Investigations into the mechanisms of formation of certain organic nitrogen salts

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NAME AND ADDRESS

DATE

ACKNOWLEDCMEMT

The author wishes to express his most sincere gratitude to Professor L. Carroll King for his inspiration and guidance throughout the course of these investigations. To the other faculty members of the Department of Chemistry, particularly professor Ralph G. Pearson, the author is indebted for their many valuable suggestions.

NORTHWESTERN UNIVERSITY

INVESTIGATIONS INTO THE MECHANISMS OF FORMATION OF CERTAIN ORGANIC NITROGEN SALTS

ti A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS for the degree DOCTOR OF PHILOSOPHY

DEPARTMENT OF CHEMISTRY

By LEE A* SUELUSKEY

EVANSTON, ILLINOIS JUNE 1950

ProQ uest N um ber: 10102022

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TABLE OF CONTENTS Page

INTRODUCTION........................................

1

i-STEROIDAL AND RELATED S Y S T E M S ....................

3

Historical

. . . . . ............. ..............

3

Cholesterylisothiuronium and Cholesterylpyridinium S a l t s .............................................. 20 23

Experimental............... Cholesteryl p-Toluenesulfonate.. ............

23

i-Cholesteryl Methyl Ether

23

. . . . . . . . .

Cholesterylisothiuronium p-Toluenesulfonate From i-Cholesteryl MethylEther

.........

From Cholesteryl p-Toluenesulfonate

23

...

24

....

24

Cholesteryl Disulfide ......................

25

Cholesteryl Mercaptan

Cholesterylpyridiniimi p-foluenesulfonate From i-Cholesteryl MethylE t h e r ........... 25 From Cholesteryl p-Toluenesulfonate

...

26

Mechanism of Formation of Cholesteryl isothiuronium Salts from i-Cholesteryl Methyl Ether. ............28 Experimental.............

31

Materials.................................... 31 M e t h o d s ...................................... 31 Kinetic R u n s ................................ 32 Calculations and Results ......................

35

Discussion...................................... 40

Page

Mechanism of Formation of 6-Ketocholestanylisothiuronium baits from i-Cholestene-6-one ........

46

Experimental.................................... 49 M a t e r i a l s .................................... 49 i-Cholestene-6-one......... Methods

49

. . .. . ............................. 50

Kinetic D a t a .................................. 50 3 (y0)-Methoxy-6-ketocholestane................ 54 Calculations

and Results ......................

Discussion . . ...................

55 59

The Preparation of Some Quaternary Nitrogen baits from Several Systems Related to i-0holestene-6-one.

61

Experimental.................................... 65 Source of K e t o n e s ............................ 65 3-Mesitoylpropylisothiuronium p-Toluene­ sulfonate ............................ . . .

65

3-Benzoylpropylisothiuronium p-Toluene­ sulfonate ........ . .......................... 65 3-Acetylpropylisothiuronium p-Toluene­ sulfonate ...................... . . . . . . Source of

65

Q u i n o n e s ..........................66

2.5-Dihydroxyphenylpyridinium Iodide 2.5-DIhydroxyphenylquinaldinium Iodide

....

66

...

66

3.4-Dihydroxy-l-naphthylpyridinium Iodide . .

66

1.4-Dihydroxy-2-naphthylpyridinium Iodide . .

66

Page

TRICYCLENIC SYSTEMS

................................

68

H i s t o r i c a l ...................... , ................ 68 Isobornylisothiuronium. baits

....................

95

The Racemization Question......................... 102 Experimental........................... Preparation of btarting Materials .......... Camphene . . . . . . . . . . . Camphene Methyl Ether

. . . . .

Ill Ill

..........

Ill

........

Ill

Tricyclene............................... 112 Bornyl p-Toluenesulfonate

.............. 113

Isobornylisothiuronium p-Toluenesulfonate From C a m p h e n e .........

114

From Camphene Methyl Ether ..............

115

From T r i c y c l e n e ......................... 115 From Bornyl p-Toluenesulfonate ..........

115

Camphane by the Hydrogenolysis of Isobornyl­ isothiuronium p-Toluenesulfonate ..........

115

Isobornyl Mercaptan ........................ 117 Isobornyl Disulfide ........................ 118 Mercuri Isobornyl Mercaptide

..............

118

Evidence for Racemic Compound Formation between d-Kcvi and L - X C V I ................... 118 The Diastereoisomeric Salts ................

119

lylsobornylisothiuronium d-Camphors u l f o n a t e ............................... 119 d-Isobornylisothiuronium d-Camphors u l f o n a t e ............................... 120

Page

d,_l-Isobornylisothiuronium Iodide from Tsobornylisothiuronium p-Toluenesulfo­ nate .........

120

1-Isobornylisothiuronium Iodide from T-Isobornylisothiuronium d-Camphors u l f o n a t e ...........

121

d-Isobornylisothiuronium Iodide from ^-Isobornylisothiuronium jd-Camphors u l f o n a t e ............................... 121 Nature of Product from Camphene, Thiourea and p-Toluenesulfonic Acid Versus Reaction T i m e ....................................... 121 Discussion..................................... 122 S U M M A R Y ............................................. 129 BIBLIOGRAPHY......................................... 131 V I T A ................................................. 136

INTRODUCTION

The beginning of modern organic chemistry can be well marked by the advent of the structural thoughts of Kelcule and the tetrahedral carbon atom concepts of LeBel and van’t Hoff in the early sixties and seventies of the last century.

Because of the herculean tasks of establishing

the structural relationships of the many compounds that were known then, and of the many that were to be isolated or prepared in the ensuing years, it is easy to understand why little or no concern was given to the study of reactions from other than a purely preparative standpoint.

As the

structural knowledge of the compounds grew, however, it became more and more apparent that many reactions are accompanied by the intriguing phenomena of inversions of carbon atom configuration and molecular rearrangements. It was only natural then that the interests of organic chemists were expanded to include reactions studies from a more theoretical standpoint in an effort to comprehend these phenomena.

The first evidences of this expansion

appears in the chemical literature of the early 1920’s. Since that time an increasing amount of research has been devoted towards this end.

Today with the contributions

and techniques of physical chemistry, the study of organic

2

.

reactions, particularly in regard to the mechanisms by which they proceed, enjoys wide popularity amongst both organic and physical chemists. The investigations which are the subject of this dissertation were directed primarily along these lines. More specifically, a general reaction for the preparation of quaternary nitrogen and S-substituted isothiuronium salts has been developed for the purpose of studying the manner in which certain systems undergo reactions with acids and strongly nucleophilic reagents.

The systems that

have been considered are ones possessing i-steroidal or potential i-steroidal structures and ones related to the bicyclic terpene, camphane.

The conclusions reached re­

garding the mechanisms of these reactions are largely based upon experimental data obtained concerning the molar dependency of the reactants and the relative amounts and nature of the products formed.

i-STEROIDAL AND RELATED SYSTEMS

The group of compounds that was first considered for study were ones possessing i-steroidal or potential i-steroidal structures.

Because of the many complexities

that will enter into a discussion of these compounds, it seems desirable to review briefly some of the more fundamental work that has been done in regards to the establishment of their structures and chemical reactivities. Historical By 1932 the basic structure of the steroid nucleus had been fairly well established by dehydrogenation, oxida­ tive degradation, synthetic and physicochemical investiga1 tions. It was not until fourteen years later, however, that the configuration of the 3-bydroxyl group in cholesterol (I) and other sterols was related to the rest of the molecule with certainty.

Ruzicka2 was actually the first to make

the correct configurational assignments to these sterols by results obtained from the application of the Auwers-Skita rule to the hydrogenation of cholestanone (II) and

1.

The history of this work is treated in detail by Eieser and Eieser, "Natural Products Related to Phenanthrene," 3rd ed., Reinhold Publishing Corp., New York, 1949, p. 119.

2.

Ruzicka, Brungger, Eichenberger and Meyer, Nelv. Chim. Acta, 17, 1407 (1934).

4

«

,CH AH' CH CH

HO' I CH COOH Cl COOH

AH Pyridine

HO,

HCl + CHCl H

H V

coprostanone (III).

IV

Although a considerable amount of

evidence had been reported to support Ruzicka's conclusions, final proof was not realized until Kendall^ was able to prepare 3,9-epoxy-ll-cholenic acid (IV) from 3 10*)-hydroxyg n 12-chloro-^* -cholenic acid (V). The formation of the 3,9-epoxide ring not only offered positive proof for the configuration of the 3-hydroxyl group but also established

3.

Mattox, Turner, Engel, McKenzie and Kendall, I. Biol. Chem., 164, 569 (1946); McKenzie, McCucken and Kendall, ibid., 152, 555 (1946).

5

.

the nature of the ring fusion between the A and B rings of desoxycholic acid.

Since the structures of the bile acids

has been previously worked out in relation to the epimeric cholestanols and coprostanols^ and consequently in relation to cholesterol, the structural problems of these sterols about the A and B ring were solved. ‘ Phis establishment of the 3-hydroxyl configurations has served as a keystone in closely correlating a great number of the reactions occurring around the lower part of the steroid molecules, particularly in regard to replacement reactions at the 3-position and the reactions of the i-steroids.

The first development of any mechanistic

interests in these reactions resulted from the reports of r

Marker5 and of Ruzicka.

Their extensive studies into the

formation of 3-chloro derivatives indicated the apparent existence of several inconsistencies.

For instance, if

cholesterol is treated with thionyl chloride or phosphorus pentachloride, there is obtained a single product, cholesteryl chloride (VT), which can readily be converted back to cholesterol by refluxing with an acetic acid solution of

4.

Ruzicka, Goldberg, Meyer, Brungger and Eichenberger, helv. CJhim. Acta, 17, 1395 U934); Ruzicka and Goldberg, ibid., 18, 668 (191?).

5. Marker, J. Am* 8hem. 3oc., 57« 1755 (1935);Marker, Whitmore and Kamm, ibid., 57» 2358 (1935). 6. Ruzicka, Wriz and Meyer, Helv. Chem. Acta, 18, (1935).

998

potassium acetate followed by hydrolysis.

Reduction of

cholesterol to cholestanol (VII) and subsequent reaction with thionyl chloride renders a product identical with the reduction product of cholesteryl chloride, 3(y#)-chlorocholestane (VIII).

Cholestanol, on the other hand, when

reacted with phosphorus pentachloride gives a different chloro derivative, 3 W)-chlorocholestane (IZ), which is, however, identical to the compound that can be obtained from 3(^) -chlorocholestane by potassium acetate treatment, hydrolysis and reaction with thionyl chloride. A correct interpretation of these observations can be credited to E. Bergmann, ^ who in consideration of results he had obtained from a study of the reactions of optically active halides with acetate ion, felt that both the conversion of 3 1**)-chloroeholestane (IZ) to cholestanol (VII) and the conversion of 3 if?)-chloroeholestane (VIII) to epicholestanol (Z) by means of potassium acetate involves an inversion of configuration about the carbon atom con­ cerned.

If replacement of hydroxyl with chloride by use

of thionyl chloride involves retention of configuration, it then follows that the configurations of cholestanol (VII), )-chloro eholestane (VTII), cholesterol (I) and cholesteryl chloride (VI) are the same.

This conclusion led Bergmann

to suggest that the reactions of these latter two compounds

7.

iii. Bergmann, Relv. Uhim. Acta, 20, 590 (1937).

7

S0C12 or PCl^ HO'

KOAc; Hydro1

Cl'

H,

H,

S0C12 HO'

Cl H

H VII

PCli

VIII

KOAc Hydro1

Cl

PCI,

KOAc Bydrol

SOC1. H IZ

H Z EpicJaolestanol

.

8

.

with reagents like phosphorus pentachloride and acetate ion, which normally produce inversion, were anomalous in their stereochemical behavior.

He further concluded that this

anomaly is due to the presence of the 5,6 double bond. Additional support to Bergmann*s conclusions has recently become available from several souces.

X-ray analyses

of the cholesteryl halides have established that the halogen atom has a ^-configuration, i.e., a configuration which is cis to the 10-methyl group or in simpler terms a configuration in which the carbon-halogen bond is directed away from the essentially planar steroid nucleus towards the reader. The hydroxyl group in cholesterol possesses this same configuration.

Both Shoppee^ by mechanistic considerations

and Dodson and Riegel^ by the stereospecifie rearrangements of the i-steroids and by the stereospecifie 1,3-elimination reaction to form i-cholestene-6-one (XI) have likewise arrived at the same conclusions. This anomalous effect of retention of configuration in replacement reactions occurring at the 3-position in 5,6-unsaturated steroids, however, is not unique.

There

are numerous cases in which compounds behave in an analogous fashion.

For example, the hydroxylation and methoxylation

8.

Carlisle and Crowfoot, Proc. Roy. Soc. (London), A184, 64 (1945); Crowfoot, Vitamines and Hormones, II, 469 (1946).

9.

Shoppee, I. Chem. Soc., 1138, 1147 (1946).

10.

Dodson and Riegel, I. Org. Chem., L3, 424 (1948).

8

of o^-bromo- and 0^ 6 -dibromopropionic acids have been found to take place without inversion*

11

To explain this retention,

cyclic intermediates have been suggested in which one of the oxygens of neighboring carboxyl groups participates in the reaction by stabilizing the configuration of the $

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