2 Physical Methods Part (v) X-Ray Crystallography By A. FORBES CAMERON Chemistry Department The University of Glasgow G12 8QQ 1 Introduction OFthe more general crystallographic publications which have become available in recent months one in particular merits special comment. This two-volume reference work contains 4473 references to 4098 distinct carbon-containing compounds the structures of which had been reported up to 1969. Both for crystallographers and for those who wish to use crystallographic results these books will greatly simplify the identification and location of structures which have already been studied. It is to be hoped that this effort will be extended to include purely inorganic compounds and that the data will be regularly updated.In previous reports structure analyses have been selected for discussion according to the types of compounds which have been studied. This approach has been abandoned in the preparation of this article which has been written in an attempt to convey an impression of the results and conclusions which are currently being derived from crystal-structure analyses. The criteria for selecting analyses for inclusion have therefore been either the reasons which provoked a particular analysis or the information which resulted from it. The discussion is under four main headings which it is hoped broadly summarize the main fields of crystallographic interest in organic compounds. By this technique the author hopes to have produced a critique which will help to demonstrate the relevance of X-ray studies during the past year.2 ConformationalStudies One interesting aspect of conformational studies has been the report of the crystallographic investigation of the orientation and conformation of a guest molecule in a clathrate inclusion-compound.2 The thiochroman (1) forms clath- rates in which the guest molecule in this case the acetylenic compound (2) is accommodated in a cavity approximating to an hour-glass in shape (3). The guest molecule is held in the clathrate with the acetylenic bond contained by the ‘waist’ of the cavity and with the bulkier tetrahedral units projecting into the ‘Molecular Structures and Dimensions,’ ed. 0.Kennard and D. G.Watson Cambridge Crystallographic Data Centre and I.U.Cr. vols. 1 and 2 1970.’ D. D. MacNicol and F. B. Wilson Chem. Comm. 1971 786. 109 A. Forbes Cameron upper and lower halves of the cavity. All the guest molecules are found to adopt a staggered conformation with statistical disorder of the hydroxy- and methyl- groups to conform with the imposed 3 crystallographic symmetry of the cavity. C Ill ;=r-6 c Me+Me I \ OH There have been several analyses of corrinoid and phthalocyanine derivatives for the most part carried out to investigate distortions of the macrocyclic ring systems whether inherent in the unsubstituted molecule or induced by the presence of oversized metal atoms. For example the corrole derivative 8,12-diethyl-2,3,7,13,17,18-hexamethylcorrole(4),3 is not strictly planar the non-planarity probably being a property of the ring system itself and attributable Me Me I Me Me both to short N-e-Nnon-bonded contacts and also to the direct C(l)-C(19) link.In this case there is in addition crystallographic evidence that the three inner hydrogen atoms are statistically distributed between the four nitrogens. A non-planar conformation is also deduced from the analysis the first in a particularly elegant series by Dunitz and co-workers of the synthetic corrinoid H. R. Harrison 0.J. R. Hodder and D. C. Hodgkin J. Chem. SOC.(B). 1971 640. Physical Methods-Part (v) X -Ray Crystallography derivative Ni"-1,8,8,13,13-pentamethyl-5-cyano-tra~~s-corrinchloride (5),4 in which the tendency of the nickel atom towards tetrahedral co-ordination is reflected in distortions throughout the entire corrin ligand-system.The synthetic precursor of (5) the c/D-seco-corrinoid Nil' complex (6),' has also been studied to investigate the role of the complexed nickel atom in holding the molecular conformation such that the cyclization reaction may easily take place. The analysis reveals that the almost tetrahedral nickel co-ordination results in the condensation centres lying close together in such a way that the reaction can CN CN take place with a minimum of molecular reorganization. In a similar investiga- tioq6 the structure of the A/D-seco-corrinoid complexes of Ni" Pd" and Pt" have been determined differences between the structures being of relevance to the case of the photochemical cyclization (7)+ (8) which has the order Pd" > Pt" with the Ni" complex completely resisting both photochemical and thermal cyclization.The analyses show that there is virtually no conformational Me Me Me Me Me> Me Me h1' ___) CN CN (7) (8) difference between the Pd" and Pt" compounds which tend to be planar and lead to the conclusion that electronic factors probably play an additional role in determining the relative reactivities of these two compounds. On the other hand the conformation of the Ni" complex is quite different showing a tendency ' J. D. Dunitz and E. F. Meyer jun. Helr. Chim. Acra 1971 54 77. ' M. Dobler and J. D. Dunitz Hrlc. Chim. Acfa 1971 54 90. M. Currie and J. D. Dunitz Hell). Chem. Acra 1971 54 98.A. Forbes Cameron towards tetrahedral co-ordination which indicates that the grossly different reactivity of this complex probably results from steric factors. Whereas dichloro- octaethylporphinatotin(~v)’is essentially planar non-planar conformations have been found both for dichlorophthalocyaninatotin(1v)’ and also for a mono- hydrated dipyridinated magnesium-phthalocyznin complex.’ These last three analyses demonstrate that for those macrocyclic ring systems which are not in-herently grossly non-planar the degree of ‘ruffling’ or ‘crumpling’ may be attributed to the size of the central metal atom in relation to the size of the available ‘hole’. Not only is the fifteen-membered cyclic diamide 5,9-dioxo-1,7,13-trioxa-4,10-diazacyclopentadecane nearly planar but the molecule almost possesses C symmetry and there is the additional possibility of multiple N-H..-0hydrogen bonding within the ring. In contrast the eight-membered ring of 3,7-dimethyl-1,5- dioxa-3,7-diazocyclo-octane-2,4,6,8-tetraspirocyclopropane (9),’’ has a crown- like conformation with the cyclopropane groups in two planes perpendicular to the general plane of the ring. Another spiro-compound which has been examined is (S)-(-)-spiro[4,4]nonane-1,6-dione(lo),‘* the crystallographically related rings adopting a conformation intermediate between envelope and half-chair forms but closer to the latter. The results of this analysis have been compared with theoretical valence-force calculations agreement within experimental limits for the most part being obtained.(10) (9) Studies of the geometries and conformations of polycyclic compounds have been nearly all directed towards seeking geometrical evidence for molecular strain which may be related to chemical or spectroscopic properties. Thus the p-chloroanilide derivative of bicyclo[5,3,l]undec-7-en-1 1 -one- 1-carboxylic acid (11)13 represents a case close to the limit for the possible existence of a bridgehead double bond. As a result the molecule exhibits unusual properties behaving in some instances as a conjugated enone and in others as though the n-bond systems were isolated. The analysis reveals a very large degree of twisting in the 7 D. L. Cullen and E. F. Meyer jun. Chem. Comm. 1971 616. n D. Rogers and R.S. Osborn Chem. Comm. 1971 840. 9 M. S. Fischer D. H. Templeton A. Zalkin and M. Calvin J. Arner. Chetn. Soc. 1971 93 2622. LO G. Samuel and R. Weiss Chetn. Conitn. 1970 1654. 11 H. Schenk Acta Cryst. 1971 B27 185. 12 C. Altona R. A. G. de Graaff C. H. Leeuwestein and C. Romers. Chem. Comm. 1971 1305. 13 A. F. Cameron and G. Jamieson J. Chetn. Soc. (B) 1971 1581. 113 Physical Methods-Part (v)X-Ray Crystallography molecule which has the effect of inhibiting complete overlap of the n-bond electrons. Similarly adamantylidene-adamantane (l2)I4 was studied because of chemical interest in addition reactions of the double bond. However the geometry of this molecule shows no abnormal features nor distortions and the molecule possesses approximate mmm symmetry.On the other hand the rather similar and unusual caged hydrocarbon decahydro[ 1,2,4 :5,6,8]dimetheno-sym-indacenedione (13)' which is the dione derivative of Binor-S does show evidence of considerable strain in the nortricyclanone subunits. Molecular strain is also inferred in both 8-carboxy-l-hydroxy-2-oxobicyclo[3,2,2]non-6-ene-9,4-carbo-lactoneI6 and tricyclo[4,3,1,1 3*8]undecane-4,5-dione,''the dihedral angle in the dicarbonyl chromophore of the latter compound being 11.9'. There is also evidence of molecular strain resulting in non-planar conformations of the substituted aromatic rings in cyclophanes. Thus in 8,16-imino-cis-[2,2]- metacyclophane (14),'*the dihedral angle between the aromatic rings is 93' and each aromatic ring is slightly distorted into a boat-like conformation while in [2,2]metaparacyclophane-1,9-diene(15),' both aromatic rings show a significant boat distortion which although only moderate for the meta-bridged ring is severe for the para-bridged ring.In this latter case the aromatic rings are inclined at 41" to each other. l4 S. C. Swen-Walstra and G. J. Visser Chem. Corntn. 1971 82. lS F. P. Boer M. A. Neuman R. J. Roth T. J. Katz J. Amer. Chetn. Soc. 1971 93 4436. l6 D. J. Pointer J. B. Wilford and K. M. Chui J. Chem. SOC.(B) 1971 895. l7 P. B. Braun J. Hornstra and J. I. Leenhouts Acta Cryst. 1970 B26 1802. A. W. Hanson and K. Huml Acta Cryst. 1971 B27 459. l9 A. W. Hanson Acra Crysr. 1971 B27 197. A. Forbes Cameron Analyses of the a-isomers (thermodynamically stable) of several S-alkylthio- hydroximates of which sinigrin and other mustard-oil glycosides are naturally occurring examples reveal that these stable forms possess the syn-(alkylthio) configuration.The particular compounds which have been studied are S-methyl- 0-(N-methylcarbamoy1)aceto t hiohydroxima te (1 6a)2 and the corresponding S-cyanoethyl derivative (16b),20 and S-(cyanoethy1)acetothiohydroximate (17).2 It is worthy of note that the mean N-0 bond length of 1.446 A in (16a) and (16b) which are substituted oximes is considerably longer than the value of 1.41 A in (17) and the value of 1.40 8 found in other free oximes. 0 / R-S \ /o-c N rCCH,CH S OH \/ 'NHMe /C=N /C=N Me H3C (a) R = Me (b) R = CH2CH2CN 3 Bonding Studies There have been several studies of molecular geometries in relation to the bonding in annulenes and related compounds.The cis,trans,cis stereochemistry of cyclodeca-2,4,8-triene-1,6-dione(18),22 which is the diketo-tautomer of 1,6-dihydroxyr lolannulene has been confirmed. The molecule is non-planar and the observed torsion angle of 160" at the traits double bond is consistent with chemical evidence that traits double bonds in medium-ring olefins are subject to considerable strain. 4,9-Methano[l llannulenone (19),23 an analogue of tropone was examined to obtain molecular dimensions for comparison with those of tropones bridged[ lo]- and bridged[ 141-annulenes. The analysis reveals alternation of bond lengths with the valency angles being considerably distorted from 120° and the carbonyl function is found to be syiz with respect to the 2o M.G. Waiteand G. A. Sim J. Chem. Soc. (B),1971 752. 21 M. G. Waite and G. A. Sim J. Chem. SOC.(B),1971 1102. 22 0.Kennard D. L. Wampler J. C. Coppola W. D. S. Motherwell D. G. Watson and A. C. Larson Acta Cryst. 1971 B27 1116. 23 D. W. Hudson and 0.S. Mills Chem. Comm. 1971 153. Physical Methods-Part (v) X -Ray Crystallography bridging methano-group. Another bridged annulene 7-methoxycarbonyl-anti- 1,6:8,13-bismethano[ 14lannulene (20)24also shows striking alternation of bond lengths confirming the polyenic nature of this anti bis-bridged compound in contrast to the aromaticity of the corresponding syiz derivatives.An example of the latter is provided by 1,6:8,13-butanediylidene[14]annulene(21),25 which shows only very slight alternation of bond lengths. 11,l l-Difluoro-1,6-methano-[lolannulene (22)26was studied to investigate the influence of bridge substituents on the hypothetical equilibrium between 1,6-rnethano[lO]annulene and bis- norcaradiene n.m.r. and chemical evidence having indicated that the difluoro- derivative should be an annulene and the dimethyl derivative a bis-norcaradiene. The analysis of the difluoro-derivative confirms that it is an annulene with a non-planar ring and some alternation of bond lengths. Considerable eflort has been devoted to studies of the bonding and conforma- tions of ylides and similar compounds with particular reference to the possibilities of extended conjugation involving d,-p overlap.The two N-ammonio-amidates (23) and (24)27are first-row ylides in which there is no possibility of d,-p overlap between the quaternary ammonium group and the vicinal electronegative atom Me Me \+ Me-.N-N-NO, \+ ~e-N-N Me/ Me/ (23) the only interactions being electrostatic in nature. The two molecules adopt almost identical conformations in which there is possible bifurcated hydrogen. -* oxygen bonding involving in each case two hydrogen atoms one from each of two N-methyl groups. On the other hand in second-row ylides as exemplified by certain sulphurane and phosphorane compounds there exists the possibility of d,-p overlap involving d-orbitals of the sulphur and phosphorus atoms 24 C.M. Gramaccioli A. Mimun A. Mugnoli and M. Simonetta Chem. Comm. 1971 796. 25 C. M. Gramaccioli A. Mugnoli T. Pilati M. Raimondi and M. Simonetta Chem. Comm. 1971 973. 26 C. M. Gramaccioli and M. Simonetta Tetrahedron Letters 1971 173. 27 A. F. Cameron N. J. Hair D. G. Morris and D. M. Hawley Chem. Comm. 1971 725. A. Forbes Cameron respectively. Amongst the sulphurane compounds studied are the two sulphonyl- stabilized ylides (25)28 and (26),” 2-dimethylsulphuranylidene-1,3-indanedione (27),30 trans-4-t-butyl-l-(l\r-ethyl-~-p-toluenesulphonylamino)-I-thionacyclohex-ane fluoroborate (28),3’ and 2,2’-bis-1,3-dithiole (29).32 The dimensions of all five compounds indicate significant levels of d-orbital participation in the bonding and in the case of the dithiole derivative (29) further evidence is provided by CNDO calculations.Similar conclusions are derived from examinations of the phosphorane derivatives (30),28(31)33 and (32).34 The analysis of hexaphenyl- carbodiphosphorane (33)3 raises several interesting if unexplained points having (p-Me . C6H&Pf Ph,P=C=PPh3 (32) (33) 28 A. F. Cameron N. J. Hair and D. G. Morris Chem. Comm. 1971 918. 29 A. Kalman B. Duffin and A. Kucsman Acta Cryst. 1971 B27 586. 30 A. T. Christensen and E. Thom Acta Cryst. 1971 B27 581. ’’ R. E. Cook M. D. Glick J. J. Rigau and C. R. Johnson .I.Amer. Chern. Soc. 1971 93 924. 32 W. F. Cooper N. C. Kenny J. W. Edmonds A. Nagel F. Wudl and P. Coppens Chem.Cnmm. 1971 889. 33 M. J. E. Hewlins J. Chem. SOC.(B) 1971 942. 34 0. Kennard W. D. S. Motherwell and J. C. Coppola J. Chem. SOC.(0, 1971 2461. 35 A. T. Vincent and P. J. Wheatley Chem. Comm. 1971 582. Physical Methods-Part (0) X -Ray Crystallography 117 been undertaken to investigate the geometry of the P=C=P system in the light of evidence that the X=C=C system is not linear when 5 has a vacant d-orbital and in the light also of the 140" angle found in the P=N=P system. However the compound crystallizes with two crystallographically independent molecules in the unit cell one of which has a P-C-P angle of 145" whereas the other has an angle of 131" there being no obvious reason for the difference. Moreover the difficulties of explaining bonding and electron delocalization solely on the basis of bond lengths are exemplified by the analyses of three sulphur-containing heterocyclic compounds.Thus S-C bond lengths of 1.719(3)8 and 1.721( 3) 8 in 4,4'-diacetoxy-5,5'-dimethyl-2,2'-bithiazolyl (34)36 are interpreted as indicating considerable double-bond character while similar lengths of 1.739(3) 8 and 1.763(3) 8 in 2-methylaminobenzothiazole (35)37 are said to be consistent with single bonds. Alternatively the exocyclic S-C bond of length 1.681(5) 8,in 4-amino-3-hydrazino-5-rnercapto-1,2,4-tria~0le~~ is taken to be consistent with contributions from the canonical forms (36) t-)(37). (35) MeOCOk=-( Me y2 N-N "-N H H A greater understanding of compounds which contain short S.-.O intra-molecular interactions has resulted from the studies of the three compounds (38) (39),39and (40),"O the shortest S. *Odistance [2.034(5) A] being found in (38) and the longest [2.373(7)A] in (40). These analyses lead to the conclusion that S...O bonding in nitro-compounds is rather similar to that in corresponding carbonyl compounds whereas stronger interactions are found in nitroso- derivatives as substantiated by the S-preference for nitroso- over either nitro- or 36 K. J. Palmer R. Y.Wong and K. S. Lee Actu Cryst. 1971 B27 1817. 37 M. Fehlmann Actu Cryst. 1970 B26 1736. 38 N. W. Isaacs and C. H. L. Kennard J. Chem. SOC.(B) 1971 1270. 39 P. L. Johnson K. I. G. Reid and I. C. Paul J. Chem. SOC.(B),1971 946. 40 K. I. G. Reid and I.C. Paul J. Chem. Sor. (B),1971 952. A. Forbes Cameron OA Ph NO2 Br (38) (39) (40) carbonyl groups. It is suggested that this may result from the importance of the ten n-electronic thiathiophen structures in the corresponding nitroso-compounds. The rather longer S. * -0interactions found in carbonyl derivatives are exemplified by 3-phenyl-l-propene-1,3-dione-l-(dimethyl mercaptole) (41),41 3,5-bis(pival- oylmethylene)-l,2,4-trithiolan(42),42 and the desaurin from acetophenone (43),43 the shortest interaction [2.509(5)A] occurring in (42),and the longest [2.727(10) A] in (43). There is also the possibility of a long-range S. * -0interaction in 5-methoxy- carbonylmethylene-2-piperidino-A2-thiazolin-4-one.44 The compound (44),45 an oxygen analogue of thiathiophthen is nearly planar and has an almost linear 0-S-0 [176.1(1)"] arrangement.The extremely long S-0 bonds [1.879(2) A] could alternatively be interpreted as representing extremely short S. -0contacts of the above type. 4 Biological Studies In addition to the effects of conformation the particular functions of biologically active molecules are in many cases determined by the possible intermolecular and intramolecular associations which they can form. X-Ray crystallographic studies can often provide information of direct relevance to such structure- activity relationships and are being increasingly applied in this field to the I. P. Mellor and S. C. Nyburg Acta Cryst. 1971 B27,1954. 42 I. P. Mellor and S. C. Nyburg Acra Cryst.1971 B27 1959. 43 I. R.Lynch I. P. Mellor and S. C. Nyburg Acfa Crysr. 1971 B27 1948. J4 A.F. Cameron and N. J. Hair J. Chem. SOC.(B) 1971,1733. 45 R. D. Gilardi and I. L. Karle Acta Cryst. 1971 B27 1073. Physical Methods-Part (v)X -Ray Crystallography 119 extent that the analyses described in this section represent only a very small fraction of the total number of biologically and pharmacologically important molecules which are being studied. Both the relative potencies of the free-acid and anionic forms of barbiturates and also the possible interference by barbiturates in the binding of calcium to phospholipids are subject to considerable controversy. As a result various derivatives and salts of barbituric acid have been extensively investigated.The analysis of calcium 5,Sdiethylbarbiturate (45)46 reveals that the deprotonated nitrogen atoms are co-ordinated to the calcium ions while the remaining pro- tonated nitrogen atoms function as hydrogen-bond donors in the formation of isolated barbital (5,Sdiethylbarbituric acid) dimers. However although the formation of sodium 5,5-diethylbarbiturate4’must also involve loss of a proton from an imine group in this case the formal negative charge is apparently dis- tributed over the oxygen atoms and the molecules are hydrogen-bonded to form ribbons with the sodium ions tetrahedrally co-ordinated by oxygen atoms. The molecular conformation of the barbital anion in the sodium salt is similar to that of barbital48 itself. Barbital also forms several polymorphs in which the individual molecules possess similar dimensions and conformations but differ in the N-Ha * -0 hydrogen-bonded frameworks extending throughout the crystals.For comparison with the above structures 5-ethylbarbituric acid (46a) and 5-hydroxy-Sethylbarbituric acid (46b)49 have been examined the rings in both compounds having a ‘flap’ conformation with C(5) displaced from other- wise nearly planar rings. In contrast with these two compounds 5-ethyl-5-(3’,3’- dimethylbuty1)barbituric acid (46~)~’ has a ring which is virtually planar with r 01 0 (45) (a) R = H (b) R = OH (c) R = CH,CH2CMe (46) the ethyl and dimethylbutyl C(5)-substituents forming a hydrocarbon chain which extends in a direction nearly perpendicular to the ring.This compound differs also in the mode of hydrogen bonding between molecules in the crystal. The activities of many chemotherapeutic and biologically active molecules may be related to the types of complexes which they form in biological environ- ments and structure analyses are now being used to investigate not only the 46 B. Berking Chem. Comm. 1971 674. 47 B. Berking and B. M. Craven Actu Cryst. 1971 B27 1107. 48 B. M. Craven and E. A. Vizzini Actu Cryst. 1971 B27 1917. 4y B. M. Gatehouse and B. M. Craven Actu Cryst. 1971 B27 1337. G. L. Gartland and B. M. Craven Actu Cryst. 1971 B27 1909. A. Forbes Cameron structures of such complexes but also the interactions which are important in their formation.An example of such studies is provided by the examination of the complex formed between the local anaesthetic phenacaine NN’-bis-(4- ethoxypheny1)acetamidium (47a)’ and bis-(p-nitrophenyl) phosphate (47b). This complex is representative of the class of complexes formed between local [p-EtO-C,jH,-NH-C-NH-C,H,-OEt-p] ’ I Me (474 anaesthetics and phosphodiesters and it has been suggested that complex forma- tion of this type may be involved in the bindings of a local anaesthetic molecule to phospholipids in the neural membranes the adduct being instrumental in blocking nerve conduction. The analysis was undertaken to compare the geometry of the complex with the similar complex formed by the local anaesthetic procaine. The analysis of the phosphate complex L-arginine phosphate mono- hydrate52 is similar to the study mentioned above in that the functions of arginine molecules and residues in living matter are characterized by the strong basicity of the guanidyl group and its ability to bind to phosphate groupings.In this complex the arginine molecule is a zwitterion possessing an unusual folded conformation and is bound to the phosphate moieties by hydrogen-bonds. Although pyridoxamine 5’-phosphate hydrochloride5 is not itself a complex of the type described above its study is nevertheless of relevance to complex forma- tion since it is generally accepted that the biological activity of Vitamin B is due in great part to the participation of a phosphorylated derivative pyridoxal 5’-phosphate as a co-enzyme in many enzymatic reactions of a-amino-acids.This analysis again shows the importance of hydrogen bonding in intermolecular associations involving phosphate derivatives. The important ability of many antibiotics to form complexes with metal ions has prompted several extremely interesting investigations of this property. Monensin (48)54 has been examined both as the free acid and as the silver salt. In the metal complex the monensin anion forms a macrocycle secured by a pair of hydrogen-bonds between the two hydroxy-groups and the carboxylate group at opposite ends of the molecule with the Ag’ ion co-ordinated to six oxygen atoms in the resulting cavity. However contrary to previous suggestions the 51 M. Sax J. Pletcher C. S. Yoo and J.M. Stewart Acta Cryst. 1971 B27 1635. ’* K. Aoki K. Nagano and Y. litaka Acfa Crysf.,1971 B27 11. F. Giordano and L. Mazzarella Acta Cryst. 197 1 B27 128. 54 W. K. Lutz F. W. Winkler and J. D. Dunitz Hela. Chim. Acra 1971 54. 1103. Physical Methods-Part (u) X-Ray Crystallography 121 OH Me CH,OH Me )-C0,H Me (48) free acid is also cyclic but differs in the number and arrangement of hydrogen bonds and hence in the relative positions of the oxygen atoms which form the complex with the metal ion. Moreover a possible mechanism for the complex formation is suggested by the mono-hydration of free monensin this additional hydrogen-bonded water molecule being oriented in such a way that it could also function in the hydration sphere of a metal ion and be subsequently displaced as H30+ when the metal ion is assimilated into the monensin molecule.Boromy- in,^ a novel antibiotic and the first well-defined boron-containing organic compound to have been found in nature has been shown to have an almost spherical molecule with a lipophilic surface and possessing a cleft lined with oxygen atoms which will accommodate metal ions with which the compound is complexing. The antibiotic X-537A (49),56 active against coccidial infec- tions in chickens forms cylinder-like dimers in its silver salt the cylinders having a hydrophobic exterior and containing the two Ag+ ions each of Me HEt O OOH Et 0 OH 'Me Me (49) which is complexed by five oxygen atoms and one phenyl ring. This arrangement for the silver salt contrasts with that found in the barium salt which consists of two antibiotic molecules forming a circular complex with a Ba2+ ion at the centre but again possessing a hydrophobic exterior.The latter authors in parti- cular suggest that it is the ability of antibiotics like X-537A to form such varied complexes which allows them to transport metal ions through membranes and hence forms the basis of their biological activities. Thus the antibiotic X-206 the largest polyether antibiotic for which a molecular structure has been established wraps itself around silver ions in such a way that the backbone of the molecule describes a path similar to the seam on a tennis ball completed by an 55 J. D. Dunitz D. M. Hawley D. MikloS D.N. J. White Yu. Berlin R. Marusic and V. Prelog Helv. Chim. Acta 1971 54 1709. 56 C. A. Maier and I. C. Paul Chem. Comm. 1971 181. 57 J. F. Blount and J. W. Westley Chem. Comm. 1971 927. A. Forbes Cameron internal hydrogen bond from O(7) to O(13). In this case the silver ion is co- ordinated unsymmetrically by six oxygen atoms. It has also been suggested that there is a possible relationship between metal ions and cancer and that a common property of some antitumour agents is the ability to function as chelating agents. Subsequent to this suggestion a large number of thiosemicarbazones were prepared and it was found that all the compounds of this class which were active as tumour inhibitors were also capable of acting as terdentate N-N-S ligands.However 2-formylthiophen thiosemicarbazone (51)'8 was anomalous in showing no antitumour activity although it could apparently act as an N-N-S chelate. The analysis reveals that the S atom is trans to N(l) whereas a cis relationship is required for chelate action. Moreover a large degree of double-bond character in the C(6)-N(2) bond acts as a barrier to the rotation necessary to produce a possibly active isomer. 1,3-Bis-(8-theophylline)propane (52 n = 3)59 is another interesting antitumour compound since theophylline itself possesses no activity and of the series of compounds (52 n = 2-8) it is the only one to show activity. This indi- cates the importance of the separation and relative orientations of the two theophylline moieties and since the analysis reveals that the molecule possesses a folded conformation there is also the suggestion of complex formation in the Me Me (52) biological activity.The analysis of the antitumour compound 9,10-bis(chloro- methyl)anthracene6' was carried out to provide structural details for comparison with other active molecules. In this case there is a slight tendency towards a boat- chair-boat conformation as a result of steric hindrance by adjacent groups on the anthracene nucleus. 58 M. Mathew and G. J. Palenik Acra Crysr. 1971 B27 59. 59 L. S. Rosen and A. Hybl Acta Crysr. 1971 B27 952. 6o E. J. Gabe and J. P. Glusker Acta Crysr. 1971 B27 1925. Physical Methods-Part (v) X-Ray Crystallography That the detailed conformations of pharmacologically active molecules are of importance has been demonstrated by several analyses.For example the prome- dols are widely used as analgesics the most active being ( +)-/?-promedo1 (53a) whereas the least active is (+ )-y-promedol (53b).61 Analyses of both isomers have not only allowed unambiguous determinations of both stereochemistries but reveal in addition that in the active 8-isomer the phenyl ring adopts an axial conformation similar to the conformations which are found in both morphine and codeine. Isoproterenol sulphate dihydrate (54)62 is used in cases of heart-block and in the treatment of asthma possessing a bronchodilatory action (a) R' = Ph;R2 = OH (54) (b) R' = OH;R2 = Ph (53) similar to that of adrenalin and noradrenalin.A feature of all three compounds is the cis relationship of the ammonium and hydroxy-groups which are close enough for possible hydrogen-bonding between them and it is suggested that interactions of this type may play an important part in the biological activities of such compounds. Similar suggestions have been made as the result of the analysis of the methylene chloride solvate of Pancuronium bromide (55),63used clinically as a neuromuscular blocking agent. The piperidino-groups at both ends of the steroid nucleus are each involved in hydrogen-bonded interactions with the adjacent acetoxy-functions resulting in a rigid conformation both in the crystalline state and in solution. The authors suggest that the cage-like hydrogen- bonded structures may be intimately involved in the biological activity of this compound.0 '' W. H. De Camp and F. R. Ahmed Chem. Comm. 1971 1102. b2 M. Mathew and G. J. Palenik J. Amer. Chem. SOC.,1971 93 497. 63 D. S. Savage A. F. Cameron G. Ferguson C. Hannaway and I. R. Mackay J. Chem. SOC.(B) 1971,410. A. Forbes Cameron Structure-activity relationships of other steroid derivatives have also been extensively For example although the introduction of a 6a,7a-difluoromethylene group generally potentiates the anti-inflammatory activities of various corticoids the 6a,7~-difluoromethylene-16a,l7a-isopropyli-denedioxy-corticoids are an exception showing decreased activities. It has been postulated that this results from impaired interaction with receptor sites owing to the two large a-face substituents causing conformational distortions of rings c and D.To test this hypothesis the steroid derivative (56)” has been examined Br I ‘fF Ph F as part of a more general investigation. The analysis reveals that there is the possibility of hydrogen-bonding between hydrogen atoms on C(17) and C(18) and the hydroxy-oxygen O(11). Similarly the fluoro-steroid (57)73has been studied because the progestational activities of steroids contaning a dioxolan 64 W. L. Duax A. Cooper and D. A. Norton Acra Cryst. 1971 B27 1. 65 C.M. Weeks A. Cooper D. A. Norton H. Hauptman and J. Fisher Acta Cryst. 1971 B27,1562. 66 W. L. Duax Y.Osawa A. Cooper and D. A. Norton Tetrahedron 1971 27,331. b7 W. L.Duax H. Hauptman C. M. Weeks and D. A. Norton Chem. Cumm. 1971 1055. 68 P. Coggon A. T. McPhail S. G. Levine and R. Misra Chem. Comm. 1971 1133. 69 D. R. Pollard and F. R. Ahmed Acta Cryst. 1971 B27,1976. 70 J. C. Portheine and C. Romers Acta Cryst. 1970 B26,1791. 71 E. Thom and A. T. Christensen Acta Cryst. 1971 B27,794. 72 E.Thom and A. T. Christensen Acta Cryst. 1971 B27,573. 73 G.W. Krakower B. T. Keeler and J. Z. Gougoutas Tetrahedron Letters 1971 291. 125 Physical Methods-Part (v) X-Ray Crystallography ring fused to the 16aJ 7a-positions of progesterone and also unsymmetrically substituted at the 2'-position have been shown to be dependent on the stereo- chemistry of the 2'-substituents. Thus the fi-methyl-a-phenylmethylenedioxy-compound (57) is more active than progesterone whereas the a-methyl-P- phenylmethylenedioxy-isomer although thermodynamically the more stable is essentially inactive.The analysis of (57) reveals that the conformation of ring D is very similar to that in 4-bromoestradiol approximating to a p-C(l3)- envelope and also that the dioxolan ring is not markedly puckered having a maximum torsion angle of only 32". However the phenyl ring is tucked well under the a-face of the steroid nucleus extending as far as ring B and is only 3.70 A distant from the fluorine atom. Such a conformation is not possible with the other isomer. Syntheses of aza-derivatives of steroids have been undertaken with the object either of enhancing activity or of reducing side-effects.Analysis of 12-keto-17-deoxo-8-azaestrone methyl ether hydrobromide (58)74 was carried out to study the geometries of such derivatives and led to the conclusion that the molecular parameters of the estrogen ring-system remain relatively constant regardless either of the insertion of nitrogen at the 8-position or of whether any of the rings possess hydroxy- carbonyl or methoxy-substituents. 5 General Structural Studies Most of the analyses described in the previous three sections have been of com- pounds of known molecular structure and were undertaken specifically to provide details of molecular geometries conformations or biological activities. Compounds of unknown molecular structure mostly natural-product deriva- tives are still widely studied by X-ray techniques.Thus there have been several studies of terpenoid derivatives. Ipecoside the first substance shown to be a nitrogenous secocyclopentane monoterpene glucoside has been examined as the dimethyl derivative 00-dimethylipecoside (59).7 Similarly the structures of jatrophone dihydrobromide (60)76 and gutierolide (61),77 both diterpenoid J. N. Brown R. L. R. Towns and L. M. Trefonas J. Heterocyclic Chem. 1971,8 273. '' 0. Kennard P. J. Roberts N. W. Isaacs F. H. Allen W. D. S. Mortherwell K. H. Gibson and A. R. Battersby Chem. Comm. 1971 899. 76 R. C. Haltiwanger and R. F. Bryan J. Chem. SOC.(B) 1971 1598. 77 W. B. T. Cruse M. N. G. James A. A. Al-Shamma J. K. Beal and R. W. Doskotch Chem. Comm. 1971 1278. A. Forbes Cameron Me0 Meo%:WOH CH,OH H' Me0,C ' H derivatives have been determined while the triterpenoid structures which have been studied include 24,25-dibromokulactone (62)78and a spirotriterpane (63)79 isolated from crude petroleum.Mi Me K. W. Ma F. C. Chang and J. C. Clardy Chem. Comm. 197 1,424. '' G. W. Smith Acta Crysf.,1970 B26,1746. Physical Methods-Part (u) X -Ray Crystallography 127 Alkaloid structures which have been resolved include bellendine (64)," narcissidine methiodide (65)," buxenine-G (66),s2 and laurepukin (67).83 Of these bellendine is the first alkaloid isolated from a proteaceous plant which has been shown to have a y-pyronotropane structure and the analysis of narcissidine methiodide proves that the previously postulated structure was incorrect.0 QyJMe OMe Meom Me0 I-Me MeHN Other natural products which have been studied include a derivative of dothi- stromin (68),'" which is a fungal toxin implicated in pine-needle blight (&)-dehydroaltenusin (69)' and the p-bromosulphonyl derivative of ophiobolin D (70).86 Several sugars and sugar derivatives have also been studied including methyl-a-~-altropyranoside,'' a-lactose m~nohydrate'~~~~1,6:2,3-dian-and hydro-P-~-gulopyranose.~~ 'O W. D. S. Motherwell N. W. Isaacs 0. Kennard I. R. C. Bick J. B. Bremner and J. Gillard Chem. Comm. 1971 133. A. Irnrnirzi and C. Fuganti J. Chem. SOC.(B) 1971 1218. R. T. Puckett G. A. Sim and M. G. Waite J. Chem. SOC.(B) 1971 935. 83 W. E. Oberhansli Helv. Chim.Acta 1971 54 1389. 84 C. A. Bear J. M. Waters T. N. Waters R. T. Gallagher and R. Hodges Chem. Comm. 1970 1705. 85 D. Rogers D. J. Williams and R. Thomas Chem. Comm. 1971 393. 86 S. Nozoe A. Itai and Y. Iitaka Chem. Comm. 1971 872. B. M. Gatehouse and B. J. Poppleton Acta Cryst. 1971 B27 871. " D. C. Fries S. T. Rao and M. Sundaralingam Acta Cryst. 1971 B27 994. 89 C. A. Beevers and H. N. Hansen Acta Cryst. 1971 B27 1323. 90 B. Berking and N. C. Seeman Acta Cryst. 1971 B27 1752. A. Forbes Cameron ~0% H 0 OMe