - E x t i n c t i o n e f f e c t s are d i f f i c u l t to overcome,. and are usually ignored. F. Fourier Series and the Phase Problem W.H. Bragg recognized i n 1915 ( 9 ) ,that the electron density i n a c r y s t a l i s a t r i p l y . p e r i o d i c function, and may be represented in. the form .of a Fourier series (px+qy+rz) (17) /0(xyz).= ^ Z Z A ( p q r ) e " 2 7 C l ( / n= a= r= p q r: where x,y,z are f r a c t i o n s of the cell-edges, It can easily, be shown that the Fourier coefficients,-.A(pqr), are equal to F(hki)/V,- so <=»o / v h= k= Jt= — L e t t i n g F(hki) ,= A+1B , F(nkl) ,= A-iB, , and 2TL (hx+ky+l'z) = 6 , .then, .= i 2 , X L T L ^ A c o s 6 + B s i n e ^ Hence the electron density, is. everywhere r e a l , and yO(-x,-y,-z) = |EEE(A cos 6 - B s i n 6 ) (l9_a) which means that the-electron d e n s i t i e s at. (X,Y,Z) and at (-X,-Y,-Z) w i l l d i f f e r unless B=0, :which,,recalling section D,.occurs when the o r i g i n of the space group i s at a center of symmetry. 17-W r i t i n g A-= | F(hk£)| cos«<(hkX) B = | F(hkl)| ,sino((hk£), equation .19 becomes ! o o /O(xyz) = ^ X E Z |F(hkJL)| cos [e-o<(hk£)] (go) Equation 20 i l l u s t r a t e s the phase problem i n x - r a y . c r y s t a l l o g r a p h y . We can f i n d the values of |F(hkl)( from t h e - r e f l e c t i o n i n t e n s i t i e s , . b u t the r e l a t i v e phases are T o s t .and must be recovered by some means, or other before the e l e c t r o n - d e n s i t y d i s t r i b u t i o n i n t h e . c r y s t a l can be c a l c u l a t e d . I l l . STRUCTURE ANALYSIS PROCEDURES A. Determination of S t r u c t u r e s (a) . T r i a l and E r r o r Methods .An approximately.correct s t r u c t u r e ( i . e . c o r r e c t p o s i t i o n i n g of.the.atoms i n the u n i t c e l l ) . i s sought from chemical c o n s i d e r a t i o n s (chemical formula, study of models of the molecules) combined w i t h c r y s t a l l o g r a p h i c data ( l i m i t a t i o n s on p o s s i b l e p o s i t i o n i n g i n the c e l l due to .packing c o n s i d e r a t i o n s ) . •An i n d i c a t i o n of an approximately c o r r e c t , s t r u c t u r e i s reasonable agreement between observed and c a l c u l a t e d . s t r u c t u r e ..amplitudes, g e n e r a l l y . i n d i c a t e d by a low ( ^  <~.4) value of the discrepancy f a c t o r R £ l l F 0 l ~ l F c | | / £ l Fol ' When t h i s i s . a t t a i n e d , . a F o u r i e r s e r i e s w i t h the measured structure-amplitudes and c a l c u l a t e d phases as c o e f f i c i e n t s can be summed,.and from the r e s u l t i n g ..electron-density, p l o t r e v i s e d and more accurate ..atomic coordinates can.be chosen, from which t o r e - c a l c u l a t e s t r u c t u r e f a c t o r s . This i t e r a t i v e procedure i s repeated u n t i l a minimum value of the discrepancy i s a t t a i n e d . (b) Heavy .'Atom Methods - the P a t t e r s o n Synthesis B y . f a r the most .widely-used method, and the one which has y i e l d e d the most r e s u l t s , i s the heavy-atom method. A heavy-atom i s one which contains a 18. much larger number of electrons than do the other-atoms, of the molecule and i s " t h e r e f o r e - o f higher-scattering power to x-rays. Hence i t s contribution to the structure f a c t o r s tends to dominate the contributions of the-other atoms for...a high percentage of the various orders (hkJL). . I f the p o s i t i o n of the heavy-atom i s known,.structure factors may.be calculated, based on.the heavy atom alone,.whose phases are near enough correct to show up the other -atoms i n an.electron d e n s i t y / d i s t r i b u t i o n p l o t t e d with.the observed structure amplitudes and heavy atom phases as Fourier c o e f f i c i e n t s . The l o c a t i o n of.the heavy-atom can usually be.ascertained by use of a 'Patterson, synthesis. In 193^  Patterson (10),showed that the function which can be computed from the observed.data-alone, has maxima whose vector distances from the o r i g i n correspond p h y s i c a l l y to a l l possible interatomic vector-distances i n the c r y s t a l . The height of a Patterson peak.is. dependent on the atomic numbers of the two;atoms, involved,. so vectors between heavy atoms w i l l give r i s e to'Patterson peaks of r e l a t i v e l y , great prominence. Systematic procedures have been developed to derive the. atomic coordinates from the vector d i s t r i b u t i o n ( l l ) . Though i t may now.appear that the structure of any c r y s t a l may be determined simply.by.interpreting i t s Patterson f u n c t i o n , . i t must be pointed out that a c r y s t a l with N atoms i n the u n i t c e l l has N 2 vectors between those •atoms, and thus f o r - a structure of moderate complexity.the resultant-Patterson map contains-a large number of broad unresolved peaks due to overlap, severely l i m i t i n g the amount of information which can be derived from i t . (c) D i r e c t Methods The phase values-are sought - d i r e c t l y , f r o m a knowledge of the structure amplitudes-alone. Harker and Kasper (12), applied Cauchy's and Schwartz's (21) 19. i n e q u a l i t i e s to -modified structure factors and derived i n e q u a l i t y r e l a t i o n s h i p s between some structure f a c t o r s which .impose l i m i t a t i o n s on phases due to crystal.symmetry. -More general systems of i n e q u a l i t i e s , have been derived by Karle and Hauptman (13) .who took. into.account the positiveness. of the-electron density. Relationships between the signs of some structure-amplitudes i n centrosymmetric space groups have been derived by Sayre (l4), Cochran (l5)> and Zachariasen (l6). The most recent-and perhaps most promising approach has been the s t a t i s t i c a l one of Hauptman .and•Karle (17)-Although some structures, have been completely, elucidated by a l l of the above methods, . these d i r e c t methods have not met -.with widespread use -as of yet, ;perhaps partly.because of t h e i r complexity. • B. Refinement of Structures (a) Fourier Methods Refinement of coordinates, by successive Fourier syntheses i s most commonly.carried out i n the f i r s t stages of refinement,.until.all.atoms are f a i r l y - a c c u r a t e l y . l o c a t e d . The major source of e r r o r i n Fourier syntheses i s due to series termination e f f e c t s , . i . e . terminating the'Fourier series while the remaining .coefficients are s t i l l . a p p r e c i a b l e . The summation of a t r i p l e Fourier s e r i e s is. extremely .laborious, and when adequate computational f a c i l i t i e s are not a v a i l a b l e i t i s customary to p l o t the -electron-density.projected onto two -or more planes'by use of a double Fourier series,.which can be computed from zonal data alone. . A normal p r o j e c t i o n :is mapped on a plane ..at r i g h t • angles to the. d i r e c t i o n of p r o j e c t i o n (usually a c r y s t a l l o g r a p h i c a x i s ) , and corresponds to .an i n t e g r a t i o n of the electron-density over the -period of the d i r e c t i o n of p r o j e c t i o n . • For example, ' o I or i n f r a c t i o n a l coordinates, C/0(XYZ) dZ . (22) /O(xy) = J 1 /0(xyz)cdz S u b s t i t u t i n g from (l8) f o r |° (xyz) .and integrating, />(xy).= 1 2 2 . F -2-rCi(hx+ky) s h k Fhko e . (23) where S'is the c r o s s - s e c t i o n a l area normal to the-axis of projeqtion. In a generalized projection,.the electron density i s modulated by .a f a c t o r e 2'^i-'-'z } where L i s a constant value of the index JL •• Thus /O(xy) = / ^ ( x y z ) e 2 * l L z cdz / L 7 o / 1 Z, 2L (2k) S h k FhkL e - 1 2 l t ( h X + k y ) = C L ( x y ) + i S L ( x y ) by the same mathematical procedure as above. Generalized p r o j e c t i o n s can .also yield-approximate t h i r d coordinates of the atoms. The expression f o r the contributions to a structure f a c t o r belonging to the Lth • layer from an .atom j.,is J p ( h k L ) , - ( f j ( h k L ) e 2 ^ i L z ) e 2 1 t i ( h X + k y ) ( 2 J L) If the zero, and Lth'layers are close together, fj(hkL) ^ fj(hkO) and.substituting into the -expressions f o r the electron d e n s i t i e s , we get J/0 (xy) ~ ^ ( x y ) e 2 7 r i L z J (26) which means that the generalized p r o j e c t i o n of the j t h atom i s the same-as i t s normal projection-except that .i t i s modulated by the f a c t o r e 2TTiLz^ Thus zj can be evaluated from the expression 2 7CLzj=tan~-'- SjJC-^ i Series termination '.errors can be eliminated from Fourier methods by .refinement by-difference s y n t h e s e s , - u t i l i z i n g (|F0| - |FC| ) as c o e f f i c i e n t s i n the Fourier s e r i e s (19)- Atoms, which deviate s l i g h t l y , from t h e i r true p o s i t i o n s ' l i e on : steep slopes of the difference-map .and should-be • s h i f t e d up the gradients. The'temperature factor, of the.atom can also be r e f i n e d by. noting i f the atom .lies i n a region of p o s i t i v e or negative density on the d i f f e r e n c e map. Difference syntheses are also commonly employed to locate hydrogen atoms. (b) D i f f e r e n t i a l Synthesis F i r s t suggested by Booth (20), the d i f f e r e n t i a l synthesis seeks the electron-density, maxima by evaluating the f i r s t d i f f e r e n t i a l s of the electron-density at the present•atomic centers. Writing P= 7f 2» F 0cos(©-©<), / -q the slope of the ele c t r o n density, i n the- x - d i r e c t i o n at the point ( x ^ y ^ Z j ^ ) "2]L S"1 h F -sin(6 -ex) , . aV ^ ° n - . (21) i s The amounts by which the point of maximum electron density- deviates from t h i s point are then the - solutions of the three equations ^ * 2 A i ^ ^ / n V ^ z i n ^ (28) etc. When the crystallographic•axes are orthogonal, and the. atoms s p h e r i c a l l y symmetric,.these equations- reduce to Series termination .errors also .affect the d i f f e r e n t i a l : s y n t h e s i s , . b u t may be .allowed f o r by. computing an F c synthesis separately .and ..applying back-s h i f t c o r r e ctions to the-atomic coordinates (21). The advantage of the d i f f e r e n t i a l - s y n t h e s i s over the usual Fourier methods i s that"the point of maximum el e c t r o n - d e n s i t y , i s p r e c i s e l y / l o c a t e d without recourse to i n t e r p o l a t i o n , and the tedious labor of p l o t t i n g Fourier maps and determining coordinates therefrom i s obviated. (c) Least- Squares The method of least, squares was f i r s t applied to c r y s t a l - structure refinement by Hughes (22), and with the increased use of d i g i t a l computers, i s becoming the most common method of refinement today. • The theory of errors, p r e d i c t s that : i f . e r r o r s i n the measured F 0's follow the normal or Gaussian law, then the best atomic parameters are those which r e s u l t - i n a minimization of the quantity "Zv(hkl) ( |F0(hk£.)| - (F c(hki.)| ) 2 where w(hki.) i s a weight inversely, proportional to the square of the probable error i n F D ( h k i ) . A small change A x n i n the x-coordinate of the nth.atom of a structure changes F c . by an amount ^ F c Changes to a l l coordinates simultaneously, r e s u l t i n a change i n F Q of amount A F = ' _ _ c 2 j ^ v j i ^ ^ O (30) n=l v dx^ dy^ ^ z „ 11J The correct .values of A x n, , etc., . are those which most nearly/equate A F C to F 6 - F c f o r all:the-equations of t h i s type possible (one f o r each F Q value). These Tinear-"observational equations" must be reduced to ;a set of "normal equations", the nth of which i s formed by.multiplying both sides of (30) by w ~ ^ F C and then, adding the q left-hand, side's and t h e q right-hand — TO sides to get equations of the. type.. m ^ x n V ^ y m > z m J) q . <L ^ 23-The f i n a l r e s u l t . i s a set of 3N simultaneous,.equations which have to be solved f o r 3N unknowns, & x ^ ^ y n , £ z n ' Refinement by l e a s t .squares has many.advantages: i t i s - f r e e from series termination e r r o r s , . i t allows, varying weights according to the r e l i a b i l i t y of the data,,and i t i s p o s s i b l e to also r e f i n e . a scale factor-and -individual i s o t r o p i c or anisotropic temperature factors f o r each,atom. (C) Assessment of Accuracy The standard deviations of electron density.and atomic coordinates have been given by Cruickshank (23) as a V C n where G n i s the c e n t r a l curvature, , at the center of the nth.atom. Similar formulas apply,for the y,and z coordinates. I f the structure does not have a center of symmetry,.each of (32) must be doubled. The standard deviation of a"bond length between two.atoms i s given by 2 2 5 2 ( d 1 2 ) . = (S^  •+ €2 (33) where (T, and (Tj. are the standard deviations of the,.atomic p o s i t i o n s in.the •direction of the bond. Differences i n equivalent bond distances under d i f f e r e n t measurements are not s i g n i f i c a n t unless they, d i f f e r by-at l e a s t about .2 to 3 times the standard deviation. The standard deviation of an angle 6 between two bonds d^g and dg^ i s given by d12 d23 ^ PART I I THE CRYSTAL AND MOLECULAR STRUCTURES OF CYANODIMETHYLARSINE, DIIODOMETHYLARSINE, , AND "CACODYL DISULPHIDE", DIMETHYLARSINO DIMETHYLDITHIOARSINATE 25-I. CYANODIMETHYLARSINE • A. • Introduction iPrevious works i n t h i s laboratory .have res u l t e d in. the determination of structures of some halogenodiphenylarsines. The O-As-C angles are 105° , •considerably/larger than the value.assumed i n an e l e c t r o n ^ d i f f r a c t i o n i n v e s t i g a t i o n of the corresponding dimethyl derivatives,. so that i t was f e l t t h a t . i t would be u s e f u l to investigate- the structure of a compound of t h i s l a t t e r type. The halogenodimethylarsines.are . a l l l i q u i d s at room temperature, but.cyanodimethylarsine (cacodyl cyanide), whose structure i s described here, • i s a solid,,m.p. 30°. This i s in. i t s e l f an i n t e r e s t i n g f a c t , and suggests that there might be some type of intermolecular i n t e r a c t i o n . by.the reaction of iododimethylarsine-with s i l v e r cyanide i n vacuo, ;the ^ desired product b e i n g . p u r i f i e d by sublimation.. The compound i s very v o l a t i l e •and extremely.toxic, and c r y s t a l s were sealed i n .thin-walled Lindemann-glass c a p i l l a r i e s . The u n i t c e l l dimensions and.space group were determined from r o t a t i o n and o s c i l l a t i o n photographs about the a-axis and OkX and lk£ Weissenberg and hOi, and hkO precession f i l m s . C r y s t a l Data B.. Experimental C o l o r l e s s needle-shaped c r y s t a l s of cyanodirnethylarsine were prepared Volume of the u n i t c e l l . = 258.7 A" D c a l c (with'Z = 2) = 1 . 6 8 g cm"3 Absorption c o e f f i c i e n t s for-X. rays, A= 1-5^2 X, jx= 76 .8 A = O.7IO7. A, JUi = 6 7 . 2 cm"1. cm -1 > 26. F ( O O O ) = 128 Space group is. PI or PI. Analysis has proceeded s a t i s f a c t o r i l y . o n the basis of PI. Due to the extreme v o l a t i l i t y , a n d t o x i c i t y , of the crystals,•no e f f o r t was made to measure the density,. but since i t seemed u n l i k e l y that it,,was •as low.as 0.8 or as, high as .3^ g cm~3, Z = 2 was assumed. This was confirmed by,the subsequent analysis of the -structure. The i n t e n s i t i e s of the Ok/ r e f l e c t i o n s were recorded on Weissenberg films (Cu Ko() ,and of. the hOZ-.and hkO r e f l e c t i o n s on .precession, f i l m s (Mo Ko<). The estimates were made v i s u a l l y , , and the - structure.-amplitudes derived as usual, the-absolute scale being e s t a b l i s h e d l a t e r b y . c o r r e l a t i o n , with, the c a l c u l a t e d structure f a c t o r s . The c r y s t a l used had cross section 0.1'X 0.1,mm and no.absorption corrections were considered necessary. •Eighty-four independent Oki. , f o r t y - e i g h t hOZ , and seventy-seven hkO r e f l e c t i o n s were observed. C Structure-Analysis The position, of the•arsenic.atom was determined from the three Patterson projections,,and the other atoms were then located on electron -density, maps..computed with signs, based on .the-arsenic contributions alone. •Structure f a c t o r s were then, c a l c u l a t e d f o r a l l three..zones, using the sca t t e r i n g f a c t o r s of Berghuis. e t • a l (2k) with an overall•temperature f a c t o r B -= 5^ 1, A2, . determined from p l o t s of l n ( | F c | / (F Q| ) against .sin2e/A.2. Refinement was completed'by computing.-successive Fourier and difference syntheses. The f i n a l electron-density.projections are shown i n Figs . - 7-and 8,.and measured and calculated.structure f a c t o r s are l i s t e d i n (25)- The discrepancy factors f o r the observed planes, are: R(0kX) ,= ik.T$>; R(h0t) = Y\.J$; R(hkO) = lU.0#. 27-3 * Fig.7- Electron-density p r o j e c t i o n along the -c-axis,.with contours at i n t e r v a l s of 2 electrons about C and N, and at i n t e r v a l s of 5, 10, 20,,30 about As,.and p r o j e c t i o n ,of the structure a l o n g c Fig.8. Electron-density projections along the a- and b-axes. ro CO 29-Coordinates and Molecular/Dimensions The f i n a l p o s i t i o n a l parameters of the As, C, and N atoms are l i s t e d i n Table' II-, ,. x,. y, and z being r e f e r r e d to the t r i c l i n i c c r y s t a l - axes and Table II F i n a l p o s i t i o n a l parameters Atom x y • z x' Y ' z' As •0.2115 0.1468 O.3316 O.381 0.657 1.713 C l O.378 0.272 O.698 O.382 T . 0 2 6 3.606 .C 2 •O.I3I+ O.329 0.169 0.358 2.397 0.873 C3 -0.106 0.174 0-339 -1 .623 0.573 •1.751 . N - 0 . 2 9 0 0.191 O.3UU ' •-2.786 0-533 1.777 expressed as f r a c t i o n s of the u n i t c e l l . edges,,and: -x ' , V , z' coordinates in-A units r e f e r r e d to orthogonal axes a A (= a . s i n / ) , b , a n d c / (normal to a 1 •• and- b). The bond distances and valency ..angles i n the molecule-are shown i n :Fig.9> The standard deviations of the.,atomic positions,- c a l c u l a t e d from Cruickshank's (23) formulae, , are <T(x) ,= S'(y) = S(z) .= 0 .005 A f o r As and 0.0U7.A for'C -and-N. These values, are probably o p t i m i s t i c , . e s p e c i a l l y . f o r the C and N atoms, because-two of the projections are poorly.resolved. D. Discussion On-.the bas i s of the - estimated standard deviations, the observed differences between As-CH^ and•As-CN bond lengths are not s i g n i f i c a n t . The mean value of the-bond lengths and•angles,.with standard deviations 'are: •As-C -= I.96+O.O3 A -C-N = I.16+0.07.. A L Me-As-Me .= 105+2° £'Me-As*CN = 91+1. 5° I. As-C-N = l80+4° 30. Fig.9- Measured bond lengths and valency angles. The valency ..angles, d i f f e r somewhat from those reported f o r the halogenodimethylarsines, which were determined by electron d i f f r a c t i o n (26). •The Me-As-Me-angle i n these halides.-was,-assumed to be 96°, the same-as i n trimethylarsine (27), and t h i s is. s i g n i f i c a n t l y smaller than the Me-As-Me angle of 105° now measured f o r the cyano derivative,.which i s s i m i l a r to the-angle i n bromodiphenylarsine,•105° (28), and i n chlorodiphenylarsine, 105° (29)- The Me-As-CN angles are s l i g h t l y l e s s than those reported f o r MegAsBr (96°). The As-C and C^N distances are•normal (30). The shortest intermolecular contact i s an•As N separation of 3-l8, A (Fig.10); t h i s i s considerably l e s s than .the• sum of the van der Waals r a d i i (3-5;A) and.suggests, a charge-transfer bond i n v o l v i n g donation .of nitrogen lone p a i r electrons to the vacant - arsenic k& o r b i t a l s . - The C=N.... As angle i s l68°,.so that the nitrogen lone pair,.which.is•expected to be c o l l i n e a r :with the C=N bond, . i s d i r e c t e d towards the arsenic . atom.. Figure 10 shows that, in.addition,.the arsenic lone p a i r (assuming t h a t . i t makes approximately equal angles with the-As-C bonds) i s d i r e c t e d - away.from the nitrogen, atom, so that the intermolecular bonding.would be T i t t l e hindered 1 by lone-pair repulsions. • Cyanodimethylarsine i s a s o l i d at room temperature,.probably -as a r e s u l t of t h i s intermolecular bonding, while the corresponding halogen derivatives-are l i q u i d s . The cyanide melting p o i n t • i s 65° higher than, that of the iodide, while i n other, series such .as methyl iodide, and cyanide and the corresponding -ethyl,,propyl, :and phenyl d e r i v a t i v e s t h i s difference i s never greater than 20°. Comparison of these differences: with-the increases i n melting point-.which usually, result, from hydrogen bonding suggests- that the energy.of the charge-transfer, bonds i s only,of the order of one or. two k i l o c a l o r i e s . per mole. The donor properties of the t r i p o s i t i v e state of the Group Vb .elements diminish with increase i n atomic number, and are pronounced only.for nitrogen; Fig.10. P r o j e c t i o n of the structure along [OOl], showing the shorter intermolecular contacts. 33-the other members of the group can. act-as electron acceptors. For arsenic t h i s i s i l l u s t r a t e d by the"formation .of complexes between, AsCl^ and various aromatic amines, which, although t h e i r structures have not been .determined, probably, involve intermolecular bonds, s i m i l a r to those i n cyanodimethylarsine; and by the formation of complex ions such as. AsCT^-. • . A l l the other intermolecular distances, i n cyanodimethylarsine correspond to normal van der Waals i n t e r a c t i o n s . I I . DIIODOMETHYLARSINE ; A. Introduction As part of a series of i n v e s t i g a t i o n s of compounds, containing arsenic, the c r y s t a l and molecular structure of diiodomethylarsine has been determined; i t . i s one of the few simple arsenic d e r i v a t i v e s which are s o l i d . a t room temperature. B. Experimental .Crystals, of diiodomethylarsine, which are yellow-orange, are v o l a t i l e and melt-at about room temperature. For recording the X-ray data,.crystals were sealed i n c a p i l l a r i e s , and cooled by,a stream of nitrogen which was f i r s t passed through.a c o i l immersed i n an ice-bath. The u n i t - c e l l dimensions and space group were - determined from various rotation,. o s c i l l a t i o n , Weissenberg (Cu Ko<) and precession (Mo Ko<) f i l m s . •Crystal data (at 5-10°C; A(Cu Ko<),= 1 -5418 A, A(Mo K<*).= O.7IO7 1). Diiodomethylarsine, CH^AsIg; M, , 3 ^ 3 . 8 5 ; m.p. 2 6 ° C : Monoclinic, . a = lU.1+5, h„= k.60, c = 1 9 . 9 7 A, ^= l l 4 ° 2 o ' . • u = 1 2 0 9 . 5 I 3 . D x (with Z=8) = 3 . 8 g.cm"3. .-.Absorption c o e f f i c i e n t , jx (Cu "Kai) .= 939 cm"1. F ( 0 0 0 ) , = 118U. 3k. Absent r e f l e c t i o n s : hkiwhen (h+k) i s odd, hOi. when X i s odd. Space group.is Cc or C2/c Analysis has proceeded s a t i s f a c t o r i l y i n C 2 / c No suitable f l o t a t i o n medium was. a v a i l a b l e f o r measuring the density;:the density.of the l i q u i d , . measured at room temperature-by means of a density b o t t l e , was 3-1 g.cm"3, and,,since i t seemed l i k e l y that the s o l i d . a t s l i g h t l y reduced temperatures, would have-a higher density,•Z=8 was assumed. This was confirmed by the structure-analysis. • Intensity/data f o r the-hOX.and h l Z -reflections, were recorded on Weissenberg films,and estimated v i s u a l l y , and the structure amplitudes were -derived as usual,.the absolute scale being established l a t e r by c o r r e l a t i o n .with the calculated.structure f a c t o r s . The c r y s t a l used was a needle, .elongated along b, with .a rectangular, cross-section O.k X 0.13 mm,.the'(OOl) face being developed. The f i l m s were textbook•examples (31) of severe -absorption -effects,,and corrections, were.applied (32). These .absorption c o r r e c t i o n f a c t o r s applied to the - i n t e n s i t i e s v a r i e d from 1•to .about'1^0, .and since they-are.approximate,.the accuracy of the measured structure •amplitudes i s probably.rather l i m i t e d . •ikO independent h0X r e f l e c t i o n s (77$ of the p o s s i b l e ) and 213 hl i , r e f l e c t i o n s (62$) were observed. C. Structure-Analysis The x- and.z-parameters-were determined from hOX Patterson, and electron- ' density projections,.and the y-coordinates by some t r i a l s with QkO .and hlJt . r e f l e c t i o n s . Structure-factors were c a l c u l a t e d by means-of the scattering •factors of Berghuis, . Haanappel, Potters, • Loopstra, MacGillavry & Veenendaal (2k) for-As and C, and of Thomas & Umeda ( 3 3 ) - f o r I ,,and with .an o v e r a l l temperature factorB=5.T A 2 determined from a p l o t of In (|F C | / [ F 0 | ).against s i n 2 6/>s 2 . Refinement.proceeded by.hOi ( F 0 - F C ) syntheses and hljt cosine.and sine difference generalized projections,, r e f i n i n g - a l l parameters simultaneously (3^ +)• Refinement was complete-after four cycles;;measured and c a l c u l a t e d structure f a c t o r s .are l i s t e d i n (35)> the f i n a l R values f o r the observed r e f l e c t i o n s being 0.l8 f or. hOX and 0.22 f o r h i JL . The f i n a l electron-density, p r o j e c t i o n is. shown i n Fig*11,,and the hlZ :cosine, and sine generalized projections i n •Fig.12. •The f i n a l - p o s i t i o n a l parameters are l i s t e d i n Table I I I , the standard deviations (23),are <f(x)= tr(y)= S (z)=0.006 A f o r I, . 0.010. A f o r As, and o 0.07-A f o r C. The bond lengths.and valency .angles are shown i n F i g • 13 > : and the shorter.'intermolecular contacts, . a l l . of which correspond to van der "Waals i n t e r a c t i o n s , , i n ' F i g . l 4 . •Table I I I . F i n a l , p o s i t i o n a l parameters .Atom x y z .• As- 0.2045 -0,3804 0.1501 I-L O.O59O 0.0436 0.1384 I 2 O.3475 0.0349 .0.1615 c 0.156 0.380 0.037 D. Discussion The structure..analysis has u t i l i z e d a large part ,of the observable three-dimensional data; the r e s t of the av a i l a b l e r e f l e c t i o n s , were not used since.-any. inaccuracies i n the f i n a l • r e s u l t s (as r e f l e c t e d i n the rather high R values) are due not to.a lack of data (353 r e f l e c t i o n s have been used to determine - twelve p o s i t i o n a l parameters), but to the poor•quality of the 'intensity, measurements-as.-a-result of the. absorption e f f e c t s . The standard deviations of the..atomic p o s i t i o n s i n d i c a t e that the carbon, atom-has been located rather imprecisely,,.in the presence of the heavier T and-As. atoms. The arsenic atom has the usual :pyramidal configuration. The>As-I distance-(2* 5^ +9• 01.'A) i s similar, to corresponding lengths in-As I^.. (2.52 A ) . Me 2AsI (2.54 A ) , and Ph 2AsI (-2.53 A ) (30,36). The I-As-I angle (l04°+0.4°) Fig.11. Electron-density p r o j e c t i o n along the b-axis; contours at i n t e r v a l s of 5, '10, 20, 30... eA - 2 at As and I atoms, and 3, k, 5 eA~2 at the C atom. Fig.12. Cosine and sine h i 4 generalized projections. 0 M i l l 1U 2 A 'Fig.lU. P r o j e c t i o n of the structure onto (010), showing the shorter intermolecular contacts. ko. i s a T i t t l e l a r g e r than the -angles i n A s l ^ • Bonds and .angles i n v o l v i n g the carbon atom have been determined l e s s p r e c i s e l y , and do not d i f f e r , s i g n i f i c a n t l y from normal values. I I I . "CACODYL DISULPHIDE", DIMETHYLARSINO DIMETHYLDITHIOARSINATE' A. • Introduction "pACODYL DISULPHIDE," [(CH 3) 2As] 252> - v a s f i r s t prepared by Bunsen (37) by passing hydrogen sulphide through a concentrated•alcoholic s o l u t i o n of cacodylic a c i d : 2(CH3) 2As0(0H)+3H 2S — • [(CH3) 2As] 2S2+S+4H20 and by reaction .of cacodyl sulphide with sulphur. • Dehn and Wilcox "(38) obtained cacodyl sulphide from dimethylarsine-and.sulphur, but found that the disulphide was formed when the .arsine•reacted with a greater -amount of sulphur: 2(CH 3) 2AsH+3S |(CH 3) 2As] 2S 2+H 2S It appears to have been generally, considered that the compound i s . a true disulphide-and i t i s l i s t e d as-a cacodyl d e r i v a t i v e • (39) s o that structure ( i ) has been assumed. However i t s preparation from cacodyl•sulphide.and.an excess of sulphur, suggests that the disulphide contains pentavalent arsenic, since t r i y a l e n t arsines usually,react.with sulphur to give pentavalent d e r i v a t i v e s . This i s substantiated by Bunsen's f i n d i n g that the sulphide reacts with metal halides to y i e l d s a l t s of d i m e t h y l d i t h i o a r s i n i c . a c i d , (CH3) 2As(S) .SH. Formulations such a s ' ( l l ) or ( i l l ) are therefore p o s s i b l e . Me jS ^Me Me ' ? S„ Me Me^ § Me As \ As^ As As ^As -As \ A s \ S ^ Me Me (I) .(II) ( H I ) Me' S' "'Me Me' ^Me Me ^ S ^ ^'Me hi. The present analysis was undertaken to determine the structure of "cacodyl disulphide" by'X-ray. d i f f r a c t i o n methods, and the r e s u l t s indicate that the compound i s dimethylarsino dimethyldithioarsinate ( i l l ) . B. Experimental "Cacodyl'disulphide" was prepared from cacodylic acid and hydrogen sulphide (37) and by reaction of dimethylarsine with an excess of sulphur (38). X-ray powder photographs ind i c a t e d that the two•samples were i d e n t i c a l 0+0). C r y s t a l s from ether are needles elongated along the a-axis. The u n i t - c e l l dimensions and.space group were determined from r o t a t i o n , Weissenberg,.and precession photographs,.and on the'G.E. Spectrogoninmeter. E f f o r t s to measure the density.by, f l o t a t i o n were unsuccessful,, since the c r y s t a l reacted with aqueous solutions and dissolved in. organic l i q u i d s of suitable density; however, _3 i t appeared to be between about 1.5-and 2.0 g.cm. J and t h i s s u f f i c e d to e s t a b l i s h the number of molecules i n .the u n i t c e l l as two. • C r y s t a l Data (Cu-Kc* =1. 5U18 A , Mo-K<^ =0.7IO7 A ) . Dimethylarsino dimethyldithioarsinate,,. C^H^gAsgSg; M,274.1. T r i c l i n i c , a ='6.3U+0.01, b.,= 7.II+O.OI, .c ,= II.35+O.O2 A, 100 ol4+5', y5 = 95°46/.+ 5 ;, Y= 89°55/:+5/. Volume of the u n i t c e l l , = 500. k- A 3. D x(with Z=2) = 1.820 g.cm."3. .Absorption c o e f f i c i e n t for'X-rays, A = 0.7107:A, ^1= 7^ cm. - 1. F(000) .= 268. No absent reflections;.space group; PI or P1;;P1 from structure analysis. The i n t e n s i t i e s of the r e f l e c t i o n s were measured on.a General'Electric XRD-5 spectrogoniometer with single c r y s t a l o r ienter, with a s c i n t i l l a t i o n counter and Mo-K<x r a d i a t i o n , an approximately monochromatic beam being obtained by.use of a zirconium f i l t e r - a n d a pulse-height•analyser. The moving crystal-moving counter technique ( U l ) was u s e d . . A l l the ref l e c t i o n s , i n the range 0 < 26 ^40° (corresponding to a minimum :interplanar spacing d,= 1.04.A) •were examined, and 805 were measurable,.87$ of the t o t a l number of r e f l e c t i o n s k2. i n t h i s range. A l l the i n t e n s i t i e s were corrected f o r background, which was found to be.a function of 0 only. The c r y s t a l used (mounted with .a* p a r a l l e l to the 0-axis of the goniostat) was small and had cross-section 0 .1 X 0.1 mm. .perpendicular to ,a and length .0-5 mm. p a r a l l e l to a; absorption was. f a i r l y low and no-correction was applied. Lorentz and p o l a r i z a t i o n corrections were made and the structure.amplitudes derived. • C Structure Analysis The l a r g e s t peaks i n the 0k£, and hOi Patterson p r o j e c t i o n s could be interpreted i n terms of two-pairs of arsenic.atoms r e l a t e d by,-a centre of symmetry. The co-ordinates, derived.for the arsenic atoms-immediately , eliminated structure ( i l ) , . s i n c e no two .arsenic atoms were close enough together to be • directly.bonded. Four-fold vector.convergence (minimum) functions were then derived by p l a c i n g the o r i g i n s of the••• Patterson functions i n turn at-.the four-arsenic p o s i t i o n s ( l l ) . The "Ok A map showed only three peaks;.two. of these, were situated at ..arsenic, • one being considerably higher than the other and probably corresponding to overlapping arsenic and sulphur ; atoms;.the t h i r d peak could be ascribed to,a single sulphur atom. -The hOl map also had three s i g n i f i c a n t peaks, and-a smaller fourth peak-.-adjacent to one of .the-arsenic atoms, but i n such a p o s i t i o n that i t could not be involved i n bonding with the second arsenic; the peaks at the arsenic p o s i t i o n s were of equal height, a n d t h e t h i r d peak was•about h a l f t h i s height. An e f f o r t was made t o i n t e r p r e t both p r o j e c t i o n s i n terms of structure ( i ) , and p o s i t i o n s •were derived for. 2 arsenic and 2 sulphur atoms. Structure f a c t o r s were c a l c u l a t e d f o r the Okjt and hOi r e f l e c t i o n s by using standard scattering .factors' ( 5 ) , with B,= k.5.A2 f o r - a l l the atoms; the discrepancy factors were R(0kjl) ,= 33-4$, R(hOX) .= 3 8 . 9 $ . A similar, c a l c u l a t i o n with arsenic atoms only gave R(0kjl) - 31-5$; R(hOJt) = 41 .5$-^3-Fourier.series, were summed f o r both projections, by-using as c o e f f i c i e n t s the measured structure .amplitudes with signs based on .the.-arsenic • atoms only. The r e s u l t i n g electron-density, maps, showed the same features, as the vector-convergence functions, including the fourth peak i n .the b-axis p r o j e c t i o n noted;above, with much improved, resolution,,and there were i n addition other smaller peaks. I t was. c l e a r . a t . t h i s stage that.neither structure ( i ) nor structure (II) could be f i t t e d to these maps, but that the-electron-density dis t r i b u t i o n s , corresponded t o - structure ( i l l ) . Co-ordinates could be derived with confidence for - 2 . -arsenic, 2 sulphur, and 2 carbon atoms; there were peaks which apparently,corresponded to two other carbon atoms, but as there was. some •ambiguity they were omitted a t • t h i s stage. Structure factors were recalculated, and the R values were reduced to 19-3$ f o r Okj0, and 25-8$ f o r hOi r e f l e c t i o n s . A second.set of electron-density.projections.-was then computed, and these maps showed good r e s o l u t i o n o f - a l l the atoms- Inclusion of the two other carbon atoms-in the structure factor, c a l c u l a t i o n s gave R(OkX ) ,= 13-2$, R(hOX),= 23-4$. Examination of the structure-factor-agreement suggested that the temperature factor-was too high. B was therefore reduced to 3-0 A 2, and structure factors.were c a l c u l a t e d f o r the complete three-dimensional data; R(hk£), f o r the observed reflections,.was 1 8 . 2 $ . Refinement The p o s i t i o n a l and i s o t r o p i c thermal..parameters of the arsenic, sulphur, and carbon atoms,, together with.an o v e r a l l scale f a c t o r were then refine d by l e a s t .squares,.with a programme described i n part I I I of t h i s t h e s i s . The function minimized was 2w(FG-Fc) > with V w.= F Q/ 3 5 when F 0 ^ . 3 5 , . and /w"'= 35/ Fo when' F Q ^..35- Refinement proceeded smoothly and was complete i n four cycles (Table V i i ) . The f i n a l measured.and c a l c u l a t e d structure f a c t o r s , . c a l c u l a t e d from the parameters output from the fourth least-squares' cycle (R .= 9-1$ f ° r "the 805 observed r e f l e c t i o n s ) , are l i s t e d i n (42). .A three-dimensional Fourier series kk. was ; summed, and superimposed sections of the r e s u l t i n g electron-density d i s t r i b u t i o n taken through the.atomic centres are shown.in Fig.15-'Co-ordinates and Molecular Dimensions The f i n a l p o s i t i o n a l and thermal parameters are l i s t e d , with t h e i r standard deviations, i n Table IV;;x, y, and z are f r a c t i o n a l co-ordinates r e f e r r i n g . t o the t r i c l i n i c c e l l axes. No e f f o r t was made to determine p o s i t i o n s of the hydrogen atoms. The bond distances and valency .angles are given, with t h e i r standard d e v i a t i o n s , : i n Table V. The shorter intermolecular.contacts are l i s t e d i n Table-VI, and the packing of the molecules i s shown,in F i g . l 6 . • D. Discussion The,-analysis has. established that the compound c a l l e d "cacodyl disulphide" i s dimethylarsino dimethyldithioarsinate ( i l l ) , ( F i g s . 15 and 17) . It therefore -contains one t r i y a l e n t and one pentavalent arsenic•atom. Other compounds are •known with two.arsenic•atoms i n the same molecule i n d i f f e r e n t valency states, and i n f a c t once one of the arsenic atoms i n compounds of the type RgAs.X.AsRg has been oxidized (say, by forming, a methiodide), i t i s often quite d i f f i c u l t to oxidize the other (4-3). Formulation ( I I I ) i s i n accord with the preparation of the compound from cacodyl sulphide, and sulphur (38).and with the formation of s a l t s of d i m e t h y l d i t h i o a r s i n i c a c i d by,reaction with metal halides- (37)-• In. dimethylarsino-.dimethyldithioarsinate the configuration around the t r i y a l e n t - a r s e n i c ( A S 2 ) i s t r i g o n a l pyramidal and that.around the pentavalent arsenic (Asj) i s tetrahedral. The angles at the pentavalent arsenic atom d i f f e r s i g n i f i c a n t l y , f r o m the regular tetrahedral value; those-angles inv o l v i n g the doubly, bonded sulphur, . S3, . (S=As V-Si +, S=Asv-C^, S=As^-Cg) are ••all'larger than 109°. 2&/ (Table V), while, the angles not in v o l v i n g S3 are smaller than the regular tetrahedral-angle, and have values which are not too . T T T ;much l a r g e r than the ..angles at the t r i g o n a l As atom. There are, i n addition, deviations from the symmetry-which might p e r t a i n i n the two parts of the molecule 111111 ' I ' ' 0 I 2 3 4 5 A Fig.15- Superimposed sections of the f i n a l three-dimensional electron-density d i s t r i b u t i o n , through the, atomic centres, perpendicular to b; contours a t , i n t e r v a l s of 2,3,4,5 e.A-3 f o r C; 2,4,6 f o r S; and 5,10,15 for-As. A perspective drawing-of.the molecule i s also shown. 46. Table IV F i n a l p o s i t i o n a l parameters ( f r a c t i o n a l ) with standard deviations (A*), and temperature f a c t o r s and standard deviations ( A 2 ) . Atom X y z S ( x ) s ( y ) ff(z) B ( A 2 ) 6(B) . . 0 . 3 1 6 1 0 . 2 2 4 0 O .3668 . 0 . 0 0 2 4 0 . 0 0 2 4 . 0 . 0 0 2 5 3 - 2 2 0 . 0 5 A s 2  . . 0 . 3 7 0 0 - 0 . 0 6 1 9 , 0 . 1 0 3 3 0 . 0 0 2 5 0 . 0 0 2 5 0 . 0 0 2 6 • 3 . 7 6 0 . 0 5 S 3 . . 0 . 6 4 1 9 o . 2 4 6 i 0 . 3 6 4 5 0 . 0 0 7 4 0 . 0 0 7 3 0 . 0 0 7 4 5 . 0 9 0 . 1 6 s 4 . . 0 . 1 7 8 9 - 0 . 0 4 9 8 0 . 2 6 4 1 O.OO69 0 . 0 0 6 5 0 . 0 0 6 8 4 . 1 8 0 . 1 4 c 5 . . 0 . 2 1 8 0 0 . 2 2 2 9 , 0 . 5 2 3 8 0 . 0 2 5 0 . 0 2 6 0 . 0 2 5 4 . 6 3 0 . 5 6 c 6 . . 0 . 1 6 6 4 0 . 4 2 6 5 , 0 . 2 9 6 9 0 . 0 2 6 0 . 0 2 5 , 0 . 0 2 3 4 . 2 9 . 0 . 5 4 c 7 . . 0 . 5 9 5 0 -0.2441 0 . 1 4 6 7 0 . 0 2 7 0 . 0 2 7 0 . 0 2 7 5-37 O .63 c 8 . . 0 . 1 7 8 6 - 0 . 2 4 3 2 - 0 . 0 1 0 0 0 . 0 2 6 . 0 . 0 2 6 0 . 0 2 7 •5.09 0 . 6 0 Table V Bond distances (A) and valency angles, and standard deviations A s 1 - S 3 2.O75+O.OO7 ;A S l-C 5 I.947+O.O25 S4-As. 1-S 3 113.3+0.3°-As1-Si|-As2 96.5+O.30 As-^S^ 2.214+0.007 As^-Cg I.963+O.O25 • S 1 +-As 1-C 5 101.0+0.7 Asg-S^ -2.279+0.007 'As2-Cj 2.009+0.027 S^-Asj-Cg IO6.2+O.7. S^-As^Cy 99.1+0.7 ,As2-Cs I.972+O.O26 ,S 3-A S ; L-C 5 115.7+0.7 S^-As^Cs 96.2+O.7 S3-As-,_-Cg III.9+O.7 Cy-As 2-C5 99.2+1-.1 C 5-A S l-Cg -107.9+1.1 separately:: S U.-As i : i : I-C 7(99-l 0) /• S ^ - A s 1 1 1 ^ (96.2°); -S^-As^C^ (101.0°) S^-AsV-Cg (106.2°); S 3=As v-C 5 (115.7°),A S 3=As y-Cg ( i l l . 9 ° ) . These differences .are probably. a r e s u l t of minor, s t e r i c i n t e r f e r e n c e s - i n the molecule; Figs.15 and 17 show that Cg i s much cl o s e r . t o A s ^ 1 1 than i s C^, and Cy i s much cl o s e r to 'S 3 than i s CQ. - S l i g h t repulsions due to these c l o s e r approaches would tend to increase S^-As v-Cg and S ^ - A s 1 1 1 - ^ . h7-Table VI Shorter intermolecular distances ( A l l distances 4 5 A between molecule 1, at x, y, z, and neighbouring molecules were calculated; only the cry stallographic a l l y , independent .distances <VA are l i s t e d . ) Atom ( i n .Atom ( i n molecule l ) to Atom i n Molecule d(A) molecule l ) to Atom in Molecule d(A) As 2 Asg 4 3-24 s 4 c 5 5 3-99 . . ASg Crj 4 3-89 c 5 c 6 9 3-93 A s 2 CQ 4 3-93 c 5 c ? 6 3-79 S3 C 5 2 3-93 c 6 Sh 7 3.81 S3 C 6 2 3.76 c 6 c 8 3 3-76 s 3 c 5 6 •3-85 c 7 s 4 2 3-97 s 3 c 5 1 0 3-84 Molecule 1.at x, y, z Molecule 6 at T - -x, -y > 1 ~ z 2 at T + x, y, z 7 at x, 1+ y , z 3 at - x , ..-y, . 8 at 1 + x, l + y > z 4 at 1. - x, -y, -z 9 . a t - x, l - y -1 - z 5-at - x , ,-y, 1 . -z 10 at 1 - x, 1- y , 1 - z Table VII Progress of refinement Coordinates from R 0k£ Rh0l Rhk£. 2 w^F 2 Patterson p r o j e c t i o n s (2As + 2S) .33-4 38.9 Patterson p r o j e c t i o n s (2As) 31-5 41-5 T s t Fourier p r o j e c t i o n s (2As + 2S + 2C) 19-3 25 .8 2nd Fourier projections (2As. + 2S + 4c) 13-2 23.4 2nd Fourier p r o j e c t i o n s + adjusted B's •18.2 2 8 l 8 1st l e a s t squares 11.1 1062 2nd l e a s t squares 9-3 824 3 r d l e a s t squares 9-2 714 4 t h l e a s t squares 9-1 700 h8. F i g . l 6 . P r o j e c t i o n of the structure along [lOO] , i l l u s t r a t i n g the packing of the molecules. The short intermolecular.contact i s shown as a broken l i n e , and the lone p a i r s are shown schematically. Fig.17- View of the molecule along the S^-A^-"bond. •50. The .angle A s 1 1 1 - S - A s V . i s - 9 6 • 5 ° ,•only,a l i t t l e ' l a r g e r than the-angle i n HgS (93°) (30)- The corresponding angles i n arsenic t r i s u l p h i d e and arsenic, sulphide (realgar) are 100°.+ 2° and about 102°,, respectively. ( 3 0 ) , and the S-As I 3 : i-S angle i n arsenic t r i s u l p h i d e i s llk° +_ 2 ° ,.very s i m i l a r to the S-As V=S-angle i n dimethylarsino .dimethyldithioarsinate ( 1 1 3 - 5 ° : j_ 0 . 3 ° ) . However,,this agreement i s probably, f o r t u i t o u s since the molecules are so .different. There -appear to-be no r e s u l t s a v a i l a b l e with which the other angles can be s t r i c t l y .compared,,data f o r pentavalent- arsenic i n p a r t i c u l a r : b e i n g very sparse. For •triyalent-arsenic in. compounds of the types RgAsX (R = a l k y l or.aryl,.X.= halogen) and R^As (R .= a l k y l or a r y l ) some measurements are a v a i l a b l e . The" C-As-X and C-As-C-angles are -each about 96-98° (within rather wide l i m i t s of e r r o r ) . i n the halogenodimethylarsines ( 3 0 ) ; . 9 5 - 9 6 ° .+ 1 ° and 105° + 2 ° , r e s p e c t i v e l y , i n the halogenodiphenylarsines ( 2 9 ) ; and 91°•+_ li° and 105° + 2 ° , , r e s p e c t i v e l y , .in cyanodimethylarsine (cacodyl cyanide) (25)• The"C-As-C angles are 96°!+ 5° i n trimethylarsine " (30) , 100° ,+_ 3 . 5 °-in perfluorotrimethylarsine ( 3 0 ) , and 102°.-+ 2° i n both t r i - p - t o l y l a r s i n e (44) and t r i - p - x y l y l a r s i n e (4-5). The angles at A s g 1 1 1 i n the present analysis ( 9 6 . 2 ° , 9 9 - 1 ° , and 99-2°) are i n the same range as the corresponding angles i n these other molecules; no s t r i c t e r comparison i s u s e f u l i n any.case since the bond angles are so r e a d i l y d i s t o r t e d by s l i g h t . s t e r i c s t r a i n s i n the various molecules. The-'As-S single bond distances are 2 .28 .+ 0.007 A f or As I i : i-S and 2.21.+ 0.007.1 f o r As v-S. The diffe r e n c e between these values i s highly s i g n i f i c a n t , and suggests a s l i g h t l y smaller covalent radius'(by 0 .07 A) f o r As v. T h e A s ^ - S g distance ( 2 . 0 7 A.) i n d i c a t e s that t h i s i s a double bond, the difference between As^-S^-and.Asv=S2 being O.lh.R, about the same as the difference between s i n g l e -and double-bond covalent r a d i i f o r sulphur (0.10 A) (46). The only. As-S •distances given i n the l i t e r a t u r e are those i n realgar ( 2 . 2 1 - 2 . 2 3 + 0 . 0 2 A) and i n arsenic t r i s u l p h i d e ( 2 . 2 5 + 0.02 A) ( 3 0 ) . 51-° I I I The .arsenic-carbon distances average T.990.+ 0 . 0 1 9 . A for. As -C and 1-955 •+ 0.018 A f o r As -C; as with the .arsenic-sulphur distances,.the bonds .involving pentavalent arsenic are s l i g h t l y shorter (0 .035 A), but on the b a s i s of the •estimated standard deviations the difference cannot be claimed to be s i g n i f i c a n t i n t h i s case. The As-C distances are very s i m i l a r to the lengths of corresponding bonds i n other arsenic d e r i v a t i v e s (mean value about 1.98 A). The thermal parameters of the.atoms vary . i n a manner '(Table IV) which might be-expected from the molecular structure. As 2,.which i s bonded to .only three other atoms, i s able to ;execute s l i g h t l y l a r g e r v i b r a t i o n s (B = 3-76. X 2) than AS]_ (B .= 3-22; A2) which i s bonded to four atoms. • S i m i l a r l y ' v i b r a t e s more than S^, and Cy and CQ, .which.are bonded to As 2, .vibrate more than C^ and Cg (we might, however, have expected that- S^ would vibrate l e s s than C^ and Cg). T T T T T T The shortest intermolecular contact i s an As ...As separation of 3-24 A (Table V i ) . This i s considerably l e s s than the sum of the van der Waals r a d i i ( 4 . 0 1 ) (46),and suggests charge-transfer bonding in v o l v i n g donation of lone-pair.electrons (probably.in sp3-hybrid o r b i t a l s ) . o n each As H I ' t o vacant 4 d - o r b i t a l s on the other arsenic atom. • The d i r e c t i o n .of the short intermolecular c o n t a c t . i s shown .in Fig.1 6 ,which indicates that the molecules are associated i n p a i r s and that the lone p a i r s (assumed to make approximately equal angles with the bonds at each arsenic.atom) are so.directed that there i s l i t t l e s t e r i c interference between them,,and each can therefore overlap with a 4 d - o r b i t a l of the other atom. Similar i n t e r a c t i o n s have been observed i n other structures, but u s u a l l y with the arsenic acting only as an electron-acceptor, ;the donor atom being nitrogen. In cyanodimethylarsine (25) an intermolecular As...W separation of 3• 18 A i s observed (sum of van d'er Waals r a d i i (46) 3 .5 A), and i n arsenic t r i c y a n i d e (47) a s i m i l a r but even shorter contact ( 2 . 8 5 A). Both these compounds have r e l a t i v e l y . h i g h melting points and low v o l a t i l i t i e s i n comparison with the corresponding halides, and 52. these f a c t s suggest that the short intermolecular distances represent charge-t r a n s f e r bonds with energies of 1 - 2 k c a l . .mole"-'- i n excess of the usual van der Waals forces. The s i t u a t i o n i n the present case i s somewhat sim i l a r , except that each tri'valent arsenic atom acts as both an electron-donor and an electron-acceptor. A l l the other intermolecular distances (Table Vi) correspond to normal van der Waals i n t e r a c t i o n s . PART I I I THE CRYSTAL AND MOLECULAR STRUCTURES OF ' CLEAVAMINE METHIODIDE AND 5-IODO- 2' -DEOXYURIDINE, . AND CRYSTAL DATA FOR SODIUM THYMIDYLYL-(5^ s')-THYMIDYLATE-(5') 5 ^ I. CLEAVAMINE METHIODIDE A . Introduction The study of the-action of -acidic reagents on some of the simpler •alkaloids i s o l a t e d from Vinca rosea Linn, provides important'information .about the e f f e c t of such reagents on the b i o l o g i c a l l y important a l k a l o i d s vincaleuk-oblastine and-leurosine. The reaction, of catharanthine"(IV) with concentrated hydrochloric a c i d y i e l d s two products, one of which is•• simply -desmethoxy-more d r a s t i c rearrangement; a n a l y t i c a l , u l t r a v i o l e t , i n f r a r e d and nuclear magnetic resonance data suggest, a t e t r a c y c l i c r i n g skeleton f o r cleavamine, with retention of the indole chromophore and ethylenic double bond, and loss of the ester function of catharanthine (48).. Consideration of the evidence thus f a r suggested a s t r u c t u r a l . r e l a t i o n s h i p between cleavamine,and the-known a l k a l o i d quebrachamine'(Vi); t h i s r e l a t i o n s h i p was strengthened by.a mass sp e c t r a l comparison of the two (49). The following describes-an-X-ray-analysis of cleavamine methiodide, which establishes the structure of the a l k a l o i d , including the absolute configuration, carbonylcatharanthine. The - second product, . cleavamine> C^cjHgijNg, . involves V IV VI as (v). This formulation i s i n accord with a l l the chemical evidence. 55-B. Experimental Crystals, of cleavamine methiodide-are p l a t e s elongated-along c with (010) developed: and.smaller (lOO).faces. The density was measured by f l o t a t i o n .in. aqueous potassium iodide,.and the u n i t - c e l l dimensions and space group were determined'from various r o t a t i o n , We'issenberg and precession photographs and on the G.E. spectrogoniometer. C r y s t a l data ( X, Cu K<x.=l. 54l8. A, A, Mo K* =0.71 C'7.A). Cleavamine methiodide,. C ^ H ^ N g l , mol.wt. 422-3, m.p. 244-245°C ( d e c ) . Orthorhombic,,a=?.86+0.02,. b=l4.86+0.03,.c=l6.32+0.04,A. u =1906 A3. . D w = 1.46 g.cm"3, Z=4, D x =1.47 g.cm"3. Absorption c o e f f i c i e n t f o r X - r a y s , A. =0.7107, A, JJL ='l6.9 cm"1. F( 000)=856. Absent spectra: h.00 when h i s odd, OkO when k i s odd, 00X when X i s odd. Space group ^ 2 ^ (D^). .A preliminary;photographic .survey•revealed, a rapid f a l T - o f f i n i n t e n s i t y •with increasing Bragg angle. The i n t e n s i t i e s of a l l . r e f l e c t i o n s . w i t h 2©(Mo' KO( ) 4t35° (corresponding .to .an .interplanar spacing d.= 1.18.A) were measured on. a General'Electric-XPdO-5'Spectrogoniometer with S i n g l e - C r y s t a l Orienter,.a s c i n t i l l a t i o n counter and Mo K « r a d i a t i o n being used, an approximately/monochromatic beam being obtained by use of a zirconium f i l t e r and a pulse height analyser. The moving crystal-moving .counter technique ( 4 l ) was used. 582 r e f l e c t i o n s i n the range 0 < 26 4 35° were observed, representing about 80$ of the t o t a l number of r e f l e c t i o n s i n this-range. •For r e f l e c t i o n s at higher Bragg angles to the T i m i t of the Cu-Kcx sphere, . only those few v i s i b l e on the preliminary, f i l m s were examined.in the spectrogoniometer, and the i n t e n s i t i e s ( a l l - v e r y weak) recorded. . A l l the i n t e n s i t i e s were corrected 56. f o r background, which-was found to be a function of O only. Lorentz and p o l a r i z a t i o n f a c t o r s were applied-and the structure amplitudes derived. The c r y s t a l used i n recording t h e • i n t e n s i t i e s was mounted with c p a r a l l e l to the (f> axis, and had dimensions 0.4 mm, 0.12 mm, 0 .03 mm p a r a l l e l to c, a and b respectively;•absorption was fairly.Tow-and no corrections,were applied. • C Structure Analysis The position, of the iodine•atom.was. determined from the [lOO] and [Old] Patterson projections, as ( 0 . 2 5 0 , .O.35O, 0.140), and structure f a c t o r s were ca l c u l a t e d f o r a l l the data f o r the. iodine only, the sc a t t e r i n g factor, l i s t e d by'Sage1 (50) f o r uncharged I being.used, with B=4.0 A2.. The value of R, the usual discrepancy f a c t o r , was. 33-0$ f o r the observed r e f l e c t i o n s . .A three-dimensional. Fourier s e r i e s was. .summed with.phases based on the iodine atom; :since x j was -y, the resulting.-electron-density'distribution had a f a l s e mirror plane at x=£. However i t was. possible to pick out fused f i v e - and six-membered rings-which obviously. corresponded ,to'.the indole nucleus. Many other atoms, were •also c l e a r l y - r e s o l v e d , but the ambiguities introduced by the f a l s e symmetry prevented the deduction , of the whole-molecular structure at t h i s stage. The nine atoms of the. indole group ,and. the,.-two carbon atoms bonded to the f i v e -membered ring.were introduced into the. structure factor, c a l c u l a t i o n s , a l l with the carbon s c a t t e r i n g .factor (50) and B=4.0.;A 2;R was reduced to 23-2$. .A second three-dimensional electron-density d i s t r i b u t i o n revealed ten more atoms, .introduction of these reduced R to 21.8$>, and the f i n a l atom was located on a t h i r d three-dimensional .electron-density d i s t r i b u t i o n . .At t h i s • s t a g e . a l l the gross features- of the molecular structure had been .established and R was. 21.5$-Refinement of the•structure Further refinement proceeded by computation of difference electron-density p r o j e c t i o n s on (010) and (OOl). • It was f e l t that these p r o j e c t i o n s , being centrosymmetrieal,. were more T i k e l y , to reveal any small deviations of x-j- from-57-than, a synthesis using the three-dimensional data.* The maps did- suggest a reduction of x t to about 0.248,.small s h i f t s i n the y and z coordinates of the iodine, and an increase i n the temperature f a c t o r to-5-5:A 2. .At t h i s stage also more r e a l i s t i c s c a t t e r i n g f actors were introduced. That f o r "I-was obtained from the curve f o r uncharged I (5) by comparison with the differences i n the values of X- and X (X=F, CI, B r ) ; • i t was. corrected f o r anomalous dispersion, according..to the-expression f(corrected),= ^4^^ ^ fT'^1 ' using the values & f ' , A f " given :in .(5)• The nitrogen s c a t t e r i n g f a c t o r was introduced f o r N(2) and the carbon curve was used f o r a l l the carbon atoms .and f o r N+(3).. These changes reduced R f o r the three-dimensional data to 15-4$>. . A l l the p o s i t i o n a l and i s o t r o p i c thermal parameters,.together with an o v e r a l l . s c a l e f a c t o r , were then r e f i n e d by l e a s t squares, using a program f o r the IBM 1620 computer (Addendum). The function minimized was 2w(JF |- |F | ) 2 , with w=Fo/40 when F G < 40, and w=40/Fo when F q > 40. Five cycles reduced R to 8.4$. The s h i f t s i n the f i f t h cycle were generally l e s s than about one-t h i r d of a standard deviation, except f o r one or two.as'large-as: one standard deviation. An.attempt was then made to r e f i n e the'structure independently/by.the d i f f e r e n t i a l synthesis method, • using c a l c u l a t e d syntheses to. .apply •''backshift' corrections, to the-atomic coordinates (51) , and corrections to the thermal parameters. S t a r t i n g with the f i n a l ' l e a s t - s q u a r e s p o s i t i o n s the f i r s t d i f f e r e n t i a l : s y n t h e s e s cycle increased R.to 9-7$, two more cycles reduced t h i s to 8 . 9 $ , and a fourth cycle caused a s l i g h t increase te 9-1^. The changes i n p o s i t i o n a l parameters from those of the least-squares refinement were generally.small, but there were several f a i r l y Targe differences i n bond -lengths and valency-angles (to be described l a t e r ) . . The temperature f a c t o r s * I..am indebted to Dr. A.W. Hanson f o r suggesting t h i s procedure. 58. were g e n e r a l l y about the same as or a l i t t l e l a r g e r than those of the l e a s t -squares a n a l y s i s . A f i n a l l e ast-squares c y c l e , . u s i n g as input the parameters from the f o u r t h d i f f e r e n t i a l s y n t h e s e s , . s h i f t e d the atoms towards the p o s i t i o n s given by the f i f t h l e a st-squares c y c l e . The f i n a l measured and c a l c u l a t e d s t r u c t u r e f a c t o r s , c a l c u l a t e d from the parameters output from the f i f t h l e a st-squares c y c l e (R=8.4# f o r the 591 observed r e f l e c t i o n s ) , are l i s t e d i n .(52). A f i n a l three-dimensional F o u r i e r s e r i e s was summed us i n g as c o e f f i c i e n t s the measured s t r u c t u r e amplitudes w i t h c a l c u l a t e d phase angles. Superimposed s e c t i o n s of the r e s u l t i n g e l e c t r o n - d e n s i t y d i s t r i b u t i o n taken through the atomic centres are shown i n Fig . l B . A l l the peak heig h t s are q u i t e low (Fig.18 and Table V I I I ) , a consequence of the r a p i d f a l l -o f f i n i n t e n s i t y of t h e ' r e f l e c t i o n s . This i s p a r t i c u l a r l y so f o r atom C(23) (Fig . l B ) , and t h i s was a l s o the atom which was l a s t to .appear i n the e l e c t r o n -d e n s i t y d i s t r i b u t i o n s , and f o r which the coordinate d i f f e r e n c e s between l e a s t -squares and d i f f e r e n t i a l syntheses were l a r g e s t ; however i n no other r e g i o n was there any e l e c t r o n d e n s i t y which might i n d i c a t e -another p o s l t i o r i f o r or any d i s o r d e r i n g of atom C(23). Coordinates and molecular dimensions The f i n a l p o s i t i o n a l and thermal parameters are l i s t e d i n Table V I I I . Two sets of parameters are l i s t e d , those from the f i f t h l e a s t - s q u a r e s c y c l e and those from the t h i r d d i f f e r e n t i a l . s y n t h e s e s ; the least-squares coordinates gr\£ a s l i g h t l y Tower discrepancy f a c t o r (8.4 as a g a i n s t 8.9$), but i t i s f e l t . t h a t . i t i s not r e a l l y p o s s i b l e to decide between them. Despite the r e l i a b l e counter i n t e n s i t i e s , i t appears t h a t the d i f f i c u l t y of o b t a i n i n g accurate carbon p o s i t i o n s i n the presence of the heavier i o d i n e i s the l i m i t i n g f a c t o r i n the a n a l y s i s . A l s o given i n Table V I I I are the standard d e v i a t i o n s of.the atomic parameters, c a l c u l a t e d from the Teast-squares r e s i d u a l s (Addendum), and the peak e l e c t r o n d e n s i t i e s from the t h i r d observed d i f f e r e n t i a l s y n thesis. a Ii 1111 I i i i 0 I 2 3 4 5 A F i g . l 8 . Superimposed sections of the f i n a l three-dimensional electron-density d i s t r i b u t i o n , through the atomic centres p a r a l l e l to (010); contours f o r the carbon and nitrogen atoms are at i n t e r v a l s of •g-eA>"3 s t a r t i n g at 2eA~3, and f o r the iodine at i n t e r v a l s of 5 e A ~ 3 s t a r t i n g at 5eA"3. Also shown i s a perspective drawing of the molecule. Both drawings show the correct absolute configuration, the p o s i t i v e d i r e c t i o n of the b-axis being towards the viewer. Table VIII. P o s i t i o n a l parameters ( f r a c t i o n a l ) thermal parameters and standard de densities (e . A ~ 3 ) 5 t h Least-squares cycle Atom x y z <s(x) 6 ( y ) <s(z) . B ( A ) 0 . 2 4 7 4 0 . 3 5 3 0 0 . 1 3 7 8 0 . 0 0 4 9 0 . 0 0 2 5 O . 0 0 2 U 5 . 7 8 o.o64 0 . 4 4 3 0 . 3 0 9 0 . 0 3 1 . 0 . 0 2 9 0 . 0 2 9 4 . 2 6 - 0 . 4 5 6 0 . 5 3 2 0.4l6 0 . 0 3 4 0 . 0 3 1 0^032 3 . 9 1 - 0 . 0 3 0 O . 5 0 9 0 . 3 3 6 -0.04l 0.040 O . 0 3 6 3.48 -0.048 O . 5 2 3 0 . 4 2 9 O.O34 0 . 0 3 1 0 . 0 3 0 3 . 2 9 0 . 0 3 1 0 . 4 3 5 - 0 . 4 5 7 0 . 0 3 3 0 . 0 3 4 0 . 0 3 2 2 . 7 2 0 . 0 5 4 0.400 0 . 5 3 2 0 . 0 4 0 0 . 0 3 9 0 . 0 3 8 4 . 0 2 0 . 1 5 8 . 0 . 3 1 7 0 . 5 3 6 0 . 0 3 7 0 . 0 3 6 0 . 0 3 6 3 . 2 0 0 . 2 0 9 0 . 2 7 8 0 . 4 6 7 0 . 0 3 6 0 . 0 3 3 0 . 0 3 3 4 . 7 0 0 . 1 9 5 0 . 3 0 8 0 . 3 8 5 0 . 0 3 4 0 . 0 3 7 0 . 0 3 4 3 . 8 1 0 . 0 9 2 O . 3 9 5 O . 3 8 5 0 . 0 3 9 0 . 0 3 7 0 ; 0 3 6 3.8O - o . i 4 i 0 . 5 8 7 0 . 4 7 7 o . o 4 o 0 . 0 3 9 0 . 0 3 8 3 . 6 5 - 0 . 1 0 4 0 . 5 8 1 0 . 2 8 6 o . o 4 o 0 . 0 3 8 0 . 0 3 6 2 . 6 9 -0.244 O . 5 4 3 0 . 2 2 3 O . 0 6 5 0 . 0 3 4 O.O32 4 . 4 7 - 0 . 4 2 8 0 . 5 3 2 0 . 2 6 4 0 . 0 3 6 0 . 0 3 4 O . 0 3 3 3 . 3 8 - 0 . 5 1 9 0 . 6 2 0 0 . 2 6 5 0 . 0 4 7 0 . 0 4 1 0 . 0 4 1 5 . 1 3 - 0 . 6 2 4 0.643 0 . 3 3 7 o . o 4 i 0.042 0 . 0 3 7 3 . 7 9 - 0 . 6 1 8 0 . 5 8 1 o . 4 i 6 0 . 0 3 7 0^034 0 . 0 3 6 2 . 3 0 - 0 . 3 2 3 0 . 6 0 8 0 . 4 4 5 0 . 0 3 9 0 . 0 4 3 o .o4o 5 . 2 7 - O . 7 5 0 0 . 7 2 7 O . 3 5 1 0 . 0 7 2 O . 0 3 5 O . 0 3 7 7 - 3 1 - 0 . 7 4 0 0 . 7 7 8 0 . 2 6 5 0 . 0 7 6 0 . 0 4 3 0 . 0 4 3 8 . 6 5 - 0 . 4 7 2 0.468 0 . 4 9 9 0 . 0 4 6 0 . 0 4 2 0.040 5 . 3 8 - 0 . 4 i 8 0 . 4 8 5 0 . 3 5 2 0 . 0 5 1 0 . 0 4 6 0 . 0 4 5 7 - 6 2 with standard deviations ( A ) , r i a t i o n s ( A 2 ) , and peak e l e c t r o n -3rd D i f f e r e n t i a l cycle A / A ^ 5(B) X y z B ( A 2 ) 0(e A 0 . 0 5 0.2486 0 . 3 5 2 8 0 . 1 3 7 8 5 8 51 8 0 . 7 2 0 . 0 6 4 0 . 4 4 2 0 . 3 1 3 4 3 5- 2 0 . 7 7 - O . 4 5 2 0 - 5 3 3 0 . 4 1 6 3 9 4 8 0 . 9 2 -0.041 0 . 5 0 8 0 . 3 4 0 3 5 4 5 0 . 7 5 - O . 0 5 3 0 . 5 2 3 0 . 4 3 2 3 3 4 . 7 O . 7 7 0 . 0 3 5 0 . 4 3 2 0 . 4 5 5 3 5 4 9 0 . 9 3 O . 0 6 3 0 , 3 9 8 0 . 5 2 8 4 0 4 3 0 . 9 1 0 . 1 5 0 0 . 3 1 9 0 . 5 3 8 4 0 4 . 2 0 . 9 0 0 . 2 1 0 0 . 2 8 0 0.468 4 7 4 . 4 O . 9 8 0 . 1 9 3 0 . 3 1 2 0 . 3 9 2 3- 8 4 . 4 0 . 9 5 0 . 0 9 0 0 . 3 9 4 O . 3 8 6 4 5 4 3 0 . 9 2 - 0 . 1 4 5 0 . 5 8 8 0 . 4 7 9 4 5 4 . 2 0 - 9 5 - 0 . 1 0 3 0 . 5 8 4 O . 2 8 7 3 5 4 . 6 0 . 8 6 •-0:2-37 0 . 5 4 8 0 . 2 2 8 5 5 3- 9 0.84 - 0 . 4 3 1 0 - 5 3 3 0 . 2 7 0 3 4 5- 0 l . l l - 0 . 5 1 5 0 . 6 2 4 0 . 2 6 7 5- 8 3- 5 O . 9 5 - 0 . 6 2 3 0.644 0 . 3 3 2 4 5 4 . 9 0 . 8 1 - 0 . 6 2 2 0 . 5 7 9 0 . 4 1 5 3 3 4 8 1 .17 - O . 3 2 6 O . 6 0 5 0 . 4 4 1 5 3 3 8 0 . 9 0 - 0 . 7 4 7 0 . 7 3 0 0 - 3 5 ^ 7 3 - 3- 7 1 .19 - 0 . 7 3 9 0 . 7 7 6 0 . 2 6 5 8 7 3- 4 1 .14 - 0 . 4 7 0 0.468 0 . 4 9 8 5 4 4 4 1 . 2 2 - 0 . 4 1 3 0 . 4 8 1 0 . 3 4 3 7 6 3- 0 6l. The bond distances i n the molecule, c a l c u l a t e d from both sets of coordinates of Table VIII, are shown i n Fig.19(a), and the valency angles (least-squares parameters) i n Fig.19(b). The standard deviations of these are about 0.05 A f o r bond distances and 3° f o r angles. The most s i g n i f i c a n t intermolecular contacts are given i n Table IX (least-squares parameters),.and the molecular packing i s i l l u s t r a t e d i n Fig.20. Table IX. Shorter intermolecular distances (For C-C, C-N,.all distances 4 3-8 A are l i s t e d ; f o r C-I, N-I, a l l distances 4 5-0 A) Atom (molecule l ) . Atom i n Molecule Distance 1 2 T 3.4l A 1 15 2 4.22 1 16 2 4.84 1 23 2 4.80 5 : i 5 ^-54 6 • ' 1 5 ^-66 7 1 . 5 .^-35 12 l 3 ^ 5 12 l 5 ^-16 13 l 3 ^38 16 1 3 ^37 17 l '3 ^-32 19 1 3 3-93 20 1 3 ^38 21 l '3 ^-33 2 18 2 3-68 4 17 2 3-77 4 18 2 3-66 5 18 2 3-50 6 18 2 3-58 8 22 2 3-73 9 7 ^ 3-78 9 8 4 3-79 11 18 2 3-62 13 20 2 3-69 Molecule General coordinates 1 x,y,z 2 l+x,y,z 3 -x , i+y , i-z 4 -Ux,2-y,i-z 5 |-x,l-y,|+z / Fig.19. (a) Bond distances from l e a s t squares, and ( i n parentheses) d i f f e r e n t i a l syntheses refinements, ("b) Valency angles ( l e a s t squares parameters). CT\ ro 6k. There are only two p a r t s of the molecule where i t i s ' u s e f u l to examine p l a n a r i t y of the atoms; one of these i s the indole group and the other the neighbourhood of the e t h y l e n i c double bond. The best plane through the nine atoms of the i n d o l e r i n g s has equation, ( l e a s t - s q u a r e s parameters): 0.8546X+0.5114Y+0.0902Z=4.2135 (A) where X , Y and Z are coordinates i n A. The plane through these nine atoms p l u s the two carbon atoms bonded to the five-membered.ring i s : 0.8532X+0.515OY+0.0831Z=4.1804. (B) The best plane through the two atoms of the e t h y l e n i c double bond p l u s the three atoms bonded to them i s : 0.7802X+0.5198Y+0.348OZ=3.OW-9. ( C ) The d e v i a t i o n s of the atoms from these various planes • (Table X ) i n d i c a t e t h a t , w i t h i n experimental e r r o r , the i n d o l e nucleus and the two attached carbon atoms are p l a n a r , and th a t the two e t h y l e n i c carbons and the three carbon bonded to them a l s o l i e i n one plane. 'Table X . D e v i a t i o n s from mean planes Atom A_ B • Atom C 2 - 0 . 0 3 8 A - O.O58 A 15 0.059 k O.O55 O.O33 16 -O.O67 5 - O.O69 - 0 . 0 8 l 17 - 0 . 0 0 9 6 0.030 0.028 18 -0 .018 7 0.030 O.O38 20 O.O38 8 -0 .0U0 - 0 . 0 2 6 9 0.013 0.022 10 -0.00k - 0 . 0 0 6 11 - 0.027 0.018 12 - 0 . 0 0 5 -0.015 -13 0;082 0.050 Absolute c o n f i g u r a t i o n The f i n a l step i n the a n a l y s i s was the determination of the-absolute c o n f i g u r a t i o n of the molecule by the-anomalous d i s p e r s i o n method (53)-S t r u c t u r e f a c t o r s were c a l c u l a t e d f o r a l l the hk&and h k l r e f l e c t i o n s , u s i n g a s c a t t e r i n g f a c t o r f o r I - of the form 6 5 -f = ( f r + A f I ) + i . A f j . With Mo K«x r a d i a t i o n the differences "between F c ( h k i ) and F c(hki,) were small, and f o r about only a dozen r e f l e c t i o n s d i d the differences seem large enough to be detectable even with the counter equipment. These differences could have been increased by using Cu K c * r a d i a t i o n , but probably only at the expense of introducing absorption corrections (and of r e a l i g n i n g the instrument). In an e f f o r t to make the determination as objective as possible the author c a l c u l a t e d the structure f a c t o r s and suggested which p a i r s of r e f l e c t i o n s were to be measured, c a r e f u l l y omitting any mention of the ..indicated d i r e c t i o n s of the d i f f e r e n c e s . Dr. J . T r o t t e r t h e n measured the i n t e n s i t i e s . The r e s u l t s are given i n Table'XI. Of the fourteen p a i r s of r e f l e c t i o n s f o r which the differences were expected to be measurable, four showed, no s i g n i f i c a n t difference; the other ten p a i r s unambiguously indicated that the parameters used to c a l c u l a t e the structure f a c t o r s (those of Table VIII r e f e r r e d to a conventional right-handed set of axes) represent the true absolute configuration. (V) and F i g . l 8 therefore also depict the correct absolute configuration. D. Discussion The present analysis has established the structure of cleavamine methiodide, incl u d i n g the absolute configuration, as that shown i n F i g s . l 8 , 19, and 20, and the structure of the parent a l k a l o i d as (V). 'The general shape of the molecule i s c l e a r from F i g s . l 8 and 20. The -atoms of the indole rings and the two attached carbon atoms a l l l i e i n one plane. In the other six-membered r i n g four of the atoms•• (those -of the C=C bond and the two attached atoms) are coplanar, C ( 2 3 ) i s only s l i g h t l y displaced (-O.lU A), but'W(3) l i e s s i g n i f i c a n t l y o f f the plane (-O.63 A); C(20) and C(2l)- do not deviate s i g n i f i c a n t l y from the plane (displacements -.+0.014 A and +0 .07 A r e s p e c t i v e l y ) . The general boat conformation of the nine-membered r i n g i s also evident from Figs. 1 8 and 20. 66. Table XI. Determination of the absolute configuration (Mo KO< rad i a t i o n ) |Fc(hkI)| |FG(hki)P I0(hk£) h k I l F o l |Fc(hkj&)| Io(hki) Io( [hklj-ioCKI) 1 2 2 12.4 3 . 8 8:2 0.21 34 59 0.58 2 3 3 2 3 . 0 18.6 13-9 1.79 39 30 1.30 1 4 6 61.5 61.. 1 65.5 O . 8 7 189 224 0.84 3 4 1 8.5 17-5 Ik.k 1.1+8 6 3 2.00 2 9 6 17.7 17-5 lk,5 1.46 8 8 1.00 1 12 3 4 l . 4 i a . 5 hj.k 0-77 64 64 1.00 1 3 3 29.7 32.9 36 .0 0.84 87 104 0.84 4 6 6 15-9 17.1+ 19-1 O . 8 3 5 6 0.83 l 11 l 3 6 . 8 • 27 .3 29. 4 0.86 31 31 1.00 2 2 3 57-3 6 3 . 7 66 .6 O . 9 1 250 291 0.86 1 3 2 35-7 40 . 8 38.7 1.11 l 4 i IS1* 1.05 2 l 5 37.8 38.1 36.1 l . l l 82 82 1.00 1 2 6 35-2 30.1+ 32.6 O . 8 7 65 81 0.80 3 3 10 35-0 32.5 35-1 0.86 34 45 0.76 The structure i s very markedly changed from that of catharanthine (ET), the atoms C ( l 3 ) and C ( l 8 ) , which are d i r e c t l y bonded i n catharanthine, being separated i n cleavamine by 4 . 6 A. The d i f f e r e n c e s between the bond distances determined by the least-squares and d i f f e r e n t i a l syntheses refinements (Fig. 1 9(a)) suggest that the measurements are of l i m i t e d accuracy; only f o r the bonds inv o l v i n g 0(23) do the differences exceed 2 (T however. The '0=0 bond, C ( l 6)-C ( l 7 ) (whose p o s i t i o n i n the molecule i s w e l l established chemically, and i n the present analysis by the; planar arrangement of the"atoms around i t ) has a length of 1-39 -A* ( d i f f e r e n t i a l syntheses parameters) or of 1.48 A (least-squares parameters); even the l a t t e r value i s less'than the mean* C-C single bond distance i n the molecule, which i s 1-55 A, not s i g n i f i c a n t l y d i f f e r e n t from the normal single bond distance. The mean C-N+ length i s 1-52 A, the mean C-C bond length i n the-aromatic s i x -membered r i n g i s 1.39 A, and the mean C-N(2) distance I . 3 8 A . The two C-C bonds i n the five-membered ri n g appear rather long (average value 1.53.A); the presence of an indole nucleus, rather than dihydroindole, i s again well established chemically and by the planar arrangement of atoms, and the length * The mean values are -averages of the least-squares and d i f f e r e n t i a l syntheses r e s u l t s . of these bonds might indicate a s l i g h t inaccuracy i n the p o s i t i o n of atom 5> the valency angles at t h i s atom being somewhat anomalous (Fig. 1 9(b)). The valency angles (Fig. 1 9(b)) are a l l quite reasonable; the mean tetr a h e d r a l angle i s 1 1 1 ° , mean angle i n the aromatic six-membered r i n g 1 2 0 ° , mean i n the five-membered r i n g 1 0 8 ° , and mean at C=C double bond 1 1 9 ° • The most s i g n i f i c a n t packing distance i s an I"-indole nitrogen separation of 3-^1 A ( l e a s t squares; 3-^7 A d i f f e r e n t i a l syntheses) as shown i n F i g s . l 8 and 2 0 . This probably represents an I...H-N hydrogen bond, although the hydrogen,, i f i t i s sit u a t e d on the b i s e c t o r of the C ( 4 ) - F ( 2 ) - C ( l l ) angle, i s displaced from the I..."N"line (N-H bond displaced l U °, Fig. 1 9(b)). A l l the other distances i n v o l v i n g the iodide ion correspond to normal separations, the next shortest being 3 - 9 3 A (Table IX). " A l l the C-C and C-N intermolecular contacts involve normal van der Waals i n t e r a c t i o n s , the shortest being 3 ' 5 0 A. This work has provided evidence f o r a novel and remarkable a c i d rearrange-ment i n the Iboga a l k a l o i d series which may have i n t e r e s t i n g mechanistic and biogenetic implications. It i s pertinent to note that cleavamine has been obtained as one of the products i n the a c i d i c h y d r o l y s i s of vincaleukoblastine and leurosine (k^). This work now provides strong support f o r the presence of a catharanthine -l i k e moiety as one of the u n i t s i n the structure of these dimeric a l k a l o i d s . 68. .ADDENDUM The least-square program was written i n FORTRAN-2 f o r the IBM 1620 computer with kOK memory and card input unit. The general method followed was that given by Cruickshank ( 5 ^ ) . The block-diagonal approximation was used, 3X3 and 1X1 matrices f o r the coor-dinates and i s o t r o p i c temperature parameters, and a 2X2 matrix f o r c o r r e l a t i o n of the scale f a c t o r and the average temperature f a c t o r (the memory size prevented the use of anisotropic temperature f a c t o r s ) . The standard deviations of the p o s i t i o n a l and temperature parameters were computed according to Cruickshank's equation ( 2 . 5 ) -The input cards (one per plane) contained the indices, s i n 0, and the sca t t e r i n g - f a c t o r s f o r that p l a n e • ( t h i s was chosen as input because these cards were a v a i l a b l e f o r the structure f a c t o r program on hand). Since the program was i n FORTRAN, and the c a l c u l a t i o n s were i n f l o a t i n g -point mode, the time taken was n e c e s s a r i l y quite long, being f o r cleavamine methiodide ( 2 3 atoms and k equivalent p o s i t i o n s , with 23 d i f f e r e n t i s o t r o p i c temperature f a c t o r s ) approximately one minute per r e f l e c t i o n . ' The•advantages of FORTRAN with f l o a t i n g - p o i n t are ease of programming and of modification of the program, and automatic handling of the decimal point. 69-I I . 5-IODC-2'-DEOXYURIDINE A. Introduction 5-iodo - 2 /-deoxyuridine (IDU) (Fig.2 2 ) has been used i n the treatment and cure of herpes simplex k e r a t i t i s (55) and i s the f i r s t a n t i - v i r a l • a g e n t to have proven c l i n i c a l chemotherapeutic value, g i v i n g the f i r s t c l ear-cut demonstration that true v i r a l disease can be e f f e c t i v e l y treated without obvious harm to the host. The blocking of the metabolic pathways of v i r a l synthesis by IDU has been a t t r i b u t e d to e i t h e r the s e l e c t i v e action of IDU on a v i r u s - s p e c i f i c enzyme system which may be involved i n the synthesis of v i r a l DNA, or to the incorporation of IDU i t s e l f i n place of thymidine into an aberrant DNA which presumably cannot be u t i l i z e d to form i n f e c t i v e v i r u s p a r t i c l e s ( 5 6 ) . IDU and the bromine analogue (BrDU) can c e r t a i n l y be incorporated i n place of thymidine into DNA of b a c t e r i a , bacteriophages, and even human and other mammalian c e l l s ( 5 7 )j h e a v i l y substituted DNA can sometimes s t i l l undergo f u l l b i o l o g i c a l functioning but with retarded growth rate, increased genetic i n s t a b i l i t y , and increased r a d i a t i o n s e n s i t i v i t y . Incorporation of IDU and BrDU into DNA r e s u l t s i n s i g n i f i c a n t l y higher melting temperatures (temperature at which the two DNA h e l i c e s separate) than that exhibited by normal DNA. Of the several explanations put forward to explain t h i s enhanced s t a b i l i t y , the most probable fyas been that the s u b s t i t u t i o n of I or Br f o r the CH^ i n thymidine a l t e r s the electron density i n the pyrimidine r i n g with concomitant strengthening of the hydrogen bonding to the purine base i n the complementary DNA chain ( 5 8 ) . I t would thus appear that the incorporation of IDU and BrDU instead of thymidine into DNA hinders f u r t h e r DNA synthesis by increasing the i n t e r - c o i l a t t r a c t i o n and thereby•impairing the a b i l i t y of the complementary chains to separate and serve as templates f o r a d d i t i o n a l DNA. The c r y s t a l and molecular structures of 5-iodo - 2 /-deoxyuridine and 5-bromo-2'-deoxyuridine have been investigated i n the hope that the d e t a i l e d structures might y i e l d some d i r e c t information on the possible role of these compounds i n ' combatting v i r a l diseases. 7°-B. Experimental Cr y s t a l s of 5-iodo-2'-deoxyuridine and 5-bromo-2'-deoxyuridine are pla t e s elongated-along a with (OOl) developed. Most of the c r y s t a l s were twinned, but some single ones were obtained from alcohol-water. The density of IDU was measured by f l o t a t i o n i n a CCl^-CHBr^ mixture, and the u n i t c e l l dimensions of both compounds were determined from r o t a t i o n , Weissenberg (CuKc* , X = 1 . 5 4 l 8 A) and precession (MoK=< , A= G.71O7 A) f i l m s . The two are isomorphous, and c r y s t a l data are given i n Table XII. The iodo-compound was chosen f o r d e t a i l e d analysis, and the i n t e n s i t i e s of a l l r e f l e c t i o n s with 2 6 ^ ^ 4 . 5 7 - 3 ° (corresponding to a minimum interplanar spacing d .= 0.74 A) were measured on a General E l e c t r i c XRD-5 Spectrogoniometer, with Single C r y s t a l Orienter, using a s c i n t i l l a t i o n counter, approximately monochromatic MoKcx r a d i a t i o n (zirconium f i l t e r and pulse height analyser), and the moving crystal-moving counter technique ( 4 l ) . A l l the i n t e n s i t i e s were corrected f o r background,• Lorentz and p o l a r i z a t i o n f a c t o r s were applied, and the structure amplitudes were derived. The c r y s t a l used was mounted with a* p a r a l l e l to the fi axis of the goniostat, and had length O.5O mm p a r a l l e l to a and cr o s s - s e c t i o n 0 . ' l6 x .0.07 mm perpendicular to a; with MoKo< r a d i a t i o n absorption i s f a i r l y low.and no corrections were, considered necessary. 1434 r e f l e c t i o n s were observed, 99-2$ of the t o t a l number ( l 4 4 5 ) i n the range 0 < 2 6 ^ ^ ^ 57-3° • C Structure-Analysis Since the compound i s o p t i c a l l y active the space group i s PI, and with only one molecule i n the u n i t c e l l the o r i g i n may be taken at the iodine atom. A three-dimensional Fourier se r i e s was. summed with a l l phase angles taken as 0 ° . The r e s u l t i n g electron-density d i s t r i b u t i o n .necessarily contained a f a l s e centre of symmetry, but the sugar r i n g and a l l i t s substituent groups were very c l e a r l y resolved. The base was poorly resolved since i t was Table XII. C r y s t a l Data Formula M.W. C r y s t a l system a (A) o (A) c (A) u (A3) E r a (gern" 3 ) Z D x(gcm" 3) F(OOO) jU.(for CuKe* ) (cm - 1) yUt(for MoK* ) (cm - 1) Space group 5 - i o a o - 2 ' -deoxyuridine C 9 H 1 1 W 2 ° 5 I 35^.1 T r i c l i n i c 4 . 9 8 + 0 ,01 6 .83 + 0 . 0 1 9.6O + 0 . 0 2 101°4©» + 5 ' 1 0 9 ° l 8 ' + 5' 98°20' + 5' 293 2.014 1 .2 .008 172 222 28 PI 5-bromo-2'-deoxyuridine c 9 H l l N 2 ° 5 B r 307.I T r i c l i n i c 4.87 + 0 .01 6.72 + 0 .01 9.56 + 0 . 0 2 100°10* + 5' 107°24 f + 5 ' 98°31 ' + 5' 285 " 1 I . 7 8 9 154 PI 72. situated close to a f a l s e centre of symmetry, but i t was possible, by making use of the atoms which were resolved and by assuming conventional dimensions, to obtain coordinates f o r a l l the atoms (excluding hydrogen) i n the molecule. Structure f a c t o r s were c a l c u l a t e d using the sca t t e r i n g f a c t o r s of the Inter-na t i o n a l Tables (5); with B = 4-5 A 2 f o r a l l atoms; the iodine s c a t t e r i n g . fa c t o r was corrected f o r anomalous dispersion according to the r e l a t i o n : C o r r e c t e d ' Vl ( f° + A f ' ) 2 + ( A ^ ' and A f S A f " were taken from the International Tables (5). R, the usual discrepancy f a c t o r , was 0.249- 'A second Fourier s e r i e s was summed with phases based on a l l the atoms, and the r e s u l t i n g three-dimensional electron-density d i s t r i b u t i o n showed very good r e s o l u t i o n of a l l the atoms, with no spurious d e t a i l . Refinement of the p o s i t i o n a l and i s o t r o p i c thermal parameters and a scale f a c t o r was then c a r r i e d out by (block-diagonal) least-squares. The function minimized was E w ( |F Q| - | F c | ) 2 , with \fw = |F Q| /20 when [ F O | < 20 and /w = 20/ | F Q | when \FQ\ > 20. Refinement was complete i n four cycles, during which R was reduced from 0.24-9 "to 0.142, and 2 w A from 12 x 103 to 5-6 x 103. At t h i s stage f a c i l i t i e s f o r computing anisotropic l e a s t squares became a v a i l a b l e , and two more cycles of refinement reduced R to 0.054 and S w A 2 to" 1.3 x 103; i n the anisotropic refinement no s i g n i f i c a n t changes i n p o s i t i o n a l parameters were indicated, so that the improvement i n structure f a c t o r agreement i s e n t i r e l y a r e s u l t of introducing a n i s t r o p i c thermal parameters. The f i n a l c a l c u l a t e d structure amplitudes are compared with the measured values i n (59) (R - O.O54 f o r a l l 1445 planes with d >0-74 A). A f i n a l three-dimensional Fourier s e r i e s was summed, and sections of the r e s u l t i n g e l e c t r o n -density d i s t r i b u t i o n , taken through the atomic centres p a r a l l e l to (lOO 1), are shown i n Fig.21. Fig.21.. Superimposed sections of the electron-density d i s t r i b u t i o n , taken through the atomic centres p a r a l l e l to (lOO). Contours s t a r t at 0 eA~3 and are .at i n t e r v a l s of 20 eA~3 about the iodine, and 2 eA-3 about the l i g h t atoms. A perspective-drawing of the molecule i s also shown. 7k. Atomic parameters and molecular dimensions The f i n a l p o s i t i o n a l and anisotropic thermal parameters are given i n Table XIII, x, y, and z being f r a c t i o n a l coordinates r e f e r r e d to the t r i c l i n i c c r y s t a l axes. Since the compound i s derived from d-ribose the absolute configuration i s established; the coordinates i n Table XIII r e f e r r e d to a right-hand set of axes give the c o r r e c t absolute configuration, and a l l the diagrams also show the true configuration. B-y i n Table XIII are the c o e f f i c i e n t s i n the expression: exp - { B 1 ; L h 2 + B 2 g.k 2 + B ^ 2 •+ B^kX + B^hi + B^hk | . The standard deviations of the atomic coordinates ( i n A) are included i n Table XIII; these were estimated from the inverses of the diagonal elements of the matrix of the l e a s t squares 'normal equations. The bond distances and valency angles i n the molecule are shown i n Fig.22; the standard deviations of the bond lengths vary from 0.015 - 0.028 A, and of the angles from l . U ° - 1.9°-The best plane through the pyrimidine nucleus and the I, 0 (2), 6 (6), and C ( l ' ) atoms ( a l l atoms, in c l u d i n g I, given equal weight) has equation 0.82253 X' + O.56395 Y' - 0.073la Z' + 0.80200 =0 (D) where X', Y', and Z r are coordinates i n A u n i t s r e f e r r e d to orthogonal axes a 1 ( = a . s i n V ) , b, and c*. A least-squares plane was c a l c u l a t e d through a l l •five atoms of the deoxyribose r i n g , but the displacements indicated that the r i n g was s i g n i f i c a n t l y non-planar. Planes through a l l possible combinations of four atoms of the r i n g were calcu l a t e d , and one of these was much more s a t i s f a c t o r y than the others, atoms C (l')>'C (3')>-C(4*), and 0 ( l 1 ) being e s s e n t i a l l y coplanar, the plane having equation O.6891O X' - O.72I+5O Y' + 0.-01496 Z' + O.98961 = 0 (E) with C(2') displaced O.59 A from t h i s plane. The deviations of the atoms Table XIII. F i n a l p o s i t i o n a l parameters ( f r a c t i o n a l ) , standard deviations (A"), and anisotropic thermal parameters (x 1C-5). Atom X y z <f (x ) <s(y) tf(z) B i l B 2 2 B 3 3 B 2 3 B 1 3 B 1 2 I 0.0000 1.0000 1.0000 •0035 .0034 •0035 3422 II85 1099 687 1748 2322 W (1) o.5809 0.6132 1-1563 . O I 3 8 •0137 .0142 4215 1285 1238 508 2396 3338 C (2) 0.5719 0.4787 1:0257 .0180' •0179' -.OI89 •3479 927 1298 1516 1767 3720 0 (2) 0.7339 0-3577 . 1.0370 .0125' .0125 .0127 4978 2282 1366 1410 1994 5416 N (3) 0.3761 0.4918 0.8902 • 0143 .0142 . 0145 3853 1340 709 395 1301 3387 C ( M Q.2192 o . 6 4 o i 0.8804 .0176 .0173 .0182 4 i 6 2 976 579 -309 1507 958 c (5) 0.23-57 0.7770 1.0065 .0131 .0128 .0140 2070 1350 320 i l l -246 2265 c (6) 0.4290 0.7627 1.1581 .0147 .0145 .G153 2503 1060 887 736 1390 1493 0 (6) O.4.554 0.8796 1.2769 .0119 .0119 .0120 4824 1525 7 6 l 192 1324 1579 c ( i 1 ' ) 0.3567 0.3480 0.7458 .0164 . 0161 .0169 2844 1215 900 474 1729 1643 0 ( i ' ) 0.4699 0.4619 0.6613 .0116 .0116 .0118 3101 1863 675 641 1162 1254 c ( 2 ' ) 0.0386 0.2374 0.6368 .0166 .0163 .0170 3121 1352 1104 604 2038 1533 c ( 3 ' ) 0.0782 O.1796 0.4804 .0169 . 0167 .0174 3095 1101 793 6 l 4 1378 1748 0 ( 3 ' ) 0.2026 0.0019 O.4789 .0130 .0130 . 0131 6380 893 1665 866 3541 3108 c ( 4 ' ) 0.3312 0.3672 0.5011 •0159 .0154 .0161 3206 1070 926 4 l 4 2095 2316 c ( 5 ' ) 0.2177 O.5277 O.4163 .0192 .0190 .0195 3088 1836 1230 1778 1418 2058 0 (5*) -0 .0101 0.5904 0.4526 .0123 .0124 .0126 2891 1550 1517 H89 1562 2423 Ci' .49 .44 <0 1.53 C5'^ /.<>o •05' C4 « ^ - N 3 0 2 3 4 .38 C5 fc ^Ni ' C 6 114 I I I 105 /—109 001 110-102 I 107 106 107/ 113 113 1.21 06 Fig.22. Bond lengths and angles i n 5- iodo - 2' - deoxyuridine. 77-from the various planes are given i n Table XIV. A l l the intermolecular separations 44.5 A were calculated, and the more s i g n i f i c a n t contacts are l i s t e d i n Table XV. D. Discussion The pyrimidine base The base i s i n the di-keto form, the two C-0 bonds having an average length of 1.22 A ( 1 .21 and 1.23 A). The four C-N bond distances are v i r t u a l l y i n d e n t i c a l ( 1 . 3 6 , 1 . 3 7 , - 1 . 3 7 , and I . 3 8 A), averaging I .37.A. The value of 1.34 A f o r the C (4) - C (5) distance confirms i t s true double-bond character, i n bet t e r agreement with the r e s u l t s of 1-35 A obtained f o r thymine monohydrate (60) and" 1.31 A f o r calcium thymidylate ( 6 l ) , than with the value of 1 . 4 l A obtained i n a s t r u c t u r a l determination of u r a c i l ( 6 2 ) . The C (5) -C (6) bond i s a single bond, measuring 1.49 A, somewhat la r g e r than the value of 1.45 A found i n thymine and calcium thymidylate, and very s i g n i f i c a n t l y longer than the 1 . 4 l A determined f o r u r a c i l . The C (5) - I length of 2 .05 A i s normal. A l l of the bond angles are almost i d e n t i c a l with those found i n thymine, the diffe r e n c e exceeding T ° only i n the exo-cyclic C-0 angles. The values of 121 and 122° about C (6) - 0 (6) i n IDU are more symmetrical than the corresponding 118 and 126° i n thymine, but the d i s t o r t i o n s may be due to intermolecular packing i n thymine; s i m i l a r l y the angles of 1 1 9 ° and 125° about C (2) - 0 (2) i n IDU (122 and 123° i n thymine) r e f l e c t the p a r t i c i p a t i o n of 0 (2) i n a short intermolecular contact. The general agreement of the structure of the base i n IDU with thymine (the s t r u c t u r a l determination of which was the most precise of the three c i t e d above) demonstrates that the su b s t i t u t i o n of I f o r GH^ does not s i g n i f i c a n t l y a l t e r the structure of the base, and suggests that perhaps the differences found between thymine and u r a c i l are not r e a l . Table XIV. Deviations from molecular planes (A) Plane D Plane E Atom Deviation Atom Deviation I .0.046 C (1') 0.015 N (1) -0.046 C (3') -O.OI3 C (2) 0.005 C (4') 0.032 0 (2) 0.077 0 (V) -0.032 N (3) -0.034 c (4) 0:010 C (2') -0.590 C (5) 0..017 c (6) -0.032 o (6) -0.033 c (!') 0.007 Table XV. Shorter intermolecular contacts (A"). A l l distances <.4-5 A between a standard molecule ( l ) and 'neigh-bouring molecules were calc u l a t e d . Only those < 3-9 A involving iodine, and <. 3-5 ^ not i n v o l v i n g iodine are l i s t e d . 79-Atom to atom (molecule l ) 0 (2) I 0 ( 5 « ) ~ ~• H—N ( l ) 0 ( 3 ' ) -H- — — — — -0 (6) 0 ( 3 ' ) — - - - - - — H — 0 ( 5 ' ) C ( 3 ' ) 0 ( 6 ) c (5«) 0 (6) 0 (!') C (2«) o ( 3 ' ) c ( 5 ' ) 0 ( 3 ' ) 0 ( 6 ) Molecule 1 x 2 x 3 " x 4 x 5 l + x 6 l + x 7 - l + x 8 -1 + x m molecule y -1 + y y - l + y y - i + y y - l + • y k 2 8 3 5 2 8 -1 + z -1. + z d (A) 2.96 2.95 2.70 2.79 3-19 3.27 3-46 3.22 3-46 -1 + z -1 + z 8o. Least-squares planes c a l c u l a t e d through a l l of the base and attached atoms, and through a l l but C ( l ' ) , showed that C ' ( l ' ) l i e s on the plane of the others. The maximum deviation from the plane (plane D of Table XIV), i s that of atom 0 (2) (0.077 A) and probably i s due to the short intermolecular I 0 (2) distance. The s i g n f i c a n t displacements of the I and N ( l ) (0.0k6, - 0 . 0 4 6 A) from the plane are probably also caused by intermolecular contacts, the deviation of N ( l ) p o s s i b l y to f a c i l i t a t e the hydrogen-bonding scheme. The sugar The deoxyribose r i n g i s puckered with atom C ( 2 ' ) l y i n g O.59 A out of the plane (plane E of Table XIV) of the other four atoms (maximum deviation of the other four from the plane i s 0 .03 A). This contrasts with calcium thymidylate, i n which C (3*) w a-s "the atom which was out of the plane of the others, and suggests that which of C ( 2 ' ) or C ( 3 ' ) deviates from p l a n a r i t y i s a function of the packing i n the i n d i v i d u a l c r y s t a l structures. The bond distances i n the r i n g are normal, the average C-C length being I . 5 6 A, and C - 0 , 1.42 A. The i n t e r n a l bond angles average 104° at C, and the angle i s 1 1 1 ° at 0 ( I ' ) ; the external angles average 1 1 2 ° at carbon. These values are s i m i l a r to those ( 1 0 5 ° , 108°, 1 1 2 ° ) predicted by Spencer (63) from a survey of s i m i l a r molecules. The g l y c o s i d i c N (3) - C ( l ' ) bond measures 1.49 A, s i m i l a r to that i n adenosine -5 '-phosphate (64) and close to the value of 1.47 A i n calcium thymidylate-Conformation of the molecule The plane of the sugar r i n g i s at a dihedral angle of 8 l ° to the base, a l i t t l e l a r g e r than the values of 76° i n adenosine -5 '-phosphate and c y t i d i n e ( 6 5 ) , and 75° i n calcium thymidylate. In discussing the conformation about the g l y c o s i d i c C-N bond, i t i s convenient to use the fi^ t o r s i o n angle defined by Donohue and Trueblood (66) This i s defined as the angle formed by the trace of the plane of the base with the projection, of the C ( l 1 ) - 0 bond when the p r o j e c t i o n i s taken along the g l y c o s i d i c bond i t s e l f . As f o r a l l of the nucleosides and nucleotides so f a r studied, IDU i s i n the a n t i conformation, with a value of fi^ of -22° (as contrasted with fi^ of about 1 5 0 ° expected, in. the syn conformation), s i m i l a r to the value i n adenosine-5'-phosphate of - 1 8 ° . Intermolecular distances An isometric p r o j e c t i o n of the intermolecular packing i s shown i n Pig.23- The most s i g n i f i c a n t approach i s an I 0 (2) distance of 2.96 A, which i s considerably shorter than the normal iodine - oxygen van der Waals contact (3-55 A), and suggests a charge-transfer bond involving'donation of oxygen lone-pair electrons to vacant 5<i o r b i t a l s of the iodine. The car'bonyl group-iodine arrangement i s not too f a r from l i n e a r , the C ( 2 ) - 0 ( 2 ) - I angle being 1.66°. Such charge-transfer bonds i n v o l v i n g halogens as acceptors have been previously reported (67) with oxygen-, nitrogen-, and even s u l f u r -and selenium-containing compounds acting as donors. The s t a b i l i t y of the bond increases with heavier halogens, and I 0 distances considerably shorte than even the one reported here have been found. The - a b i l i t y of the iodine to form such charge-transfer bonds may be the molecular, b a s i s f o r the a n t i -v i r a l a c t i v i t y of 5-iododeoxyuridine. DNA which has had some thymidine substituted by IDU e x h i b i t s a higher melting temperature than does normal DNA; t h i s may r e f l e c t extra i n t e r - c o i l a t t r a c t i o n caused by the formation of a charge-transfer bond by the iodine with an oxygen or nitrogen on the complementary purine base (or p o s s i b l y on the complementary h e l i c a l skeleton i t s e l f ) , e i t h e r i n a d d i t i o n to the normal hydrogen-bonding scheme, or by replacing i t with an alternate one. The r e s u l t would be hindrance of strand 83-separation,.thus impairing the a b i l i t y of the DNA to reproduce i t s e l f . In the case of herpes simplex k e r a t i t i s treatment with IDU, t h i s may k i l l the v i r u s DNA, or merely retard i t s growth s u f f i c i e n t l y to allow the body to overcome i t (68). The other short distances correspond to normal hydrogen bonds, and are shown by dashed l i n e s i n Fig.23- Each hydroxyl group on the sugar r i n g (0 (3') and (5 1)) i s involved i n two hydrogen bonds; 0 (3') uses i t s hydrogen i n an H-bond to a carbonyl 0 (6) and shares an 0 (5') hydro gen i n a second a t t r a c t i o n , while the second 0 (5 1) bond i s through an N ( l ) hydrogen. The O....H-N distance i s 2-95 A, while the 0...H-0 distances average 2-75 A. Together with the iodine - 0 (2) contact; t h i s system holds the c r y s t a l together i n a three-dimensional network. Of the po s s i b l e hydrogen-bonding atoms, only 0 ( l ' ) does not appear to take part i n the intermolecular bonding scheme. A l l other approaches correspond to normal van der Waals i n t e r a c t i o n s . 8k. I I I . CRYSTAL DATA FOR SODIUM THYMIDYLYL- (5 • — 3 * ) -THYMIDYLATE - (5 • ) A. Introduction The key r o l e of deoxyribonucleic a c i d (DNA) i n transporting genetic information has r e s u l t e d i n a great deal of attention being drawn, i n recent years, to the problem of e l u c i d a t i n g i t s molecular structure. Because of the complexity of DNA, and the f a c t that i t gives only f i b r e d i f f r a c t i o n patterns, a s i n g l e - c r y s t a l x-ray i n v e s t i g a t i o n of i t s structure i s not f e a s i b l e . Several early attempts at constructing molecular models which would agree with the known chemical, p h y s i c a l and b i o l o g i c a l properties of DNA, r e s u l t e d i n the double-helix model of Watson and Crick (69) which f i t s remarkably w e l l with a l l of the experimental evidence gathered before and since. However, as Crick (70) and others have stated, further elaboration and understanding of the structure must await the accumulation of a d d i t i o n a l basic p h y s i c a l chemical data, i n c l u d i n g precise data on the i n t r a - and intermolecular geometrical r e l a t i o n s h i p s i n polynucleotides. The structures of several nucleosides and nucleotides have been accurately determined, but of only one nucleotide of the deoxyribose series ( 6 l ) . One phosphate-linked dinucleoside (71) has been s t r u c t u r a l l y elucidated, but the linkage was 2 ' : 5 ' rather than 3*5' as i s the case i n DNA; to date there have been no structure determinations of true dinucleotides reported. The i n v e s t i g a t i o n of the structure of the dinucleotide, sodium thymidylyl-( 5 ' — * - 3 ')-thymidylate - ( 5 ' ) , was undertaken to provide the f i r s t s t r u c t u r a l information on the mutual arrangement of the two mononucleotides, and the geometry of the internucleotide linkage. Such information would be of great i n t e r e s t and importance i n the establishment of the geometrical r e l a t i o n s to be expected i n polynucleotides and hence i n DNA. 8 5 . Thymidylyl - ( 5 ' — * - 3 ')-thymidylic a c i d - ( 5 ' ) was . f i r s t prepared (calcium s a l t ) by Michelson and Todd (72) by the condensation of 3 ' - O-acetylthymidine with thymidine 3 ' - ( ^ e n z y l phosphorochoridate) 5 '-(dibenzyl phosphate) and subsequent removal of the pr o t e c t i n g groups. This represented the f i r s t preparation of a dinucleotide by chemical means, and since the synthetic material behaved toward enzymes exactly as the d i n u c l e o t i d i c fragments obtained by degrading deoxyribonucleic acids, the postulate of a 3 ' " 5 , _ i n t e r n u c l e o t i d i c linkage i n the l a t t e r was further confirmed. A more general method f o r synthesizing polynucleotides with 3 ' : 5 ' i n t e r -n u c l e o t i d i c linkages was reported by Gilham and Khorana (73)> w n o achieved the 3 ' : 5 ' linkage by reac t i n g a su i t a b l y protected deoxynucleotide with a second protected deoxy-nucleoside or -nucleotide i n the presence of dlcylcohexylcarbodiimide or p-toluenesulfonyl c h l o r i d e . The thymidine-dinucleotide sample used i n t h i s a nalysis was prepared by t h i s l a t t e r method and very k i n d l y provided to me as the sodium s a l t by Dr. G.M.-Tener. 0 H V I I 8 6 . B. Experimental C r y s t a l s of sodium t h y m i d y l y l - ( 5 ' — * ~ 3 ' )-thymidylate-(5 ' . ) (VTl) are c o l o r l e s s p l a t e s elongated along a with (OOl) developed. Most of the c r y s t a l s gave d i f f r a c t i o n patterns with extended streaky r e f l e c t i o n s , but suitable s i n g l e c r y s t a l s were u l t i m a t e l y recrystalTLzed from 50$ ethanol solutions. The density was measured by f l o t a t i o n i n CHCl^-CHBr^ solution, and the unit c e l l dimensions and space group were determined from various r o t a t i o n , o s c i l l a t i o n , Weissenberg, and precession photographs, and on the G;E. spectrogoniometer. C r y s t a l data ( A , iCuKo< = I.5U18 A, A , MoKcx = O .7107 A) Sodium t h y m i d y l y l - ( 5 ' — * - 3 ' )-thymidylate - ( 5 ' ), C ^ H ^ N ^ O } ^ ] ^ , mol-.wt. 6 9 2 . 4 Orthorhombic, a = I6.O6 + .04, b = 1 5 . 1 3 + . 0 4 , c = I 5 . 6 5 + . 04 A U = 3803- A 3 DJJJ = I . 5 8 8 g.cm.-3 , Z = 4 , D X = 1 . 2 1 0 g.cm. " 3 With 12 HgO of hydration per molecule of dinucleotide D X = I . 5 8 7 g-cm."3 Absorption c o e f f i c i e n t f o r x-rays, A = l - 5 4 l 8 A, = 2 3 - 0 cm - 1 F ( 0 0 0 ) = 1904 Absent spectra: hOO when h i s odd, 0k0 when k i s odd. 3 Space group ^2-^2.^2. ( D 2 ) Although Gilham•and Khorana ( 7 3 ) reported 13 H 2 0 'of hydration per molecule of dinucleotide•(sodium s a l t ) on the b a s i s of chemical analysis, the density measured here corresponds c l o s e l y with a value of 12 H 2 0 per dinucleotide molecule ( d x f o r 1 1 , 1 2 , and 13 H 2 0 = 1-555, 1 - 5 8 7 , 1 . 6 l 8 g.cm~3 respectively, while d m = I . 5 8 8 ) . A preliminary photographic survey revealed a r a p i d f a l l - o f f i n i n t e n s i t y with increasing Bragg angle. The i n t e n s i t i e s of a l l r e f l e c t i o n s with 8 7 . 20 (CuK<* ) 4 80° (corresponding to an interplanar spacing d = 1.20 A) were measured on a General E l e c t r i c XRD 5 Spectrogoniometer with Single C r y s t a l Orienter, a s c i n t i l l a t i o n counter and CuKoc r a d i a t i o n being used, approximately monochromatic r a d i a t i o n being obtained by use of a n i c k e l f i l t e r and a pulse height analyser. The moving crystal-moving counter technique was employed (hi). 953 r e f l e c t i o n s with 26 4 80° were observed, representing about 70$ of the t o t a l i n t h i s range. For those r e f l e c t i o n s at higher Bragg angles, only those few v i s i b l e on the f i l m s were examined and t h e i r i n t e n s i t i e s ( a l l weak) recorded. The i n t e n s i t i e s were corrected f o r background, Lorentz and p o l a r i z a t i o n corrections applied, and the structure amplitudes derived. The c r y s t a l used i n recording :the i n t e n s i t i e s was mounted with a p a r a l l e l to the 0 axis of the goniostat, and had dimensions O.85 mm p a r a l l e l to b and 0.013 ™ i p a r a l l e l to c; no absorption corrections were applied. C Attempts.at Structure E l u c i d a t i o n The s c a t t e r i n g power of' an atom declines r a p i d l y with s i n &/\ because of destructive interference from d i f f e r e n t parts of the electron cloud as the s c a t t e r i n g d i r e c t i o n departs from that of the d i r e c t beam. But i f a l l of the s c a t t e r i n g matter of the atom.were concentrated at a point, t h i s c o l l e c t i o n of electrons would scatter i n phase i n a l l d i r e c t i o n s , and the s c a t t e r i n g power of the atom would be a constant value, the atomic number,,Z. , We may denote the structure f a c t o r which would r e s u l t i f the c r y s t a l were composed of point atoms, a l l of type 1, as s F j , and i t follows that SF-, (hki) = Z l F - i(hkt). C r y s t a l s are not u s u a l l y composed of only ^ ( h k l ) one type of atom, but the f-curves of most atoms have s i m i l a r shapes, and d i f f e r mainly by a s c a l e - f a c t o r , the r a t i o of the atomic numbers. This suggests that f o r a p a r t i c u l a r c r y s t a l one can f i n d an average shape of the s c a t t e r i n g curves of the several atoms present, scaled to u n i t s c a t t e r i n g power, f . The scattering power of any atom i s then approximately Zf. 88. We can then "sharpen" the F's by the relation-F ( h k j L ) = F(hkX) . f(hkjt) The usual use f o r sharpened structure amplitudes i s as c o e f f i c i e n t s i n a Patterson synthesis, r e s u l t i n g i n a sharpening and b e t t e r r e s o l u t i o n of the Patterson peaks. A three-dimensional sharpened Patterson series was computed f o r the dinucleotide. Since the i n t e n s i t i e s of most of the planes at the highest values of s i n 0 were very weak, and hence had the highest probable error, the curve used a's the sharpening function was made to peak i n the middle si n 0 range and t a i l o f f at the maximum recorded s i n 0 values. The Patterson p l o t was i n t e n s i v e l y studied f o r the l o c a t i o n s of the peaks due to phosphorus, but because of the complexity of the molecular structure and the resultant high degree of overlap of peaks, no p o s i t i o n s f o r the phosphorus could be confidently and unambiguously derived. 'The r e s u l t s that could be drawn from the three-dimensional Patterson synthesis were: (a) the concentration of peaks on the Z = 0 section confirms the space group as P2^2^2. (b) choosing P-P vectors to l i e on the stronger regions, the only p o s i t i o n s which f i t the Patterson map are Pj_(^ 2.,"3^ 5., 0) and Po (15_, 11_, o}-. These are not too convincing, .as f i r s t l y they 60 60 both have z=0, and secondly they seem to be too close together f o r best packing (when a d i f f e r e n t equivalent p o s i t i o n i s chosen f o r one of them they then seem too f a r apart f o r best packing). A comparison of the o r i g i n peak height with £ Z j ( l l ) ( j summed over a l l atoms of the c e l l ) , f u r t h e r i n d i c a t e d that the h e i g h t s expected f o r the P-P peaks could be very small, so that the P-P vectors need not be chosen on the l a r g e r Patterson peaks. However, even the consideration of the smaller peaks l e d to no other reasonable p o s i t i o n s f o r the phosphorus atoms. 89. An e i g h t f o l d vector convergence (minimum) function was then computed, superimposing the Patterson function at the eight phosphorus p o s i t i o n s i n the u n i t c e l l (the two given above and t h e i r equivalent p o s i t i o n s ) . The r e s u l t i n g three-dimensional Fourier map had regions of density scattered through i t , but unfortunately i t could not be interpreted i n terms of any recognizable structure. (The superposition program could not i n t e r p o l a t e , but could only superpose at the nearest l a t t i c e point ("jgTj ths of the a x i a l lengths), and perhaps t h i s contributed to the lack of r e s o l u t i o n of the Fourier map). Several attempts were then made by the author and Dr. G.M. Tener to prepare c r y s t a l l i n e heavier metal s a l t s of the dinucleotide, with caesium, rubidium, s i l v e r , and t h a l l i u m as the p o s i t i v e ion, but i n no case could a c r y s t a l l i n e sample be obtained. A f t e r extensive and intensive re-consideration of the Patterson synthesis of the sodium s a l t f a i l e d to y i e l d any f u r t h e r r e s u l t s , the project was shelved. Recently the i n t e n s i t y data were given to M. Sundaralingam at the U n i v e r s i t y of Washington, where they have a superposition program which can interpolate between l a t t i c e points. At the time of t h i s w r i t i n g no information has been received from them. The i n t e n s i t y data f o r sodium thymidylyl-(5'—*-3')-thymidylate-(5') have been recorded by the author and are not given here. APPENDIX A BRIEF DESCRIPTION OF SOME CRYSTALLOGRAPHIC PROGRAMS WRITTEN FOR THE IBM 1620 AND 70UO COMPUTERS 91-The programs were o r i g i n a l l y written f o r the IBM 1620 computer, with U0,000 d i g i t s core memory, card input/output, and p r i n t e r output. They have been written i n Fort r a n - 2 , and are e a s i l y adaptable to many other IBM computers; they have already been adapted here f o r the IBM JOkO computer. A b r i e f l i s t i n g and summary of the programs i s given below. A d e t a i l e d d e s c r i p t i o n of t h e i r operation and a complete l i s t i n g of the actual program i n s t r u c t i o n s i s obtainable from the Chemistry Department, U n i v e r s i t y of B r i t i s h Columbia, c/o Dr. J. Trotter. (1) Goniostat Settings The program generates indices hkjl f o r a l l planes with s i n © below a s p e c i f i e d maximum value, and computes the three s e t t i n g angles (26, yi,$) .for the General E l e c t r i c Spectrogoniometer and Single C r y s t a l Orienter. I t i s required that the c r y s t a l be mounted with a r e c i p r o c a l axis p a r a l l e l to the p axis of the goniostat. The input i s only.two cards, one spe c i f y i n g the c e l l constants, and the other the i n i t i a l values and i n t e r v a l s desired f o r the indices h k i . The output i s on cards ( l 6 2 0 computer) or magnetic tape (7OU0) i n order to be conveniently sorted before l i s t i n g . The computations may be started at any value of the'H^ index, and zones of data may be obtained i f desired. (2) Intensity Reduction (Equi-incTination' Weissenberg f i l m s or G.E. Spectro-goniometer data). Lorentz and p o l a r i z a t i o n corrections are c a l c u l a t e d and applied to each i n t e n s i t y and the structure amplitudes derived. A scale f a c t o r or an absorption 2 c o r r e c t i o n may be applied to each r e f l e c t i o n . Values of F Q are also output f o r a Patterson synthesis, and i n the 'JOkO version, s c a t t e r i n g f a c t o r values are also output. 92. (3) Bond Lengths and Valency Angles The program requires as input the u n i t c e l l constants, f r a c t i o n a l atomic coordinates, and bond angles required. I t computes, and outputs on the p r i n t e r , orthogonal coordinates i n A re f e r r e d to axes a 1 (=a.sinV), b, and c' (perpendic-u l a r to a' and b), and f o r three atoms 1, 2, and 3, "the distances 1-2, ; 2-3 (A), and angle 1-2-3 (degrees). (k) Mean Molecular Plane The program requires as input the un i t c e l l constants and f r a c t i o n a l atomic coordinates. I t outputs on the p r i n t e r the values of A, B, C, D i n the equation of the l e a s t squares best plane: .AX'+BY'+CZ'+B^O (X',Y', Z', are coordinates i n A with respect to the same orthogonal axes as i n program (3)). The deviation of each atom from the plane i s also output. Atoms may be given zero -weight i n the c a l c u l a t i o n of the plane, and t h e i r deviations computed. (5) Intermolecular Distances The program requires f r a c t i o n a l atomic coordinates f o r a standard molecule ' •and the general coordinates of up to 14 or more equivalent molecules. I t then generates the atomic coordinates f o r the< equivalent molecules and computes and p r i n t s out a l l the distances between a l l atoms of the standard molecule and a l l atoms of the generated molecules which are l e s s than a s p e c i f i e d maximum distance. (6) Standard Deviations of Atomic Coordinates The program computes and p r i n t s the standard deviations of the atomic coordinates and of the electron density, according to Cruickshank's formulae (23). The input required i s the structure f a c t o r data and the atomic curvatures. 93-(7) Least Squares'Refinement This program has been already described, i n Part I I I of t h i s t h e s i s (p. 68 ), It uses a block-diagonal approximation to r e f i n e the atomic coordinates. Refinement of a scale f a c t o r and of i n d i v i d u a l i s o t r o p i c temperature factors i s also performed, and the standard deviations of the positional•and thermal parameters computed. In the IBM 70^0 adaptation of the program, p r o v i s i o n has been made to • compute and r e f i n e i n d i v i d u a l anisotropic temperature f a c t o r s as well, l x l matrices being presently employed f o r each b i j . REFERENCES 95-1. A. Bravais, J. ecole-polytech. (Paris) 19, • 1 (1850). 2. E. 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