ATTEMPTED SYNTHESES IN THE ADAMANTANE SERIES

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

By

HARMAN SMITH LOVv'RIE, B.So. The Ohio State University 1952

«I !>••#* ) # , * * } *J # •» ' , 9 *3 ® ' ^ ■•; ; V : - ;

Approved by ;

. / l / k c t i r ^ , T.'.. Lju/luof/y.. Adviser il

ACKNOWLEDGMENT

The author wishes to express his deepest appreciation to Dr. Melvin S. Newman for suggesting this problem and for constant aid and guidance throughout the work.

9 1 8 1 3 7 6 1

SYNTHESES IN THE ADAMANTANE SERIES

INTRODUOTION

In 1932, Ziegler^ developed a reaction in which one mole of acetonitrile was condensed with three moles of an alkyl bromide to yield an “trisubstituted acetonitrile:

OH^ON 4* 5RBr + NaNHg RjCON +3NaBr 4* 3NH3 About the same time, Prelog^ prepared a number of bicyclic compounds having a nitrogen atom on the bridgehead by con­ densing an alkyl tribromide with ammonia:

^(OHg)xBr ^/(OHa)xx

OH— (OHgjyBr + 4NH3 ------0.H-— (OHg)y—^ + SNH^Br

^(CH2)zBr ^(CHg)^

The present work was started in part to see if the principles of these two reactions could be combined as follows :

+ GH.CN

This synthesis would be a novel addition to those known for 1 polycyclic molecules. Judging from Ziegler's research, it could be expected to work also with secondary bromides

1.Ziegler, K. and Ohlinger, H., Ann., 495. 84 (1932) 2. See references in Table I, p.18. ill

Table of Gentents

Page Acknowledgment

Introduction . . . • 1

Historical Section • . . 5

Discussion of Experimental Results . 31

Experimental Section . . 52 a Trimesic Acid, XXIV; Preparation 52

Trimethyl Trimesate, XXXVI; Preparation 54 Trimethyl 1,3,5-Oyclohexanetricarboxylate, IV; Prep. 56

1.3, 5- Tris(hydroxymethyl)cyclohexane, V; Preparation 58

1.3, 5-Tris(bromomethyl)cyclohexane, I; Attempted Prep.6l

Tris-Methanesulfonate of 1,3,5-Tris(hydroxymethyl)- 62 .cyclohexane, XIX; Preparation

l-Azatricyclo(3,3,l,l^*'^)decane, VI; Attempted Prep. 65

1,3,5-Cyclohexane tricarboxylic Acid, VII; Preparation 69

Triamide of 1,3,5-Cyclohexanetricarboxylic Acid, XXIX Preparation 71 Pyrolysis ; 72

Triammonium 1,3,5-Cyclohexanetricarboxylate, XXX; Pyrolysis 73

Summary ...... 7 8 i' Appendix A - Infrared Spectrograms . . . . 8 0

Appendix B - X-Ray Powder Photographs . . 94

Autobiography ...... IO8 20 to produce molecules substituted next to the bridgehead:;

^ ( O H g ) ^ r R^_(CH|)^Br. CON

(OH ):Br k

Moreover, the nit rile group can easily be converted by known methods into a variety of substituents, thus establishing

a direct route to analogs of the polycyclic molecule. These

analogs would be particularly interesting for the study of

ionic reactions which are known to involve a planar config­ uration of the substituted atom; i.e., those reactions in­

volving carbonium ions or formation of a double bond..

Of equal importance to testing the synthesis above was

the conversion of certain of the intermediates in the prepar­

ation of I, (see proposed syntheses on p. 4$. ), into compounds

having the adamantane structureylll;

cyH,'

These conversions would serve the double purpose of

confirming the configuration (as cis^) }of the intermediates

1.. Reference $, p* 4*' 3 while at the same time furnishing analogs to adamantane.

Not only has, the configuration of this type of cyclohexane derivatives been of some interest,^»5 but also compounds of the adamantane structure have received more than passing attention.^ In addition, VÏ would be interesting as a tri­ cyclic base whose properties could be compared with those of quinuclidine in studies-of stereochemistry..^ Finally,, the compound VIII would constitute a most unusual case of a triamide on a bridgehead..

The following reactions were therefore planned for this work;' the conversion V — XIX— ^ VI was attempted

1. Hassel,, 0., Research^2.,504 (1950) and other articles by this author.. 2*. Fuson, R. 0. and McKeever, 0. H., J. Am. dhem. Soo.^ 6 2 j 2088 (1940); Van der Zanden, J. M. and DeVries, G., Rec. trav. ohim..67,998 (1946). 3• Ohiurdoglu, G-;^ Fierens, ,P. J . 0 , and Henkart,, 0.,, Bull. soc. chira. Belles'. 59^156. .174 (1950).. 4. Prelog, Vi’ and Seiwerth; R., Ber., 74B ^1644. 1769 (1941), and references mentioned there. 5*. Brown, H. 0. and Eldred, N. R., J. Am. Ohem. Soc. 71. 445 (1949). 5 : HISTORICAL SECTION

The Preparation of Adamantane

Adamantane has been of interest to earlier workers principally, hecause of tne similarity of its carbon skele­ ton with that of the diamond. In fact, it was first named

"dlamantene'% In 1924, and designated as the "elemental cell" " of the diamond;^ later "diamantane" was used.^*^ When the compound was actually isolated for the first time in 1933 4 from petroleum, , the present name was assigned and was adopt- 5 ed by Prelog when he first synthesized adamantane in 1941.

The first synthesis which was attempted of a compound having the adamantane skeleton occurred before any of the work above, and was done without recognition of the signifi­ cance of the structure. During an investigation of tetra- methyl bicyclo(3,3 ,1 ) nonadion-2 ,6 -tetracarboxylate-l, 3 ,5 ,7 ,

(IX), an attempt was made to condense the sodium salt of this ester with methylene iodide and thus obtain a 3,7 methy­ lene bridge. The failure of the reaction was attributed

1. Decker, H., Z-i angew. Ghem.,2Z,795 (1924). 2. Bttttger. 0.. 3er..70B,3l4 (1937). 3. Prelog, V. and Balenpvik," K., Ber..Z]^. 875 (1940). 4. Land a, 8. and Machacek, V., Collection Czechoslov. Chem. Comm.,^ 1 (1933)., 5. Prelog,'v. and Seiwerth, R., Ber.j 7^ ^ 1 6 4 4 (1941). later when the sequence V — ^ I — *-VI proved unfeasible.'

1 ,3 , 5 -0 6 H^( OOgCHj ) , 3 ,5- ^ H g ( OH^OH ) 3 - . - 1 .3 ,5 -CgHg ( CHgBr ) 3 1 1,3,5-OP HgfOOgH), 1.3,5-OgHg(^gOSOgOH^)^ VII

CH. c«r T'CN CHj

1. 1,3> 5-cyclohexane derivatives of the type I, IV, V, VII, or XIX may exist in one of. two isomeric fonns if only the relative positions of the substituents are considered and;ring bending is disregarded. For brevity, these forms will be referred to as cis and trans, respectively. Only the cis isomer will give the reactions to produce the adamantane structure. III.

"Os" •'-T-Trans '•

l(cis),3 (cis),5 (cis) 1 (cis),3 (ois), 5 (trans) (in part, incorrectly; see reference 2, p= 5 )» to the extra-­ ordinary sensitivity of the product, X, to base,.

fHx

+ C H , I , CO^^CH;

The idea of a triple alkylation, similar to that pro­

posed in this work, to produce the adamantane skeleton is by no means new. The first research program which had this

structure as its primary goal was carried out by Kleinfeller 2 and Frercks, and attempted in the beginning to use a triple

alkylation of the type ; :

RC(CH,Cn, *

1 •. Meerwein, K *, J . pralct. Ohem. (2), 104 ^180 (1922),. 2. Kleinfeller, H.'i and Frerckis, W., J, prakt. Chem,. 138 ^ 184 (1933). jl r \ Earlier work, by Kleinf eller in this line had established that the isobutane fragment could not be introduced into ■ a hydroaromatic molecule; for instance, tris (chloromethyl) nitromethane, XII, could not be used in the Wurtz synthesis since hydrochloric acid is split out and self-condensation products, are formed. An attempt was made nevertheless to condense XII with phloroglucin, XIII, but gave only, a poly­ mer, the formation of which was attributed to enolization of phloroglucin and subsequent ether formation*?

0,NC(CH,CI), ‘ U K ■ * CHz JBL

Abandoning this means of synthesis, diethyl hexahydro- benzylmalohate, XI%Ê, was reacted with both acidic and basic condensing agents but failed (understandably) to give a tri­ cyclic intramolecular condensation product. The m-hydrogens were assumed to be too inactive.

1. Kleinfeller, H.', Ber.^ 62.1582, 1590 (1929) 2. See referencee2, p. 6 . 8

Therefore, the p-ketone corresponding to XIV, was prepared, , 1 but could not be intramolecularly cyclized. J

The synthesis attempted by Meerwein was carried out

successfully by Bfittger • Methylene bromide was used instead of the iodide. X could be hydrolyzed to the acid XV which could not be decarboxylated by any of several methods.

Treatment of X with alcoholic alkali gave XVI, which upon estérification and heating to ,240-70° gave back X. The ketone groups in X could not be reduced beyond the corres­ ponding alcohols.

1. Ref erence 2, p.. 6 . 2. Reference 2, p. 5., cOjitte

I.Na. w XH

Œ

/If j/i. l.lïlcOH W S>.Z40'Z7Û*

.w.ce" cr n v CCljri ■f"' JET 33T

It was finally Prelog who sucoessfully synthesized 1 } adamantane. His first attempt, however, was much like the second part of Kleinfeller ' s work. Starting with triethyl methane^ripropionate in the Dieckmann condensation, he attempted to prepare a hi- or tricyclic system, but obtained only the cyclohexanone derivative shown, which is quite simi­ lar to the p-ketone used by Kleinf slier.

1. Reference 3, p. 5. 10

co^et

andino product as:

Ç H i-Ç H -Ç H , or: CH, C H - ,x c o - 4 - * c o ^ CQjEt

, Since sBttger was unable to decarboxylate the adaman­

tane,^derivative he prepared or to reduce its ketones to

methylene groups, Prelog used a simpler starting material

hoping to avoid the latter difficulty, at least. Meerwein

had worked out the reactions: of blcyclo (3,3yl) hOnane deri­

vatives and had shown that the starting material used by

Bttttger, IX, could be selectively hydrolyzed and decarboxy­

lated in good yield to give dimethyl bicyolo(3,3,l)nonadione-

2,6-dicarboxylate-3,7 (XVII).?

1. Reference J, p.

ÏJ 11

.CO

JM

Using XVII and the conditions worked out by BÜttger,

Prelog obtained the corresponding adamantane derivative.

Hydrolysis gave the corresponding keto-acid which could be reduced by the Wolff-Kishner reaction to adamant ane-1,3, " dicarboxylic acid, XVIII. Decarboxylation over copper-bronze at 400° gave a 2^ yield of adamantane,^ III.

1. Reference 5,p. 5*- 12

.co' CA^Me Cq^H

CH.iï \W, .CMj'âî! CO,H TL S.WIII

The preparation of XVIII was repeated, in slightly better yield (57^)« Decarboxylation was carried out in one of two manners as shown

1. Prelog, V. and Seiwerth, R., Ber.^74B ^1769 (1941). 13

COCl

.CM CO^H COC(

.Br^ N a O B t

J^aotvie l.dfCÛQ cm; 'CH Ra-Ni-H^ X.PBr^ c4 % ( U £ % ) /(«,

Adamantane (III), as Isolated by Landa,^ forms color­ less crystals which melt in a sealed tube at 268°. It sub­ limes readily at atmospheric pressure, and is stable to sulfuric acid, chromic acid, neutral or alkaline potassium permanganate, or prolonged boiling with concentrated nitric acid. Landa postulated the structure on the basis of an­ alysis, molecular weight, stability, and crystal structure.

The material Isolated by Prelog^ melted at 267.^5 -269° in a sealed tube. It sublimed under atmospheric pressure

1. Reference 4, p. 5.\ 2. Reference 1, p. 12. 14 on a bath at 60-80°, and was stable to the conditions above and even to boiling neutral or alkaline permanganate. Crystal structure determinations leave no doubt as to the structure.^ The Ziegler Preparation of Acetonltrlles p Ziegler studied the alkylation of acetonitrile and

Its homologs with alkyl halides. He tested various deri­ vatives of alkali metals as condensing agents, and was able to develop conditions for the preparation of mono-, dl-, and trlsubstltuted acetonltrlles In good yields. By slowly adding a suspension of sodium amide In a neutral solvent such as benzene to a solution of the nitrile and bromide, he obtained a smooth condensation and suppressed side reactions.

Although trlsubstltuted acetonltrlles were notably more difficult to prepare than the corresponding mono- or di-derlvatlves, moderate yields of such compounds could be obtained, even though steric factors might be expected, in certain cases, at least, to make their preparation difficult.

In particular, di-isopropyl ethyl acetonitrile was prepared from «=<-Isopropyl butyronitrile In 45^ yield; better yields were obtained in a number of examples having no branching

1. Nowacki, W. and Hedberg, K. W., J. Am. Chem. Soc., 70 , 1497 (1946). 2. Reference 1, p. 1. 16

CH. I % Hbt ix r other examples of this type of reaction are known; in addi­ tion, the Dieckman condensation is of general application for closing a second hing of five or six members

CO;;Ei

"Two-fold intramolecular alkylations" constitute a sec­ ond method of synthesis, and may be formulated so

X OH (OHg) Br ----- ^ OH- (CHo); :N (OHg)gHHg •(OHo)2'z 2 3 Oompounds of the types XX and XXI have been prepared in this manner, which is considered by Prelog to be the most

1. Olemo, G. R., J. Ohem. Soc.)(1937) 1989. 2. (a) Prelog, V., Heimbach, S., and Oerkovnikov, E., Ann.. W 243 (1940). Y V y V (b) Prelog, V., Sostaric, N., and Gustak, E., Ann..545. 247 (1940)., ^ 3. Prelog, V., Heimbach, S., and Rezek, A., Ann..545.231 (1940). ’ ^ 15 - to the nitrile and to the halogen®

Prelog's Preparation of Azabioyclics

Prelog has discussed three methods for the preparation

of bicyclic compounds having a nitrogen atom on the bridge­ head.^ In the first, hetero-monocyclic compounds are used which have proper substitution which allows the closure of p a second ring. Thus quinuclidine (XX, R»H) and cf-methyl

quinuclidine^ (XX, R=OH^) have been prepared by treating

the properly substituted piperidine with base.

'HZ

In the same manner, 1-azabicyclo (2,2,1) heptane^ (XXI, C R=H) and the 3-propyl horaolog^ (XXI, R-n-Pr) have been pre­

pared •

1. Prelog, V., Ann.,^ , 2 2 9 (1940). 2. Reference 5, P» 3» and other references there. 3. Winterfield, K.,Arch. Pharm., 26 8 .308 (1930). 4. Olemo, G-. R. and Prelog, V., J. Chem. Soc., (1938) 400. 5. Koelsch, 0. P., J. Am. Ohem. Soc. ^ 146 (1946% 17 generally applicable of the three syntheses.^ This and the previous method have been used most extensively. However, the third method, a triple condensation on ammonia as out­ lined on page I > has been used to produce a number of bi­ cyclic structures; in general, lower yields are obtained than in either of the other two syntheses. Table I summa­ rizes the use of the triple condensation.

1. Reference 1, p. 15; compare; Elderfield. Heterocyclic Compounds , John Wiley & Sons, Inc. Nev/ York, N. Y. TÏ952) vol. 3)P. 374. 18

Table I ^(0H„) OHBr \ OH-- (O'd ) Br + NH3 — -- **- (j^ (OHg) N 2 y ^(OHg)^Br

X y z R Yield Reference

1 ■ 2 2 H 50^ 1

2 2 2 H . 11.8^ 2

1 2 2 OOgH 53^ 2

1 2 2 H 3

0 2 2 -OH3 9^ 4

0 2 2 -02H5 16.5^ 4 The reaction vms carried out in a sealed tube using a 20% solution of ammonia in methanol and the tribromide, by heating for several hours at 120-130° o

1. Prelog, V., Kohlback, D. OerkoVnikov, E., Rezek, A., and Plantanida, M., Ann.,532^69 (1937)• 2. Prelog, V, and Oerkovnikov, E., Ann..^532■>83 (1937) 3. Prelog, V. and Oerkovnikov, E., Ann.^ 5251292 (1936) 4.. Prelog, V.,•Oerkovnikov, E., and Heimbach, S., Collection Czechoslov, Ohem. Oomm. 10 399 (1938)* ) » 19 The Alkylation of Ammonia with Sulfonates

When it v;as found after beginning this work that the sequence on page 4 , V — 1— *-VI, could not be carried out easily because of the anticipated difficulty in preparing

the synthesis V -^*-XIX— *-VI was taken as an alternate route which also would establish the configuration of V

(assuming that no inversion occurred on the ring) and furnish a synthesis of VI. The work of Reynolds and of Tipson, which is described below, furnished the background for this syn­ thesis •

Conditions have been worked out for the preparation of

N-substituted piperidines from the dibenzene- or dimethane- sulfonate of 1,5 pentanediol and the proper primary amine, 2 in good yields.

0H2(OH2CH2O8OgR)2 + R ’NHg ------^ R - GgH^-, p-CH^0gH2|_“ , or CH^-

R' '- n-Butyl-j cyclohexyl-;

In addition, it was shown that secondary amines could be alkylated in the same way to yield a tertiary amine. The disulfonates were prepared at low temperatures (0-5°) which prevented several possible side reactions from occurring."^

1. See experimental section. 2. Reynolds, D. D. and Kenyon, W. 0., J. Am. Chem. Soc.j 12 1597 (1950). 3. Tipson, R, S., J. Org. Ohem.^9^235 (1944). 20 The Preparation of Trlamides

A fair number of tr lam Ides of type XXII have been re­ ported.

R , C O COR,

7 COR, . Un.

The methods for their preparation from amides were discussed

In 1904^, and while improvements and modifications of cer- O tain of these methods have been reported, no new syntheses have been developed since then. The methods which were

glven^ did not Include all known methods of formation of

trlamldes^ at that time, but they do seem to be the most

generally useable. Unfortunately, from the view of the pre­

sent work, very few of the trlamides known have saturated

alkyl groups In all three R positions; there seems to be no

reason, per se. why such trlamides could not exist, nor why the methods which have been used in the preparation of

1. Titherley, A. W., J. Chem. Soc. 8^ 1673 (1904). 2. For example: (a) Thompson, Q. E., J. Am. Ohem. Soc.) 5841 (1951). (b) Evans, T.. W. and Dehn, W. M., J. Am. Chem. Soc., ^^ 2 5 3 1 (1930). 3. See methods of formation of triacetamide and tribenz- amide in Beilsteins Handbuch der Organlschen Ohemie, Edward Brothers, Inc. Ann Arbor, Mich. (1942), Vol. 2, p. 181 and Vol. 9, p. 214,respectively. 21 the few cases known^ could not be extended to other homo- logs in the series. However, since there have been several observations of the difference in behavior between deriva­ tives of aliphatic acids and derivatives of aromatic acids in the preparation of triamides, it would seem unwise to expect that all the methods which have been used for the preparation of triamides which contain an aromatic acid group would apply in the same manner to the preparation of tri­ amides containing only aliphatic acid residues.

Titherley^ summarized the methods for the acylation of mono- or diamides as follows;

A. Direct action of an acid chloride on an amide.

B. Acyl chloride and an amide in pyridine.

0. Acyl chloride and the sodium salt of the amide.

D. Esters and the sodium salt of the amide.

E. Anhydride and the sodium salt of the amide.

F. Anhydride and the amide,

N-Acetyl succinimide has been prepared by method F^, tri- acetamide by method O'] and by the action of acetic anhydride

1. Reference 1, p. 20. 2. Reference 2a, p. 20. 3. Reference 1, p. 20. 4. Tafel.J. and Stern, M . , Ber.,^.2225 (1900). 5. Rakshit, J. N., J. Chem. Soc.^1913) 1561. 22

on methyl cyanide at 200°.^ Tributyrylamlde is claimed to have been prepared by method A, but no analysis or melting

point was given.^ Esters of ammonia tricarbonic acid, (ROCO)^N^ have also been reported,^ as has N-carbethoxysuccinimide,^

■using method 0 for preparation. To this writer's knowledge

these are the only cases reported in which at least one R group in XXII is not phenyl or its equivalent.^

A rough correlation has been suggested between the acid­

ity of the parent acid and its ability to diacylate acetamide

or its own amide under similar conditions to method It would seem reasonable that the stability of a triamide would

be dependent in some way upon the acidity of the acids from which it was derived. The benzoyl residue is known to dis­

place acetyl under some conditions,*^ which could suggest a difference in stability that in turn could be correlated

to the strength of the acid. A similar displacement does not necessarily occur under all conditions, however.^ It does not seem possible, therefore, at this time to account

1. Wichelhaus, H., Her.,^^84? (1870). 2. Tarbouriech, J ., Qompt. rend. > 137,128 (1903). 3. Diels, 0., Ber..]6 736 (1903). ' 4. Heller, Q-. and Jacobson, P., Ber.. 54 B .1107 (1921). 5. i.e., in which R-'; = O^Hr--, substituted 0^H_-, 0>HrC=C- 8,, or furoyl. 1 ^ 5 6 5 6 « ’ 6. Reference p. 20. 7. O.'f. preparation and reaction of N-Benzoylsuccinimide, Reference 2b, p. 20» Although displacement of a'succinyl ' residue is not exactly comparable to the displacement of acetyl, it may serve as an analogy, when examining the results discussed by Titherly, Reference 1, p. 20. 23 for scarcity of examples of triamides derived completely from aliphatic acids bn the basis of a possible instability of these compounds. No study has been made which examines the stability of triamides, and only fragmentary information is available from the literature concerning those derived from aliphatic acids. In general, they are fairly readily hydrolyzed in the presence.of base^»^ but may be distilled unchanged,at reduced pressure in some cases.^ •- m A Two isomers must be considered for symjetrical triamides.

nco. .con otoH N RCON-Cn ton m z n i A

It has been shown that the N-carbethoxy derivatives of phthal- imide and succinimide are stable to prolonged boiling with ethanol, while the corresponding 0-derivatives are cleaved

1. See reference 7, p. 22. 2. Reference 5, Pi 21; Reference 3, p.,22. 3. Reference 3, P* 22; Reference 4, p. 21.. 4. Cis-trans isomerism in'XXir A has been disregarded in this discussion since both such isomers are of the gen­ eral type XXII A. 24 to the imlde :.1

OCOj^Bt

Stable

The reactivity and tendency to rearran)),gemsat of iraino ether derivatives similar to XXII A have long been known^»^»

Triamides are frequently recrystallized from ethyl alcohol, by contrasty which can leave little doubt as to their structure.

Repeated attempts to isolate two isomers of substituted diacyl amides have failed^* ^; : 01 RO = NR' + R ’'CO^Na RCNGOR'' R " G = NR' + ROOgNa

Amides Involving a Nitrogen Atom Located on a Bridgehead

To this writer's knowledge, no authentic example has been reported of an amide involving a bridgehead nitrogen atom in a bi- or tricyclic system where the resonance usually

1. Reference 4, p. 22. 2. Wheeler, H. L., Walden, P. T.,and Metcalf, H.F., J. Am. Chem. Soc. 20 73 (1898). 3* Munn, 0., Hesse, H., and Volquartz, H., 5e r . ^ 379 (1915) 4. Reference 1, p. 20. ' ^ 25 associated with the amide would create a double bond that violated Bredt’s rule* : :

hro

234 Nuïfierous attempts to prepare such compounds have failed. * '

The subject has been recently reviewed,^ and an extended discussion here would therefore, be repetitious. The possi­ bility of existance of such a system has not been excluded, however^; rather, it has been assumed that resonance' in the manner above would be inhibited, that the carbonyl would exhibit the properties of an isolated ketone,^ and that the stability of the system would consequently be different from that expected for an amide or for the parent bicyclic system.2,3

The same assumptions would apply to a di- or triamide on a bridgehead nitrogen. Luk&s has commented on them in P the discussion of monoaraides.

1. It is well known that Bredt‘s rule may be violated if n is large enough (Ref. 4). The discussion here applies to the smaller-values of n as Q), 1, or 2 . 2. Lukes, R., Collection Czechoslov. Ohem. Comm., 10,148 . (1938). 3 . Topper, Y. J., Ph.D. Thesis, Harvard,(1946). 4. Fawcett, F. S., Ohem. R e v . ^219 (1950). 26

The Préparât Ion and OonfiKuratlon of 1«3.5-Oyolohexane Deri­ vatives During a study of the polymerization of vinyl-mesltyl ketone, Fuson and MOKeever obtained as the main product a

trlmer which was proved by synthesis to be a 1,3,5""trlmesltoyl

cyclohexane. 1

Two Xiowers: RC O C H = CH, A : trip. ZtO- ZIZ.^ 3; fnp.iSO"" 1^1 * m u

I.NaOM l.McOH a . ™ , Ofie isomer ohl

If the pdlymerlzatlon mixture was heated eight hours, XXIII

A and B were obtained In 40^ and 17^ yields respectively,

while by heating sixteen hours, 70% XXIII A was obtained

and only a "small amount'- of XXIII B. A and B were presumed

tb be stereoisomersJ the lower-melting Isomer, B, was more

soluble than A In methyl alcohol,.

1. Puson, R. 0. and McKeever, C. H . , J. Am. Ohem. Soc., 62. 2088 (1940). 27

IV was obtained as an oil which crystallized after stand­ ing two days; and upon recrystallization from methyl alcohol ■ . St Q or petroleum ether, gave colorless needles, meltingy^42-44 •

A similar preparation was carried out by Van der Zanden n and De Vries.

COR

RCOCH!.CHiCl

iC/? ~ f>" N\tOC^H^3 ■ m i B 6 114. S'

H One rsoiwer onfy M m O^H CHa CO^M< Isomeric M\xturc

crtjR

i m ÎXSA mp. HAi"' COR ‘

1. Van der Zanden, J . M. and DeVries, G., Rec. trav. chim.. 61^998 (1948). 28

XXV A and B ard. XXVI A and B were suggested as sets of stereo­ isomers; in the: latter pair, the lower melting isomer, XXVI B, was the more soluble* By recrystallization of the isomeric mixture, IV, various solid fractions were obtained having melting ranges between o 43 and 47 V Hydrolysis of either this solid or the mixture of isomers gaye only one,isomer of 1,3,5-oyclohexanetrioar- boxylic acid, VII*.

The stereochemistry of cyclohexane and certain of its derivatives has been recently discussed.In the "chair" form, which has been calculated to be the most stable, tv/o types of carbon-hydrogen (or carbon-substituent) bonds have been described : those parallel to the threefold axis of the cyclohexane ring are called "polar", and those which are approximately perpendicular to this axis are called "equa­ torial"*^»^ The equatorial, bonds are calculated to be thermo­ dynamically more stable* Therefore, the ois 1 , 3 * cyclohexane derivatives should, be more stable than the trans; the latter would involve one polar bond and two equatorial bonds instead of three equa­ torial bonds found in the cis-compounds.

1* Reference 1, p. 3* 2. BartonjD*-H. R. and Rosenfelder, W* F., J. Ghem* Soc*, (1951) 1048* 3» These bonds are denoted as "yU" and "ô" respectively, by Hassel* 30 Table II

1,3,5-Cyclohexanes: R ’CgHQ(R)o Melting point Boiling point R R' ois trans ois trans Least sol,; Configuration proved: Ref, o 1 1. NHg NHg 1^8 2. OH OH 184° 1459 cis^ 3. OH, 0H_ "43.2° -84.5° 138.41° 141.22° ^ 3 3 . CH_ OH, -50° -107.5°138.50-.85° 140.4-.6°" ___^

Configuration postulated:.*

4.. CH_ OH 39-40° 16° 79-80° 83.4° ^ 6 CH^ OH 41-42° 20°______

Isomers separated but configuration not postulated : Melting Point R=R* High Low Least sol.; Ref, (CH^)^CgHgCO- 210-212° 150-151° High m.pj

p-(OH,)OCgH^OO- 196,5-197° 158,5-159.5° ____ ®

p-(0H^)0CgH2^0Hg- 151.5-152.0° 111-112.5° High m.p,®

1. Anderson^ P. and Hassel, 0,, Acta Ohem. 8cand., 1349 (1951). This was the only form obtained by reduction of 1,3,5-cyclohexane trioxime. 2. (a) Lindermann, H. and Baumann, H., Ann., 477. 78 (1929). (b) Anderson, P. and Hassel, 0,, Acta Ohem. Scand., 2, . 527 (1948). 3. Bowers, 0. E., M. S. Thesis, Ohio State University^(1949). 4. Ohiurdoglu, &,, Fierens, P. F . 0;, and Henkart, 0^, Bull, soc. chim. Beiges, 156, 174 (1950). 5. Skita, A. and Faust, W., Ber., 72B. 1127 (1939). 6. Cornubert, R. and Hartmann, P., Bull, soc, chim. France 867 (1948). 7# Fuson, R. 0. and McKeever, 0. H., J. Am. Ohem. Soc., 62, 2088 (1940). 8. Reference 3, p. 31* 29

H w R' R

(C-R* e^ua+oriaf) (C'R* polà.r) The configuration of three such derivatives has been . definitely established (#'s 1, 2, & 3) and a structure postu­ lated on the basis of physical properties in a fourth case

(^4); (R\“ OH,, R' = -OH)* Table II lists these compounds I'. ^ along with other 1,3,5 derivatives for which both isomers appear to have been isolated. It is interesting to note that the cis isomer is the lower-boiling, the higher melting, or the least-soluble form, insofar as these characteristics have been given; it remains to be seen if this situation will.be true for all such isomers* 31 DISCUSSION OF EXPEREAENTAL RESULTS^

The Preparation of 1.3,5-Oyolohexane Derivatives

As will be recalled from the Introduction, the purpose of this work was to test the reaction of 1 ,3 ,5-tris(bromo- methyl)cyclohexane, I, with acetonitrile, on the one hand, and to prepare certain compounds having the adamantane struc- p ture, on the other. The syntheses proposed required a fairly large quantity of trimethyl 1 ,3 ,5-oyclohexanetricar- DL boxylate^as starting material. The conversion of mesitylene into this ester and its subsequent hydrolysis to the corresponding acid followed very closely the work of Van der Zanden and DeVries and confirmed their experimental results.^ It should be noted that tri­ methyl triraesate was purified before reduction; were this not done, impurities made the purification of the product difficult.

The separation of a solid isomer from the isomeric mixture of trimethyl 1 ,3 ,5-oyolohexanetricarboxylates was

1. Infrared spectrograms and X-ray powder photographs are given in Appendix A and B, respectively. 2. Page 4. 3. Van der Zanden, J. M. and DeVries, G-., Rec. trav. chim., 6%, 998 (1948). 52 accomplished quite readily by low-temperature (ca-80*^) re­ crystallization from anhydrous ethyl ether.^

The colorless hexagonal prisms (IV) obtained in 62.% yield by three such recrystallizations melted^48.0-49.0°Addi­ tional crops could be obtained by condensation of the mother liquors.

Hydrolysis of either this isomer or of the mixture of isomers yielded a single form of 1,3,5-cyclohexanetricar- boxylic acid, (VII), thus confiraing the observations of

Van der Zanden.^ The structure of this acid was related to the solid trimethyl ester by treating with diazomethane; .

1. Beal, P. and Newman, M. S., Private Communication, sepa­ rated the corresponding triethyl ester, which had been prepared in the same manner as the trimethyl ester above, in a slightly impure form, melting point 25-30°, by lo^-temperature recrystallization from low-boiling (35- 39 ) petroleum ether. The trimethyl ester was chosen for the present work since it would be expected to have a higher melting point. 2. By recrystallization from methanol. Van der Zanden ob­ tained various fractions which melted in ranges between 43 and 47 . Fuson recrystallized from methanol or petro­ leum ether and obtained needles melting at 42-44°. On the basis of the information on p. 20-BO, this was assum­ ed to be the cis-isomer in the present work. 3. Reference 3, p. 31» In contrast to the "very long time" required, according to Van der Zanden, to isolate this acid by continuous ether extraction, it was found that by saturating the aqueous layer with sodium sulfate, the extraction was virtually complete in twelve hours. 33 1.3.5-GgHg(OOgH)^ l,3,5-0gHg(0bg0H^)^

(VII) m. p. 215-18° (IV) m. p..48-49°

The lithium aluminum hydride reduction of the solid isomer of trimethyl 1,3»S-cyolohexanetricarhoxylate, IV, afforded the solid isomer of the corresponding trialcohol,

V. Because of the fairly large losses which occurred in the purification of the solid isomer of IV, the overall yield . of solid V, calculated on the quantity of crude IV, was lower than that obtained by the reduction of crude IV follovfed by purification, which gave small losses of the solid alcohol,

V. The former sequence was necessary, however, to relate the configuration of the solid ester, IV,. to the solid alcohol,

V.l

1.3.5-0gHg(CO2OHj)5 l,3,5-CgHg(OHgOH)3

IV m. p. 48-49° V m. p. 101-102° The preparation of 1,3,5-tris(bromomethyl)-cyclohexane

(I) was attempted from impure trialcohol (V), by refluxing with 48^ hydrobromic acid. An oil separated which on working li up either by distillation or by recrystall^tion at low tem­

peratures afforded various fractions whose analysis agreed

1. Assuming that this reduction does not affect the con­ figuration of an oC -carbon. This has been shown to be true in a number of cases; Brown, W. G., in Organic Reactions. Vol. VI, John Wiley & Sons, Inc.,New York, N. Y. (1951) p. 469. 34 best with dibroraide shown: l,3,5-0gH^(GH2OH)^ --- 1,3,5 iCHg)

Calculated % for : 0 H Br l,3.5-0gHg(0HgBr)3 29.8 4.2 66.1 l,3,5-CgHg(0HgBr)g(=0H2) 38.3 5.0 56.7

1,3, 5-OgHg ( OHgBr)^ (OHgOH) ■ ' 36.0 5.4 53.3

Found : 41.6 5.1 59.3 57.6

The above preparation was also attempted using

us tribromide, but due to uhcertainity about the purity of

the starting material, V, no conclusions may be drawn.

These results cannot be regarded as conclusive. It

seems reasonable that the tribromide. I,may be prepared,^

but under milder conditions. However, since the structure

of this series of cyclohexane derivatives had not been proved,

and in view of the difficulties encountered above, it was

decided to concentrate first on establishing the structure

of the series, by synthesizing VI and VIII, and if this was

successful, then to return to the preparation of I.

1. For instance, by the following scheme:

l,3,5-OgHg(OHgOSOgOH^) l,3,5-0gHg(0HgBr)^ 35 The Attempted Préparât Ion of 1-Azatrlcyolo (3,3,1,1^**^ )decane. n Attention was therefore directed toward the prepara­ tion of VI in the following way :

ÇH;^ÛSO^CH^

XDC CH;^OH

\ i ^ s n r

The preparation of the trisulfonate, XIX, followed the methods which have been worked out by earlier workers.^

The preparation of VI from XIX, outlined above, was attempted three times and gave, in each case, material,

XXVII, having the correct analysis for the hydrochloride of l“Azatricyclo(3,3»l»l^*'^)«iecane, VI*H01^. In one of the preparations, carefully purified XIX, m.p. 126«8-127.4°, was used, and gave the same yield (2 to ^%) as did the other

1. Tipson, R. S., J. Org. Ohem. £, 235 (1944). 2. The product of the first run was analyzed; those from the other runs showed identical X-ray powder photographs to it and were therefore assumed to be identical. 37 and the isomers of 0^. It de^orized alkaline permanganate immediately at room temperature. Both adamantane and quinu- clidine

Adamantane Quinuclidinè VIA are stable to boiling permanganate; ^ by analogy, VIA should be, and therefore may be ruled out as a structure for XXVII.

This leaves B2 as the probable structure for XXVII.

XXVII was reacted with bromine and gave two crystalline forms which were manually separated and then analyzed.

^C % n ^Br

Calculated for C^H^^N'RBr 49.5 7.4 3 6 .6

Found for XXVII A 48.8 7.0 36.7

Found for XXVIII 37.4 5.2 52.9

Calculated for 36.4 5.1 53.8

1., In addition, the unusually high melting points of XXVII and XXVII A (p. 38), which are over 400°, rule out iso­ mers of 0.'; 2. (a) Prelog, V. and Seiwerth, R., Ber., 74B. 1769 (1941). (t) Lttffler, K. and Stiezel, F., Ber., 42, 124 (1909). 3« The discrepancies ip the analyses below may easily be explained by assuming that the manual separation was imperfect. 36 runs. This would indicate that the product, .XXVII, arose from the solid isomer of XIX and not from an impurity such as the other isomer. Three types of isomers of VI*KOI could form directly from XIX: tricyclic (A), bicyclic (B), and monocyclic (0).^

/i-Hcr

/, (CHi OSO j,CH^)£’ YJ 6 CH

JL'HCl

C

The reaction product, XXVII, showed no absorption in the 5.8-6.2^ region of the infrared.^ This rules out Bl

1 . Only one of several possible isomers of 0 which could arise by rearrangement of the double bonds is shown since the evidence to be presented against this double-unsatu- rated, monocyclic system applies equally well to any of these isomers* 2. Absorption in this region has been assigned to double bonds. In certain oases however, double bonds in a ring have showed little or no absorption. Terminal methylene groups or double-unsaturated systems are not, in general, included in this catagory. 38

If XXVII, (which was known to be an amine hydrochloride), was placed in hydrobromic acid and the water evaporated,

XXVII A was obtained. It appears from the results above that treatment of

XXVII with bromine substitutes one bromine atom in the mole­

cule itself and exchanges a bromide ion for a chloride ion

in the salt. The former could be explained by addition of

one molecule of bromine to a double bond followed by split­ ting out hydrogen bromide* Whatever the mechanism, this would

indicate, especially when coupled to the behavior of XXVII to permanganate, the presence of a double bond in the mole­

cule. The infrared data suggests that this bond is not a terminal methylene group; it must therefore be in the ring.^

1. The rearrangement necessary to give,B2 from Bl is well known for cyclohexane derivatives. In fact, in a number of cases the endo-double bond has been shown to be more stable than the exo-. 39 The following scheme is one of many that could explain the results above.^

H'HBh

3ZT82 f m B r H o t - XT

Br 2 x n n Br C H , _

XXVIII melts at 204-206° while XXVII A is unmelted at 400 . Considering the similarity of their postulated structures, this seems unusual, but no explanation can be offered at the present time. Other structures could also be suggested for XXVIII, such as;

Br

Which could be formed by the intramolecular elimination of hydrogen bromide. The low melting point of XXVIII would make this structure doubtful. 40

Pyrolysis of the Triamide of 1,3,5*Cyclohexanetricarboxylic

Acid

One reason for attempting the previous preparation of l-Azatricyclo(3,3,l,l^»'^)decane, VI, was to establish the

structure (as cis) of the starting material, XIX. Since

this reaction did not give the desired product, the prepa­

ration which follows of a tricyclic triamide was undertaken.

It is well known that derivatives of glutaric acid,

such as the ammonium salt or the amide^ readily form glutar- imide on heating.^ (

In the latter case, the reaction occurs at the melting point

of the diamide. Although a triamide has not been prepared

in this way, and no work has been done on their thermal sta­ bility, one might expect, from certain of their methods of

preparation and charaAteristies, some stability to heat.

Triacetamide was prepared from acetonitrile and acetic

1. Hurd, C. D . , The Pyrolysis of Carbon Compounds. The Chemical Catalog Co. New York, N. Y. (1929),pp. 516, 583, 599. Compare this proposed synthesis with that of camphor imide, p. 517. 41 anhydride at 200°^, tribenzamide, m. p. 207-8°, may be sub­ limed unchanged^, and N-acetylsuociniraide may be distilled

(b. p. 167°).3 The preparation of VIII was therefore attemp­ ted by pyrolysis: Y com m CONH-

The preparation of XXIX from the corresponding acid via the acid chloride was easily effected. Heating the triamide to its melting point (ca 290°) caused a white solid,

XXXI, to sublime in 78^ yield. From the analysis, an empiri­ cal formula of was deduced for which four isomers are possible if it is assumed that no rearrangement took place.

1. Wichelhaus, H., Ber., 847 (I870). 2. Curtius, T., Ber., 3041 (1890) • 3 . Tafel, J. and Stern, M., Ber., ^ 2225 (1900). 42

V

The infrared spectrogram of XXXI shows sharp absorption at 4.5-4.6^ indicative of a cyanide group. The material when dissolved in water was neutral, remained neutral after boiling five minutes, and was recrystallized twice from boil­ ing water but remained unchanged. Thus D may be ruled out because it would show no cyanide absorption, and C because it would be acidic.

The structure B could accommodate the data for XXXI, but poorly. If the attempts to isolate isomeric imides of the type.

(i ÇCOK QC.OR* R C= N R' R''C=NR'

Which are discussed on page % , are to be regarded as signi­ ficant, it must be concluded that B is unlikely and would ‘b. 43 be quite reactive If It existed.^

The behavior of XXXI Is well accounted for by the struc­ ture XXXI A.whose formation fromXXIX might occur In the se­ quence shown.2

CONH,

CONH.

CM CM

Pyrolysis of the Ammonium Salt of 1.3,5-Cyclohexanetrloar- boxyllo Acid

Coincident with the work above was the pyrolysis of triammonium 1,3»5-cyclohexanetrlcarboxylate, XXX, as shown

1. In addition, glutarlmldes are known to form very readily from the dlamIdes, and without evidence to the contrary It seems reasonable that this reaction followed the us­ ual path. (See reference which follows.) 2. -These reactions are known to occur In the glutarImlde or In the aliphatic series very readily. The direct dehydration of XXXII to yield XXXI Is considered less likely than the sequence shown since aliphatic amides are difficult to dehydrate by heat alone. This must not be disregarded as a possibility, however. See Hurd, loc. clt. (Reference 1, p. 40), pp. 507, 583, 587, and 516. 44 on page 41. This pyrolysis, carried out in the manner above, yielded a white powder, X>DCIII, from whose analysis was de­ duced the empirical formula of of which four for­ mulas are possible

COLH

B 0,H o m O^H m u The pyrolysis product, XXXIII, was slightly soluble in cold water and gave an acidic reaction to litmus. It showed no absorption at 4.4-4.6y(i in the infrared, indicating that a cyanide group is not present; the spectrogram in the region 5-12yu. was almost identical with that of XXXI. XXXIII could be recrystallized unchanged from hot water. The neu­ tralization equivalent was found to-be quite variable; values from 262 to 297 were obtained on the same sample. It appeared that the length of time taken for the titration may affect the result.

This would indicate that XXXIII is not a single sub­ stance. Using the same line of reasoning as was applied in the previous reaction, it may be shown that XXXIII A i is probably the principle constituent, especially in view

1. Again assuming that no rearrangement took place. 45 . of the similarity of the infrared spectrogram of XXXIII and the pyrolysis"product^XXXI^of the triamide.

If XXXIII was treated with thionyl chloride and sub­ limed, a crystalline compound, XXXIV, was obtained which

it was assumed, in spite of a low chlorine analysis (Found:

01=13.2^; Calculated for G^H^q O^NOI, 01=16.4^),, to be the acid chloride corresponding to XXXIII. Support for this assumption was obtained as follows : :

The infrared spectrogram of XXXIV showed the appear­

ance of a second strong carbonyl band at 5 * 6 ^ in addition to the one, found in both XXXIII and XXXI, at 5«8-6 . 1 ^ •

An acid chloride band falls about 5*6y*. . XXXIV did not

liberate iodine from potassium iodide, indicating that the

chlorine was not attached to the nitrogen. On boiling with water, XXXIII was obtained.

When XXXIV was treated with ammonia and the product

sublimed, XXXI was obtained.

These data indicate that the structures of XXXI and

XXXIII are quite similar, and that XXXIV is the acid chloride

derived from XXXIII. The reactions carried out are outlined

below using the structures which have been postulated. 46

CONH^ 1 P

\ ^ î E r CH COCl

If the structure shown for XXXIV is correct, it might

seem surprising that dehydrohalogenation did not occur to give VIII. Two explanations may be given.

COCl

+hc _ mo lecul arExamination of.molecularmolecularExamination model of XXXIII shows that

the trans-position of the carboxyl group involves an equa­

torial bond, which is more stable. Consequently, even though

XXXIII formed from the cis-isomer of VII, it should be ex­

pected, to isoraerize readily under the conditions of the 47 reaction to give the more stable (trans) configuration of the

carboxyl group. Conversion to the corresponding acid chloride,

XXXIV, should not change this configuration, and in this

position intramolecular dehydrohalogenation could not occur.

The other explanation would be the difficulty that is known in the preparation of an amide on a bridgehead. It has been pointed out^ that' the triamide structure itself could

probably be prepared, but whether this amide could exist on

a bridgehead has not been determined. The results of this P work, in agreeing with those of previous workers, would

indicate that such a structure is not readily formed.

The Configuration of 1,3.5-Cvclohexane Dérivâtives

The following series of 1,3,5-cyclohexane derivatives

has been prepared in this work and the configuration of these

isomers has been shown to be the s a m e . 3

l,3,5-06Hg(00oH)3 ;2M*..i,3,5.0gHg(CO2CH,)i^l,3,5-C5Hq- VII m.p. 215-218® . IV m.p.^48-49®-^p.^48-49®-' ^ (CHoOH),(CH%0 V m.p. 101-102®

1,3,5-OgH (CHpOSOgCH^)_ XIX ra.è. 126.8-127.4®

1. Page 20. 2. Lukes, R., Collection Czechoslov. Chem. Comm..10. 148 (1938): Topper, Y.J., Ph.D. Thesis, Harvard (1946); Fawcett, F.S., Ohem., Rev.,42» 219 (1950). 3i The reactions outlined above are all known to involve no change in configuration of the er-carbon atoms. 48 Since equilibration of the isomeric forms of VII, m.p. 215-

218°, is known to have occurred in Its preparation from

IV,^ it seems reasonable that this isomer is the most stable

of the pair. If this is the case, the conversion to the

amide would hardly be expected to change the configuration

so that the acid chloride and the amide may be assumed to be of the same configuration as VII, m.p. 215-218°, l,3,5-0gHg(0Q2H)^— *.l,3,5-OgHg(0001)^— *.l,3,5-OgHg(OONHg)^ VII m.p. 215-218° XXXV XXIX m.p., 287.5- 288.5° For the same reasons, the preparation of derivatives of VII

(viaeXXXV) by Fuson and McKeever^ and by Van der Zanden

and DeVries^ should have provided the most stable isomer.

In each case only the high-melting isomer of the pair was

obtained; the lov/-melting isomer was prepared by other means.

It would appear, therefore, that VII is the high-melting iso­ mer of its pair. In the cases where the configuration of 1,3,5-cyclohex-

ane derivatives is definitely established and the data re­

garding solubility is also given,^ the high-melting isomer

has been of the cis configuration and has been the least

1. . Only one form of VII is obtained upon hydrolysis of the isomeric mixture of IV.. 2. This work is outlined on page 26. 3. This work is outlined on page 27* 4. Table II, p. 30. 49 soluble. All work on 1,3^5-cyclohexane derivatives has shown the cis configuration to be the most stable.^

For the compounds prepared in this work, the solid iso­ mer of each that was obtained was easily purified by recrys­ tallization. This would suggest that they are the least

soluble of the pair.

Therefore, for the reasons given above, it seems likely that Î :

1.) VII, m.p. 215-218°, is the high-melting isomer of its pair, and consequently,

2.) VII, m.p. 215-218°, and the other compounds which have been related to it structurally,^ are of the cis config­ uration.

The failure in this work to obtain tricyclic systems

from the various cyclohexane derivatives prepared does not necessarily refute the conclusion that their configuration

is cis.^ An integral part of the discussion of this con-

1. Hassel, 0., Research, 504 (1950); Barton, D. H. R. and Rosenfelder, W. J., J. Ohem. Soc., (1951) 1048; & ref, given therein; :& Reference 4, p. 30. 2. Pages 47 and 48. 3. The following discussion must be limited to the prepar­ ation of VI from XIX since no isomerization would occur under the reaction conditions. If isomerization occurs, an alternate explanation of the failure of the reaction is possible (comjpare page 46). For this reason the at­ tempted preparation of VIII, under conditions that allow isomerization^cannot be used as an argument. 50 figuration is the assumption that the substituents in the ois-isomer would be bound by equatorial bonds; thus the mole­ cule must be roughly planar if this is true. Such a mole­ cule, E, must.

however, change to the polar form, P, in order to form a tricyclic system. Although this intraconversion is known to occur easily,^ the necessity of its occurring before a tricyclic system may be formed constitutes a possible ex­ planation of the failure to obtain VI from XIX. It was shown that XIX was very unstable to heat; presumably olefin formation occured. If then, the isomer must convert to the less stable polar fora, P, before VI may be formed, it stands to reason that the olefin formation may become important as a competing reaction.

In addition to the attempts described above to establish the configuration of these derivatives, their infrared spectro­ grams were compared with those of cis-1,3»5-trimethyl cyclo-

1. Hassel, 0., Research, 504 (1950). 51 hexane (LI)^ and trane-1,3>5-trlmethyl cyclohexane (LII)^.

No conclusions could be drawn from this comparison.

9 c H;

CH

1. Bowers, C. E,, M. S. Thesis,. Ohio State University (1949) 52 EXPERIMENTAL SECTION^

Preparation of Trimesic acid, XXIV

In the best of several experiments, carried out essen­ tially by the procedure of earlier workers,^ 60g. (69.4 ml., 0.50 moles) of mesitylene, Ig. of solid potassium hy­ droxide, and 1200-1500 ml. of water were placed into a two- liter Morton flask equipped with a high-speed stirrer. The contents were heated to reflux, and then, while stirring very rapidly,^ 474g. (2.00 moles) of potassium permanganate was added portionwise over a seven-hour period, waiting after each addition until the pink color was discharged (ca hour) before adding more permanganate. The mixture was heated for thirty minutes after the final addition until no pink color remained and then filtered to remove manganese dioxide, which was washed with hot water. The filtrate and washings were extracted three times with ethyl ether to recover unreacted

1. (a) All melting points are corrected for stem exposure unless otherwise noted* (b) Microanalyses reported in this work were carried out by the operator designated by letter as follows ; (G) Galbraith - Microanalytical Laboratories, Knoxville, Tenn. (K) Klotz -, Ohio State University*. (r ) Renoll - Ohio State University. (c) Infrared spectrograms and X-ray powder photographs are given in Appendix A and B, respectively* 2. Fusco, R*, Palazzo, G., Chiavarelli, S., and Bovet, D*, Gazz. chira. ital*, %8, 511 (1948)* 3* Ullmann, F., & Uzbachian, J. B., Ber., 1799 (1903)* 4* The stirring motor used was rated at 10,000 rpm at 115 volts. A setting of 40-50 volts on a Powerstatt was used, 53 mesitylene. This ether layer was dried and distilled, giving lO.Og. {17%ï of a colorless oil boiling at 158-162°.^ The water layer was boiled to remove traces of ether, then acidified while hot with concentrated hydrochloric arid (d=lyl8). A voluminous white precipitate first formed, which on further acidification past the change of Congo-

Red paper became a white," powdery solid.

The precipitate which first formed on partial acidification of the reaction after oxidation is presumed to be complex potassium salts of tri­ mesic acid. If this precipitate was collected and dried, it was quite insoluble in methanol, but upon addition of sulfuric acid, the major portion dissolved. The material remaining was quite soluble in water and was presumed to be inorganic salts. If the acidification was car­ ried well past the color change of Congo-Red pa­ per, a powdery precipitate formed, the major portion of which was soluble in methanol. The yield was corrected to allow for the insoluble material.

The solution was cooled to 5°0. and filtered, the solid was washed with cold water, and after drying weighed 62.2g.

Extraction of the filtrate and washings with ether gave an additional 2.5g. of material. The precipitate, thought to contain some inorganic salts, was stirred with ten times its weight of hot^dry methanol which contained ten ml. of concen­ trated sulfuric acid.

The insoluble material when removed and dried amounted

1. Bowers, C. E., M. S. Thesis, Ohjo State University (1949) gives a boiling point of 164.64 for mesitylene. 54 to 15.2g, of a solid which was very soluble in water, and appeared to be an inorganic substance. By the difference in weight, there was 47«0g, of methanol-soluble material, which, when combined with the 2,56» of material from the ether extraction, amounts to a 4?^ yield or 56^ conversion, calculated for trimesic acid. Because of the inconveniently high melting point of trimesic acid (ca 375°), this material was not purified but used as such in the next step.

Preparation of Trimethyl trimesate. XXXVI

The methanol solutions obtained above of the oxidized product of mesitylene were used for estérification. In the best of several experiments, one liter of methyl alcohol con­ taining 91.5g. (0.436 moles based on trimesic acid, XXIV) • of soluble material and twenty ml. of concentrated sulfuric acid was refluxed eighteen hours, with the condensate passing through a Sohlet extractor filled with calcium oxide. During the reaction, the solution deposited white crystals, and on cooling, a mass of crystals separated. The solution was filtered and the crystals were dissolved in ether.

The filtrate was poured into one liter of water, made basic with 50^ sodium hydroxide, and extracted with ether, which was combined with the other ether solution. This solu­ tion was washed once with 10^ sodium bicarbonate and three times with water; it was dried and the ether removed, giving

88g. (80^ yield) of white needles, which after one recrystalli­ zation from methanol melted at 144-146°. 55 Further purification was carried out as outlined below.

The filtrate, after extraction with ether, and the sodium bicarbonate washings of the ether solution were combined and condensed to 600 ml. Acidification with concentrated hydrochloric acid, and working up as in the previous reaction gave 18.6g, (20^) recovered acid which was soluble in methyl alcohol.

It is known that uvitinic acid (5-methyl isophthalic acid) is formed in the oxidation of mesitylene.^ Since Van der Zanden obtained a relatively large amount (27%) of low boiling material, which on hydrolysis gave uvitinic acid, from the reduction of trimethyl trimesate, it was thought that some, of this acid might have been present (as the di­ methyl ester) as an impurity. In the present work, reduction of unpurified trimethyl trimesate yielded a low-boiling fraction which upon hydrolysis gave white crystals that, after one recrystallization, melted (uncorrected) at 285-288°, had a neutrali­ zation equivalent of 91^2 and 92.5, and were assum­ ed to be uvitinic acid. The large amounts of low-boiling material obtained by Van der Zanden could also have been caused by reduction of ester groups in addition to, or instead of, the benzene ring. Fusbn obtained only 8^ low-boiling material upon reduction of recrystallized trimethyl trimes­ ate. He used a temperature of 175° while Van der . Zanden records 175-200°. In the present work, using trimethyl trimesate which had been distilled and- then recrystallized twice, a temperature of 175° was used and between 3»7^ and 8.7^ of low-

1. Beilsteins Handbuch der Organischen Ohemie, Edward Bro­ thers, Inc.,Ann Arbor, Mich. (1942), Vol. £, p. 864; gives the melting point of 290-1°, (NE-90), for uvitinic acid.

J! 56 boiling material was obtained.^

Purification of Trimethyl Trimesate. XXXVI

Crude trimethyl trimesate, 132g., obtained as outlined above but not recrystallized, was distilled at 0.05 mm., bath 240-250°, from a modified Olaisen flask. The boiling point was not taken since it was necessary to heat the sides of the flask. All the material distilled. Two recrystalli­ zations from methanol gave 115g. of white needles, melting point 145*0-146.0°^. Condensation of the mother liquor gave additional crops melting slightly lower; the second crop melted at 144.0-145*8°.,

Preparation of Trimethyl 1,3.5-Cyclohexanetricarboxylate, n In the best of several experiments, trimethyl trimesate, melting point 145*0-146.0°, 133s* (0.448 moles), was placed with 400 ml. of dry, peroxide-free dioxane^ and one teaspoon- ful of Raney-nickel into a one-liter, stainless-steel bomb.

After sealing and flushing out the bomb, hydrogen was added to 1850 p.s.i. and the bomb heated, while shaking to 175°

1. Two low-boiling fractions were obtained boiling, at 0.05 mm., at 90-127°, (4.0g., 3*7^), and at 127-131°, (5*3S*, 5*0^), respectively. Since the boiling point of , trimethyl 1,3,5-cyclohexanetricarboxylate was 131-134 under the same conditions, the second fraction is assumed not to be entirely low-boiling material. 2. Fuson, R, C. and McKeever, C . H., J. Am. Chem. Soc., 6 2 . 2088 (1 9 4 0 ); reports melting point 144-145°* 3 . Fieser, L. F. Experiments in Organic Chemistry. Part II, D. C . Heath and Co., New York, N. Y., 1941, p. 36 9 . 57; in one hour* ^The pressure rose to 1890 p.s.i. during the first forty-five minutes, then dropped to 16OO p.s.i. in the next 15 minutes and to 1550 p.s.i. in the next 20 minutes,

(Final theoretical pressure - I6OO p.s.i.). Shaking was

stopped, and the bomb was cooled overnight. Final pressure was 450 p.s.i..

The contents of the bomb were diluted with acetone, filtered, and the solvents removed. Fairly rapid distilla­ tion of the yellow oil at 0.05 mm. from a modified Olaisen flask gave lllg. (96% calculated for trimethyl 1,3,5-cyclo- hexanetricarboxylate) of a water-white oil boiling at 115-

166°, mainly^l55-l66^, bath^ 1^0-203°, which partially solidi­

fied on standing. Redistillation of this oil through a ten cm., helice-

packed column at 0.05 mm., bath^206-210°, gave the following

fractions: (1) 4.0g., boiling at 90-127°; (2) 5*3s«» boil­

ing at 127-131°; (3) 90.7g., boiling at 131-134°; Residue 7.0g. All fractions deposited crystals on standing; frac­

tion 3 became almost solid.

Separation of Isomers of Trimethyl 1.3.5-Ovclohexanetricar­

boxylate. IV

"""'(I " In the. best of several experiments, 33*3s« of a reduc­

tion mixture corresponding to fraction 3 above, was recrys­

tallized three times from dry ethyl ether by cooling a solu­

tion slowly in a dry-ice-acetone bath, and gave 20.6g. (62^) 58

of solid Isomer of IV, melti^ point 48.0-49.0°.^ By conden­

sation of the mother liquors, and cooling, additional crops

could be obtained.

Preparation of 1.3,5-Trls(hydroxymethyl)cyclohexane, V

The usual method^ of lithium aluminum hydride reduc­

tion of esters was used, on both the solid Isomer^ Part A,

and the Isomeric mixture,' Part B, of trlmethyl 1,3i5-cyclo­

hexanetricarboxylate, IV.

Part A. Into a slurry of 8.25g. (0,217 moles, 25^ excess)

of lithium aluminum hydride In 410 ml,°^dry ether In a one-

liter, 3-necked, round-bottom flask equipped with reflux con­

denser, stirrer, and dropping funnel, was added, while stlr- ji ring, 30.Og. (0.116 moles) of trlmethyl 1,3,5-cyclohexane-

trIcarboxylate, IV, melting point 48.0-49.0°, In 325 ml»of

ether, at such a rate as to maintain gentle refluxIng. After

completing the addition, which took two hours, the solution,

from which a white complex had precipitated, was stirred

four hours at room temperature. Fifty ml, of water was

added slowly to decompose the complex and any unreacted

hydride, followed by sufficient 10^ sulfuric acid (800 ml.)

1. Van der % and en, J. M. and DeVries, Q-., Rec, trav, chlm., 67, 998 (1948), obtained èj, solids melting In various ranges between 43 and 47°.. i ! 2, Brown, W, G-., In Organic Reactions, Vol. VI, John Wiley & Sons, Inc., New York, N. Y., 1951, P* 469. 59 to dissolve the aluminum salts. The water layer was saturated with sodium chloride and continuously extracted with ether, giving the following fractions;

Fraction Hrs. extrac.beyond Material obtained after previous fraction passing through AlgO

1 20 3*0g.. yellow oil

2 34 3«0g. oily-yellow-white solid 3 90 5.2g. oily-yellow-white solid 4 72 1.6g. yellow-white solid

5 276 1.6g. yellow-white solid

6 312 0.2g. yellow oil

Each ether fraction was diluted with methanol to dissolve

any material which had separated, and the solution passed

through a column of activated alumina. The solvents were

removed, and the remaining material was evacuated to 0.1 mm.,

overnight. The total of 14.6g. represents a 72^ yield calcu­

lated for 1,3,5-tris(hydroxymethyl)cyclohexane, V.

A portion of the combined fractions 3, 4, and 5 was

recrystallized for analysis three times from acetone and

gave white rods, melting point 101.0-102.0°. Analysis (G-) ;

Found; 0-62.1^ H-10.6^

Calculated for OgH^'gO^; : 0-62.0^ H-10.4^

Certain difficulties were encountered in this reaction.

The first few runs gave V as an oil which could not be crys­

tallized. It was later shown, by refluxing this oil with

10^ sodium hydroxide and extracting the solutions with ether,

that V, which was originally an oil, could be obtained as a 61 then 19.0g. (64.4^), Two reoryetalllzatlons from acetone of a portion afforded pure material, melting point 101-102°..

Attempted Preparation of 1,3.5“*Tris(bromomethyl)cyclohexane,^

I This preparation was attempted several times and the runs which gave the most conclusive results are reported.

In each case, crude alcohol, V, having the purity of Frac­ tion 1, page 59 was used.

1,3,5-Tris(hydroxymethyl)cyclohexane, V, 2.5s» (0.0144 moles), was placed in 75 ml. of 48^ hydrobromic acid and refluxed, removing the water formed through a 10 cm, column..

After ten minutes a dark oil separated from the solution; refluxing was continued overnight until only azeotrope was obtained in the distillate, where a very small quantity of clear oil appeared as a second phase.

The solution was cooled and then extracted three times with benzene-ether, which dissolved the oil that had separat­ ed.. The organic layers,were combined and washed with water,

10^ sodium hydroxide, water, 10^ hydrochloric acid, three

times with water, three times with saturated sodium chloride

solution, passed through sodium sulfate, and the solvents

removed. Distillation of the residue at 0.1 mm. gave 1.56*-

1. The method is that used in the preparation of bromides, Kamm, 0. and Marvel, C. S., in Organic Syntheses. Col­ lected Vol. I, John Wiley & Sons, Inc., New York, N. Y., 1941, pp. 25-35. 62

(32^ for ) of a yellow oil, boiling at 105-122°, mainly at 112-113°, bath temperature 160-170°. The sample was redistilled for analysis under the same conditions, and four fractions were taken, but the amount of material was too small to give an accurate boiling point. Some decompo­ sition was noticed during each distillation. Analysis of one of the middle fractions gave (K) :

Found: 0-41.6^ H-5.1^ and of the other^ : r

Found: Br-59.3^

Calculated for 0_,H B r _ : 0-38.3^, H-5.0^, Br-56.7^ y 14 d Since it appeared from these results that dehydration or dehydrobromination had occurred during the reaction, the experiment was repeated without distillation of the product.

Three grams of alcohol reacted as above and gave l.Og. of orange oil on removal of the ether solution. This oil was recrystallized twice from petroleum ether (b.p. 65-110°) by cooling in a dry-ice-acetohe bath. The low-melting solid obtained was analyzed for bromine; Found; Br-57.64^ (R),

Preparation of the Tris(methanesulfonate) of 1.3.5-Tris(hy- droxymethyl ) cyclohexane. XIX

1, This analysis was carried out by hydrogenating the oil in 30 ml. of absolute ethanol containing one gram of potassium and one gram of pal 1 adiumj*calcium carbonate catalyst, then diluting with water, acidifying, and add­ ing silver nitrate. The precipitate was dried and weighed as silver bromide. 63

Using a known procedure^ the tris-methanesulfonate ester of 1,3»5-tris(hydroxymethyl)cyclohexane was prepared several times, and the best of these runs is reported.

1,3»5-Tris(hydroxymethyl)cyclohexane, V, m.p. 101-102°,

2.10g. (0.012 moles), was dissolved in 25 ml. of pyridine, which had been dried over barium oxide and filtered, and the solution cooled to -5° while protected from moisture with a drying tube. To this solution was added in one por­ tion, 3»1 ml. (0.040 moles, 10^ excess) of comraerôial methane- sulfonyl chloride that had been cooled to 0°. The solution was swirled occasionally, and allowed to stand for three hours at -5°« Crystals began to deposit after about five minutes, and the solution turned light yellow. It was poured into one hundred ml. of cold, 10^ sulfuric acid, and the solid that separated was extracted in about 600 ml. of cold chloroform. This solution was washed two times with water, one time with^sodium hydroxide, two times with water, one time with!^sulfuricA acid, ^ five times with water, one time with(s*ulfuric acid, ten times with water, one time with saturated sodium chloride, was passed through sodium sulfate, and the chloroform was removed with an air stream at room temperature giving 4.6g. (93*4^) of a yellow solid. This

1. Tipson, R. S., J. Org. Ohem., £, 235 (1944). 64 was dissolved in acetone and passed through a column of activated charcoal, (Norit A), and the acetone removed at room temperature with an air stream, giving 4.4g. (89.3^) of white crystals, m.p. 125.5-126.5°. Two recrystallizations, carried out by dissolving in acetone at room temperature, adding ether until just cloudy, and cooling to 0°, afforded crystals melting at 126.8-127.4°.. Analyzed (G-) {:

Found:; 0-35.5^ H-5.9^ 8-23»5^ Calculated for : 0-35.3^ H-5.9^ 8-23.6^ It was found that better yields and a purer product were obtained by maintaining the reaction at -3° to -5*^» In addition, in working up the reaction, the chloroform solu­ tion had to be washed very thoroughly to remove all traces of pyridine.

The trisulfonate, XIX, was quite unstable to heat. If a pure sample was dissolved in acetone at room temperature, a clear, water-white solution resulted. If this solution was heated to reflux, as might be done to recrystallize, it turned light yellow. A sample recrystallized twice in this manner from acetone-petroleum ether (b.p. 65-69°); softened at 125-126° and melted at 126-127°. Analysis (G):

Found : 0-34.0^ H-5.8^ S-24.8^

Calculated for C-35.3^ H-5.9^ 8-23»6^ 65 Attempted Preparation of 1-Azatrlcyolo(3,3 . ) decane.

VI

The conditions for alkylation of amines with raethane- sulfonate esters used by Reynolds^ were duplicated insofar as the nature of the reaction allowed. In the best of three runs, 35s* (O.O865 moles) of slightly impure tris(methane- sulfonate) of 1,3,5-tris(hydroxyrnethyl)cyclohexane, XIX, m.p. 108-118° on rapid heating, was placed in a 1750 ml. steel bomb with 500 ml. dry dioxane.^ After flushing the bocnb three times with dry nitrogen, ammonia was added to l'8QVpySr4V and the bomb sealed. On shaking and.Btà n d d n g ' ight the pressure dropped to 25 p.s.i.

The bomb'was heated slowly to 85° and held there overnight whilb the^^^ sure, 60 p.s.i., showed no change. The bomb was cooled, ammonia added to 80 p.s.i.,” the bomb resealed, and heated at 95° for 24 hours; the. pressure rose to 150 p.s.i. then dropped to 120 p.s.i. The bomb was cooled, final pressure 40 p.s.i., and, opened; the contents were poured into water, which was made acid with 10^ sulfuric acid and steam distilled to remove the dioxane. The water solution was made strongly basic with 40^ potassium hydroxide and steam distilled until the distillate, which was collected in

1. Reynolds, D. D. and Kenyon, W. 0., J. Am. Chem. Soc.,72.. 1597 (1950). 2. Fieser, L. F. Experiments in Organic Chemistry, Part II, D. C. Heath and Co., New York, N . Y ., 1941, p. 369. 66 excess 10% hydrochloric acid, was no longer basic. The water was removed by an air stream, while heating on a water bath at 45-50°. The yellow white solid thus obtained was dried in vacuo over phosphoric anhydride. It was stirred with dry acetone two times to remove some colored material, then three times with dry chloroform. On evaporation of the acetone, a small amount of gummy residue was obtained.

Removal of the chloroform solution gave 0.42g. (2»8% yield) of a white, crystalline solid. One recrystallization from ethanol-toluene afforded white crystals, XXVII, having an identical X-ray powder photograph v/ith a similar product,

XXXVII, from a previous run which had been analyzed (G-) :

Found: 0-62.1%H-X9*l% N-8.1,8.1%

Calculated for G^H^gNOl : 0-62.2^H-9.3^ N-8.1^ XXVII sublimed readily at atmospheric pressure when heated to 180-200®. Identical samples sealed in melting point tubes and heated together in a block melted (uncorr.) after darkening and some charring at 445-450° and at 460- 0 465 ^ respectively . Other similar samples melted in ranges

from 408 to 470°. Thus, the size of the melting point tube,

the amount of sample, and the position of sealing of the tube

appeared to affect the melting point. Powder photographs were therefore used instead to establish identity. 60 solid. This indicates that appreciable amounts of unreacted ester were present. The ether solutions obtained from extraction of the reduction mixture were diluted with methanol and passed through alumina, in order to remove any acid which may have been extracted, before removing the solvents. If this pre­ caution were not followed; the material that resulted was darker. The continuous extraction referred to above which was used to work up the reduction mixture was found to func­ tion much more efficiently if the aqueous layer was first saturated with sodium sulfate.

Part B. , The procedure of Part A was followed, using 14.5g.

(0.385 moles, 50^ excess) of lithium aluminum hydride in

700 ml. ether, to which v/as added 43»8g., (O.I7 moles) of trimethyl 1,3,5-oyclohexanetricarboxylate, (Fraction 3, page 57» boiling at 131-4°/0.1mm.) .in 400 ml.^ether. Work­ ing up as before gave a total of 32.5g* of material on 560 hours of extraction. (Theoretical: 29.5s* of *^9^18^3 * These fractions were recrystallized once from acetone; and gave 8.4g. of crystals melting between 97 and 100°. The mother liquors were combined and after removing all solvent, the material was boiled with 200 ml. of 10^ sodium hydroxide for 2 hours. This solution was cooled, saturated with sodium chloride, continuoMy extracted with ether for a total of

315 ^ours, and gave 10.6g. of solid, melting between 95 and

100°. The total yield of this slightly impure isomer is 67 Sinoe, by analogy to quinuclidine^ and adaraantane,^ l-azatricyclo(3,3,l,l^»'^)decane, VI, should be stable to

alkaline potassium permanganate, O.lg. of XXVII was added

to a large excess of potassium permanganate dissolved in

10^ potassium hydroxide* The color of the solution immedi­

ately turned from purple to green, and a brown precipitate

formed. Sufficient potassium permanganate solution was

added to restore the purple color, and the solution was heat­

ed slowly to boiling and refluxed one hour. It was then steam

distilled, collecting the distillate in excess hydrochloric

acid. Removal of solvent from the distillate gave less

than five mg. of a white solid, XXXVIII^which by its powder

photograph, was shown to be ammonium chloride.

Although XXVII showed no definite double-bond absorption

in the infra-red, the above oxidation indicated that unsatu­

ration was present. Therefore, 0.08g. (0.46 millimoles)

of XXVII was placed in dry chloroform and a solution of

bromine in tetrachloride dropped in. The first drops were

declorized rapidly, but the addition was continued until

the bromine color remained after standing a few minutes.

The solvents were removed with an air-stream, the orange

1, Lttffler, K. and Stiezel, F., Ber., 42, 124 (1909). 2. Prelog, V. and Seiwerth, R., Ber..74B. 1644 (1941). 69

(OgHj^^N)*.HGl + HBr --- + HOI a few milligrams of XXVII were dissolved in, 48^ hydrobromic acid and the solvent removed by an air stream. The solid was recrystallized from acetone-benzene with a small amount of methanol added, and gave cube-like crystals, XXXIX, which showed an identical powder photograph to that of XXVII A.

Preparation of 1.3.5-0vclohexanetricarboxvlic Acid. VII

Following the methods of previous, workers^»20.5g.

(0.0795 moles) of trimethyl 1,3»5-cyclohexanetricarboxylate,

IV, (Fraction 3, page 57» the isomeric mixture) was refluxed with 150 ml. 10^ sodium hydroxide until all the oil dissolved.

The solution was concentrated to, 125 ml., strongly acidified with concentrated sulfuric acid and saturated with sodium sulfate, causing a white precipitate to form. Oontihuous ether extraction for twelve hours of this mixture caused the precipitate to dissolve, and gave, on removal of the ether, iB.Og. (93^ calculated for GgHg(002H)^*liH20^) of a white, powdery solid; m.p. : pulls away at 205-8°, melts at 208-213°. Three recrystallizations from acetone-benzene gave white needles, which pulled away at 210-15° and melted at 215-218°^.

1. Fuson, R. 0. and McKee ver, C. H., J. Am. Chem. Soa, 6 2 .

2088 (1940).

2, Van der Zanden, J. M. and DeVries, G., Rec. trav. chim.,

67. 998 (1948); this m.p. is given 216-18° for pure material. 68 solid remaining was taken up in a small quanity of absolute ethyl alcohol and precipitated by addition of excess petro­ leum ether (b.p. 90-97°)• The yellow solid thus obtained was washed with a small quanity of acetone, which removed the yellow color, giving white crystals.

These crystals were dissolved in hot acetone. On boil­ ing, the solution turned light yellow and smelled slightly of acid. It was filtered, apd the acetone allowed to evapor- I' ate slowly at room temperature. Two definite white crystal^ forms were deposited: XXVI13^ long needles, fairly soluble in acetone, and XXVII A, small cube-like crystals; rather insoluble in acetone. These two forms were mechanically separated and each washed with cold acetone, dried, and analyzed. XXVIII: 20.3 mg. (15^ yield calculated on the analysis below.) m.p.: darkens slightly at 200°, melts (with decom­ position) at 204-206°. Analysis (G-) :

Found: 0-37.4^ H-5.2^ Br-52.9^

Calculated for OgH^^^NBr^: 0-36.4^ H-5*l^ Br-53«8^ XXVII A: 14.7 mg. (15^ yield calculated on the analysis

below.) m.p.: darkens slightly up to 380°, unmelted at

400° (uncorr.). Analysis (G):

Found : : C-48.8^ H-7.0^ Br-36.7^

Calculated for C^H^gNBr:: C-49.5^ H-7.4^ Br-36.6^

In order to demonstrate that XXVII A was the hydrobromide

formed by replacement of chloride in the starting material, 70 RelatlIve GonfIguratlon of 1.3.5-Gyclohexanetrloarboxyllc

Acldj VII

sl,3,5-0yclohexanetricarboxyllc aoid, VII, m.p.: pulls away at 210-15°, melts at 215-18°, 1.30g. (6.0 m. moles caloiilated for the dry acid) was added portionwise to a large excess of diazomethane in ether^ solution at 5°« The solu­ tion was allowed to warm to room temperature overnight, then the solvent was removed by an air stream and the remaining solid evacuated. This solid was dissolved in ether, and the solution washed successively with 10^ sodium hydroxide, two times with water, two times with 10^ hydrochloric acid, three times with water, one time with saturated sodium chloride, was passed through anhydrous sodium sulfate, and the ether removed". The yellow solid obtained was evacuated for a short time, amounted to 1.22g. (79^)> and melted at 43-47°* It was distilled at 0.01 mm. to give, on cooling the distillate, l.lOg. {11%) of a white solid, m.p. 46-48.8°, which on one recrystallization from ether at -80° gave fine needles that melted at 48.0-49.0 . A 50-50 admixture of.these needles and the solid isomer of trimethyl 1,3,5-cyclohexanetricarbox­ ylate, IV, m.p. 48.0-49*0°, showed no depression of melting point.

1. Prepared as Arndt, F. in Organic Syntheses,Goil., Vol. II John Wiley & Sons, Inc., New York, N. Y., 1943, P* 166^ but not dried. 71 Preparation of the Trlamide of 1.3,5~Gyolohexanetricarboxvlic

A d d . XXIX

A portion of the acid, VII, obtained in the previous reaction was used without recrystallization, after drying in vacuMin over phosphorus pent^oxide, following the method of Fuson.^ Into 90 ml. (a large excess) of thionyl chloride was added portionwise with shaking, 7 .6g. (0.033 moles) of the above acid, and the solution allowed to stand overnight at room temperature. It was then refluxed three hours, and the excess thionyl chloride removed la vacunh with a water aspirator, and dry benzene added. This solution was added

slowly with stirring to concentrated (28^) ammonium hydroxide, and the resulting mixture cooled to 0°, and filtered. The precipitate was washed with cold water, and recrystallized from boiling water, giving 1.64g. (23^ yield, 51^ conversion) of white crystals which on fairly slow heating softened and darkened at 283*5° and melted with decomposition at 288-291°*

Condensation of the mother liquor from the recrystallization gave a second crop of tan crystals. A portion of the first

crop, recrystallized from water for analysis, softened and darkened at 283*5° and melted with decomposition at 287*5-

288*5° on very slow heating*. Analyzed (G) :

Found: 0-50.5^ H-7*0^ N-19*8^

Calculated for : C-5Ô* H-7*l^ N-19*7^

1* Reference 1, p. 69* 72 This material was practically insoluble in the usual organic solvents, and very slightly soluble in cold water.

The filtrate and washing from the reaction with ammonium hydroxide were concentrated, acidified, saturated with sodium sulfate, and continuously extracted with ether for two days.

By removal of the ether and drying 3*4g. (45^) of a white solid was obtained which softened at 208° and melted at 210-

212°.and was therefore assumed to be starting material, VII.

Pyrolysis of Triamide of 1.3.5-Oyolohexanetrioarboxylic Acid. '

XXIX

The triamide of. 1,3,5*cyclohexanetricarboxylic acid, XXIXj'

1.24g. (5.82 m. moles) (from first crop page 71) was placed in a sublimination apparatus and heated slowly in a Wood's-

Metal bath to 250 at atmospneric pressure. A: very small amount of liquid collected on the cold finger and was v/iped off. The temperature was raised slowly to 205°, causing the solid to turn dark and melt, and a white solid to sublime slowly. The odor of ammonia was strong; and small amounts of liquid collected above the solid on the cold finger during the pyrolysis which took about six hours. During this time various fractions were collected which melted, after evac­ uation over phosphorus pent ox ids, in approximately 20 degree ranges between 210 and 240° and totaled O.Blg. (78^ calcu­ lated for OgH^gNgOg).

This material was boiled with absolute ethyl alcohol 73 but proved rather insoluble, and the alcohol was removed.

Two reorystalligations from acetone afforded white crystals,

XXXI, which softened at 230-1°, melted with darkening at 239-

43°: Analysis (G)î:

Found: 0-^60.3^ H-5.3^ N-15.<

Calculated for G^^QNgOg : : O-iôO.T^ H-5.7^ N-I5 . A portion of these crystals was dissolved in hot water and boiled about five minutes but the solution remained neu­ tral to litmus. On cooling, crystals were deposited which were recrystallized from boiling water, giving white crystals,

XL,, whose melting point and powder photograph were identical to those of the analytical sample.

Pyrolysis of Triammonium 1,3» 5-Cyolohexanetricarboxylate,

XXX

l,3»5-0yclohexanetricarboxylic acid, VII, 1.28g. (5.9 m. moles calculated for the dried acid), was placed in 5 ml.

(about a 5 mole excess) of concentrated ammonium hydroxide and heated slowly on a Wood's metal bath. Water and ammonia came off at first, and then from 270 to 300° a white solid, m.p.: softened at 190-220°, melted with decomposition at

230-50°, rapid heating, sublimed from the dark melt. A portion of this solid was recrystallized two times from ethyl ' ' alcohol-toluene for analysis; m.p.; darkens and pulls away at 220-240°, softens and darkens at 240-244°, melts with decomposition at 244-247°, XXXIII.. 75 crystals were recrystallized from hot water and gave crystals,

XLIIli softening at 225-231°, melting at 231-244°. Their powder photograph v/as identical with the analytical sample from the first experiment, XXXIII.

The neutralization equivalent of the remainder of XLII was taken using phenolphthalein as an indicator. Addition of a portion of base prodùced an immediate change to pink, which slowly faded on standing. By extending the total time of titration to about one hour, a lower average value of the neutralization equivalent was obtained ; : Ml. 0.1004 N Approx. Number Weight of sample sodium hydroxide req. N.E. Time

1 0.0998g. 3.52 282 i hr,.

2 0.10l6g. 3.40 297 i hr. :

3 0.3139s. 11.00 284 iv hr.; . 4 0.3720g. 14.13 262 1 hr.

Molecular weight of * 197,.

The remainder,of XLI not recrystallized above was re- . acted with thionyl chloride. Thus, 3.0g. (0.0152 moles) was added portionwise-to-50"mlv „(a “lairge excess) of thionyl : ", 'o ° ° chloride and the solution allowed to.stand two days. It was, then warmed on a water bath at 50° for one day, and the ex­ cess thionyl chloride removed with a water aspirator. The tan solid, XLIV, remaining softened at 150° and melted at

159-65°; 0.25s* (7*6^ calculated for O^H^qO^NCI) was removed and reacted as below. 74 Analysis .(G-) î

Pound: G-55.59^ H-5.70^ N-7.07^

Oalculated for G^H^^O^N: G-54.82^ H-5 .62^ N-7.10^ After about half of the material had sublimed, a 0.1 mm. vacuan was pulled, and caused almost all of the remaining material to sublime rapidly. A total of 0.9g. (78^ calcu­ lated for O H 0 N) of sublimate was obtained. The portion 9 11 if not recrystallized above was resublimed at 1 mm. heating bath to 230°, giving white crystals which softened at 200-

228°, and melted at 228-251° on rapid heating. About one- fourth of the material did not resublime but remained as a yellow oil.

The sublimate was soluble in the lower alcohols and water - a solution in the latter solvent gave an acidic re- action to litmus - and was relatively insoluble in benzene, ether, petroleum ether, and acetone at room temperature.

This experiment was repeated using 10.77S» (0.0498 moles) of 1,3,5-oyclohexanetricarboxylic acid, VII. The reaction and resublimâtion were both carried out at atmospheric pressure and gave 6.6g. (67^) of white powder, XLI, which softened and melted with decomposition from 190 to 245° on rapid heat-

Ins. , A portion of this product, 3»2g., was dissolved in ethyl alcohol and boiled about one hour, then recrystallized using benzene. The crystals, XLII, softened at 225-235°, and melted with decomposition at 235-247°• A portion of these 76 The remainder of the m^erial was redissolved in thionyl chloride, refluxed a short time and the liquid removed as before. The solid remaining was sublimed at 35 mm., bathifvnp.

180-190°, to give O*65go (20^) of white crystalline solid,

XXXIV, which melted between I70 and 180° on rapid heating.

The material remaining in the sublimation apparatus melted, turned dark, and bubbled and did not all sublime.

XXXIV did not liberate carbon dioxide from 10^ sodium bicarbonate, nor iodine from potassium iodide solution.

Qualitative analysis showed nitrogen and halogen present, sulfur absent. Although it was assumed to be slightly im­ pure, quantitative analysis for halogen was carried out (R)$.

Found : 01-13*2^

Oalculated for C^Hj^QO^NOU : 01-16.4^

XLIV, 0.25g«, was added to 50 ml. of dry benzene that had been saturated with ammonia, and the solid stirred and allowed to stand about one hour. The solvent was removed with an air stream, and the solid remaining was sublimed at

35 mm., heating the bath slowly to 270°. Practically all the material sublimed.

The sublimate, XLV,, was partially dissolved in acetone

and the mixture was filtered. The crystals, XLVI, were wash- i ed with water, acetone, and ether, and after drying softened

at 250-260°, melted with decomposition at 260-266°. The material in the acetone filtrate, which did not include the 77 wash solutions, was recrystallized using benzene. The crys­ tals, XLVII, softened at 210-226°, and melted with decom­ position at 226-244^. The infra-red spectrogram showed weak, but definite absorption in the 4.4-4.6^ range indicative of a cyanide group.

This experiment was repeated using 0 .27g. of XXXIV.

This was dissolved in dry ' chloroform which had been satur­ ated with ammonia and allowed to stand about one hour. Not all the solid dissolved. The solution was filtered to re­ move the suspended solid, then the solvent removed with an air/stream. The solid obtained was sublimed ’ at atmospheric pressure, heating the bath slowly” to .280°, and gave 0 .05g. . of white crystals which were recrystailized from acetone- benzene. The crystals, XLVIII, softened and darkened at

255-250°, and melted with decomposition at 260-5°«

The mother liquor from the recrystallization was evap­ orated to dryness giving a small quantity of tan crystals,

XLIX. which softened at 200-205° and melted at 207-220°.

Their powder photograph and infra-red spectrogram were almost iü^dentical with those of XXXI.

Reaction of XXXIV with Water

XXXIV, O.lOg., was boiled with water, filtered, and evaporated to dryness with an air stream. The solid, L, on rapid heating softened at 190°, melted at 200-205°« The powder photograph was almost identical with XXXIII. 78 SIMÆARY

The preparation of certain analogs (VI, VIII) of ada­

mant ane, III, by a new route from 1,3,5-cyclohexane deriva­

tives has been attempted, ndt only,to obtain these analogs

but also to establish the configuration of the series of

cyclohexane derivatives. The reactions shown in Table III

were carried out but failed to give the analogs desired; .

A solid isomer of each monocyclic cyclohexane deriva­

tive shown was isolated and the configuration of these iso­

mers was proved to be the same for VII, IV, V, and XEC.

'Evidence is presented that the solid isomer of XXIX is also

of. this configuration, which is postulated to be cis.

The structures of the products, XXVII, XXXI, and XXXIII, i'.’>thà'b were obtained in the attempts to prepare the analog , .

of adamantane have been elucidated, and explanations of .

their formation have been suggested. 79 Table III

m u

C H ^ O H fiO^O^CH

HL 1 3®V O-

c p co

m n

» tONHg 80 APPENDIX A

During tlie period of this research the Baird Infrared

Spec.tromether was adjusted, which caused a small shift of wavelength in certain of the spectrograms, (ca 0 ,lyu)»

However, this creates little difficulty in interpretation since the relative positions of the absorption bands remains about the same.

Spectrograms are arranged in order of number. Except for LI and LII, which were taken on the pure liquids, the spectrograms shown were taken on Nujol mulls of the solid. /vy./ WAVE NUMBERS IN CM-' WAVE NUMBERS IN CM-' 900 ■ : '...BOO. 5000 4000 2000 ISPO 1400 I I I I

31

-oo i

It 5 6 7 12 ■ 13 WAVE LBI6TH IN WK»tONS WAVE LB46TH IN KOCRONS lÜtelllIiMl

WAVE NUMBERS IN CM-< WAVE NUMBERS IN CM-> 625 5000 4000 3000 2500 2000 1500 1400 1300 1200 1100 1000 900 MO 100 100

WAVE IB46TH IN MICRONS WAVE LB4&TH IN MICRONS PERCENT TRANSMITTANCE N

Ul

E l

Il 11

!iül

liii I

tmiii

il!

PERCENT TRANSMITTANCE m m m

WAVE NUMBERS IN CM-i WAVS NUMBBtS IN CM-> 5000 «MO 3000 2500 . , 2000 * 1500 1400 1300 - 1200 I I I ' i -iii n

E M M f

r r t m M 5 6 7 12 .13' 14 WAVE La<6TH IN MICRONS WAVE LB4GTH IN kUCRONS WAVE NUMBERS IN CM-' WAVE NUMBERS IN CM-i 5000 4000 3000 2500 2000 1500 1400 1300 1200 1100 lOOO 900 800 100 100

20 '

WAVE IB I6 T H IN MICRONS w a v e l b is t h in m ic r o n s PERCENT TRANSMITTANCE

K»

s*

# m ü? g y: •«

PERCENT TRANSMITTANCE

<9S a L

WAVE NUMBBtS IN CM-> WAVE NUMBERS IN CM-' 5000 4000 3900 2500 2000 1500 1400 1300 1200 1000 900 «00 625 I I I I I I I I I 1,1 1.1 .1 100 100

W- rï

WAVE LENGTH M MKXONS WAVE LENGTH IN MICRONS î

WAVE NUMBERS IN CKf' WAVE NUMBERS IN CM-' 5000 4000 3000 2500 2000 1500 1400 1300 1200 11.00 1000 900 800

m

Î 3

5 6 7 12 13- WAVE IB46TH M MKXONS WAVE LENGTH IN MICRONS WAVE NUMBERS IN CM-' WAVE NUMBERS IN CM-< 625 5000 4000 aim 2000 1500 1400 1300 1200 1100 1000 900 800 lool I . * ‘ too

■80-

tc î-t

WAVE IB4GTH IN MICRONS WAVE LBieTH IN MICRONS

• 1 WAVE NUMBBtS IN CM-* WAVE NUMBERS IN CM-< 5000 4000 3000 2500 2 (m 1500 1400 1300' 1200 900 000

5 6 7 I I 12 13 WAVE U m e p i IN MICRONS WAVE im G TH IN MICRONS

cP. o,.'

.. PERCENT TRANSMITTANCE

-I

zAxanss

—V * „ fî o - Cî. ••.♦•••• *

N É S H 3 T PERCENT TRANSMITTANCE /t Wav# Numb#» m cm

•o ,r W«v# Ungfh in ^Æcront 94 ' APPENDIX B

The powder photographs were taken using a camera of

57,3 mm. diameter and Oug emission of 1.54 A°. Exposures were for to 1 hour, as noted on the print, by ^ or 1.

I- 95 Ammonium chloride

F,^.14 Wav# Numbew m cm

Wav# Length In M crons IIAXX 96 VIIAXX

1 6 99 © XXXI

%. 100

XXXIII (5 101

XXXVII

/=“/

O • o

0.0 Lr/ S_,. ' ' c' » o _ .• oo ^ o o 0 o ■■■ « ’■• 0 0 . ■■ o.' o ° - % * o. ?.f" *4" ° 9 « O o o ■ o e » 0 .0 *

l / p

IIIAXX

86 _

@ 102

XXXVIII 103 XXX DC 104

XL

©

@ 105 *

© 0 106 O LE) X L IX

108 AUTOBIOGRAPHY I, Hannan Smith Lowrie, was born in Soochow, China,

June 30, 1926. I received the major part of my secondary school education in the public schools of the city of Bowl­ ing Green, Ohio. My undergraduate training was begun at the University of Notre Dame and completed at The Ohio Stale

University, from which I received the degree of Bachelor of

Science in 1948. While completing the requirements for the degree of Doctor of Philosophy at The Ohio State University,

I acted as an Assistant in The Department of Chemistry from

1948 to 1951, and held the Cincinnati Chemical Works Fellow­

ship from 1951 to 1952..