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Conformation analysis of some novel isomeric phosphate esters by phosphorus nuclear magnetic resonance… Malcolm , Robert Bennet 1969

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CONFORMATIONAL ANALYSIS OF. SOME NOVEL ISOMERIC PHOSPHATE ESTERS BY PHOSPHORUS NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY by ROBERT BENNET MALCOLM . B . S c , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1966 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n t h e Department o f CHEMISTRY We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THB! UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1969 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 r e q u i r e m e n t s f o r an advanced degree a t the U n i v e r s i t y o f B r i t i s h Columbia, I a g r e e t h a t 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 r e f e r e n c e and Study. I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u rposes may be g r a n t e d by the Head o f 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 u n d e r s t o o d t h a t c o p y i n g or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department of ~7 The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada (ii) ABSTRACT A series of isomeric, six-membered, cyclic phenyl phosphate esters has been obtained by column chromatography of the mixtures of isomers obtained by reaction of phenyl phosphorodichloridate with appropriate 1,3-diols. The con-formational analysis of the isomers was undertaken using both 1 31 H and P n.m.r.. The basic conformation of the 2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane ring system is that of a "flattened-chair". The thermodynamic free energy difference between "chair" conformations is sufficiently large for the basic ring to exist essentially in one favoured conformation, rationalized to have an axial phenoxy substituent. The stereospecific nature of ^ pg^ has been confirmed by using *H n.m.r. to determine conformations. 4 31 1 Long-range, J, P- H coupling constants have been found to be stereospecific in nature and useful in facilitating assignment of conformations for methyl-substituted-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinanes. Similar ring systems having different substituents at phosphorus have been studied and the conformations of these derivatives are seen to differ depending on the nature of the phosphorus substituent. The conformation of a cyclic nucleotide 31 has been determined from its P n.m.r. spectrum. The use of computer programming techniques and hetero-( i i i ) nuclear double resonance techniques, greatly f a c i l i t a t e d the analysis of the n.m.r. spectra discussed. An ..interesting deceptively-simple type of ABX n.m.r. spectrum has been found for many of these cyclic phosphate derivatives and the explicit analysis of this system is presented. (iv) TABLE OF CONTENTS INTRODUCTION 1 RESULTS AND DISCUSSION 7 Section A: The isomeric 4,6-dimethyl 2-oxo-2-phenoxy-1,3,2-dioxaphosphorinanes 8 Section B: Further isomeric pairs of cyclic phenyl phosphates .28 31 Section C: Stereospecific dependencies of P n.m.r. parameters 38 Section D: Other 2-oxo-l,3,2-dioxaphosphorinane systems.. 51 EXPERIMENTAL 62 General Methods 63 Cyclic Phenyl Phosphates 64 Miscellaneous Dioxaphosphorinanes 68 Analysis of Spectra 69 APPENDIX 72 Appendix A: The n.m.r. spectrum of 5,5-dimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane....73 Appendix B: Homonuclear and Heteronuclear Double Resonance Techniques and Computer Program.75 (v) Appendix C: Configurational Assignment at Phosphorus..78 --. Appendix D: Calculation of the Rotamer Populations of Adenosine-21-Phosphate 80 Appendix E: Deceptively-simple ABX Spectra 82 REFERENCES.. .85 (vi ) LIST OF TABLES TABLE 1 N .M.R. Parameters for 5,5-dimethyl-2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane 12 TABLE 2 N.M.R. data for the isomeric 4 , 6 - d i m e t h y l - l , 3 , 2 -~ dioxaphosphorinanes 17 TABLE 3 N.M.R. Parameters, f or 2-oxo-2-phenoxy- l ,3 ,2-dioxaphosphorinane 21 TABLE 4 N.M.R. Parameters f o r 4 , 4 , 6 - t r i m e t h y l - 2 - o x o - 2 -phenoxy-1,3,2-dioxaphosphorinane 32 TABLE 5 N.M.R. data for 4-methyl-2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane 33 TABLE 6 N.M.R. Parameters for o-hydroxybenzyl a lcohol c y c l i c phenyl phosphate 48 TABLE 7 N.M.R. Parameters for 5 ,5 -d imethy l -2 -ch loro-2 -oxo-1,3,2-dioxaphosphorinane 61 TABLE 8 Normal ABX Energies 85 TABLE 9 Decept ive ly-Simple ABX 86 (vii) LIST OF FIGURES Figure 1 P N.M.R. spectra of the 4,6-dimethyl-l,3,2-dioxaphosphorinanes 13 Figure 2 (a) *H n.m.r. spectrum of 4,6-dimethyl-l,3,2-dioxa-phosphorinane. Isomer 11(a) 14a (b) *H n.m.r. spectrum of 4,6-dimethyl-l,3,2-dioxa-phosphorinane. Isomer 11(b) 14b (c) n.m.r. spectrum of 4,6-dimethyl-l,3,2-dioxa-phosphorinane. Isomer 11(c) 14c Figure 3 Structural Parameters of 2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane 25 Figure 4 Plot of JpQCH V S ' °i n e c i r a l Angle 40a Figure 5 A Deceptively-Simple ABX Spectrum 47 Figure 6 *H N.M.R. Spectra of Substituted 5,5-dimethyl-2-oxo-l, 3,2-dioxaphosphor inane 55 (viii) ACKNOWLEDGEMENT I wish to express my sincere appreciation to Dr. L.D. Hall for his patient guidance throughout this study and acknowledge valuable discussion with other members of this laboratory and Dr. CA. Fyfe. I thank my wife and son for their infinite patience. INTRODUCTION Knowledge that the phosphorus atom plays a v i t a l r o l e i n the "chemistry o f the l i f e process has ex i s ted s ince the e a r l y years o f t h i s century . The o r i g i n a l d i scovery that the presence o f inorganic phosphate ions was e s s e n t i a l to the process o f a l c o h o l i c fermentation was fol lowed by the d iscovery that many organic phosphate es ters were intermediates i n b i o s y n t h e t i c r e a c t i o n s . More r e c e n t l y , i t has a l so been found that phosphorylat ion reac t ions e f f ec t the t r a n s f e r and storage of energy i n c e l l s . Other phosphate esters form important s t r u c t u r a l components o f c e l l s and c o n s t i t u t e the " molecular backbone " of the v i t a l l y , important n u c l e i c a c i d s . The study o f the chemical synthesis and r e a c t i o n s , e s p e c i a l l y h y d r o l y s i s , o f phosphate esters i s now wel l developed (1). The synthes is o f most of the n a t u r a l l y - o c c u r r i n g phosphate esters has been we l l descr ibed i n the l i t e r a t u r e and i t has been, p o s s i b l e to t o t a l l y synthesize po lynuc l eo t ides . Such processes as the mechanism and r e l a t i v e rates o f h y d r o l y s i s o f d i f f e r i n g phosphate esters and the r e l a t i v e ease o f formation o f c y c l i c phosphates from a c y c l i c phosphates, have a l so been s t u d i e d . The development o f the organophosphorus f i e l d as a whole has been extensive from a synthe t i c v iewpoint , the d i f f e r e n t p o s s i b l e valence s tates o f the phosphorus atom leading to a wide range o f c lasses of compounds. Throughout the organophosphorus f i e l d and, i n p a r t i c u l a r , concerning organophosphate e s t e r s , s tereo i someric and conformational proper t i e s of molecules have not , -3-in general, been investigated. The gross geometry of DNA is known to be helical but l i t t l e of the detailed conformation in solution has been determined. The conformational analysis of mononucleotides by proton magnetic resonance, p.m.r., spectroscopy has been undertaken with some success but l i t t l e is known about the conformation of the phosphate group in such systems. The conformational properties of the relatively more simple cyclic phosphates are similarly undetermined as are those of most organophosphorus heterocyclic compounds in general. The lack of a generally applicable technique for studying these properties is evident. P.M.R. spectroscopy has been successfully developed as a technique for the study of the conformational properties of organic molecules in general. In particular, this technique has the distinct advantage when considering bio-organic molecules that i t examines molecules in solution, potentially.approaching the " in vivo " state. Of the two fundamental experimental observables associated with p.m.r. spectroscopy, the chemical shift (<5), and the coupling constant ( J ) , i t is the coupling constant which has provided the greatest information with respect to molecular geometry. The dependence of the magnitude of the coupling constant between vicinal hydrogens (•Jj.jrjQj) o n the dihedral angle (<!>) between the projected C-H bonds is well known ( 2 ) . This familiar 2 Ja:cos T function has been the subject of considerable modification (3) -4-in attempts to include the further apparent coupling constant dependencies on such things as deviations of the system from tetrahedral carbon, electronegativity of neighbouring substituents, and configurational effects of these latter. Basically, however, it is usually possible to derive an experimental plot of J versus $> for a particular family of molecules i f a few model compounds of known geometry are available. In this manner, dependencies of the coupling constant on factors other than the dihedral angle are kept to a minimum. Using such an approach, conformational studies have recently involved similar dependencies of couplings of nuclei other than hydrogen. Considerable use has been made of known 13 31 H^CCF dependencies o n $ (4) and C and P dependencies'are being developed (5). A previous study by the author had established the partial angular dependence of vicinal POCH coupling constants(6). 31 The analysis of the P n.m.r. spectrum of 5,5-dimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (I) showed that J trans >> J gauche. -5-It was suggested that POCH coupl ing constants might provide" use fu l informat ion concerning the conformations o f phosphate es ters i n a s i m i l a r way that p . m . r . couplings had p r e v i o u s l y f a c i l i t a t e d s tudies o f other organic systems. It f u r t h e r seemed l i k e l y that phosphorus-proton couplings should be more s e n s i t i v e to changes i n stereochemical environment than proton-proton coupl ings* . The i n i t i a l purpose of the present study i s concerned i n part with the development of the above suggest ion, namely, 31 that P n . m . r . cons t i tu te s an e f f e c t i v e and genera l ly a p p l i c a b l e technique for s tudying conformations o f phosphate e s t e r s . Our approach has involved a study of a wide range o f c y c l i c phosphate d e r i v a t i v e s . During the synthes is o f the requ ired d e r i v a t i v e s , a novel type of isomerism at phosphorus has been d i scovered . Furthermore, a number o f other i n t e r e s t i n g s t e r e o s p e c i f i c 31 dependencies o f P n . m . r . parameters have been e l u c i d a t e d . Methyl s u b s t i t u t e d six-membered c y c l i c phosphates appeared to be i d e a l model systems for the study. A wide v a r i e t y o f compounds were a v a i l a b l e v i a s t ra ight forward synthet ic J trans * R e l i a b l e values for J and about 2 Hz. for J gauche. HCCH average about 10 Hz. for - 6 -procedures . The phenyl esters* were chosen for a number o f reasons: they are so luble i n a v a r i e t y o f organic so lvent s , they are not expected to have pH and i o n i c dependent n . m . r . s p e c t r a , and phenyl p . m . r . resonances do not mask important r i n g proton resonances. We were f u r t h e r a t t r a c t e d to d e r i v a t i v e s o f the 1,3,2-dioxaphophorinane system because many o f these are , i n f a c t , important m a t e r i a l s . Thus, the 2-hydroxy-2-oxo-dioxaphosphorinane r i n g system occurs i n nature . Furthermore, c e r t a i n d e r i v a t i v e s have commercial importance as p e s t i c i d e s , l u b r i c a n t s , p j a s t i c i z e r s , and nerve gases, among o thers . The r e s u l t s obtained were thus a n t i c i p a t e d to have some general i m p l i c a t i o n s . The main theme of t h i s thes i s then, i s concerned with the synthes is and separat ion o f c y c l i c phenyl phosphates and with a study o f t h e i r n . m . r . spectra and conformations. The p o t e n t i a l a p p l i c a t i o n of some of the r e s u l t s obtained during t h i s work to b iochemica l ly important molecules i s i l l u s t r a t e d at the end of t h i s t h e s i s . * 2-oxo-2-phenoxy-l ,3 ,2-dioxaphosphorinanes RESULTS AND DISCUSSION ) -8-This part of tlie present thes i s has been d iv ided i n t o four main s e c t i o n s . The f i r s t two sect ions deal with the s y n t h e s i s , separat ion and conformational ana lys i s o f severa l methy l - subs t i tu ted , six-membered c y c l i c phenyl phosphates. E s t a b l i s h e d n . m . r . parameter dependencies on s t ruc ture are used to determine the conformational proper t i e s o f the c y c l i c e s t e r s . The t h i r d sec t ion describes the s t e r e o s p e c i f i c nature of n . m . r . 31 parameters assoc iated with the P nucleus as e s tab l i shed and confirmed by the r e s u l t s o f the f i r s t two sec t ions . The f i n a l s ec t ion i s intended to b r i n g the r e s u l t s o f the present study i n t o the perspect ive o f t h e i r p o t e n t i a l a p p l i c a t i o n to s tudies o f phosphate d e r i v a t i v e conformations i n genera l , e s p e c i a l l y those concerning n a t u r a l l y occurr ing m a t e r i a l s . The i someric 4 >6 -d iniethyl-2 -oxo-2 -phenoxy- l,3,2 -d ioxaphosphorinanes The most simple synthet i c route to the 2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane r i n g sytem involves r e a c t i o n of an appropriate 1,3 - d i o l with phenyl phosphorodichlor idate ( A ) . T h i s reagent has been widely used under a v a r i e t y of condi t ions to synthesize c y c l i c phenyl phosphate esters in good y i e l d (7 , 8 ) . In a previous study (6) by the author, r e a c t i o n o f A with 2,2 - d i m e t h y l p r o p a n - l,3 - d i o l af forded a s ing l e c r y s t a l l i n e product ( I ) . -9-The n.m.r. spin system of I is formally of the type " AA 'BB'M^N^X " * for which explicit analysis of the observed n.m.r. transition frequencies and intensities, in terms of the n.m.r. parameters, is not possible. Fortunately, since many of the long-range coupling constants are very small, the observed spectrum was considerably more simple than that possible and a so-called " first-order analysis"** of the spectrum was immediately obtained. * Using the notation of reference 9. ** The term " first-order analysis " is used to describe the assignment of coupling constants and chemical shifts to spectral splittings and multiplet centres respectively, as they appear experimentally. For " weakly coupled " (coupling constants small relative to chemical shift differences) spin systems, the errors involved are usually negligible. For more highly coupled systems, the first order analysis can be misleading and subject to considerable error. -10-31 It was from the first order analysis of the P spectrum that the stereospecific dependence of «JpQQ[ w a s first determined as ^trans = 21.3Hz. "^ gauche = 2.8Hz.. The explicit analysis of the complete n.m.r. spectrum of I has since been reconsidered in the light of heteronuclear double resonance experiments and with the aid of computer-simulated * spectra. Pertinent aspects of the explicit analysis of the n.m.r. spectrum of I are presented in Appendix A and the data summarized in Table 1. The refined values for JpQQj thus lead to a reformulation of the dependence, thus =22.5 Hz. >> J , =1.7 Hz.. 1 trans gauche Throughout the present study, use has been made of both heteronuclear and homonuclear double resonance techniques and a modified LA0C00N III computer program to aid in spectral assignment and obtain accurate n.m.r. data where necessary. Use of these techniques is summarized in Appendix B. In an attempt to explore the further generality of the above angular dependence, the synthesis of several other methyl-substituted 2-oxo-2-phenoxy-l,3,2-dioxaphosphorinanes was undertaken. Whereas reaction of A with 2,2-dimethylpropan-l,3-diol afforded a single, crystalline product, a similar reaction * Although a general explicit solution does not exist for many n.m.r. spin systems, computer methods enable numerical approximations, well within experimental error, to be made of the desired parameters, providing sufficient experimental data are available. -11-with a commercial sample o f p e n t a n - 2 , 4 - d i o l afforded a syrupy 31 mater ia l ( I I ) , shown by TLC to have three components. The P n . m . r . spectrum of the mixture ( f igure 1) showed three separate resonances, one o f these having a l a r g e , ~ll H z . , s p l i t t i n g . Column chromatography ( s i l i c a gel / e thy l acetate) o f the syrupy mixture , monitored by T L C , provided an e f f i c i e n t means of separat ing the three components, l a b e l l e d 11(a) , 11(b), 11(c) , i n order o f decreasing Rf va lue . The r e s u l t i n g , c r y s t a l l i n e 31 component 11(a) had m.p. 9 4 ° C . and R.chemical s h i f t +125.8 p .p .m. ( r e l a t i v e i n t e n s i t y =1) while the syrupy components 11(b) and 11(c) 31 had 6 P +125.9 p .p .m. ( r e l . i n t . =1) and +123.6 p .p .m. ( r e l . i n t . =1), r e s p e c t i v e l y . These phosphorus chemical s h i f t s are cons is tent with those o f phosphate t r i e s t e r s i n genera l . The elemental analyses of a l l three components are i d e n t i c a l and cons is tent with that expected for s t ruc ture I I . The 100 M.Hz. p . m . r . spectra ( f igure 2) o f a l l three components are very s i m i l a r and the general features of these spectra are cons is tent with a t t r i b u t i n g the three components to the -12-Table 1 N.M.R. Parameters for 5,5-dimethyl-2-oxo-2-phenoxy-l,3,2- dioxaphosphorinane A B Chemical shifts x H. =5.78 4a T H. = 6.05 4e T Me = 8.74 9.16 a T Me = 9.16 9.32 e 631P =126.5 Coupling  Constants 4e,4a = 10.9 11.0 4e,6e = 3.0 4e,6a = 0.0 4e,P = 22.5 23.3 4a,6a = 0.0 4a,P = 1.7 A. Room temperature CDCl^ B. -80°C. in CH2C12 -13-Figure 1 n.m.r. spectra of the 4,6-dimethyl-l,3,2-dioxaphosphorinanes A 123 124 125 126 127 ppm. B OPh D A: Spectrum of the unseparated mixture of isomers. B: Isomer 11(a). C: Isomer 11(b). D: Isomer 11(c). Figure 2a H n.m.r. spectrum of 4,6-dimethyl-l,3,2-dioxaphosphorinane. Isomer 11(a). A: Normal spectrum. B: Spectrum obtained while irradiating P. * Spinning sidebands of the methyl resonance. Figure 2b A: Normal spectrum. B: Spectrum obtained while irradiating P. Figure 2c ^ H n.m.r. spectrum of 4,6-dimethyl-l,3,2-dioxaphosphorinane. Isomer 11(c). j H4(6) A: Normal spectrum. B: Spectrum obtained while irradiating P. / -15-three p o s s i b l e geometrical isomers o f 4 ,6-dimethyl -2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane depicted below. Thus the spectra show a complex m u l t i p l e t centered i n the T 5.2 - 5.4 range, o f r e l a t i v e i n t e n s i t y 2, due to protons on carbon atoms 4 and 6 being coupled to v i r t u a l l y every other nuc lear species present . A fur ther complex m u l t i p l e t centred i n the range T8.0 - 8 .2 , o f r e l a t i v e i n t e n s i t y 2, due to the methylene r i n g protons , i s fol lowed by methyl proton resonances o f r e l a t i v e i n t e n s i t y 6 centered i n the range T8 .5 - 8.7 . The phenyl resonances at ca . t2 .8 o f r e l a t i v e i n t e n s i t y 5, have not been i l l u s t r a t e d . The complete assignment o f these p . m . r . spectra was f a c i l i t a t e d by heteronuclear decoupling and the spectra obtained while i r r a d i a t i n g the phosphorus resonances demonstrate, i n comparison with the normal s p e c t r a , removal o f extensive long-range, 4 J coupl ing o f t h i s nucleus in to the methyl and methylene protons D e t a i l e d s p e c t r a l data for each o f the isomers has been obtained 16-i n p a r t , by a f i r s t order ana lys i s and i n part with the a i d o f computer-simulated s p e c t r a . Th i s data i s presented i n tab le 2. The appearance of a l a r g e , =17Hz . sp l i t t ing i n the 31 P n . m . r . resonance o f isomer 11(b) impl ies a trans POCH coupl ing i n accord with the r e s u l t from I . This enables assignment o f the s t r u c t u r e 11(b), the c y c l i c phenyl phosphate e s ter o f d , l - p e n t a n - 2 , 4 - d i o l , as dep ic ted , to t h i s product . The presence o f two, non-equivalent methyl resonances i n the p . m . r . spectrum confirms t h i s assignment. . Me oPh M b 31 The absence o f any large s p l i t t i n g s i n the P resonances o f components 11(a) and 11(c) suggests gauche POCH coupl ing r e l a t i o n s h i p s for these isomers. The p . m . r . spectra of these two isomers are v i r t u a l l y i d e n t i c a l and the s ing le methyl resonance i s cons i s tent with the s truc tures 11(a) and 11(c) . 1 I I CHEMICAL SHIFTS x 4e 11(a) x 4a 533.1. x 6e x 6a 533.1 x 5e 813.0 x 5a 831.2 x Me^  863.9 x Me a 5 p 125.8 11(b) 516.0 520.0 816.1 793.5 856.2 852.7 126.0 11(c) 525.9 525.9 815.4 834.7 865.9 123.6 COUPLING CONSTANTS 4e5a 4e5e 4e6a 4a6e 4a6a 4a5e 6a5e 4a5a 6a5a 5e5a P,4e P^ 4a P,6a P.5e P,5a| P,Me P-,Me, 4e, Me 5a, Ae 4a,Me 5a,Me 11(a) 0.0 2.9 10.3 13.2 2.9 2.4 0.8 2.7 6.4 11(b) 5.0 3.2 0.0 4.3 8.6 14.7 17.0 M.O 2.0 1.3 2.3 0.8 6.5 6.9 0.0 2.4 11.3 11(c) 14.2 3.1 2.4 0.7 2.3 6.4 a. Unequivocal assignment has not been possible. Interchange i of these values has been assumed for the discussion of this molecule in the text. -18-By us ing the observed s t e r i c dependence o f JpQ^^> i t has been poss ib l e to ass ign s t ruc tures and b a s i c , approximate c h a i r conformations to the three geometrical isomers o f I I . Assignment o f absolute conf igura t ion at the phosphorus atom, however, i s based on a r a t i o n a l i z a t i o n o f c e r t a i n c i r c u m s t a n t i a l da ta . A d i scuss ion o f the data a v a i l a b l e concerning c o n f i g u r a t i o n a l assignment at phosphorus i s presented i n Appendix C . A proposed r a t i o n a l e o f the fac tors governing conformational preference i n these compounds i s also presented as the bas i s o f the c o n f i g u r a t i o n a l assignments of t h i s t h e s i s . It i s f e l t , however, that s u f f i c i e n t data i s not yet a v a i l a b l e to confirm these assignments,and the conf igurat ions dep ic ted , though i n t e r n a l l y c o n s i s t e n t , are thus t e n t a t i v e . More d e t a i l e d conformational information about the '" c h a i r " s t ruc tures o f isomers II i s a v a i l a b l e from the p . m . r . data f o r these compounds. As mentioned i n the i n t r o d u c t i o n , 3 use o f J , HCCH coupl ing constants to determine d ihedra l angles between v i c i n a l hydrogen atoms i n organic systems has been widespread and a good deal i s known o f the quant i ta t ive l i m i t s of the method. In order to minimize many of the inherent inaccurac ie s of t h i s type o f a p p l i c a t i o n , the n . m . r . data of 2-oxo-2-phenoxy-l ,3 ,2-dioxaphosphorinane ( I I I ) for which an X-ray s t ruc ture determination i s a v a i l a b l e , w i l l be used as a s tandard. -19-Thus, gross e f fec t s o f changes i n t o t a l e l e c t r o n e g a t i v i t y o f the system, i n r e l a t i v e symmetry about the various carbon atoms, and i n s o - c a l l e d " o r i e n t a t i o n a l e f fec t s " o f the v i c i n a l protons , are expected to be n e g l i g i b l e * and comparisons o f p . m . r . data o f compounds II with t h i s standard should provide i n s i g h t to subt le conformational changes. The n . m . r . spectrum o f III has been prev ious ly s tudied 4 3 1 1 by the author (6) and an i n t e r e s t i n g long-range, J P- H , coupl ing constant dependence re su l t ed from a f i r s t - o r d e r ana lys i s o f the C<- methylene proton resonances. With the subsequent p u b l i c a t i o n (11) o f an X-ray determination of the s t ruc ture o f t h i s molecule , the complete ana lys i s o f t h i s n . m . r . system has been undertaken. Due to the very h igh ly - coup led nature o f t h i s seven sp in system, an approximate, f i r s t - o r d e r ana lys i s o f the n . m . r . spectrum was imposs ib le . * For a summary of the s i g n i f i c a n c e of these e f fec t s i n general a p p l i c a t i o n s o f the Karplus equation see reference 10. -20-Extensive use of a s u i t a b l y modified version of the LA0C00N III computer program * provided the r e s u l t s presented i n table 3, f o r a t h e o r e t i c a l spectrum which corresponds c l o s e l y to that observed experimentally f or I I I . These r e s u l t s should provide an i d e a l model f o r r e l a t i n g p.m.r. data of o t h e r , s i m i l a r , compounds to conformational properties, provided the preferred conformation of III i s well determined. The c r y s t a l structure of I I I , determined by X-ray d i f f r a c t i o n techniques, has recently become ava i l a b l e (11) and i t i s intended to assume the pertinent s t r u c t u r a l parameters of t h i s r e s u l t . There are two fundamental assumptions to be made i n t h i s regard. The f i r s t , that the shape of the ri n g i n s o l u t i o n i s e i t h e r the same as, or very s i m i l a r to that of the c r y s t a l l i n e form, i s a basic assumption which cannot e a s i l y be circumvented but must nonetheless be made i n order to place the r e s u l t s of the present study in an absolute perspective. The f i n a l discussion of t h i s thesis w i l l deal more with t h i s point. The second assumption to be made at t h i s time i s that the molecule i n s o l u t i o n e x i s t s e x c l u s i v e l y i n one conformation. This assumption can be e i t h e r confirmed or overcome by comparing the n.m.r. spectrum of the compound at room temperature with that obtained at very low temperatures** * See Appendix B. ** For a discussion of low temperature n.m.r. experiments see page 53. Table 3 N.M.R. Parameters f o r 2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane I i CHEMICAL SHIFTS T4a T 4e T 5e T 5a : 5.49 i 5.57 8.25 a 7.7S a 126.0 COUPLING CONSTANTS 1 4a,4e j 4a,5e 1; 1 4a,5a j 4a,6e 1 ' -1 " ! 4a,4a . 4a,P 4e,5e 4e,5a 4e,6e 4e,P 5e,5a 5e,P 5a,P il 10.9 \ .2.7 i b 11.4° j 0.0 \ I . .—; 0.0 2.9 d 2.7 5.2 b • — 21.9 15.3 2.7 c < 0.9 a F i r s t order numbers. N . b "probable e r r o r " 0.8 Hz. \ c homonuclear spin-decoupling r e s u l t ! d Successive computer runs vary t h i s value s e r i o u s l y since these / t r a n s i t i o n s cannot be assigned directly,± 1 Hz. •22-Unfortunately, we have not yet been able to s a t i s f a c t o r i l y perform t h i s experiment due mainly to instrumental d i f f i c u l t i e s *. At t h i s time, on the basis of some preliminary low temperature n.m.r. r e s u l t s f o r I and X**, we f e e l that III exi s t s i n a sin g l e conformation to an extent of greater than 95%. In terms of the above two assumptions we accept the conformation of III as depicted i n figure 3. E s s e n t i a l l y the structure i s a cyclohexane-type c h a i r which has been flattened and widened at the phosphorus end of the r i n g . The s t r u c t u r a l data around the r i n g fragment.C^-C^-C^, i s i d e n t i c a l to that f o r cyclohexane within experimental e r r o r , the f l a t t e n i n g being e x c l u s i v e l y found i n the phosphorus end. From the data of table 3, i t . i s seen that a -IpQ^j] trans value of 21.9Hz. corresponds to a dihedral angle of 173° and that a JpQQj gauche value of 2.9;iz. corresponds to a dihedral angle of 67°. The above values f o r JpQQ] trans and gauche are s i m i l a r to those obtained f o r I and on t h i s b a s i s , the conformation of I i s taken to be that of I I I . Having thus j u s t i f i e d the preliminary conformational assignments of the isomers II using JpQ£^» i t i s appropriate to now discuss t h e i r p.m.r. spectra. * The low-temperature c a p a b i l i t y of the Varian HA-100 spectrometer (ca.-80 ) i s not s u f f i c i e n t l y low to be sure that the p o s s i b l e equilibrium process would be slow enough. Also, the very high r e s o l u t i o n of peaks required to properly analyze t h i s 7-spin system i s l o s t due to v i s c o s i t y broadening at these temperatures. ** See Appendix A and p. 53 r e s p e c t i v e l y . -23-Isomers 11(a) and 11(c) have very s i m i l a r n.m.r. spectra and the" data of table 2 i s s i m i l a r f o r each isomer. The differences which do e x i s t f o r J . r and J . r are not s u f f i c i e n t l y 4a,5e 4a,5a ' s i g n i f i c a n t , beyond experimental e r r o r , to a t t r i b u t e to any differe n c e i n the conformations of the two molecules. In comparison with the data f o r I I I , i t i s seen that only the geminal, 5e, 5a, coupling constant does not agree within experimental e r r o r . Since the 4a, 5e and 4a, 5a coupling constants of 11(a) and 11(b) "agree well with those of I I I , the conformation of the C^-Cj.-C^. parts of these molecules i s taken to be the same. The s i m i l a r i t y of the JpgQj gauche couplings (P,4a) i s taken to mean that the P-O-C-H dihedral angles are s i m i l a r . Thus, isomers 11(a) and 11(c) e x i s t i n the fl a t t e n e u - c h a i r conformation t y p i c a l of I I I . A s a t i s f a c t o r y measure of the accuracy of t h i s statement, based on other s i m i l a r applications would be a ±5% l i m i t on possible changes i n dihedral angle f o r the relevant bonds. The p.m.r. data f o r isomer 11(b) i s perhaps more i n t e r -e s t i n g , since there are more comparisons possible due to asymmetry of the molecule. The t r a n s - d i a x i a l 4e,5a coupling constant f o r 11(b) i s smaller than f o r III by ca. 2.5Hz., J4e,5e i s l a r £ e r ^ £a.l.6Hz.) as i s , perhaps, J 6 a ) 5 e (by ca. 0.5IIz.). The JpQQj trans coupling of 17.0Hz. i s somewhat smaller than f o r III and I by (ca. 3IIz.) Such data can u s u a l l y be explained i n one of three ways. -24-E i t h e r the molecule i s undergoing rapid conformational inversion as i n B, or i t e x i s t s i n a d i s t o r t e d conformation, or both. Bl B2 For B, i n which the molecule e x i s t s i n two now " t y p i c a l " , f l a t t e n e d chair conformations which d i f f e r only i n the configuration at the phosphorus atom, the room temperature n.m.r. data i s expected to be the weighted average of that f o r each conformation. The observed n.m.r. coupling constants for 11(b) are consistent with conformational "time-averaging" between the two " t y p i c a l " conformations as i n B. The 4a, 5a coupling constant (8.6 Hz.) would be expected to be somewhere between the values of 4e,5e (2.7 Hz.) and 4a,5a (11.4 Hz.) for I I I , depending on the r e l a t i v e populations of the two conformers. S i m i l a r l y , the value f o r 4e,5e i s somewhere between*that of 4e,5e and 4a,5a f o r I I I . The experimental values for J . c and J . c as well as those 4e,i>a 4a,be f o r J ™ — , and J n n „ „ M also agree well with the suggestion of a PuCh POCGH o . ot> conformationally i n v e r t i n g system. -25-Figure 3 St r u c t u r a l Parameters of 2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane' o: .0, 3 OPh 0 Central Bond P2-°l ° r c 6 C 6 - C 5 C5- C4 C4-°3 Dihedral Angle 43° 54° 59° 59v 52^ ° 3 - P 42^ * From reference 11. -26-By assuming that' the c o n f i g u r a t i o n at the phosphorus atom does not a f f ec t s e r i o u s l y the magnitudes o f the i n d i v i d u a l coupl ings * , the r e l a t i v e populat ions at room temperature o f the two conformations o f 11(b) may be c a l c u l a t e d . The express ion J = a J n l + ( 1 - a ) J „ _ , where a * average Bl v B2 i s the f r a c t i o n o f the populat ion i n conformation B l , J D 1 i s the value of the coupl ing constant for B l , and J D . i s the value o f the coupl ing constant for conformation B2, can be used. For the conformational e q u i l i b r i u m between Bl and B2, the value for a can be c a l c u l a t e d us ing f ive d i f f e r e n t sets of coupl ing constants . The r e s u l t s , us ing III as the standard are as fo l lows: J POCH a=0.74 J P , C H 3 " ° - ° ' 7 S J P , H 5 ** " - O - 6 2 J r , a=0.68 5a,6a J . _ a=0.92 4e,5a It i s f e l t that the v a r i a t i o n of these values i s due to the v a r i a t i o n i n the accuracies o f the proton-proton coupl ing constants as determined for III and 11(b). That the values c a l c u l a t e d from the two phosphorus coupl ings agree w e l l , can be taken as a measure of the s e n s i t i v i t y with which these depend * A good approximation i n view of the s i m i l a r i t y o f the coupl ings for 11(a) and 11(c) . ** Using the s t e r e o s p e c i f i c dependence of these couplings discussed on pp.44-50 and us ing 11(a) as the model. -27-on d i h e d r a l angles . F o r t u n a t e l y , the phosphorus-hydrogen coupl ing constants can often be accurate ly determined i n systems f o r which the remaining p . m . r . ana lys i s i s d i f f i c u l t . The low temperature n . m . r . spectrum ( - 8 0 ° C . ) o f 11(b) was not e n t i r e l y s a t i s f a c t o r y * and values for J . ^ and J, were not s i g n i f i c a n t l y d i f f e r e n t . At t h i s time i t i s not p o s s i b l e to f i r m l y decide that 11(b) i s conformat ional ly time averaging though the above observat ions tend to suggest t h i s . The isomer B l , having the same c o n f i g u r a t i o n at phosphorus as I , 11(a) and I I I , i s expected to be the p r e f e r r e d one**. 4 The cons iderable number of J , long-range coupl ing constants determined for these isomers w i l l be discussed l a t e r . * See footnote bottom of p .22 . ** See a l so Appendix C . -28-Further isomeric p a i r s of c y c l i c phenyl phosphates In an attempt to explore the generality of the isomeri-sation at phosphorus as described in the previous s e c t i o n , several other "asymmetric" d i o l s were reacted v/ith phenyl phosphorodichloridate. The conformational analysis of some of the r e s u l t i n g isomeric phenyl phosphates was undertaken 31 by p.m.r. and P.m.r. spectroscopy both i n order to e s t a b l i s h the g e n e r a l i t y of the " f l a t t e n e d c h a i r " c h a r a c t e r i s t i c s of the r i n g system and also to provide more data i n support of 31 1 the i n t e r e s t i n g long-range P- H coupling observations f o r the system I I . In a now t y p i c a l r e a c t i o n , 2-methyl-pentan-2,4-diol was reacted with phenyl phosphorochloridate to give a semi-c r y s t a l l i n e mixture of products IV. IV The product mixture showed two components by TLC and had two 31 resonances of about equal i n t e n s i t y i n the P n.m.r. spectrum. Column chromatography of the mixture provided separation of a c r y s t a l l i n e , faster-running (on TLC and column) component [IV(a)] -29-from a syrupy component [IVfb-)]. The p.m.r. spectra of both isomers were v i r t u a l l y i d e n t i c a l and consistent with the structures depicted below f or the two expected isomers of 4,4,6-trimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane. r-Assignment of the n.m.r. spectra of both isomers was effected by standard f i r s t order methods and subsequently confirmed by computer techniques. Due to the very highly-coupled nature of the Cj. protons i n both isomers, an unequivocal assignment of the n.m.r. spectra was impossible. As a r e s u l t , some df the n.m.r. parameters have not been determined. Such data as are av a i l a b l e are presented i n table 4. In a manner analogous to that used to assign structures and conformations to isomers I I , the n.m.r. data suggests that isomers IV(a) and IV(b) have i d e n t i c a l , f l a t t e n e d - c h a i r conformations, s i m i l a r to that f o r I I I . Thus a small JpQQj implies an a x i a l hydrogen at C^. A Large v i c i n a l 5a,6a coupling constant defines a trans d i a x i a l r e l a t i o n s h i p and the 5e,6a coupling constants compare favorably 31 1 with that from I I I . B a s i c a l l y the same long-range P- H -30-coupling constant dependencies are noted as before. S i m i l a r r e s u l t s have been obtained from 4-methyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (V). Reaction of phenylphosphorodichloridate with butan-1,3-diol provided a mixture of the isomeric phosphates. This mixture was r e a d i l y separated into a c r y s t a l l i n e isomer [V(a)] and a syrupy isomer [V(b)] by column chromatography. The n.m.r. spectra of these compounds have been obtained and analyzed as completely as possible using techniques a v a i l a b l e . The n.m.r. parameters are l i s t e d i n table 5. The data f o r V(a) suggest that the conformation of t h i s molecule i s i d e n t i c a l to that f o r the model I I I . In p a r t i c u l a r , the large, 23 Hz., trans POCH coupling constant agrees well with that of III and I. The large 5a,6a trans d i a x i a l coupling constant and the small 5e,6a gauche coupling constant are consistent with those for I I I . The conformation of V(a), depicted above, shows assignment of the presumably stable, equatorial phosphoryl oxygen configuration. -31-There has been i n s u f f i c i e n t data obtained from the high l y complex n.m.r. spectrum of isomer V(b) to adequately describe the conformation of t h i s molecule. The somewhat low values obtained f o r JpQQj trans (=10 Hz.) and JpgcQj (1-9 Hz.) tend to suggest that t h i s molecule i s undergoing rapid conformational inv e r s i o n at room temperature and that there i s an equilibrium mixture of s i g n i f i c a n t populations of both conformations. Table 4 N.M.R. Parameters f o r 4,4 )6-trimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinahe CHEMICAL SHIFTS T Me 4 a xMe 4 e x Me 6 e T 6a x 5e 31 T 5a i 8 P 1 IV (a) 8.47 8.53 8.61 5.22* 8.24* 8.06* | 127.0 IV (b) . 8.49 i 8.66 8.69 5.24* I 8.20* i 8.11* | 126.0 COUPLING CONSTANTS P. Me. 4a P.Me 4 e . P,Me, ' 6e P,6a I ]6' M e6 P,5e P,5a 5e,5a 5e,6a 5a,6a IV (a) >0.7 2.85 2.65 1.3 6.30 2.3 1.0 14.7 3.5* • 10.5* IV(b) j >0.5 * ' 1 • t 2.2 2.1 <\,2* 6.35 2.2 \ 0.8 14.7 * F i r s t order numbers only. j -33-Table 5 N.M.R. data f o r 4-methyl-2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane I — • CHEMICAL SHIFTS xMe T4a x6a x6e [ 31 V ( a ) 8.64 5.30 5.59 5.65 125.7 V ( b ) 8.57 5.15 125.2 COUPLING CONSTANTS CH 3,4a j CH_,P | 6e,P 0 1 5e ,5a 5a,6a 5e ,6a V ( a ) 6.5 ! 2.8 22.7 10.5 10.0 2.6 V f b ) 6.5 1.9 10 a I i a ±5Hz. -34-As f u r t h e r support for the generality of formation of isomeric p a i r s of c y c l i c phenyl phosphates i n reactions of unsyrmnetrical d i o l s with phenyl phosphorodichloridate, several other compounds were made. In each case, the isomeric p a i r s of compounds could be separated r e a d i l y by column chromatography. Thus both geometrical isomers of S-methyl-S-nitro-2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane (VI), 5-methyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (VII), and 5,5-dimethyl-4-isopropyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (VIII) have been synthesized. To t h i s point i n the discussion, we have been p r i m a r i l y concerned with d e l i n e a t i o n of a somewhat novel type of isomerization around the phosphorus atom i n a series of c y c l i c phosphate esters. Since a considerable amount of synthetic work involving these r i n g systems ex i s t s i n the l i t e r a t u r e (12) i t i s perhaps s u r p r i s i n g that existence of t h i s type of isomerization has not been, previously noted. In p a r t i c u l a r , compounds IV and V have previously been reported by a d i f f e r e n t method (13), i n v o l v i n g displacement of halogen on phosphorus by phenoxide -35-ion, but the p o s s i b i l i t y of isomers was not discussed. It i s hoped that the c h a r a c t e r i z a t i o n of isomeric pairs of compounds by n.m.r. presented herein w i l l enable the course of such displacement reactions on phosphorus to be more c l e a r l y recognized. The c y c l i c phenyl phosphates, synthesized using phenyl phosphorodichloridate, which have been reported i n the l i t e r a t u r e (14) are expected to, i n f a c t , consist of a 1:1 mixture of the two possible geometrical isomers at the phosphorus atom. P r i o r to the p u b l i c a t i o n of some of the preliminary r e s u l t s of the present study (15) , a mixture of isomeric methyl phosphates as hydrolysis products of five-membered c y c l i c oxyphosphoranes, had been reported by Ramirez (16). The n.m.r. data f o r these five-membered c y c l i c methyl phosphates are included i n the discussion of a Karplus-type r e l a t i o n s h i p f o r JpgrjLj t 0 follow. Denney and Denney had also reported (17) the presence of isomeric six-membered c y c l i c methyl phosphates as oxidation products of c e r t a i n c y c l i c methyl phosphites and reported separation of the methyl phosphate analogs of V by d i s t i l l a t i o n and glpc . Recently, confirmation of the physical properties of IV, V and VIII has been published (IS). 31 The use. of P n.m.r. parameters lias so f a r been r e s t r i c t e d to a p p l i c a t i o n of the experimental observation from compounds III and I that JpQQj trans i s much greater than J gauche. The conformations i n so l u t i o n of the seven -36-compounds of I I , IV and V, have been considered i n terms of t h i s dependence and also from d e t a i l e d study of the p.m.r. data. In a sense, d e t a i l e d consideration of the p.m.r. data over-determines the system i n question since the general shape of the r i n g system i s implied from the phosphorus n.m.r. spectrum. The p.m.r. data, however, has been obtained i n order both to confirm the generality of the JpQ£|_| dependence and also to give i n s i g h t into i n t e r e s t i n g dependencies of long-range, 4 J phosphorus-hydrogen coupling constants, to be discussed. The conformation of the parent, 2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane r i n g system has been taken to be that of the f l a t t e n e d - c h a i r described i n the X-ray r e s u l t . The a c t i v a t i o n energy required f o r the conformational inversion process which could take place, i s assumed*to be accesible at room temperature. Thus the assumption made i s that an e q u i l i -brium mixture of the two basic conformations possible e x i s t s and that the thermodynamic free energy d i f f e r e n c e between these i s such that, at room temperature, one conformation predominates to the extent of greater than 95%. The conformation i n which the phenoxy substituent i s a x i a l i s taken to be the most stable. The structure of I i s by analogy and isomers 11(a), 11(c), IV(a), IV(b) and V(a) are a l l taken to be s i m i l a r l y conformationally pure; isomers 11(c) and IV(b) having the * By analogy with t h i s observation f o r other sin g l e six-membered r i n g systems. -37-opposite c o n f i g u r a t i o n at phosphorus. The free energy d i f ferences between the conformations of 11 (a) , I V ( a ) , and V(a) would be expected to be even greater than that for I and II i n that c l a s s i c a l non-bonded i n t e r a c t i o n s o f a x i a l methyl groups i n the inver ted conformers, would be expected to fur ther d e - s t a b i l i z e these s t r u c t u r e s . Presumably, the free energy d i f f erences a t t r i b u t e d to these s t e r i c i n t e r a c t i o n s of a x i a l methyl groups are s u f f i c i e n t l y l a r g e , compared with those of the a x i a l - e q u a t o r i a l subs t i tuents at phosphorus, to populate the depicted conformations o f 11(c) and IV(b) ( inverted conf igurat ions at phosphorus) by greater than 95%. It i s thus p o s s i b l e to estimate the thermodynamic free-energy d i f f e r e n c e of conformational preference at phosphorus as being much less than that o f the conformational preference of two c i s 1,3-methyl subs t i tuent s . The suggestion that s i g n i f i c a n t populat ions of both conformers o f 11(b) and V(b) e x i s t at room temperature i s c o n s i s t e n t , i n that the f ree -energy d i f f e r e n c e of subst i tuents at phosphorus i s now no longer g r e a t l y d i f f e r e n t than that for a s ing l e ax ia l -methyl s u b s t i t u e n t . -38-S t e r e o s p e c i f i c dependencies of P n.m.r. parameters -- Having now established the conformations of several sets of isomeric phosphates i t i s appropriate to more c l o s e l y examine the nature of the Jporj^ dependence used. Although the terms J and J , have been used f r e e l y , i t i s evident trans gauche ' from the X-ray data f o r III that trans f o r t h i s system has been used to imply a dihedral angle of 173° and gauche , s i m i l a r l y , 67°. Thus Jf and J . as used i n the conformational ' trans gauche analysis so f a r do not correspond to coupling constants f o r P-O-C-H dihedral angles of 180° and 60°. This d i s t i n c t i o n i s an important one i n considering applications of the r e s u l t s outside the basic 1,3,2-dioxaphosphorinane r i n g system. Two aspects of t h i s are s i g n i f i c a n t . One, the establishment of an experimental curve of J p _ Q Q H v s ' ^ l n e C j 1 r a ^ a ng^ e> requires a number of accurate coupling constants corresponding to a range of known dihedral angles. This curve would be of considerable value i n considering conformations of d i f f e r e n t sized r i n g systems, as well as of some t h e o r e t i c a l i n t e r e s t . The other important aspect of these coupling constant dependencies i s t h e i r a p p l i c a t i o n to conformationally mobile systems ( i . e . a c y c l i c phosphate esters) which requires r e l i a b l e values of J p Q Q L j f ° r dihedral angles 180° and 60°. A l l of these more quantitative considerations require knowledge of the r e l a t i v e signs of the JP0CI! c o u P l i n S 5 -It i s not f e l t at t h i s time that s u f f i c i e n t data e x i s t -39-either in the literature or as a result of the present study to attempt to define a complete experimental plot of JpQ^ vs. dihedral angle but such data as a r e available has been plotted in figure 4. The superimposed curve is a typical Karplus-type curve* as theoretically formulated (19) for H-C-C-H fragments and has been included for comparison only. Somewhat more successful at this time is a consideration of conformationally mobile, acyclic systems, the observed N.M.R. coupling of phosphorus into the hydrogen nuclei of a freely-rotating methyl group in a compound such as trimethyl phosphate (D) should be the weighted average of the rotamer 6 O G H 3 O E * > p = 0 I J oca coupling constants as in E, F and G. Thus, J a v = (3^Q+23^Q)/3 assuming the idealized rotamer condition that the energy minima occur at 120° intervals of rotation around the 0-C bond. Using the values of 3^ and J , for compound I, J =8.7 6 trans gauche 1 av. * The JJJCQLJ a x i s of this curve has been expanded to provide comparison with the somewhat larger ^pg^ data. Hz. -40-H. H/ The experimental value f o r trimethyl phosphate i s 11.2 Hz.. Presumably, the use of values not corresponding to exact 180° and 60° dihedral angles accounts f o r the largest part of t h i s d e v i a tion, and, assuming the general c h a r a c t e r i s t i c s of the Karplus curve (figure 4) to hold f o r Jpoc^ vs. <j> , J 1 Q r t o i s expected to be larger than J. and J,„o larger 180 1 b trans 60 b than J , At t h i s time an estimate * of J,ono gauche. 180 and J ^ Q O i s 25 Hz. and 3 Hz. r e s p e c t i v e l y . These numbers now give a J value of 10.3Hz., i n good agreement with the av. experimental number. Once r e l i a b l e values for J j g Q 0 a n c * J ^ Q 0 have been established, the "reverse" process can be used to estimate the populations of d i f f e r e n t rotamers i n any given system, using the observed value f o r JpQQ^- An example of t h i s * These numbers are a r r i v e d at by extrapolating an assumed Karplus curve f o r JpQQt|- The expected error i n thes numbers due to experimental error and the above assumption i s ±2 Hz. -40a-Figure 4 Pl o t * of J D n r , , vs. Dihedral Angle _.. _ Dihedral Angle Reference 16, This molecule maybe s i g n i f i c a n t l y time averaging. Reference 23, The o r i g i n a l discovery that JpQQ]( trans i s greater than J , , determined for t r i c y c l i c molecules, gauche • J * The curve i s that of the Karplus equation(2) as derived for J H r r , . couplings i n ethane fragments. -41-kind of a p p l i c a t i o n using the above estimated values of JjgQ ,and J^Q , i s presented i n Appendix D . The probable accuracy of the r e s u l t i n g rotamer populations i s l i k e l y to be *5-10%. One very useful r e s u l t from c a l c u l a t i o n s such as these, however, i s confirmation of the r e l a t i v e signs of the two coupling constants. The absolute sign of the averaged POCH coupling constant i s known to be p o s i t i v e (20). Although analysis of the n.m.r. spectrum of I, aided by computer techniques, r e s u l t s i n assignment of s i m i l a r signs f o r J__ and J , , t h i s could not be confirmed unambiguously trans gauche b J . by double resonance techniques due to the o v e r a l l complexity of the n.m.r. spin system. However, since i s p o s i t i v e , then J , and must also be p o s i t i v e since the previously gauche trans , r c a l c u l a t e d J (+8.7 Hz.) agrees more c l o s e l y with experiment. 3.V • Calculated values f o r J of +6.4 Hz. and -6.4 Hz. would r e s u l t av. from opposite signs of J , and J With the recent 1 1 & gauche trans. 2 f i n d i n g (21) that c e r t a i n J phosphorus hydrogen coupling constants have d i f f e r e n t signs f o r d i f f e r e n t r e l a t i v e molecular geometries, i t was f e l t that a further, independent determination of JpQQj r e l a t i v e signs would be appropriate. The six-membered c y c l i c phenyl phosphate derived from o-hydroxybenzyl alcohol (IX ) was chosen, the expected "ABX" n.m.r. spin system being amenable to unequivocal r e l a t i v e sign determination by double resonance techniques. -4 2-A c r y s t a l l i n e product IX was obtained upon reaction of phenyl phosphorodichloridate with o-hydroxybenzyl alcohol Elemental analysis and n.m.r. data f or the compound are e n t i r e l y consistent with the structure depicted f o r the c y c l i c phenyl phosphate. The conformation of t h i s molecule i n s o l u t i o n i s expected to be the " h a l f - c h a i r " (H) f o r which the dihedral OPh angles of the P-O-C-H bonds are thought to be close * to those f o r the t y p i c a l " f l a t t e n e d - c h a i r " conformations discussed previously. The p.m.r. spectrum of t h i s molecule i s presented i n fig u r e 5. * From studies of a molecular model, the differences o are expected to be less than 10 . -43-This spectrum i s quite unlike that expected f o r the "AB" part of a t y p i c a l "ABX" spin system. This observed, s o - c a l l e d "deceptively-simple" spectrum has been previously reported i n the l i t e r a t u r e (22) and was thought to be unsuitable f o r a n a l y s i s . To the best of the author's knowledge, no explanation or analysis of t h i s type of deceptively-simple spectrum has been reported i n the l i t e r a t u r e . Since a f o r t u i t o u s equivalence of several n.m.r. paramenters of an "ABX" spin system causes the observed phenomenon, the t r a n s i t i o n frequencies f o r t h i s deceptively -simple spectrum can quite simply be r e l a t e d to those expected f o r a " t y p i c a l " ABX spectrum. The deceptively-simple spectrum can thus be e x p l i c i t l y analyzed as i s to give the n.m.r. parameters and the r e l a t i v e signs of the AX and BX coupling constants. This treatment i s discussed i n E*and has been confirmed by a computer-simulated spectrum f or compound IX. A double resonance, " s p i n - t i c k l i n g " experiment has also been done on t h i s spin system and confirms that "Ipgrj^ = 6.84 Hz. and JpQQ^ = 19.64 Hz. have A B the same r e l a t i v e sign. D e t a i l s of t h i s experiment are also included i n the appendix. Complete n.m.r. spectral data f o r compound IX are presented i n table 6. In summary of the cur r e n t l y a v a i l a b l e r e s u l t s on 31 1 s t e r e o s p e c i f i c dependencies of P-O-C- H coupling constants i n phosphate t r i e s t e r systems the following observations are presented. * Appendix E. -44-Th e POCM coupling constant i s very s e n s i t i v e to changes i n r e l a t i v e geometry of the phosphate system, i n p a r t i c u l a r , of the dihedral angle between the P-0 and C-H bonds i n the POCH fragment. This observation and the r e s u l t s of s i m i l a r studies (23-30) on other classes of phosphorus d e r i v a t i v e s are i n general agreement with the suggestion that *H-^H and 31 1 P - H couplings have s i m i l a r s t e r e o s p e c i f i c i t i e s , although magnitudes of the i n d i v i d u a l couplings d i f f e r . The sign of JpQ^j_j does not change i n going from a gauche to a trans arrangement of the coupling n u c l e i . The conform a t i o n a l analysis of further c y c l i c phosphate d e r i v a t i v e s and quant i t a t i v e estimates of rotamer populations f o r a c y c l i c phosphate systems should be possible using the r e s u l t s of the present study. The d e t a i l e d study of the n.m.r. spectra and conformations of compounds I I , I I I , IV and V gives considerable i n s i g h t to the s t e r e o s p e c i f i c behaviour of long-range, 4 J, POCCH coupling constants. 4 The magnitude of the J phosphorus coupling through oxygen into a methyl group i s dependent on the dihedral.angle between the P-0 and C-CH^ bonds. A trans coupling (J) of 2.3 - 2.8 Hz. i s observed i n compounds 11(a), ( c ) , and IV(a) -45-from phosphorus into an equatorial methyl group while a gauche coupling (K) of less than 0.8 Hz. * i s observed i n compound IV(a) from phosphorus into an a x i a l methyl group. The P-O-C-CHj coupling constant of 2.80 Hz. observed f o r compound V(a) would suggest that t h i s isomer i n fac t has s i m i l a r geometry to that of the model conformation ( I I I ) . The intermediate coupling constant values f o r V(b) (1.90 Hz.) suggests that t h i s isomer has a s i g n i f i c a n t population of the inverted conformation. The value f o r 11(b) (2.30 Hz.) may not be inconsistent with the previous determination that t h i s isomer e x i s t s to a s i g n i f i c a n t extent i n the inverted conformation i f th apparently low trans value (2.30 Hz.) f o r 11(c) i s a t t r i b u t e d to the e f f e c t of the o r i e n t a t i o n of the phenoxy substituent**. The value of 2.10 Hz. f o r IV(b) would thus be consistent with * Estimated from the l i n e width of the resonance. ** An e f f e c t which might be due to d i f f e r e n t e f f e c t i v e e l e c t r o n e g a t i v i t i e s of the phosphoryl oxygen and phenoxy groups. -46-a t y p i c a l , s i n g l e conformation. Thus, JpQrjQj trans = 2.80 Hz. fo r an a x i a l phenoxy substituent and JpgrjQj trans= 2.30 Hz. f o r an equatorial substituent, would be t t e r formulate t h i s s t e r e o s p e c i f i c i t y . 4 Long-range, J , POCCH coupling has also been assigned from phosphorus into the hydrogen atoms of compounds 11(a), (b), ( c ) , I I I , and V(a). Thus coupling into an equatorial .Hj. nucleus ranges from 2.4 Hz. to 2.8 Hz.(L) while coupling into OPh M an a x i a l (M) i s i n the range 0.7 Hz. to 1.0 Hz.. The couplings f o r 11(b), as expected, are intermediate between these ranges. Confirmation that these changes i n magnitude of the long-range coupling constant are due to changes i n molecular geometry and that a l l of these couplings have the same sign comes from consideration of the averaged coupling constant observed f o r f r e e l y r o t a t i n g systems *. Consider a t y p i c a l isomer N, having * The sign of the long-range coupling constant i n ^ r i e t h y l phosphate i s known to be the same as that of the J coupling, p o s i t i v e (31) i Figure S~ I 4.00 t * i i t t i i < t i 1 ' t * t _l I ! 1_ II N.M.R. Spectrum of o-hydroxybenzyl alcohol c y c l i c phenyl phosphate X 5.00 A Deceptively-Simple ABX Spectrum -48-Table 6 N.M.R. Parameters f o r o-hydroxybcnzyl alcohol c y c l i c phenyl phosphate P — O OPh Chemical S h i f t s TA~ 4.486 TB = 4.550 631 P= 147.5 p.p.m. Coupling Constants J n u = 6.84 Hz. P,HA P,H 19.64 Hz. B J . = 14.40 Hz, A ' B -49-an a x i a l methyl substituent at C.. The dihedral angles between the P-0 bond and the C^-C^ bond and the P-0 bond and the C^-CHg bond, a l l r e l a t i v e to the C-0 bond, are approximately the same (gauche). From C^, Hj. i s now trans to the C-0 bond while the CH^ hydrogen atoms are f r e e l y r o t a t i n g . As a 4 3 1 1 te s t that a l l the J , P- H coupling constants previously described are indeed s t e r e o s p e c i f i c and that t h e i r signs' are a l l the same, one should be able to pr e d i c t the magnitude of the coupling into a x i a l methyl groups using the couplings i n t o the C c protons. Thus J . ,= ( J c + 2 J C ) /3. The coupling constants t> axxai. be D a to be used f o r J_ and J r , however, should be one-half of the 5e 5a' ' observed coupling constants , since coupling into the methyl group proceeds by only one bonding pathway and coupling into 5'' the C^ protons proceeds by two e s s e n t i a l l y i d e n t i c a l bonding pathways. The r e s u l t predicted f o r an a x i a l methyl group i s 0.63 - 0.72 Hz. ( from 11(a), 11(c), and III) which agrees well with experimental data f o r IV(a) and IV(b). The 0.8 Hz. value f o r 11(b) i s s l i g h t l y higher due to the s i g n i f i c a n t Ha OPh N -50-conformational "exchange" of the a x i a l methyl group to an equatorial p o s i t i o n i n the other conformer. -51-Other 2-oxo-l,3,2-dioxaphosphorinane systems The f i r s t three sections of t h i s discussion have involved the study of a se r i e s of isomeric p a i r s of c y c l i c phenyl phosphates, 31 1 From t h i s study, several dependencies of P- H coupling constants have been established and the conformational analysis of these phosphorus-containing heterocycles, i n terms of these dependencies has been considered. These c y c l i c phenyl esters have been considered as su i t a b l e model systems f o r a more general study of the conformational analysis of phosphate esters and t h e i r d e r i v a t i v e s . It i s the purpose of t h i s section to probe some aspects of the a p p l i c a t i o n of the established r e s u l t s . In p a r t i c u l a r , the e f f e c t of changing the substituent on the phosphorus atom i n six-membered r i n g s , w i l l be considered. The synthesis of a large number of six-membered c y c l i c phosphate d e r i v a t i v e s (P) has been reported i n the l i t e r a t u r e (32). The n.m.r. spectra of many of these d e r i v a t i v e s have recently been reported (22). The analysis of soiiie of the n.m.r. spectra -52-was undertaken, but f o r several compounds the spectra were of the deceptively-simple type, discussed previously f o r IX and not analyzed. N.m.r. data f o r the three compounds (Q) was interp r e t e d i n a s i m i l a r sense to that of t h i s thesis i n that X = a C H 3 b C H 2 P h •c N H C M e : Q ^POCH a x * a * w a s g l v e n a s 7.8 - 10 Hz. and JpQQjj equatorial as .13.8 - 16.3 Hz.. Although these J , values are less than b gauche the J values, the magnitude of the couplings c l e a r l y do trans hot agree with those of the present study ( 1.7 and 22.5 Hz.). Other workers (33) report equal J , and J (11 Hz.) 1 n gauche trans coupling constants f o r a system s i m i l a r to Q(b). Since the authors of the above r e s u l t s appear not to have considered the p o s s i b i l i t i e s of rapid conformational exchange i n the above systems, the temperature dependence of the n.m.r. spectrum of 5,5-dimethyl-2-oxo-2-phenyl-l,3,2-dioxaphosphorinane (X) has been investigated. -53-X This molecule, a c y c l i c phenyl phosphonate, i s the analog of I, lacking one oxygen atom. The room temperature p.m.r. spectrum of t h i s compound contrasts sharply with that of I as shown i n fig u r e 6. The two methyl resonances of X are apparently equivalent and analysis of the spectrum provides values, J . . =11.1 Hz., J n r t-„ " a x i a l " = 11.1 Hz., and ' 4e,4a POCH ' JpOCfl " e q u a t o r i a l " = 11.1 Hz.. The p.m.r. spectrum of X was subsequently obtained at ca. -80° C. and analysis provided values J , = 7.8 Hz., J_. = 15.9 Hz.. At t h i s temperature, gauche trans r the methyl resonances were well chemically s h i f t e d . These r e s u l t s are i n t e r p r e t e d , at l e a s t i n part, to suggest that X e x i s t s . i n an equilibrium mixture of both conformations at room temperature, and that the populations of these are about the same. The observed room temperature coupling constants are thus the average of those f o r each conformation and as the temperature i s lowered, the p o s i t i o n of equilibrium s h i f t s s u f f i c i e n t l y to show s i g n i f i c a n t l y d i f f e r e n t values f o r the averaged couplings. Unfortunately, with the low-temperature -54-c a p a b i l i t y of the instrumentation c u r r e n t l y a v a i l a b l e l i m i t e d to - 8 0 ° C , a s u f f i c i e n t l y low temperature was not obtained i n order to reach a "coalescence temperature" f o r t h i s equilibrium* This experiment, i f s u c c e s s f u l , would confirm the existence of two conformational species. It i s nevertheless f e l t , however, that the r e s u l t s of the l i t e r a t u r e discussed are due to equilibrium mixtures of both p o s s i b l e " f l a t t e n e d - c h a i r " conformations e x i s t i n g i n s i g n i f i c a n t amounts such that the observed room teperature n.m.r. data i s simply the weighted average of that f o r each conformation. It thus seems l i k e l y that the conformational preference f o r a phenoxy substituent at phosphorus, which provides a preferred conformation for compound I, i s not shared by a phenyl substituent as i n X. Thus the conformational preference of a phosphoryl oxygen and a phenyl substituent seem.to be about the same, whereas, as depicted throughout t h i s thesis the conformational preference of a phenoxy substituent seems to be d i s t i n c t l y a x i a l . The 2-chloro-2-oxo-l,3,2-dioxaphosphorinane r i n g system i s an important intermediate i n the synthesis of c y c l i c phosphate d e r i v a t i v e s i n general. The n.m.r. spectrum of 5,5-dimethyl-2-* The coalescence temperature i s that below which two separate n.m.r. resonances are observed, one f o r each conformation. -55-Figure 6 •M.R. Spectra of Substituted 5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinanes 5.50 6.50 T 8.75 ' 9.25 T * decomposition impurities -56-chloro-2-oxo-l,3,2-dioxaphosphorinane (XI) (figure 6) has been analyzed i n the same manner as f o r I . The n.m.r. data ^are presented i n table 7. This compound has a deceptively-.simple spectrum of the type i l l u s t r a t e d i n figure 5 when run at 60 M.Hz., and has been previously reported as unsuitable for ABX analysis (22). The deceptively-simple spectrum i s , however, completely analyzable by analogy with that described for IX i n Appendix E. The r e s u l t s are the same as for the analysis of the more normal appearing spectrum at 100 M.Hz. (figure 6). The JpQQft trans value of 28.6 Hz. and the JpQQ^ gauche value of 2.9 Hz. are considerably larger than the corres-ponding coupling constants f o r the phenoxy analog I . There are several possible explanations f o r t h i s discrepancy. The conformation of XI could be such that the observed values f o r JpQQ[ correspond to dihedral angles of very close to 180° and 60°. This could be due to a very strong preference for the chloro-substituent to be a x i a l . A l t e r n a t i v e l y , the conformation of XI could be that of the basic r i n g structure and the conformational standard III as well as I could be equilibrium mixtures of. conformations having s i g n i f i c a n t populations of phenoxy-equatorial at room temperature. T h i r d l y , the conformation of XI could be the same as that f o r I and III and the increased values of the coupling constants could be a t t r i b u t e d to e f f e c t s of the chloro-substituent, e l e c t r o n e g a t i v i t y or otherwise. At t h i s time, i n the absence of adequate low-temperature measurements and without firm knowledge of the configuration at the phosphorus atom i n XI, i t i s not possible to unequivocally d i s t i n g u i s h between these three r a t i o n a l e s . The second r a t i o n a l e would tend to suggest that compound V(a) should e x i s t more i n the preferred, phenoxy-axial, conformation than I or III due to s t e r i c i n t e r a c t i o n s of an a x i a l methyl group which are absent f o r I and I I I . ^ P Q Q J trans for V(a) would thus be larger than that f o r I and III and t h i s i s not the case. That the e l e c t r o n e g a t i v i t y of OPh i s larger than that of CI i s consistent with r a t i o n a l e three. At t h i s time we are only able to suggest that i t i s e i t h e r the f i r s t or the t h i r d case. It i s i n t e r e s t i n g to consider whether d i p o l a r i n t e r a c t i o n s of the substituent on the phosphorus atom with the oxygen "lo n e - p a i r s " play a v i t a l r o l e i n determining the conformations of these systems. This s o - c a l l e d "anomeric e f f e c t " (34) tends to -58-influence substituents v i c i n a l to the oxygen lone-pairs such that the most d i p o l a r substituent tends to cancel the net dipole through the oxygen lone-pairs. Thus the preferred conformation of trimethylene sulphite(R) has the d i p o l a r S=0 bond a x i a l , tending to cancel the e f f e c t i v e dipoles of the oxygen lone-pairs (35). The preferred conformational behaviour of the electronegative OPh substituent of I as opposed to the less electronegative CH^Ph substituent f o r Q(b) of presumably conformational inhomogeneity, i s i n agreement with such an idea as i s the proposed r e s u l t f o r XI. Ap p l i c a t i o n of the r e s u l t s f o r the s t e r e o s p e c i f i c i t y of JpQQ] to phosphate systems of na t u r a l l y - o c c u r r i n g materials i s s i m p l i f i e d by the inherent e q u i l i b r a t i o n at phosphorus, 5,5-dimethyl- . due to proton exchange. The p.m.r. spectrum of 2-hydroxy-2-oxo-1,3,2-dioxaphosphorinane XII i s presented i n figure 6 . -59-Me As would be expected f o r a symmetrical molecule of t h i s type, the n.m.r. spectrum shows the averaged parameters f o r the two conformations. The JpQQ^ value of 12.0 Hz. i s i n good agreement with that predicted f o r the average of the two couplings (12.1 Hz.,from I ) . Thus the change from OPh to OH at phosphorus does not change the magnitudes of the POCH couplings. 31 The P n.m.r. spectrum of adenosine 3',5'-cyclic phosphate (XIII) was obtained at room temperature, i n TLO so l u t i o n The resonance at +114.3 p.p.m. had a large s p l i t t i n g of 20.7 Hz. due to POCH coupling to the H5^ proton. In accordance with the s t e r e o s p e c i f i c i t y of J p n r u determined e a r l i e r , the -60-conformation of t h i s molecule i s defined to be that of the f l a t t e n e d - c h a i r depicted. The e s s e n t i a l assumption that has been made at the beginning of t h i s discussion concerning the absolute structure of 2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane, has not been further dealt with. It i s f e l t that the assumption of the X-ray r e s u l t has been j u s t i f i e d i n the sense of a p p l i c a t i o n of the developed r e s u l t s by the i n t e r n a l consistency with which these r e s u l t s have been able to both r a t i o n a l i z e and predict the spectroscopic parameters of a number of molecular conformations. However, u n t i l a very good independent method fo r determining the conformations of organic molecules i n s o l u t i o n i s developed, accepting the p h i l o s o p h i c a l dilemma of extrapolating from the s o l i d state w i l l remain an inherent part of applied spectroscopic techniques i n conformational a n a l y s i s . -61-Table 7 N.M.R. Parameters for 5 >5-dimethyl-2-chloro-2-oxo-l,3,2- dioxaphosphorinane Chemical S h i f t s 5.69 5.93 8.70 9.09 115.0 Coupling Constants 4a,P = 2.86 4e,P = 28.56 4e,6e = 3.35 4a,4e = 11.1 4e,6a = 0.0 4a,6a = 0.0 t4a x4e xMe xMe e 6 3 1P EXPERIMENTAL -63-General- Methods (a) '" Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. (b) Micro-analyses were c a r r i e d out by Mr. P. Borda of t h i s department. (c) A l l *H n.m.r. spectra were measured with a Varian HA-100 spectrometer operating i n the frequency sweep mode using tetramethylsilane (T.M.S.) as i n t e r n a l reference. Proton chemical s h i f t s are a l l reported i n the T scale. 31 (d) P n.m.r. spectra were measured at 40.477 M.Hz. using a Varian HA-100 spectrometer with a sealed c a p i l l a r y of as i n t e r n a l reference. The spectrometer was used i n e i t h e r the HR-mode or i n the locked f i e l d sweep mode. Chemical s h i f t s are reported i n p.p.m. r e l a t i v e to P.O -64-C y c l i c Phenyl Phosphates --' C y c l i c phenyl phosphates were prepared by the following general method adapted, from Meston (37). Phenyl phosphoro-d i c h l o r i d a t e (1.1 mole equivalents)* was added dropwise with s t i r r i n g to a s o l u t i o n of ca. 0.03 moles of d i o l dissolved i n ca. 40 ml. of anhydrous pyridine cooled i n an i c e bath. The reaction mixture was l e f t to stand i n the r e f r i g e r a t o r ( %3°C.) overnight. A small quantity (ca. 10 ml.) of water was added to the reaction mixture to dissolv e p r e c i p i t a t e d pyridinium hydrochloride and the ent i r e s o l u t i o n was added to ca_. 100ml. of water i n a separatory funnel. The r e s u l t i n g s o l u t i o n was extracted f i v e times with chloroform. The combined chloroform extracts were dried over anhydrous ^250^ f o r several hours and then evaporated to give the product. For reactions of unsymmetrical d i o l s , the product obtained as above was, i n f a c t , the expected mixture of a l l possible 31 geometric isomers. Using EtOAc as eluant, TLC and P n.m.r. showed these mixtures to contain the c i s and trans isomers i n approximately equal amounts. Thin layer chromatography using s i l i c a gel**with ethyl acetate as eluant was used r o u t i n e l y to i d e n t i f y mixtures * This reagent was a commercial product obtained from the A l d r i c h Chemical Co., Milwaukee, Wisconsin. ** Fischer S-662 or B.D.H. 15049.. -65-of isomers and monitor the contents of column chromatography f r a c t i o n s . Column chromatography was used to separate mixtures of isomers and a standard technique was used throughout. A 45 cm., 16 mm. d i a . s i l i c a gel column was prepared and ca. 0.5 gm. of compound mixture dissolved i n ca_. 5 ml. of ethyl acetate introduced. The column was eluted with ethyl acetate or, f o r s l i g h t l y b e t t e r separation i n c e r t a i n cases, 50/50, v/v, ethyl acetate/benzene, and cja. 2 ml. f r a c t i o n s were c o l l e c t e d . These f r a c t i o n s were conveniently monitored using TLC and appropriate s e r i e s of f r a c t i o n s were combined and evaporated to give the pure isomers. 2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane ( I ) : -5.5- dimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane ( I I I ) : -The synthesis of these compounds has been previously described by the author (6) and i n the l i t e r a t u r e (37,38). 4.6- dimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane ( I I ) : -The mixture of the three isomers of t h i s compound was prepared by the general method using the commercially a v a i l a b l e * mixture of meso- and d l - pentan-2,4-diol. The mixture gave three spots on TLC corresponding to three isomers 11(a), * Frinton Laboratories, South Vineland, N.J. -66-11(b), 11(c), i n order of decreasing Rf value. The syrupy mixture was separated by column chromatography, as i n the 1 31 general method, into the three pure (by TLC and H and P n.m.r.) isomers. Isomer 11(a) c r y s t a l l i z e d spontaneously and had m.p. 93.0 - 95.5° C . Isomers 11(b) and 11(c) were syrupy 31 l i q u i d s . The P chemical s h i f t s of these compounds were, r e s p e c t i v e l y , 125.8 p.p.m., 126.0 p.p.m., and 123.6 p.p.m.. Analysis c a l c u l a t e d f o r C ^ 1 1 ^ 0 ^ c» 54.6; H, 6.2 . Found: 11(a): C, 54.3; H, 6.4 . 11(b): C, 54.3; H, 6.3 . 11(c): C, 54.4; II, 6.3 . 4-methyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (V):-The mixture of isomers of t h i s compound derived from butan-1,3-diol were separated as above to give the f a s t e r running (on TLC) isomer 11(a) and the other isomer 11(b) i n approximately equal amounts by TLC. C r y s t a l l i n e isomer 11(a) had m.p. 91-92°C. 31 and P chemical s h i f t 125.7 p.p.m.. The syrupy isomer 11(b) 31 had P chemical s h i f t 125.2 p.p.m.. Analysis calculated for C 1 Q H 1 3 0 4 P : C, 52.6; H, 5.7 . Found: 11(a): C, 52.6 ; H, 5.8 . 11(b): C, 52.6 ; H, 5.6 . 4,4,6-trimethyl-2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane (IV):-The r e a c t i o n of phenyl phosphorodichloridate with 2-methyl-pentan-2,4-diol afforded a mixture of two isomers. These isomers were r e a d i l y separated using column chromatography as before. -67-Th o c r y s t a l l i n e , f a s t e r running isomer on TLC, IV(a), had m.p. 104 -. 106°C. and 3 1 P chemical s h i f t 127.0 p.p.m. . The 31 slower running isomer 11(b) had P chemical s h i f t 126.0 p.p.m.. Analysis c a l c u l a t e d f o r C^H^O^: C, 56.3; H, 6.7 . Found: 11(a): C,56.4; 11,6.6; 11(b): C,56.1 ; H, 6.5 . 5-methyl-5-nitro-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (VI):-5-methyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane (VII);-5,5-dimethyl-4-isopropyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane(VIII) Synthesis and separation of isomers for each of these compounds was e n t i r e l y by the general method. Only the two isomers of VII were n o n - c r y s t a l l i n e products. Isomer VI(a), f a s t e r running on TLC, had m.p. 156.5 - 157.5°C. Isomer VI(b) had m.p. 118.0 - 119.5°C. Analysis calculated f o r C-„H.-NO-P: C, 44.0; H, 4.4; N, 5.1 . Found: VI(a): C, 44.1; H, 4.6 N, 5.2 . VI(b): C, 43.9; H, 4.6; N, 5.1 . Isomers VIII were as reported i n the l i t e r a t u r e (18). o-hydroxybenzyl alcohol c y c l i c phenyl phosphate(IX):-The c r y s t a l l i n e product from the reaction of o-hydroxybenzyl alcohol and phenyl phosphorodichloridate had m.p. 79.5 - 81.0°C. 31 and P chemical s h i f t 147.5 p.p.m. . -68-Miscellaneous Dioxaphosphorinanes 5,5-dimethyl-2-oxo-2-phenyl-l,3,2-dioxaphosphorinane (X):-This compound was prepared by the method of McConnell and Coover (39) and had m.p. 106 - 108°C; lit.m.p. 103 - 105°C. 31 P resonance at 98.0 p.p.m. was an apparent quintet J= 11 Hz.. 2-chloro-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane (XI):-5,5-dimethyl-2-hydroxy-2-oxo-l,3,2-dioxaphosphorinane (XII):-These compounds were prepared by the method of Edmundson (40) and had i d e n t i c a l melting points. Adenosine-2'-phosphate (XIV):-Adenosine-3',5'-cyclic phosphate (XIII):-The compounds were the generous g i f t of Dr. M. Smith. -69-Analysis of Spectra 31 P chemical s h i f t s are accurate to 0.1 p.p.m. unless otherwise s p e c i f i e d . A l l spectra were run i n CDCl^ s o l u t i o n at concentrations of 2 0 - 30% wt./vol. unless otherwise s p e c i f i e d . Assignment of methyl resonances i s on a f i r s t order b a s i s . * H chemical s h i f t s are accurate to within 0 . 0 2 T and coupling constants to within 0 . 2 Hz. unless otherwise s p e c i f i e d . The spectra f o r I are discussed i n Appendix A. The spectra f o r compounds II were i t e r a t e d using the LA0C00N III computer program to best f i t . The only parameters that could not be i t e r a t e d were the P,4e and P,4a coupling constants. These couplings as estimated from the phosphorus spectra and the bandwidths of the 4,6 protons, and are thought to be accurate to ±0.5 Hz. f o r 11(a) and 11(c) and ±1.0 Hz. f o r 11(b). The assignment of 4e5e and 4a5e for 11(b) i s not unambiguous. These numbers could be reversed. Unfortunately, homonuclear double resonance experiments i n which the methyl resonances are i r r a d i a t e d , have not been successful due to the proximity of the methylene protons. The removal of the methyl coupling into the ^^,C^ protons would have permitted assignment of these couplings. The remaining coupling constants for 11(b) and 11(c) are thought to be well within the stated -70-l i m i t s above. For 11(a) the coupling constants from the computer program are s l i g h t l y less accurate but should be within 0.2 Hz. fo r the smaller couplings. J . and J are probably within 0.5 Hz., having "probable errors"* of 0.34 and 0.53 Hz. re s p e c t i v e l y . The chemical s h i f t assignment f o r 4e and 6a of 11(b) may also be reversed. The analysis of the n.m.r. spectra f o r III i s described i n some d e t a i l i n Appendix B. Complete analysis of the spectra f o r compounds IV proved to be impossible due to t h e i r highly-coupled nature i n the deceptively-simple C^ proton region. The deceptively-simple spectra were again of the type discussed i n Appendix E. Although e x p l i c i t analysis was not p o s s i b l e , a nearly complete assignment of t r a n s i t i o n s was possible and i s consistent with the data of table 4. Several of the numbers are f i r s t - o r d e r approximations and are expected to be within 10% of t h e i r true values. The p.m.r. specti'um of V(b) has not yet been f u l l y assigned. The C^ proton resonances are, i n part, taken to be 31 of a deceptively-simple form. The s p l i t t i n g i n the P resonance spectrum i s much less than 20 Hz., i n contrast to 31 the 22.7 Hz. s p l i t t i n g i n the P resonance of V(a). The p.m.r. spectrum of V(a) has been assigned on a f i r s t -order basis with the aid of computer-simulated spectra. A s u f f i c i e n t l y good assignment of the t r a n s i t i o n frequencies -71-was not obtained to permit an i t e r a t i v e , b e s t - f i t c a l c u l a t i o n to be made. With the exception of the data regarding the methyl resonance, which i s within experimental accuracy, the accuracy of the parameters i s expected to be within 10%. The n.m.r. analysis of IX i s given i n Appendix E. The n.m.r. analyses of X and XII are precise and expected to be well within computer analyses. The analysis f o r XI i s s i m i l a r to that f o r I and the computer i t e r a t e d parameters have "probable e r r o r s " within experimental accuracy. 31 The P n.m.r. spectra of XIII and XIV were obtained by summing repeated scans ( 22 scans and 31 scans, respectively) of t h e i r spectra obtained at saturation concentration conditions i n HO. A Varian C-1024 computer f o r time-averaging was used. APPENDIX I -73-APPENDIX A The n.m.r. spectrum of 5,5-dimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphosphorinane The n.m.r. spectrum of 5,5-dimethyl-2-oxo-2-phenoxy-1,3,2-dioxaphosphorinane (figure 6) i s of the type A A ' B B ' • Since the M-jN^  (methyl resonance) region of the spectrum i s f i r s t - o r d e r with respect to the AA'BB1 region, t h i s spin system has been analyzed as an AA'BB'X system. The 31 P spectrum was b a s i c a l l y a t r i p l e t e d - t r i p l e t due to a large coupling with the u p f i e l d set of chemically equivalent protons and a small coupling with the downfield set of protons. A homonuclear spin-decoupling experiment was performed i n order to assign these protons. I r r a d i a t i o n of the l o w - f i e l d methyl resonance produced v i s i b l e sharpening of the low- f i e l d set of methylene resonances while leaving the u p f i e l d set unaffected. In accordance with the established s t e r i c dependence of long-range proton-proton coupling constants of methyl groups (41), the l o w - f i e l d methylene protons, having the small coupling with phosphorus, were designated a x i a l . It was not possible to d i r e c t l y c a l c u l a t e the true n.m.r. parameters of t h i s system since e x p l i c i t t r a n s i t i o n frequencies and energies cannot be formulated (42). The LAOCOON III computer program was thus used to reproduce the t h e o r e t i c a l n.m.r. spectrum associated with the -74-chemical s h i f t s and coupling constants which were approximated from the above i n t e r p r e t a t i o n of the experimental spectrum. The c r o s s - r i n g , a x i a l - a x i a l , long-range coupling constant was entered as zero and the c a l c u l a t e d spectrum best resembled 4 the experimental when the s i m i l a r a x i a l - e q u a t o r i a l , J , coupling was set to zero. The experimental t r a n s i t i o n frequencies were then entered as data and, a f t e r two i t e r a t i o n s of the n.m.r. parameters, the root mean square er r o r of the matched t r a n s i t i o n frequencies was reduced from 2.718 to 0.275 Hz.. The largest probable error of the parameters, as calculated by the program, was 0.16 Hz. for Jp ,^ , for which experimental a x i a l t r a n s i t i o n frequencies were expected to be s l i g h t l y inaccurate due to broadening of resonances by the a x i a l methyl coupling r mentioned above. That the r e l a t i v e signs of the two phosphorus coupling constants are the same was confirmed by comparisons of the t r a n s i t i o n i n t e n s i t i e s of the two possible assignments. The p.m.r. spectrum of t h i s compound was also obtained at -80°C. i n CH 2C1 2 s o l u t i o n . Although the value for J p Q C L ] trans was found to be s l i g h t l y larger than the room temperature r e s u l t , the accuracy with which the t r a n s i t i o n energies were assigned was low due to broadening of the resonances. The r e l i a b i l i t y (*lHz.) of t h i s determination thus does not permit any s i g n i f i c a n c e to be attached to the d i f f e r e n c e . -75-APPENDIX B Momonuclear and Meteronuclear Double Resonance Techniques-and  Computer Program The use of *H homonuclear decoupling experiments was l i m i t e d throughout t h i s study. With the exception of that used to assign the spectrum of I, these experiments were not of general use i n aiding s p e c t r a l assignment due to the very wide bandwidth of many of the proton resonances. In general, the large amount of power required to decouple protons having large s p l i t t i n g s was such that neighbouring resonances of other protons were perturbed, leading to ambiguous r e s u l t s . Meteronuclear decoupling was, however, extremely useful i n analysis of spectra. Experiments i n which the proton resonances were observed while i r r a d i a t i n g strongly at the phosphorus resonance frequency, were p a r t i c u l a r l y useful i n assigning the spectra of isomers II (see figure 2). A l l of the long-range phosphorus hydrogen coupling constants reported were confirmed by c o l l a p s i n g the s p l i t t i n g s due to these by 31 i r r a d i a t i n g the P resonance. The heteronuclear decoupler used i n t h i s study was b u i l t by Mr. R. Burton of t h i s depart-ment (43). The equipment consists of a double-tuned probe adapter 1 31 f o r observing H at 100 M.Hz. while i r r a d i a t i n g P. The decoupling frequency i s produced by a Hewlett Packard Frequency Synthesizer which i s coupled to a Hewlett Packard Power Amplifier • t . -76-(Model 230A). The use of double resonance experiments has been well reviewed i n the l i t e r a t u r e (44,45). Throughout the analysis of spectra, considerable use was made of a LAOCOON III computer program. The o r i g i n a l program was kindl y provided by Aksel Bothner-By*. The program has been s u i t a b l y modified for the IBM 360/67 system currently i n use at t h i s u n i v e r s i t y . Part of t h i s program has been modified to include a histogram p l o t sub-program adapted from the LAMC n.m.r. program kindly provided by Dr. John Martin**. Further modification of the program has extended the number of i n d i v i d u a l t r a n s i t i o n s calculated from 300 to 500. This i s p a r t i c u l a r l y u seful f o r 7-spin systems. Thus the program used has the ad d i t i o n a l options of a histogram p l o t of the n.m.r. spectrum and a c a l c u l a t i o n of up to 500 t r a n s i t i o n frequencies. Two kinds of applications of t h i s program are useful and are i l l u s t r a t e d i n the analysis of the p.m.r. spectrum of I I . The observed spectrum, at f i r s t s i g h t , i s depressing. Only the h i g h - f i e l d resonance i s assignable and t h i s i s seen to be of the F l ^ proton, a sextet due to 5 equal coupling constants to the ^ protons and phosphorus. This i s confirmed by i r r a d i a t i n g phosphorus, causing collapse of t h i s resonance to * Mellon I n s t i t u t e , Pittsburgh, Pa.. ** U n i v e r s i t y of Alberta, Edmonton, Alberta. -77-a quintet. Close examination of the l o w - f i e l d ^ resonance reveals four very intense t r a n s i t i o n s . These are immediately suspected of being deceptively-simple i n the sense of Appendix E. The coupling due to H^ . i s seen and the other coupling of t h i s quartet must, by d e f i n i t i o n of the condition for seeing t h i s deceptively-simple spectrum, be the average of the 4e,5a and 4a,5a couplings. The outer t r a n s i t i o n s of the other AA'BB' sub-spectrum can be determined and the large s p l i t t i n g i n the 31 P resonance gives a f i r s t - o r d e r dpQ^jj value. Using f i r s t -e order, guessed chemical s h i f t s , a l l data i s entered into the LAOCOON III program and a set of calculated t r a n s i t i o n frequencies i s obtained. These frequencies are matched with the experimental frequencies i n a subsequent computer run and a least-squares i t e r a t i v e f i t i s obtained. The output n.m.r. parameters are given i n table 3. It i s f e l t that the accuracy of these parameters i s considerably higher than that quoted since better f i t t e d spectra have been obtained using ser i e s of "AB MN" (4-spin) approximations, which are not e n t i r e l y v a l i d . U n t i l more t r a n s i t i o n s can be d e f i n i t e l y experimentally assigned (perhaps at 200 M.Hz.) however, i t i s not possible to reduce the random erro r i n assigning frequencies to a small number of t r a n s i t i o n s . -78-APPENDIX C Configurational Assignment at Phosphorus Throughout t h i s study, the configuration at the phosphorus atom has been t e n t a t i v e l y assigned. No d i r e c t r e s u l t s have been reported i n the l i t e r a t u r e regarding t h i s question. Edmundson(46) has discussed the p o s s i b i l i t y of using the I.R. s t r e t c h i n g frequency of a P=0 bond to d i s t i n g u i s h between a x i a l and equatorial phosphoryl oxygen and discounts t h i s on the basis of s i m i l a r observed frequencies f o r compounds assumed to have d i f f e r e n t configurations at phosphorus. In f a c t , the n.m.r. data a v a i l a b l e for these compounds (33) suggest that neither molecule e x i s t s i n a s i n g l e conformation*. It i s f e l t that the usefulness of I.R. f o r determining con-f i g u r a t i o n at phosphorus should remain an open one u n t i l d e f i n i t e c o n f i g u r a t i o n a l isomers have been studied. Other workers have r a t i o n a l i z e d configuration at phosphorus i n other systems by considering the consequences of s t e r i c i n t e r a c t i o n s of the expected configurations (47), on the basis of *H chemical s h i f t s (16), and dipole moment measurements (50). We have assumed the phenoxy-axial configuration on the basis of the X-ray r e s u l t f o r I I I . Compound I has also been assigned t h i s structure, assuming i t to be the more * By analogy with compound X of t h i s t h e s i s . -79-thermodynamically stable one. I n t e r e s t i n g l y , f o r the isomeric p a i r s of compounds studied, the faster-running isomer on TLC i s c r y s t a l l i n e whereas the other isomer i s often a syrup. The 31 P chemical s h i f t s f o r the p a i r s of isomers are separated by ca. 1 p.p.m., the c r y s t a l l i n e one being to higher f i e l d . Since these, h i g h e r - f i e l d , chemical s h i f t s more c l o s e l y correspond to those of I and I I I , these isomers have been assigned the same configuration at phosphorus. -80-APPENDIX D Ca l c u l a t i o n of the Rotamer Populations of Adenosine-2'-Phosphate •*1 The observed " P n.m.r. spectrum of adenosine-2 1 -phosphate contains a 7.4 Hz. s p l i t t i n g due to coupling of the phosphorus with the 2' proton. H O C H O H OP03 The population of each of the three favoured rotam'ers can be calcuated using the JpQ^jj values f o r 180° (25 Hz.) and 60° (3 Hz.) determined previously. For two of these rotamers, the dihedral angle of the PO-CH bond i s 60° and fo r the other i t i s 180°. Let the f r a c t i o n of the trans (180°) rotamer be a, then the following equation gives J i n terms of the f r a c t i o n a l populations and coupling constants for the i n d i v i d u a l rotamers. J a v . = a J180 + V-a)J60 The r e s u l t i s ct= 0.20, or, the trans rotamer i s only populated to the extent of 20% while the two gauche rotamers are populated 40% each. a. -81-Si m i l a r c a l c u l a t i o n s have recently been published (48) using JpQQi values s i m i l a r to those above but derived i n a somewhat less s a t i s f a c t o r y manner, in that the trans value was not obtained d i r e c t l y by experiment. a. -82-APPENDIX E Deceptively-Simple ABX Spectra Deceptively-simple n.m.r. spectra have been treated i n the l i t e r a t u r e (49) and, for the ABX system, may occur when 6AB, (the chemical s h i f t d i f f e r e n c e between the AB protons) i s equal to or nearly equal to zero. The r e s u l t i n g 11 l i n e spectrum compares with the 12 l i n e s usually expected (ignoring combination l i n e s ) . When L* i s also zero a f i v e l i n e spectrum i s obtained corresponding to an spin system. For both cases of these deceptively-simple spectra, the observed AB resonances are completely symmetrical about v ^ (the average resonance frequency of A and B) and the X region collapses from a f o u r - l i n e resonance to a t r i p l e t or a doublet. The n.m.r. spectrum of IX i s a deceptively-simple ABX having an unsymmetrical 5 l i n e AB region and a normal 4 l i n e X resonance. The analysis of t h i s type of spectrum has not previously been brought to the general attention of the l i t e r a t u r e presumably because the conditions f o r t h i s deceptively-simple appearance of an ABX system do not often occur i n a l l proton "ABX" cases. This kind of spectrum has, however., been found f o r compounds I I I , V(b), IX, and XI of t h i s t h e s i s . Since deceptively-simple spectra r e s u l t from f o r t u i t o u s l y degenerate t r a n s i t i o n s , complete analysis of * L = l> 2 <JAX-JBX> -83-spectra i s not u s u a l l y possible and i t i s desirable to t r y to destroy the simple appearance by changing solvents and /or resonance frequencies*. For the nine - l i n e case of IX t h i s a t t i t u d e i s not warranted and, i n f a c t , quite the opposite i s t r u 2 . The t r a n s i t i o n energies and i n t e n s i t i e s f o r a normal ABX spectrum are presented i n table 8. The condition f o r observing t h i s deceptively simple spectrum i s that 6AB=L ; thus the chemical s h i f t d i f f e r e n c e between A and B i s equal to one-half the difference of the AX and BX coupling constants. Inserting t h i s condition into the expressions f o r the t r a n s i t i o n frequencies of the normal case r e s u l t s i n the t r a n s i t i o n frequencies and i n t e n s i t i e s of table 9, the deceptively-simple case. The spectra are completely and simply analyzed. The separation of the s i n g l e , intense peak of i n t e n s i t y 4, and the centre of the AB sub-quartet gives N , one-half the sum of the two X-couplings. This can be checked in the X-resonance. The separation of t r a n s i t i o n s 2 and 6 or 4 and 8 r e s u l t s i n a value for D. can be determined d i r e c t l y , and thus L can be obtained from the equation i n table 9. L and N define and J B X . ' A s p i n - t i c k l i n g experiment, i r r a d i a t i o n of a s i n g l e * Thus changing chemical s h i f t differences of the A and B resonances such that the deceptively-simple conditions no longer hold. -84-t r a n s i t i o n , confirmed the s i m i l a r i t y of signs of and J g ^ . Computer techniques also confirmed the assignment. Thus deceptively-simple spectra of t h i s type are of considerable advantage, p a r t i c u l a r l y as sub-spectral parts of more complex spectra where i d e n t i f i c a t i o n of the intense t r a n s i t i o n i s comparitively greatly f a c i l i t a t e d by the presence of t h i s type of deceptively-simple spectrum. -85-Table 8 Normal ABX Energies ABX * Energy 1 vAB-l/2J B-1/2N-"D-2 vAB-l/2JAB+./2N-D+ 3 vAB+l/2J A B-l/2N-D-4 vAB+l/2J A B+l/2N-D+ 5 vAB-l/2J A B-l/2N+D-6 vAB-l/2J +1/2N+D+ 7 vAB+l/2J A B-l/2M+D-8 vAB+l/2J +1/2N+D+ 9 vX - N 10 vX + D - D-+ 11 vX - D + D-+ 12 vX + N 13 2vAB - vX 14 vX - D - D-+ 15 vX + D + + D-Rel. Intensity 1-sin 2<p-1-sin 2<j> + 1+sin 2<j)-1+sin 2<)> + 1+sin 2$>-1+sin 2<() + 1-sin 2<j>-1-sin 2<j> + 1 cos (<{' + -<ti_) Cos 2 W+-<t»_) 1 0 2 s i n (*-<(> ) T — 2 s i n (<j>+-<(>_) L = 1/2J AX 1/2J BX N = 1/2J A X + 1/2J B X D±= l/2[ (6AB ± L ) 2 + J A B D±sin 2tj)± = 1/2J A B D±cos 24.± = 1/26AB± 1/2L 2 ^ 1/2 -86-Table 9  Deceptively Simple ABX 6AB = L # Energy 1 vAB-J A R-l/2N 2 vAB-l/2J +1/2N-D+ 3 vAB - 1/2N 4 vAB+l/2J A B+l/2N-D+ 5 VAB-1/2N 6 vAB-l/2J +1/2N+D+ 7 vAB+J A D-l/2N AB 8 vAB+l/2JAB+l/2N+D+ 9 vX-N 10 vX+D +-l/2J A B 11 vX-D ++l/2J A B 12 vX + N 13 2vAB-vX 14 v X - D + - l / 2 J A B 15 vX+D + - r l/2J A B Rel. Intensity 0 1-sin 2<j> + 2 1+sin 2(f> + 2 1+sin 2<j> + 0 1-sin 2<f> + 1 c o s 2 (4>+-45°) c o s 2 0 + -45°) 1 0 s i n 2 (<(. -45°) s i n (<j> + -45°) D + « 1/2(4L 2 + J A B 2 ) " 1 / 2 D- = 1/2J A B s i n 2*+= J A R / 2 D + 45' REFERENCES -88-1. H. G. Khorana, "Some Recent Developments i n the Chemistry of Phosphate Esters of B i o l o g i c a l Interest", Wiley, New York (1961). 2. M. Karplus, J . Chem. Phys., 30_, 11 (1959). 3(a)D.H.Williams and N.S. Bhacca, J.Am.Chem.Soc., 86_, 2742.(1965). (b)H. Booth, Tetrahedron L e t t e r s , 411 (1965). 4. P. Steiner, M.Sc. Thesis, U n i v e r s i t y of B r i t i s h Columbia (1969), and references t h e r e i n . 5(a)G.J. Karabatos e t . a l . , J . Am.Chem.Soc. , 88^ 1817 (1966). (b)D. Gagnaire, J.B. Robert and J . V e r r i e r , Bull.Soc.Chim. France, 2392 (1968). 6. R.B. Malcolm, B.Sc. Thesis, U n i v e r s i t y of B r i t i s h Columbia, (1966). 7. R.S. Edmundson, Tetrahedron, 20, 2781 (1964). 8(a)W. Jachymczyk, L. Menager and L. Szabo, Tetrahedron, 21, 2049 (1965). (b) J . Baddiley, J.G. Buchanan and L. Szabo, J.Chem.Soc, 3826 (1954). (c) J.L. Barnwell, W.A. Saunders and R.W. Watson, Can.J.Chem., 33, 711 (1955). 9. J.A. Pople, W.G. Schneider and H.J. Bernstein, "High-Resolution Nuclear Magnetic Resonance", McGraw-Hill, New York (1959). 10. see references 3 and 4. 11. H.J. Geise, Rec.Trav.Chim., 86, 362 (1967). 12. R.S. Edmundson, Chem. and Ind., 1770 (1962). 13. U.S. Patent 2,661,366 (1953). 14. see reference 8 and reference 1, p.46. 15. L.D. H a l l and R.B. Malcolm, Chem. and Ind., 92 (1968). -89-16. F. Ramirez, a t . a l . , J.Am.Chem.Soc., 8J7, 549 (1965). 17. D.Z. Denney and D.B. Denney, J.Am.Chem.Soc., 88_, 1830 (1966) 18. "Jean-Pierre Ma j o r a l , e t . a l . , CR. Acad,Sc.Paris, 266, 235 (1968). 19. see reference 2. 20. E. Duval and E.A.C. Lucken, Moi: Phys., 10, 499 (1966). 22. K.D. B a r t l e , R.S. Edmundson and D.W. Jones, Tetrahedron, 23, 1701 (1967). 23. J.G. Verkade, R.H'. King, Inorg.Chem., 1_, 948 (1962). 24. W.A. Anderson, R. Freeman, and R e i l l y , J .Chem.Phys., 39_, 1518 (1963). 25. A.M. Aguiar and D. Daigle, J.Org.Chem., 30^ , 3527 (1965). 26. W.M. Daniewski, M. Gordon and C.E. G r i f f i n , i b i d . , 31_, 2083 (1966). 27. G.L. Kenyon and F.H. Westheimer, J.Am.Chem.Soc., 88, 3557 (1966). 28. G. Ourisson and C. Benezra,Bull.Soc.Chim.France, 1825 (1966) 29. D. Gagnaire, and J.B. Robert, i b i d . , 2240 (1967). 30. M. Tsuboi, F. Kuriyagawa, K. Matsuo and Y. Kyogu, B u l l . Chem.Soc.Japan, 40, 1813 (1967). 31. Reference 20. 32. R.S. Edmundson and E.W. M i t c h e l l , J.Chem.Soc.(C), 2091 (1968). See also reference 22. 33. . K.D. B e r l i n , e t . a l . , Tetrahedron, 2£, 323 (1964). 34. E.L. E l i e l , N.L. A l l i n g e r , S.J. Angyal and G.A. Morrison, "Conformational A n a l y s i s " , Interscience, New York (1966). 35. D.G. H e l l i e r , e t . a l . , Chem. and Ind., 1956 (1963). -90-37. A.M. Meston, J.Chem.Soc., 6059 (1963). 38. H.G. Khorana, CM. Tener, R.S. Wright and J . C Moffatt, J.Am.Chem.Soc., 79_, 430 (1957) . 39. R.L. McConnell and H.W. Coover, J r . , J.Org.Chem., 24, 630 (1959). 40. R.S. Edmundson, Tetrahedron, 21_, 2379 (1965). 41. M.J.J. Robinson, Tetrahedron L e t t e r s , 1685 (1965). 42. R.E. Richards and T. Schaefer, Proc.Roy.Soc., 246A, 429 (1958) 43. R. Burton and L.D. H a l l , to be published. 44. J.D. Baldeschwieler and E.W. Randall, Chem.Rev., 6_3, 81 (1963). 45. R.A. Hoffman and S. Forsen, i n "Progress i n Nuclear Magnetic Resonance Spectroscopy", V o l . I , J.W. Emsley, J . Feeney and L.H. S u t c l i f f e , eds., Pergamon, New York (1966). 46. Reference 7. 47. Reference 5 (b). 48. M. Tsuboi, Private communication. 49. R.J. Abraham and H.J. Bernstein, Can.J.Chem., 39_, 216 (1961). 50. D.W. White, C K . McEwen and J . C Verkade, Tetrahedron Letters, 5369 (1968). 

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