A STUDYOF THE SYNTHESISAND REACTIONS OF NKW POLYNUCLEARAROMATIC ACIDS ANDRELATED COMPOUNDS

by . Edward James Greenwood, B.S., M.S.

Thesis submitted to the Graduate Faculty of the Virginia Polytechnic Institute in candidacy for the degree of

DOCTOROF PHILOSOPHY in Chemistry

APPROVED:

Chainnan, Dr. F. A. Vingiello

Dr. L. K. Brice, Jr. Dr. P. E. Field

Dr. J. G. Mason Dr. J. F. Wolfe

February, 1966 Blacksburg, Virginia -2-

TO PATAND DEBBIE -3-

ACKNOWLEDGEMENTS

The author wishes to express his sincere and earnest appreciation to Dr. Frank A. Vingiello for his guidance and encouragement throughout the course of this work. Thanks are also extended to the other faculty members and to fellow graduate students for their valuable assistance. Particular appreciation is due to Mr. Thomas Greenwood who performed elemental analyses on six compounds prepared in this work. Financial assistance received in the form of a part-time instructorship from Virginia Polytechnic Institute and a research fellowship from the National Institutes of Health is gratefully acknowledged. Finally, the author wishes to express his appreciation of the help and encouragement provided by his wife which was essential to the successful completion of this work. -4-

TABLEOF CONTENTS Page

I. INTRODUCTION• • • • • • • • • • • • • • • • • 8

II. NOiwlliNCLATURE• • • • • ...... 12 III. HISTORICAL ...... • • • • • 14 IV. DISCUSSIONOF RESULTS. . • • • • • • . . . • • 29 A. Preparation of Starting Materials • • • JO

1. l-Bromo-3-chloronaphthalene • • • • JO 2. 2-(J-Chloro-l-naphthyl- methyl)bromobenzene •••••••• 32 B. The Unequivocal Synthesis of

Dibenzo[hi,l]chrysen-9-one •••• • • • 47 1. 2-(J-Chloro-l-naphthylmethyl)- 2'-carboxybenzophenone and 6-chloro-7-(2-carboxyphenyl)-

benz[a)anthracene ••. • • • • • • . 47 2. 14-Chlorodibenzo[hi,l]- chrysen-9-one •••.•.••••• 52 J. Dibenzo[hi,l]chrysen-9-one ••••• 56 C. The Synthesis of Naphtho[J,2,1-fg]-

naphthacen-9-one ••••••••• • • • 59 1. 2-(3-Chloro-l-naphthylmethyl)- benzophenone and 6-chloro-7-

phenylbenz[a]anthracene •• • • • • 59 -5-

TABLEOF CONTENTS(Cont.) Page

2. 2-()-Cyano-l-naphthylmethyl)- benzophenone and 6-cyano-7- phenylbenz[a]anthracene •••••• 69 ). Naphtho(),2,1-fg]naphthacen-

9-one •••••••••••• • • • 70 D. The Synthesis of Phenalo[2,),4,5-

defg]naphthacene-4,8-quinone ••• • • • 74

E. Infrared Spectral Interpretations • • • 78 F. The Partial Resolution of 7-(2-

carboxyphenyl)benz[a]anthracene • • • • 82

v. EXP~RIMENTAL••••••••••••• • • • • 89

VI. SUMMARY.• • • • • • • .' . • • • • • • • • • • 124 VII. APPENDIX • • • • • • • • • • • • • • · • • • • 130

VIII. LITERATUR.I!;CITED • • • • • • • • • ••.•••• 148

IX. VITA •••••• . . . • • • • • • • • • • • • • 157 -6-

TABLEOF SPECTRAIN APPENDIX Infrared Page Spectra

1. 2-{J-Chloro-1-naphthylmethyl)bromobenzene • • • 131

2. 2-Bromophenyl 3-chloro-1-naphthyl ketone •• • • 131

3. 2-Bromophenyl-1-(3-chloronaphthyl)carbinol. • • 132 4. 2-{J-Chloro-1-naphthylmethyl)-2'-

carboxybenzophenone • • • • • • • • • • • • • • 132 5. 2-{J-Chloro-1-naphthylmethyl)-2'- carbomethoxybenzophenone • • • • • • • • • • • • 133 6. 6-Chloro-7-(2-carboxyphenyl)- benz[a]anthracene ••••••••••••••• 133 7. 6-Chloro-7-(2-carbomethoxyphenyl)-

benz[a]anthracene • • • • • • • • • • • • • • • 134

8. 14-Chlorodibenzo[hi,l]chrysen-9-one •••• • • 134

9. 14-Chloro-9H-dibenzo[hi,l]chrysene ••••• • • 135

10. Dibenzo[hi,l]chrysen-9-one ••••••• • • • • 135

11. 2-{3-Chloro-1-naphthylmethyl)benzophenone • • • 136

12. 6-Chloro-7-phenylbenz[a]anthracene •• • • • • • 136

13. Dibenzo[a,l]pyrene ••••••••••• • • • • 137

14. 2-(3-Cyano-l-naphthylmethyl)benzophenone • • • • 137

15. 6-Cyano-7-phenylbenz[a]anthracene • • • • • • • 138

16. Naphtho[3,2,l-fg]naphthacen-9-one • o • e • • • 138 17. 6-Cyano-7-(2-carboxyphenyl)benz[a]anthracene •• 139

18. Phenalo[2,J,4,5-defg]naphthacene-4,8-quinone • • 139 -7-

TABLt OF SP~CTRAIN APPENDIX(Cont.) Ultraviolet-Visible Page Spectra 1. 6-Chloro-7-(2-carboxyphenyl)-

benz[a]anthracene • • • • • • • • • • • • • • 140 2. 6-Chloro-7-(2-carbomethoxyphenyl)-

benz[a]anthracene • • • • • • • • • • • • • • 140

J. 14-Chlorodibenzo[hi,l]chrysen-9-one • • • • • 141

4. 14-Chlorodibenzo[hi,l]chrysen-9-one • • • • • 141

5. 14-Chloro-9H-dibenzo[hi,l]chrysene. • • • • • 142

6. 14-Chloro-9H-dibenzo[hi,l]chrysene. • • • • • 142

1. Dibenzo[hi,l]chrysen-9-one. • • • • • • • • • 143

s. Dibenzo[hi,l]chrysen-9-one. • • • • • • • • • 143 9. 6-Chloro-7-phenylbenz[a]anthracene •• • • • • 144 10. Dibenzo[a,l]pyrene •••. • •••• • • . .. • • 144 11. 6-Cyano-7-phenylbenz[a]anthracene • • • • • • 145

12. Naphtho[J,2,l-fg]naphthacen-9-one • • • • • • 145 13. Naphtho[J,2,l-fg]naphthacen-9-one ...... 146 14. 6-Cyano-7-(2-carboxyphenyl)-

benz[a]anthracene • • • • • • • • • • • • • • 146 15. Phenalo[2,3,4,5-defg]naphthacene-

4,8-quinone • • • • • • • • • • • •••••• 147 16. Phenalo[2,J,4,5-defg]naphthacene-

4,$-quinone 0 8 0 0 8 I I 8 I • I • .. • .. 8 .• 147 -8-

INTRODUCTION -9-

INTRODUCTION

It is now well established that many polynuclear aromatic compounds possess a measurable degree of physiological activity. However, only limited deductions have been made regarding the correlation of molecular structure with degree of biological activity. This is complicated by the fact that certain polycyclic systems substituted with different groups show extreme differences in biological activity, i.e., 7,12-dimethylbenz[a]- anthracene1 is a potent carcinogen, and 7-phenylbenz[a]- anthracene 2 is an anti-tumor agent. In order to gain further insight into the relation of structure and mechanism of physiological activity, a significant amount of work has been done on the synthesis of polynuclear aromatic compounds to be used for biological testing. At the same time much has been learned about the unique chemical properties of these compounds and the study of· their synthesis has made a definite contribution to the field of organic chemistry. Recently, in This Laboratory 3 , this author synthesized 7-(2-carboxyphenyl)benz[a]anthracene (1) *

*This compound, NSC #76322, has recently been tested and has shown activity against Sarcoma-180.4 -10-

which underwent cyclodehydration to give either dibenzo[hi,l]chrysen-9-one (2) or naphtho[J,2,l-fg]- naphthacen-9-one (l) on treatment with polyphosphoric acid. Only one product was recovered and was assigned

>

2 1 l

structure~ on the basis of infrared spectra studies and consideration of electron localization energies and electron densities of the two possible sites of cycliza- tion. -11-

The purpose of this investi~ation is to unequiv- ocally synthesize compounds 2 and land conclusively establish which product resulted from the acid 1. These syntheses as well as that of phenalo[2,J,4,5- defg]naphthacene-4,8-quinone (i) will be discusJed in detail in this dissertation and interesting results and conclusions will be presented. It can be speculated that the acid 1 should behave as other optically active biphenyl compounds with bulky substituents in the positions ortho to the pivot 5 6 bond. ' The resolution of the acid into its enantiomers was studied and a discussion of this will be presented. -12-

NOMENCLATURE -1)-

NOMENCLATURE

The nomenclature presented throughout this thesis is in accordance with the "Definitive Rules for Nomenclature" set forth in the Journal of the American Chemical Society, 82, 5545 (1960). For example:

2 12 1 ) 2

4 3· 10 9

9 g 7 6

Benz[a]anthracene Chrysene

8

10 11 12 l 9 2 6

g ) 5

7 6 5 4 4 )

Naphthacene Phenalone

In this thesis, all rings are aromatic unless otherwise specified. -14-

HISTORICAL -15-

HISTORICAL

Cancer has been known to man for centuries. The first indication that cancer could be due to external 7 factors came in 1775 when Pott observed that a high percentage of chimney sweeps exposed to soot developed scrotal cancer. It was not until 1915 that Yamagiwa and Ichikawa 8 first induced skin tumors in animal~· using coal tar. With the synthesis and testing of . dibenz[a,h]anthracene, Kennaway9 and associates in 1932 first demonstrated that cancer could be induced in animals by a pure chemical. Further experimentation 10 by Cook and Kennaway indicated that many of the more potent carcinogens consist of the benz[a]anthracene ring system with alkyl substituents at either the 7,8,9, or 12 positions. Rea~ons for the high degree of carcinogenicity of these compounds have been attributed in part to the electronic effect 11 of the alkyl substituents, and to their close structural resemblance to steroids. Conversely to the fonner, 12 Badger has found that both electron repelling (methyl) and electron attracting (cyano) groups increase the carcinogenic activity of benz[a]anthracene. -16-

In recent years, there has been a renewal and inten- sification of interest in the study of carcinogenesis. Despite the tremendous effort put forth, all attempts to correlate biological activity with chemical structure have met with only limited success. This is due to the fact that the exact mechanism of carcinogenesis remains a mystery. Many polycyclic aromatic compounds have been found to be tumor inhibiting (carcinostatic) 13 or tumor re d ucing. ( carcino . l ytic . ) • 2,J One such compound is the aromatic acid 1, mentioned in the Introduction. Being an analog of an optically active biphenyl, it exists as a racemate of two optically active forms. It has been observed that the biological activity of a racemic mixture is greatly altered by its resolution into 14 optically active forms. In many cases, one enantiomer was found to be very active while the other isomer was relatively inactive. The acid 1 was partially resolved and a brief review of optical activity due to steric restriction and molecular overcrowding is in order here. I n 1922 , Christie. . an d Kenner 15 resolved 2,2'- dinitrodiphenic acid (2) into a pair of enantiomorphs. -17-

This was the first instance of the resolution of a compound containing no asymmetric carbon atoms. The work was carried out on the suggestion of Kaufler1 6 · in 1907 that biphenyl existed as a folded, clam-shaped molecule.

N02

,) ......

N02 co2H N02 C02H l.... . •, ..L ... ..

This erroneous theory was generally accepted until 1926 when Turner 17, Be1118 , and Mills 19 simultaneously proposed the view that in all biphenyl derivatives, the two benzene rings are coaxial, but in the optically -18-

active ones, the rings are held in approximately perpendicular planes by the repulsions of the ortho substituents.

It then became apparent why 2,2'-diphenic acid(~) was unresolvable, because the two ortho groups are

6 not bulky enough to prevent both rings from easily assuming a planar configuration. Further studies revealed that at least three ortho substituents are necessary for optical isomerism, and the ease of racemization is correlated with the 20 number and size of these substituents. Adams has fonnulated an empirical rule based on substituent -19-

size which can be used to predict whether a given 21 biphenyl can be resolved. Westheimer and Mayer have developed the mathematical theory for the calculation of the activation energy for the racemization of any optically active biphenyl. The first extension of the stereoisomerism of biphenyl was into fused ring systems. Here the attached aromatic rings act as ortho substituents upon the biphenyl system to which they are fused. 22 In 1928, Kuhn resolved the dicarboxylic acids 1 and~.

0

0 1 g

The study has been expanded into substituted phenanthrenes, which are actually rigidly bound biphenyl derivatives. This newer development in molecular asymmetry was first pointed out in 1940 by -20-

23 Newman , and was later demonstrated by his partial 24 25 resolution of acids 2 and 10.

2 10 26 The resolution of hexahelicene (11) by Newman in 1955 was unusual because it was accomplished by complex fonnation and not by the classic acid-base salt formation technique. This compound can be considered to exist as a pair.of right and left handed helices.

ll -21-

Since a major part of the work discussed in this dissertation centers around the preparation of polycyclic derivatives of benzanthrone (12) it is appropriate to present a brief review of the synthesis of benzanthrone and related compounds. Benzanthrone (12) can be prepared by the heating 27 of 1-benzoyl naphthalene with aluminum chloride or by the cyclization of the acid J1. with sulfuric acid. 28

>

12

Mono benzene derivatives of benzanthrone begin with dibenzo[b,i]phenalone (14), which is prepared by the cyclization of 9-benzoyl phenanthrene with aluminum chloridee 29 -22-

Dibenzo[b,j]phenalone (12.) is prepared by the treatment of benzanthraquinone with glycerol and sulfuric acid followed by the loss of three molar 30 equ1.va. 1 ents o f H2o. The isomeric naphtho[l,2-b]- phenalone (16) is also a product of this reaction and

+

16 _j

17 -23-

this compound has been prepared independently by Scholl3l by the cyclization of 1,1'-dinaphthyl ketone (17) with aluminum chloride. Naphtho[2,3-b]phenalone (18) is the result of a series of reactions starting with the unusual condensation of 2-naphthoyl chloride with 1-methyl- naphthalene in the presence of aluminum chloride to give compound .!.2.• This is oxidized to the acid 20

+

12 \V COOH

18 -20 -24-

with barium oxide in boiling nitrobenzene and subsequent decarboxylation with copper-quinoline gives ia.32 When l,l'-dinaphthyl-8,8 1 -dicarboxylic acid is partially cyclized with zinc chloride in acetic acid, the acid 21 is fonned. This can be decarboxylated with copper-quinoline to give the desired naphtho[2,l-b]- phenalone (~). 30

-21 22 Bradsher and Vingiello3 3 have prepared coeranthrone (23) by means of the anhydride synthesis. The Grignard reagent of .- o-bromodiphenylmethane reacts with phthalic anhydride to give keto-acid ~. This can be doubly cyclodehydrated with phosphoric acid to give coeranthrone (~) directly, or £1 can be obtained in two steps by the initial cyclization of~ to the intermediate acid £2 with hydrobromic acid. -25-

HBr ;:> > c=o + c)COOH

CQ ~ 0 \~r04l?-;~ 3P04.

Dibenzo[b,f]phenalone (~) has been prepared by Clar. 34 Benzoyl chloride condenses with octahydro- anthracene and aluminum chloride to give ketone 1:1_. Pyrolysis with copper powder at 400° gives dibenzo- [b,f]phenalene (28) which is oxidized to 26·with selenium dioxide in boiling acetic acid. -26-

-26

An expansion into systems containing six fused rings was made by Vollman35 with the preparation of naphtho[J,2,l-cd]pyren-8-one (29) by the cyclization of 3-benzoyl pyrene with a sodium chloride-aluminum chloride melt. -27-

36 Clar prepared tribenzo[b,f,j]phenalone (l.Q), which is isomeric with compounds~ and l prepared by this author. He employed the aluminum·chloride cyclization of ketone .l! which was prepared by the condensation of benzaldehyde in pyridine with benz- [a]anthrone.

0.CHO

lQ

The symmetrical triangulene-4,8-quinone (B) is of interest due to its similarity to quinone ! (see Introduction). The tritolyl carbinol ll, prepared from the reaction of 2-tolyl chloride with 2-tolyl lithium, is oxidized with hot dilute nitric acid to give the acid~ in small yield. This is cyclized with sulfuric acid.and copper powder to give the hydroxy compound 12, which is easily reduced to triangulenequinone (~).37 -28-

OH

-> I -29-

DISCUSSIONOF RESULTS -30-

DISCUSSIONOF RESULTS

A. Preparation of Starting Materials. 1. 1-Bromo-J-chloronaphthalene. The preparation of 1-bromo-J-chloronaphthalene (!Q) was achieved through a known series of reactions outlined in Chart I, and is a good example of the use of a blocking group (acetamido-) to position substituents in naphthalene. Aceto-1-naphthalide (1§) is obtained commercially and was selectively brominated in the 4-position in 95% yield using the procedure of Hodgson. 38 Chlorination of N-acetyl-4-bromo-l-naph- thylamine (1.Z) was performed by bubbling chlorine gas into a stirred suspension of 'J1.in acetic acid. 39 The product precipitated upon fonnation and was recovered quite pure by filtration in 75% yield. The next step was the hydrolysis of the naphthalide J1!with dilute sulfuric acid. 4-Bromo-2-chloro-l-naphthylamine (,l2) was recovered as tan crystals. The amine 12 was easily reduced to 1-bromo-J-chloronaphthalene (~} by diazotization followed by treatment with ethanol and cuprous oxide. The crude reaction product was chromatographed on acid alumina to remove colored impurities and the product was recovered upon -31-

CHARTI

0 0 ,, II

o5CH3Br o5CHJ 2 > Br ~ n_

Cl2

\!I 0 II NHCCHJ H+ Cl ~ Wc1 H2o Br Br. 12 ~

1 .. HN02 2. EtOH Cu2o \!I

WCl Mg > WCl Br MgBr !Q ll -32-

concentration of the percolate as white crystals in 70% yield. 2. 2-(J-Chloro-l-naphthylmethyl)bromobenzene. The two methods used for the preparation of 2-(J-chloro-l-naphthylmethyl)bromobenzene (46) are outlined in Chart II. The cross condensation reaction between an aryl Grignard reagent and a benzyl halide . 42 was successfully used by Quo and Sheridan. More recently,43,44,45 this reaction has been gainfully applied to other related systems and is the desired route because of higher yields obtained and there is less time and work involved in obtaining the products as compared to other routes. Thus, the preparation

of 2-(J-chloro-l-naphthylmethyl)bromobenzene (lt§.) was first attempted by the reaction of 3-chloro-1-naph- thylmagnesium bromide (41) with 2-bromobenzyl bromide (48). The reaction went smoothly but suffered from a low yield of 24% of J±Q. This was surprising since the Grignard reagent fonned easily

and in good yield 1 and all reagents were pure. This method of synthesis was discontinued because of the unnecessary waste of the difficultly obtainable 1-bromo-J-chloronaphthalene (lt;Q)e The 2-(J-chloro- l-naphthylmethyl}bromobenzene (li£) recovered was -33-

CHARTII

MgBr o::O+ Cl(X) Cl

!±2,X = H,OH 46, X = H2 47, X = 0

+ -34-

crystallized, and was characterized by elemental analysis and its infrared spectrum (see infrared spectrum 1 in the Appendix). The other method of preparation of 46 which was adopted was the reaction of 3-chloro-1-naphthylmagnesium bromide(!!) with 2-bromobenzaldehyde (lilt), followed by the reduction of the carbinol lt.2· Here the product was obtained in an overall yield of about 60%. In the past, 2-bromobenzaldehyde (~) was prepared by two general procedures. The more accessible method involved the chromic acid oxidation of 2-bromotoluene. 46 However, the average yield is about 40%. The second method is more tedious and involves the side chain bromination of 2-bromotoluene, followed by the 47 hydrolysis of the benzal bromide to the aldehyde. Although the yield is about 70%, this process requires several days for completion. 2-Bromobenzaldehyde (44) was prepared by a newer method involving the reaction of 2-nitropropane and 2-bromobenzyl bromide in sodium ethoxide.4 8 By this procedure, the product is obtained in 70% and is very pureo Polss 49 has discussed in detail the unusual mechanism of this reaction. -35-

When 3-chloro-1-naphthylmagnesium bromide(~) was reacted with 2-bromobenzaldehyde (l!Ji) and the product was worked up, only a slight amount of the expected 2-bromophenyl-1-(J-chloronaphthyl)carbinol (~) was recovered. Instead, the majority of the product consisted of a mixture of 2-bromophenyl J-chloro-1-naphthyl ketone (l.tZ) and 2-(J-chloro- l-naphthylmethyl)bromobenzene (46), as determined by the infrared spectrum. This unusual reaction was first observed in This Laboratory by Light 50 with the reaction of 1- and 2-naphthylmagnesium bromide with 2-bromobenzaldehyde. Upon observing the same phenomenon, Delia 51 began an investig~tion of this reaction. He studied the reaction involving 1-bromo- naphthalene, and identified the components of the reaction product as one part methylene compound and four parts ketone with the exclusion of the carbinol. His method of determination was a quantitative study of the infrared spectra of the reaction productso Polss 52 studied this same reaction with the thought that the anomalous products could be formed during hydrolysis of the Grignard complexo He ·subjected four different reactions to hydrolysis with hydrochloric -36-

acid, sodium hydroxide, water, and the inverse procedure of pouring the reaction mixture into hydrochloric acid. In each case, after work-up, the ratio of methylene compound to ketone was about five to one with the complete absence of carbinol. Henson 53 observed in a similar reaction of 2-bromobenzaldehyde with an aryl lithium reagent that a ratio of 5:1 of methylene compound to ketone was obtained with no carbinol present. Likewise, Ojakaar 54 reported that the methylene compound and ketone were present in a 2:1 ratio in the reaction of 2-chlorobenzaldehyde with 2-naphthylmagnesium bromide. It has been observed that in the reaction of substituted benzaldehydes with aryl Grignard reagents, that if the aldehyde is present in any significant excess, then oxidation of that amount of the resultant carbinol to the ketone takes place, and the excess aldehyde is reduced to the corresponding benzyl alcoho1. 55, 56 However, this explanation is not valid because it does not explain the presence of the methylene compound and the very slight amount, if any, of carbinol. -37-

It was noticed by this author that in all previous cases where anomalous products were reported, the reaction product was vacuum distilled. The average boiling point of the products recovered at reduced pressure is about 200°. However, under the conditions of the distillation, the "distillation pot" is heated by a metal bath at 280-300°. Due to the fact that equilibrium conditions of pressure do not exist throughout the system because of inadvertent flooding of the fractionating column by the viscous distillate, the temperature of the contents of the "distillation pot" approach that of the surrounding metal bath. Delia 57 indicated that carbinols of this type are thennally stable, but the actual experiments used were heating of the carbinol in refluxing methanol (bp 64°) and pyridine (bp 115°). In order to test this hypothesis of thermal instability, the carbinol l±.2 was prepared by an independent method. See Chart III. By this route, the ketone 47 could also be prepared and characterized. This was accomplished by the reaction of 2-bromobenzoyl chloride (.2Q) with the / cadmium reagent lt:2.5· This method was used because the cadmium reagent does not react appreciably with -)8-

CHARTIII

MgBr CdC1 Cd ClJ):) 2 > Cl(O 2 Ji! h:2. oC-Cl,0, Br

iQ

Cl

Cl -39-

the newly fonned ketone, and the undesired tertiary alcohol is not produced. This same effect could be achieved by the inverse addition of the Grignard reagent 41 into the acid chloride, but past experience 56 indicated that the ketones produced via the cadmium reagent are purer and are obtained in better yield. A portion of ketone !:J1.was reduced to carbinol lt..2with sodium borohydride using pyridine as the solvent. Fortunately, the carbinol lt.,,2crystallized from methanol, which made purification easy since distillation was undesirable here. Both the ketone l£l. and carbinol lt.2, were characterized by elemental analysis and infrared spectra (see infrared spectra 2 and 3 in the Appendix). By using standard conditions,* the retention times of the methylene compound lt2, ketone !iJ., and carbinol 1t2 upon gas chromatography were determined as 5 min 20 sec, 6 min JO sec, and g min, respectively. By this means, it was determined that the product from the reaction of

*This study was performed on a Micro-Tek 2500R gas chromatograph. The column was 6 ft x 0.25 in. copper tubing packed with 3.5% SE-30 on Gas Chrom z. Column temperature was 200°C. Helium was the carrier gas at a flow of 60 ml/min, and a hydrogen flame detector was used at 245°C. The inlet port was at 230°C, and the sample volume was 6 µl, containing a concentration of 25 mg/ml of sample in acetone. -40-

3-chloro-l-naphthylmagnesium bromide (41) with 2-bromo- benzaldehyde is entirely the carbinol lt2, prior to distillation. During the course of the distillation of this crude reaction product, three well spaced fractions of high boiling product were cut and were analyzed by gas chromatography. The percentage composi- tion of each fraction was determined by a measure of the relative peak areas of the components. This is shown· in Table I.

TABLEI

Distillation Fractions Initial Middle Final %methylene compound l:J&. J.2 47.4 77.6 %ketone l:tJ.. 2.8 21.6 19.0 %carbinol ~ 94.0 Jl.O J.4 methylene/ketone 1.1:1 2.2:l 4.1:1

It is now clear that the carbinol lt.,2 is decom- posing into the other two components during distillation. See Chart IV. All three compounds co-distill and the methylene-ketone ratios are not due to fractionation. In order to determine if this phenomenon was caused by the.catalytic effect of unreacted starting -41-

CHARTIV

Cl lt.2.

+

Cl Cl -42-

materials or byproducts, a study was made on the thermal stability of pure carbinol. Weighed samples of carbinol l±.2.(15 - 28 mg) were heated under nitrogen at different temperatures over varying lengths of time and the resulting residue was dissolved in sufficient acetone to make the concentra- tion of all samples 25 mg/ml. By this means, gas chromatographic analysis was uniform for all samples and also permitted a good determination of the extent of decomposition of the three components into insoluble residues, tars, etc., by comparing their total areas against that of untreated carbinol. The results are summarized in Table II. It can be seen that the formation of methylene compound and ketone from the carbinol 1±2.is temperature dependent. (This is illustrated in Figure I.) However, these data present two problems. When the carbinol was heated at 250°, the methylene-ketone ratio varies from 1:3 to 1:1.l» while upon heating at 300°, the ratio is reversed and is approximately constant at 1.7:1. It is assumed that the reaction proceeds as a disproportiona- tion58 or oxidation-reduction of the carbinol, and the methylene-ketone ratio should be 1:1. One could -43-

TABLEII

Heating carbinol l±.2.at 200°c. 1 hr 3 hrs 5 hrs 18 hrs %methylene cmpd. 46 0 0 0 0 %ketone il 0 0 0 0 % carbinol 1t2 100.0 100.0 100.0 91.8 % decomposition 0 0 o· 8.2

Heating carbinol l±.2at 250°0. l hr 3 hrs 5 hrs 7 hrs %methylene cmpd. !±§. 0 4.0 8.8 31.6 ~~ ketone 47 0 11.6 22.4 35.6 % carbinol l±.2 87.2 · 68.9 49.0 12.4 methylene/ketone 1:2.9 1:2.5 1:1.1 % decomposition 12.8 15.5 19.8 20.4

Heating carbinol ~ at J00°C.

1 hr 3 hrs 5 hrs 7 hrs

%methylene cmpd. ~ 56.8 58.7 56.4 46.0 %ketone l±7. 32.1 34.7 33.9 27.4 % carb inol lt,2 11.1 2.0 0 0 methylene/ketone 1 ..8:l 1.7:1 1.7:1 1.7:1 %decomposition 0 4.6 9~7 26.6 0--0 - METHYLENECOMPOUNO !§_+KETONE 47 8--E] - CAHBINOL45

HEATINGAT 250°C HEATINGAT J00°C 100 100

801 80 I \ / - >Zj H 0 I ~ .;- .,.60[ " 0,060 f V I~ I 40 \/ 40

20 20

O• C 0

1 3 5 7 1 3 5 7 TI ME (hours) Tl ME ( hours) -45-

speculate that at 250° the ketone l£J.decomposes to a lesser degree than the methylene compound 46, and vice versa at 300°, but this assumption is not justified by the present data. The other problem shows up in the percent decomposition or material unaccounted for, for the reactions run at 250° and 300°. After heating the carbinol at 250° for one hour; 12.8% of the original sample is unaccounted for, and no methylene compound or ketone has been fonned. But after heating at 300° for one hour, 100% of the material shows up and methylene compound and ketone are present in good amounts. The same is true at three and five hours, where a consider- ably larger portion of material is unaccounted for at 250° (15.5% and 19.8%) than at 300° (4.6% and 9.7%). This points to the possibility of the formation of a high molecular weight intermediate in the reaction from carbinol to methylene compound/ketone which was not detected in the gas chromatogram due to its inability to move through the column. Delia 59 suggested the formation of an intennediate ether from two molecules of carbinol, since this reaction is common to this type 56 compound. Fortunately, Denk is presently carrying out an extensive study of this anomalous reaction, and -46-

detailed information about the mechanism, intennedi- ates, and product ratios will shortly be forthcoming. One more subject deserves mention before leaving this section. As indicated in Chart II, the method employed for the preparation of the methylene compound I l!§. was the lithium aluminum hydride and aluminum 61 chloride reduction of the mixture of carbinol ~, ketone 47, and methylene compound lt:2• In order to obtain complete reduction of all components to the methylene comppund 46, the reaction necessitated the use of large molar excesses of lithium aluminum hydride and aluminum chloride, as well as the need for running the reduction twice on the same material. This produced an optimum overall yield from the aldehyde and Grignard reagent of 57%. It appeared that the ketone 47 was difficult to reduce. This problem was circumvented by the omission of the distillation of the product of the Grignard reaction. The crude carbinol 1t.2 was then reduced with lithium aluminum hydride and aluminum chloride, and the overall yield from the aldehyde l±f± was 6)%0 -47-

B. The Unequivocal Synthesis of Dibenzo[hi,l]chrysen- 9-one. In order to ascertain if dibenzo[hi,l]chrysen- 9-one (2) is the product of the cyclodehydration of 7-(2-carboxyphenyl)benz[a]anthracene (1) (see the Introduction), as was originally proposed by this author,3 this synthesis was undertaken. The method which was employed involved the use of a chlorine atom for the purpose of blocking in the preparation of 14-chlorodibenzo[hi,l]chrysen-9-one (..2.Z), and this was dehalogenated to give the title compound 2 (see Chart VI). 1. 2-(3-Chloro-l-naphthylmethyl)-2'-carboxybenzo- phenone and 6-chloro-7-(2-carboxyphenyl)benz- [a]anthracene. The synthesis of 2-(3-chloro-l-naphthylmethyl)-

2'-carboxybenzophenone (_2l) and 6-chloro-7-(2-carboxy- phenyl)benz[a]anthracene (.2!!:) is outlined in Chart V. The procedure for the preparation of the keto- acid 22, involves the reaction of phthalic anhydride (~) with the Grignard reagent .21~ The preparation of keto-acids in this manner was first perfonned by Weizmann62 in 1904j and has been used to advantage by -48-

CHARTV

0 11 + C(? II 0 .8 \y -

HBr < HOAc -49-

a number of workers.J,JJ, 63 In this reaction there is the possibility that the intennediate keto-acid salt could react further with the Grignard reagent to give the hydroxy acid as shown below. Although this

0 0 R II II I C-R C-R 1. RMgI;:,. RMgX>(). 'on (:('c/o 2. H20 C-OH II O.C-OMgXII II 0 0 0 possibility is remote due to the fact that the R-group is very bulky, this side reaction was eliminated by always maintaining an excess of the anhydride. This was accomplished by the "inverse- addition" procedure of slowly adding the Grignard reagent to a boiling solution of phthalic anhydride in benzene. The reaction produced the keto-acid .2.l in 52% as pale yellow crystals which melted at 216.5-217°. Its structure was characterized by elemental analysis and its infrared spectrum (see infrared spectrum 4 in the Appendix). The absorption -1 band at 1690-1665 cm is due to the acid and ketone carbonyl groups, and the weaker bands at 2660 and -50-

2550 cm-l are indicative of the carboxylic hydroxyl group absorptions. A methyl ester derivative of the keto-acid 22. was prepared by allowing an acidic solution of 2.l in methanol to reflux for 48 hrs. 2-(3-Chloro-l-naphthyl- methyl)-2'-carbomethoxybenzophenone (.22) was recovered as white crystals melting at 113-113.5°. Its infrared spectrum (see infrared spectrum 5 in the Appendix) -1 shows ester absorption at 1730 and 1300 cm , and the compound gave a good elemental analysis. The method employed for the cyclodehydration of the keto-acid .2.lwas that developed by Bradsher 71 in 1940. Here, treatment of 2,l with a 4:1 mixture of glacial acetic acid and 48% hydrobromic acid under reflux produced 6-chloro-7-(2-carboxyphenyl)benz[a]- anthracene (.2lf:) in good yield. It is interesting to note that a reaction time of 2-1/2 hrs was required· to produce~ quantitatively, wnereas, in the similar preparation of 7-(2-carboxyphenyl)benz[a]anthracene (1), the same high yield was obtained only after one hour reflux. This can be explained by the fact that the chloro substituent on the naphthyl group in .2J.is deactivating the position of cyclization, and thus the lower rate of reaction, since the electrophilic -51-

attack of the intennediate carbonium ion on the naphthyl system has been shown to be a rate deter- 6 . mining step. 4 ,b5 Also it can be reasoned that the steric factor of the chlorine atom thus positioned is responsible for some loss of reactivity. 6-Chloro-7-(2-carboxyphenyl)benz[a)anthracene

(2.!t) was obtained as pale yellow crystals which melted at 247.5-248.5°. A methyl ester derivative of 2!t was prepared by heating to reflux an acidified solution of .2!t in methanol for 74 hrs. 6-Chloro-7-(2-carbo- methoxyphenyl)benz[a]anthracene (_22) was recovered in 87% as yellow plates which melted at 153.5-154.5°. Both the acid 2!t and its ester .22 were characterized in the usual' way* (see infrared spectra 6 and 7, and ultraviolet spectra 1 and 2 in the Appendix).· The acid and ester carbonyl absorptions are present at -1 lo80 and 1725 cm , respectively, and the ultraviolet spectra are typical of benz[a]anthracene derivatives.**

*This refers to characterization by elemental analysis, and infrared and ultraviolet spectra where appropriate. **The absorption maxima for benz[a]anthracene are 222, 227, 254, 267, 280, 290, 316, 329, 344, and 359 mµ, and all such derivatives prepared in this investigation exhibit this characteristic absorption pattern. A slight bathochromic shift is noted, however, which is due to the increased conjugation induced by the substituents. -52-

i · 2. 14-Chlorodibenzo[hi,l]chrysen-9-one. The preparation of 14-chlorodibenzo[hi,l]chrysen-

9-one (.21) was accomplished as shown in Chart VI by either the double cyclodehydration of .2l or the cyclo- dehydration of 2lt• In the past,3,33, 66 polyphosphoric acid has been successfully used as a cyclizing media for aromatic acids and its application here was equally advantageous. In the cyclization of the keto-acid 2.l, treatment with polyphosphoric acid at 220-230° for 10-20 minutes produced 2]_ in an average yield of 50%. The poly- phosphoric acid used was obtained from two sources. It was prepared in the laboratory by addition of phosphorus pentoxide to 85% phosphoric acid until a viscous paste resulted. The other source was the commercially available 115% polyphosphoric acid obtained from the FMCCorporation as a clear viscous liquid. The latter proved to be the ·superior reagent because of the slightly higher yields obtained, which no doubt were due to the more homogeneous nature of the commercially available material. Also the handling and measuring of this material was more convenient. -53-

CHARTVI

HBr ---~HOAc

-2 *Polyphosphoric acid. -54-

The cyclization of il was attempted with liquid · hydrogen fluoride, and the double cyclodehydration product 21. was obtained in only 11%. This was surprising in view of the previous success with hydrogen fluoride in reactions of this type.3, 67 There was a 22% recovery of the intennediate acid .21±, but a majority of the material was unaccounted for. The cyclization of the acid 2!± to 14-chloro- dibenzo[hi,l]chrysen-9-one (2.Z) with polyphosphoric acid was accomplished using similar conditions employed on the keto-acid .2J., and the product 21_ was obtained in a slightly higher yield of 55%. 14-Chlorodibenzo[hi ,l]chrysen-9-one· (.21) was obtained initially as crude red-brown material, but purification was easily accomplished by column . chromatography on either florisil or neutral alumina using benzene as the eluent. Concentration of the percolate gave the pure product as orange feathers, mp 251.5-252.5°. This compound was characterized in the usual way (see infrared spectrum 8 and ultra- violet-visible"' spectra 3 and 4 in the Appendix) •

.* The highly colored compounds prepared in this investigation show appreciable absorption in the visible region (375-900 mp) of the spectrum, and these curves are included. -55-

The carbonyl group exhibits a strong band at 1640 cm-1 in the infrared. To further substantiate the assigned structure, 2]_ was reduced with lithium aluminum hydride and aluminum chloride, as shown in Chart VI. The reduction gave 14-chloro-9H-dibenzo[hi,l]chrysene (~) in 76%, mp 172-174°. The compound was characterized in the usual way (see infrared spectrum 9 and ultraviolet-· visible spectra 5 and 6 in the Appendix). The aliphatic carbon-hydrogen absorption bands at 2800 -1 and 2850 cm are present and the carbonyl band at 1640 cm-1 is absent as expected. The ultraviolet spectrum of -2!!is very similar to that of 6-chloro- 7-(2-carboxyphenyl)benz[a]anthracene (.2!t), with the exception that the former exhibits a bathochromic shift of 15 millimicrons over the latter. This similarity would be expected since-the presence of the CH2 group in .2.f!would cause a decrease in conjugation with the lower phenyl ring, and the electron system would approach that found in the benz[a]anthracene derivative~. -56-

J. Dibenzo[hi,l]chrysen-9-one. Although the need to remove halogen from aromatic compounds does not arise often, it is some- times necessary in a synthetic sequence to remove a halogen atom used for the purpose of blocking a position from reaction. Such was the case here. As is shown in Chart VI, the halogen in 6-chloro-7- (2-carboxyphenyl)benz[a]anthracene {~) pennitted the cyclization of the carboxyl group into only the 8 position of the benz[a]anthracene system. By this means, the dehalogenation of the resulting .21.would produce dibenzo[hi,l]chrysen-9-one (2) unequivocally. The choice of a reagent for the reductive dehalogenation was not easy because of the possi- bility of reaction with the carbonyl group in 21_. Most of the accepted procedures work well for the removal of bromine from polycyclic ring systems, but due to the better overlap of pi-electrons in the carbon-chlorine bond, the chlorine atom is more firmly bound and requires more severe conditions for its removal. Also, the sterically restricted position of the halogen in 21 is somewhat inaccessible to -57-

to attack. This is illustrated by an examination of the Fisher-Taylor-Hirschfelder model. The dehalogenation was attempted with lithium metal, but this failed because of numerous side 68 reactions. A procedure involving the use of palladium charcoal catalyst in p-cymene also failed. Recently, 69 the combination of 85% hydrazine hydrate and 10% palladium on charcoal has been successfully applied to the dehalogenation of haloaromatic compounds. High yields are obtained if the halo- aromatic compound is thus treated in a boiling solution of methyl Cellosolve. * When this procedure was applied to 21., dehalogenation occurred smoothly and dibenzo- [hi,l]chrysen-9-one. (2) was produced in 55%.** Work-up was simplified because the water soluble properties of methyl Cellosolve and hydrazine hydrate permitted their easy removal from the product after the separation of the catalyst.

*Methyl Cellosolve is the commercial name for ethylene glycol monomethyl ether. **Thanks are due to Dr. C. Ke Bradsher for suggesting this dehalogenation procedure. -58-

Dibenzo[hi,l]chrysen-9-one (2) was recovered as red crystals, mp 216-218°. Its infrared and ultra- violet-visible spectra are completely superimposable with those of the product obtained from the cyclode- hydration of 7-(2-carboxyphenyl)benz[a]anthracene (1) (compare infrared spectrum 10 and ultraviolet-visible spectra 7 and 8 with those in ref. 70). Also the compounds agree in color and melting point, and the melting point of the mixture was not depressed.

1 2

It can thus be concluded that the cyclodehydration of l occurs at the g position of the benz[a]anthracene system with the formation of i. This adequately demonstrates the validity of the previous. proposal) as to the position of cyclization. -59-

c. The Synthesis of Naphtho[J,2,l-fg]naphthacen-9-one. l. 2-(3-Chloro-l-naphthylmethyl)benzophenone and 6-chloro-7-phenylbenz[a]anthracene. At the outset, the synthetic procedure devised for the preparation of naphtho[J,2,l-fg]naphthacen- 9-one (l) involved the initial preparation of 2-(3-chloro-l-naphthylmethyl)benzophenone (£.Q) by the reaction of the Grignard reagent .2.!.with benzoyl· chloride (.22) (see Chart VII). In this case, the "inverse-addition" technique of adding the Grignard reagent to the acid chloride was used in order to forego the possibility of tertiary alcohol fonnation from the reaction of excess Grignard reagent with newly formed ketone. The ketone 60 was recovered, after fractional distillation, in 52% as a high boiling, viscous yellow oil. Crystallfzation was impossible until the oil was tediously chromatographed on acid alumina. The resulting colorless oil yielded white crystals melting at 99-100°. This was characterized by its infrared spectrum (see infrared spectrum 11 in the Appendix) and elemental analysis. Before the column chromatography technique of ultra purification was employed, attempts were made to crystallize the -60-

CHARTVII

0 II + oc-ci___ Cl

-61 60 CuCN CuCN

62 -61-

ketone from ethanol. When the ketone was dissolved in ethanol, pale green crystals were noticed in the solution, the amount varying with different runs from 16% to 0% of the weight of ketone. These crystals, which melted at 179-180°, were identified as the cyclized material, 6-chloro-7-phenylbenz[a]anthra- cene (Q1). The compound was characterized in the usual way (see infrared spectrum 12 and ultraviolet spectrum 9 in the Appendix). Polss 72 has also observed in the preparation of ketones from the reaction of Grignard reagents and acid chlorides that a small amount of cyclized material appeared. Although his proposed mechanism of cyclization occurring during the Grignard reaction fits his data, it is not consistent with the experi- mental observations in the preparation of 61. The highest yield (16%) of 61 was observed when the ketone 60 was vacuum distilled twice. The possibility that cyclization occurred during distillation was considered, because cyclodehydration here, although not an usual phenomenon, is certainly plausible at the high temperatures employed. A gas chromatographic -62-

analysis * of the reaction product before and after distillation indicated that this indeed was the case, and the cyclized material 61 did result during the distillation. This was not a very practical method of preparing 61 because of the high loss of ketone 60 by pyrolysis, but unfortunately, it proved to be the only method. The attempted preparation of 61 by more conventional means of cyclizing 60 proved futile. A number of usual cyclizing media which were applied to the ketone 60 without success are as follows: 1) hydrobromic and acetic acids at 110°, 2) hydro- bromic and acetic acids in a sealed tube at 180°, 3) 100% liquid hydrogen fluoride, 4) cold concentrated sulfuric acid, and 5) hydriodic and acetic acids in a sealed tube at 180°. This extreme resistance to cyclization is undoubtedly due to the deactivating effect of the chlorine atom. The electron density of the reaction site is thus lowered sufficiently to

*The instrument used was a Micro-Tek 1600 gas chromatograph. The column was 5 ft x 1/8 in. stain- less steel packed with 5%SE-30 on 60-80 mesh Gas Chrom Z. Column temperature was 290°C. Helium was the carrier gas at a flow of 60 ml/min, and a hydrogen flame detector was used at 300°C~ The inlet port was at J00°C. The retention times of 60 and 61 were 2 min and 4 min, respectively. ~ ~ -63-

prevent the attack of the carbonium ion which is necessary for cyclization. It can be seen that a very active carbonium ion would be required for attack. The possible contribution of the resonance structure 60a would stabilize the carbonium ion, but also lower its reactivity by lowering the positive charge intensity.

H~ Cl V + -60a It is of interest here that the keto-acid 22,, which also contains this deactivating chlorine atom, was quantitatively cyclized under relatively mild condi- tions (see section B.l., Discussion of Results). This can be adequately explained by pointing out that the carboxyl group can facilitate reaction in at least two ways. The possibility of a resonance structure similar -64-

to 60a is greatly diminished because of the very probable existence of the doubly protonated form~. Her~ the protonated carboxyl group lowers the influx

fil of electrons into the carbonium ion involved in cyclization, and this center remains very active toward electrophilic attack. It had previously been observed that pyridyl ketones of this type exhibit a high rate of cyclization, and this has also been attributed to the presence of a di-protonated inter- mediate.40 Also, a physically bonded structure such as 53b is possible, which would greatly stabilize the carbonium ion. When the cyclization of .§.Qwas attempted using more drastic conditions, an unexpected product -65-

resulted. The use of polyphosphoric acid at 240-250° produced 45-55% of an inseparable mixture of compounds and 26-2$% of dibenzo[a,l]pyrene (66). Likewise, the heating of a mixture of 60 and alumina 73 at 250-260° produced about$% of the same mixture and 39% of dibenzo[a,l]pyrene (.2.9.). Column chromatography on

> + mixture

60 66 acid alumina made easy the separation of 66 from the rest of the reaction product. The yellow hydrocarbon, 74 dibenzo[a,l]pyrene, was first prepared by Clar , and the identity of the compound produced from 60 was determined by its color, melting point, elemental analysis, infrared and ultraviolet spectra (compare infrared spectrum 13 and ultraviolet spectrum 10 in the Appendix with those in ref. 75). -66-

The ultraviolet spectrum of the inseparable mixture produced in the reaction indicated a mixture of benz[a]anthracene derivatives. Separation of the components by column chromatography and fractional crystallization proved unsuccessful. A logical proposal is that the mixture was largely composed of 7-phenylbenz[a]anthracene and a very small amount of the 6-chloro derivative 61. This is supported by the mixture's melting range, a weakly positive Beilstein test, its infrared spectrum, and gas chromatography (the mixture gives one peak, and pure 7-phenylbenz[a]anthracene and 61 have equal retention times on the column used). At the high 76 temperatures employed, alumina has been reported to remove halogen, and it has been found by this author that polyphosphoric acid was slightly effective in the dehalogenation of !2J..(see section B.J., Discussion of Results). The formation of 66 from ketone 60 requires a mechanism involving a rearrangement with the loss of one molecule each of water and hydrogen chloride. It is likely that the reaction is initiated by the -67-

loss of chlorine from 60. The following mechanism involving the intermediates 21. and 68 was considered.

60 68

-H 2 66t

This scheme was discarded because neither 67 nor~ gave 66 when treated on alumina under the * 77,78 same conditions as ketone 60. Also, Borkovec had previously reported a similar treatment of 67 and 68 with no formation of 66. These facts have led to the proposed mechanism shown in Chart VIII. The initial step of this

*It should be pointed out that Clar41 success- fully prepared 66 by treatment of 68 with aluminum cnloride in benzene. -- -68-

CHAI-lTVIII

-Cl

60

-H2 0

66 -69-

mechanism involves a rearrangement in naphthalene from an ~lpha to a beta position after loss of chlorine. This is not uncommon in compounds of this type, when 19 heated to high temperatures. Cook has observed a similar rearrangement upon the heating of 2-methyl- 1,1'-dinaphthoyl ketone. l-Benzyl-2-methylnaphthalene hcts also been reported to rearrange upon distillation 80. with zinc dust. This proposed mechanism provides for the preliminary formation of ketone .§2, which should immediately cyclodehydrate to 66 under the reaction conditions employed. 2. 2-(3-Cyano-l-naphthylmethyl)benzophenone and 6-Cyano-7-phenylbenz[a]anthracene. The preparation of 2-(3-cyano-l-naphthylmethyl)- benzophenone (62) was accomplished as shown in 81,82 Chart VII, by the improved procedure of allowing the ketone 60 to react with cuprous cyanide in N-methylpyrrolidone. This reaction was somewhat difficult, however, for it was necessary to maintain it for 72 hrs in order to get complete formation of 62. The product was recovered initially as a crude dark oil, and was carefully chromatographed on acid alumina to give 62% of a yellow oil. Vacuum distillation was -70-

avoided. Further purification by chromatography was necessary before crystallization of the oil was achieved. Recrystallization from ethanol gave white needles, mp 119.5-120°. The ketone 62 was characterized in the usual way (see infrared spectrum 14 in the Appendix). As a consequence of the presence of a small amount of 6-chloro-7-phenylbenz[a]anthracene (61) in the starting ketone (see section C.l., Discussion of Results), the reaction with cuprous cyanide produced 6-cyano-7-phenylbenz[a]anthracene (22) amounting to an additional 15% of reaction product. This precipitated as yellow crystals when the total crude reaction product was initially dissolved in ether. Recrystal- lization from benzene gave crystals, mp 259.5-260°. Characterization was made in the usual way (see infrared spectrum 15 and ultraviolet spectrum 11 in the Appendix). J. Naphtho[3,2,l-fg]naphthacen-9-one. Unexpectedly, naphtho[J,2,l-fg]naphthacen-9-one (l) was produced directly from 62 and 21, as shown in Chart IX. Various attempts were made to hydrolyze .§2. to 6-carboxy-7-phenylbenz[a]anthracene (2.!±) in order to gain this intermediate for the preparation of l• The treatment of .§1 with a mixture of hydrobromic and -?1-

CHARTIX

62 -72-

acetic ~cids and heating to reflux for 16-1/2 hrs had no effect. An unsuccessful attempt at alkaline hydrolysis was made by treating 63 with 10% potassium hydroxide in ethanol-water under reflux for 48 hrs. This failure to hydrolyze under usual conditions is attributed to the fact that the cyano group is ~terically hindered. A similar experience was recently reported in This Laboratory. 83 \I.Thenthe hydrolysis of 63 was attempted with a 4:1 mixture of glacial acetic and hydrobromic acids in a sealed tube at 180° for 8 hrs, naphtho[J,2,l-fg]- naphthacen-9-one (l) was produced. Purification necessitated the use of column chromatography with acid alumina, and 3 was recovered in 22% as orange crystals. Since the yield was low, it is logical to assume that the acid 64 was also a product of the reaction, but was trapped on the alumina during work-up. However, 64 was never isolated. The original intention in the treatment of the cyano-ketone ~ with polyphosphoric acid at 250° was to prepare .§1.. Such drastic conditions were deemed necessary, since previous experience with the corres- po~dir.~ chloro-katone 60 indicated that deactivation -73-

of the site of cyclization was significantly large. However, instead of obtaining 63 from the reaction, naphtho[J,2,l-fg]naphthacen-9-one (..l) was produced in 40%, preslli~ably via the intermediate acid 64. The preparation of l from 62 involves the hydrolysis of the cyano group. The use of polyphosphoric acid in

A hydrolysis reaction of this type is somewhat novel, since it is considered a useful dehydrating agent, and the high reaction temperature (250°) is not conducive to hydrolysis in the conventional sense. Stevens 2 has observed the hydrolysis of the cyano group with phenyl acid phosphate, which is closely related to poly- phosphoric acid in that they both consist of poly- phosphates. Undoubtedly, the hydrolysis involves the reaction of the phosphate hydroxyl groups, instead of the usual addition of water.

Naphtho[J,2,l-fg]naphthacen-9-one (..l) was charac- terized in the usual way (see infrared spectrum 16 and ultraviolet-visible spectra 12 and 13 in the Appendix).

*Phenyl acid phosphate is a mixture of mono- and dihydrogen phosphate esters containing varyin~ amounts :;,;' polyphosphates. -74-

Tne melting point of l (215.5-217°) is coincidentially near that of its structural isomer 2 (216-218°).

D. The Synthesis of Phenalo[2,3,4,5-defg]naphthacene- 4,8-quinone. A synthetic route to phenalo[2,3,4,5-defg]- naphthacene-4,8-quinone (4) which was laboriously exploited without success was the attempted oxidation of 7-(2,6-dimethylphenyl)benz[a]anthracene (70) with aqueous sodium dichromate at 250°. This recently devised method 84 ' 85 of oxidation has the advantage

70

of oxidizing methyl groups in high yields without destroying the aromatic system. The dimethyl compound 1.Slwas prepared by a known series of reactions previously reported by Borkovec. 86 , 87 Several attempts at the oxidation of 1Q were made. Although the reaction -75-

variables of time, temperature and quantity of aqueous sodium dichromate were modified, no! or intennediate di-acid 71 resulted. Only starting material J!d was recovered. The successful synthesis of phenalo[2,J,4,5-defg]- naphthacene-4,8-quinone (!) was achieved as shown in Chart X. 6-Chloro-7-(2-carboxyphenyl)benz[a]- anthracene (2lf:) was prepared as previously described (see section B.l., Discussion of Results). The reaction of .2Jt.with cuprous cyanide in N-methyl- pyrrolidone produced 6-cyano-7-(2-carboxyphenyl)- benz[a]anthracene (69) in 45% as yellow crystals, mp 261-263°. The cyano-acid ,22 was characterized by its infrared and ultraviolet spectra (see infrared spectrum 17 and ultraviolet spectrum 14 in the Appendix), but a satisfactory elemental analysis was not obtained. This lack of supporting data was due to the inability to render the compound free of all impurities. Nearly all such reactions with cuprous cyanide produce very dark, cnide reaction products. Purification by column chromatography was useless here because the extreme difficulty in removing the acid from the column necessitated the use of solvents which -76-

CHARTX

CuCN

HBr HOAc 180° \V -77-

inadvertently pulled down other impurities. The other alternative, fractional crystallization, furnished 69 as yellow crystals, but failed to remove other impuri- ties which were co-crystallizing. In all probability, these slight impurities are unreacted starting material and partially hydrolyzed cyano-acid. Phenalo[2,J,4,5-defg]naphthacene-4,8-quinone (~) was produced directly from .§..2in 45% yield by treatment with a 2:1 mixture of glacial acetic acid and 48% hydrobromic acid in a sealed tube at 180° for 4 hrs. This reaction failed when attempted with polyphosphoric acid. This was surprising in view of the success achieved with this reagent in the preparation of l (see section C.J., Discussion of Results). The quinone 4 was purified by column chromatog- raphy and resulted as bright red crystals, mp 340-366° (dee.). The very similar triangulene-4,8-quinone (~), which differs from~ by only one fused ring, was prepared by Clar 37 (see the Historical). It also melts above )00° with decomposition. Characterization of~ was made in the usual way (see infrared spectrum 18 and ultraviolet-visible spectra 15 and 16 in the Appendix). -78-

E. Infrared Spectral Interpretations. The infrared spectra of polynuclear aromatic compounds are complex. The features of primary importance include the carbon-hydrogen stretching -1 vibrations near 3030 cm , the C=C skeletal in-plane vibrations at 1600-1450 cm-l and the strong bands in the 900-690 cm-l range due to out-of-plane carbon- gg hydrogen defonnations. The latter region can be conveniently divided according to the number of adjacent hydrogen atoms on an individual phenyl ring. -1 For this reason, the 900-690 cm region has been extremely useful as an aid in structure identification. A study of the infr~red spectra of the four polycyclic carbonyl compounds 2, l, !, and 5J..was made and the corresponding out-of-plane carbon-hydrogen bending absorption frequencies are listed in Table III. All four compounds exhibit at least one isolated hydrogen atom and all show appropriate absorption in the designated region. The same holds true for the region designated for four adjacent hydrogen atoms. Of the four compounds, only compound l exhibits two adjacent hydrogen atoms, and thus, it alone absorbs at 838 cm-1 • Compound l is the only one without -79-

TABL!!:III OUT-OF-PLANEC-H BENDINGABSORPTIONS CM-l

770-735 610-750 860-800 900-860

755 778 875 745

750 780 838 875 745

2

756 888 741 l

746 770 879 -80-

three adjacent hydrogen atoms, and as a result, l does not exhibit the typical band in this region. This information gives added support to the validity of the structures of the isomeric compounds 2 and l, and it is apparent that one can differentiate between the two by close examination of their infrared spectra. The carbonyl absorption frequencies of compounds 2]_, 2, l, and! are listed in the table below.

frequency cm-l

14-Chlorodibenzo[hi,l)chrysen-9-one (57) 1640 Dibenzo[hi,l]chrysen-9-one (2) 1640 Naphtho[J,2,l-fg)naphthacen-9-one (J.) 1660 Phenalo[2,3,4,5-defg]naphthacene- ·1660 4,8-quinone (4) 1640

It is well known that conjugation with a carbonyl group results in a decrease of the stretching frequency, or bathochromic shift. This is explained by the increased single bond character which requires less

I .1:C, o::;.,-"' -81-

energy for stretching (hence lower frequency). The more extended the conjugation, the greater is the contribution of the single bond type 11:., and thus, the greater the bathochromic shift. As is shown in the above table, the carbonyl group absorption of compound 2 exhibits a noticeable bathochromic shift over that of its isomer l• This can be explained by a consideration of the resonance forms of the compounds involving the single bond type 72. The number of such resonance structures which can be drawn for 2 and l approach. 100 . each, * but only compound 2 exhibits eight resonance struc- tures where the charges are separated by a conjugated system of nine carbon atoms. Compound l has none such structures. Because of this extended conjugation in 2, its carbonyl group would be expected to absorb at a lower frequency (hence a greater bathochromic shift) than that of l•

*According to Dre C. Y. Kramer, Dept. of Statistics, a statistical formula for the determina- tion of the exact number of structures is impossible to derive because the variables which determine the possibilities are not well defined. -82-

As was expected, the quinone ~ exhibits both the carbonyl bands of land lat 1660 and 1640 cm-1 • However, the presence of a band at 1720 cm-1 was unforeseen. This band, although unidentified, has been observed in the infrared spectra of other quinones. *

F. The Partial Resolution of 7-(2-carboxyphenyl)- . benz[a]anthracene. The synthesis of 7-(2-carboxyphenyl)benz[a]- anthracene (1) was carried out via the keto-acid 'Jl., as shown in Chart XI.· A detailed discussion of this synthetic procedure along with characterization of 1 89 and 11 has been presented. The great.majority of optically active compounds owe their activity to the presence of at least one asymmetrically substituted atom. However, with the discovery of certain optically active biphenyl derivatives, a different kind of optical isomerism has come to ·light. The asymmetry here originates from the steric restriction of rotation of

*See Sadtler Standard. Infrared Spectra, Sadtler Research Laboratories, Philadelphia, Nos. 12477 and 13790. -83-

CHARTXI

0 II + ex>8

HBrl HO~

d & l (-) Brucine ;:> salts -84-

unsymmetrically substituted biphenyls. Although the usual graphic representation of biphenyl derivatives does not indicate the magnitude of the steric hindrance, the effect is surprisingly great. In 7-phenylbenz[a]anthracene, steric interference occurs between the hydrogen atoms at the 6 and 8 positions of

the benzanthracene ring system a_nd the ortho positions of the substituted phenyl group. In this way, the assumption of a coplanar configuration is prevented. Jones 90 has calculated that the plane of the phenyl ring cannot approach the plane of the benzanthracene ring system closer than an angle of 57°. This, of course, applies to the rigid model and does not take into account the fact that parts of the system will distort to allow free rotation at elevated temperatures. -85-

The introduction of a carboxyl group into an ortho position of the phenyl ring would be expected to increase the amount of steric hindrance, and also introduce asymmetry resulting in the formation of two enantiomorphic modifications.

COOH HOOC ~ ' I , .>

1 l

The resolution of l was attempted by the forma- tion of d and 1 salts with (-)brucine. The use of cinchonine was also attempted, but no crystalline 91 salts were recovered. Bell has reported in a similar resolution, that brucine is preferred over cinchonine because the former gave a less soluble 92 salt. The procedure of adding an equimolar quantity of brucine to a boiling solution of 1 in ethanol was used. Upon concentration and cooling, one salt crystallized. Several recrystallizations from -86-

ethanol gave a salt with a specific rotation of -10.77°. The elemental analysis indicated a 1:1 brucine-acid salt. Treatment of the brucine salt with dilute hydro- chloric acid liberated the optically active acid. After one re·crystallization from ethanol, the acid had a specific rotation of +18.84°, and melted at 227-228°. A further recrystallization from ethanol produced complete racemization, and the melting point· was lowered to 218-219°. Because the acid racemized fairly easily, it is believed· that maximum resolution was not achieved. The different melting points of the(+) acid and racemic acid pair is common. Instances where the melting point of the racemic mixture is higher than that of the individual enantiomers, and vice versa, 93,94 have been reported. The racemic acid! is polymorphic, and melting points of 199-200° and 218-219° were observed. Only one brucine salt was recovered. The remainder of the material existed as a crude, dark, viscous oil which resisted crystallization and 24 25 . purificatione Newman ' has reported in similar -87-

resolution attempts where the acids easily racemized, that only the salt of the(+) acid was recovered. He also reported similarly low specific rotation values for the acids recovered. Although the fact that the (+) acid 1 easily racemized was disappointing, it was not completely unexpected. Sufficient energy was introduced into the system during recrystallization to enable the carboxyphenyl group to rotate about the pivot bond. Adams2o,95 has f ormu 1 ate d an empi rica · l rue, l based on substituent size, which enables one to make a fairly reliable prediction of the resolvability of any given biphenyl derivative. The acid! was tested by this rule as follows: The distance between the two ortho carbon atoms

0 when the rings are coplanar was estimated to be 2.90 A

The amount of interference to rotation is detennined by the size of the ortho group or atoms. The -88-

measurements of the size of substituents are the internuclear distances from the ortho carbon atoms to the centers of the substituents. Assuming that groups Band C could be considered as methyl groups, 0 0 these distances are: c-cH3 - 1.73 A, C-COOH- 1.56 A, and C-H - 0.94 1. A measure of the ability of the compound to be resolved is defined as the interference ·value, which is obtained according to the equation

dA + dB + de + dn) _ Interference value= ( 2.90 2 where dA, etc. are the internuclear distances. If the interference value is negative, no resolution is to be expected. If the interference value has a small positive value (0.01-0.20), resolution is possible but easy racemization can be predicted. A large positive interference value, indicates that resolution is possible with very difficult racemization predicted. The interference value for the acid l was calculated as +0.08, which indicates resolvability with easy racemization. This gives added support to the experimental observations. -89-

EXPERIMENTAL· -90-

EXPERIMENTALa,b

2-Bromobenzyl bromide(~).

To a solution of 342 g (2.0 moles) of 2-bromo- toluene in 800 ml of anhydrous benzene in a 2-1., )-necked, round bottom flask, was added 5 g of benzoyl peroxide. This was heated to vigorous reflux and a mixture of 356 g (2.0 moles) of N-bromosuccinimide and· 5 g of benzoyl peroxide was added as fast as foaming would allow. After the foaming had subsided, the boiling was continued for one-half hour, and then the solution was allowed to cool to room temperature. After cooling in an ice bath, the precipitated succinimide was filtered by suction and washed with 150 ml of anhydrous benzene. The filtrate was concen- trated and the.fraction distilling at 115-130° (9 mm) [Lit. 60 128-140° (16 mm)] weighed 435.4 g (87%).

aAll melting points were taken on a Fisher-Johns melting point apparatus and are corrected, except the one marked with an asterisk which was taken on a Mel-Temp capillary melting point apparatus and is uncorrected. All boiling points are uncorrected. bAll analyses were performed by Galbraith Laboratories, Inc., Knoxville, Tennessee, except those marked with an asterisk which were perfonned in This Laboratory on a F & M Scientific Corporation, Model 185, C, H, and N analyzer. -91-

2-Bromobenzaldehyde (~). To 2120 ml of.absolute ethanol in a 5-1., )-necked, round bottom flask was added portionwise 40.02 g (1.74 g atoms) of sodium metal with stirring. After all the sodium had reacted, 160 g (1.80 moles) of 2-nitropropane was added, followed by the rapid addition of a solution of 435.4 g (1.74 moles) of 2-bromobenzyl bromide in 700 ml of absolute ethanol. Stirring was continued for 20 hrs. The solid sodium bromide was removed by suction filtration, and the filtrate was concentrated. The resulting oil was dissolved in 800 ml of ether and 600 ml of water. The ether layer was separated and the aqueous layer was washed once with water. The ether solutions were combined and were washed twice with 200 ml portions of 10% sodium hydroxide solution and twice with 200 ml portions of water. The ether solution was dried over magnesium sulfate, concentrated and vacuum distilled. The product boiling at 71-76° (2.0 mm) [Lit. 4g 118-119° (12 mm)] weighed 209.5 g (65%)o

2-(1-Naphthylmethyl)bromobenzene. A Grignard reagent was prepared by the addition of 150.9 g (0.728 mole) of 1-bromonaphthalene in -92-

500 ml of anhydrous ethyl ether to 17.7 g (0.728 g atom) of magnesium in a 2-1., )-necked, round bottom

" flask. A drop of methyl iodide was added to initiate the reaction. After complete addition, the solution was allowed to reflux for 1 hr. The ether was replaced with anhydrous benzene. To this was added a solution of 121.J g (0.486 mole) of 2-bromobenzyl bromide in 250 ml of anhydrous benzene over a period of 1 hr. The solution was heated to reflux for 9 hrs. The · complex was decomposed with 250 ml of 10% hydrochloric acid. The benzene layer was separated, dried over mag- nesium sulfate, and concentrated. The product was collected as a colorless oil boiling at 176-181° (0.1 mm) [Lit. 96 220-223° (2-3 mm)] in a yield of 109.5 g (76%).

N-Acetyl-4-bromo-l-naphthylamine (l.Z).

A solution of 56 g ( O.J02 mole) of. aceto-1- naphthalide in 360 ml of glacial acetic acid in a 1-1. beaker was maintained at 16-20° by an ice bath. Over a period of JO min, 48 g (O.JOO mole) of bromine in 175 ml of glacial acetic acid was added with vigorous stirring. After the addition was complete, the precipitated product was filtered by suction and ' . was washed with glacial acetic acid and water. The -93-

dry crude product weighed 76.3 g (96%). One recrystal- lization from 800 ml of ethanol gave white needles; mp 191-192°, (Lit. 38 mp 193°).

N-Acetyl-4-bromo-2-chloro-l-naphthylamine (J1!). Chlorine gas was bubbled through a stirred suspension of N-acetyl-4-bromo-l-naphthylamine (165 g) (0.625 mole) in 1.4-1. of glacial acetic acid at room temperature for 6 hrs. The mixture became very "thick" and stirring was difficult. The solid was filtered and water was added to the filtrate. The resul ti_ng precipitate was recrystal- lized (charcoal) from ethanol and combined with the residue from the first filtration. The total combined product was recrystallized from 4-1. of 70% ethanol. The product was obtained as white needles; mp . 228-228.5°, (Lit.3 9 mp 231°), yield 16).2 g (87.5%).

4-Bromo-2-chloro-l-naphthylamine (l,2).

A mixture of 165 g (0.553 mole) of N-acetyl-4- bromo-2-chloro-l-naphthylamine, 980 ml of 95% ethanol, 590 ml of water, and 395 ml of concentrated sulfuric acid was stirred and heated to reflux for 14 hrs. After this, 500 ml of water was added and, upon -94-

cooling, a solid precipitated which was filtered. This precipitate was dissolved in ethyl ether and the solution was filtered to remove an insoluble residue. The filtrate was concentrated to dryness on a steam bath, and the resulting product was recrystallized from 1500 ml of 2:1 ethanol-water. This gave 111.3 g (78.4%) of tan needles; mp 112.5-113.5°, (Lit.39. mp 113 °). l-Bromo-3-chloronaphthalene (1!:Q).

4-Bromo-2-chloro-l-naphthylamine (80 g) (0.312 mole) was dissolved in 900 ml of glacial acetic acid and the solution was slowly added to a stirred, freshly prepared solution of sodium nitrite (28 g) in concen- trated sulfuric acid (180 ml) kept below 20° •. The reaction was run in a 2-1. beaker which was cooled by an ice bath. After the addition was complete, stirring was continued for 10 min. The mixture was then added to a stirred suspension of cuprous oxide (84 g) in 720 ml of ethanol in a 4-1. beaker. After evolution of nitrogen had ceased, the mixture was filtered by suction and the residue was washed with 800 ml of boiling ethanol. The filtrate and washings were poured into water and an oil precipitated which -95-

solidified in the refrigerator. This brown solid was separated and dissolved in a minimum amount of n-hexane. The solution was chromatographed on acid alumina. On concentration of the percolate, white crystals precipitated. Recrystallization from acetone-water-methanol gave 59.7 g (79.2%) of white needles; mp 59-60°, (Lit.39 mp 56.5°).

2-Bromobenzoyl chloride (.2Q).

Into a 250 ml, 1-necked, round bottom flask was placed JO g (0.1495 mole) of 2-bromobenzoic acid and 97.S g (0.822 mole) of thionyl chloride. The flask was fitted with a reflux ·condenser, the outlet of which was fitted with a long piece of rubber tubing to which a funnel was attached. The funnel was set just above a beaker of sodium hydroxide solution to trap the escaping sulfur dioxide. The solution was heated to reflux for 5-1/2 hrs. The excess thionyl chloride was removed by vacuum distillation with the aspirator. The residual oil was distilled at 6.5 mm. The product boiling at 119-120° [Lit.97 125° (20 mm)] weighed 29.4 g (89.5%). -96-

2-(3-Chloro-l-naphthylmethyl)bromobenzene (46).

A. A Grignard reagent was prepared by adding 10 g (0.0415 mole) of l-bromo-3-chloronaphthalene in 50 ml of anhydrous ethyl ether to 1.01 g (0.0415 g atom) of magnesium in a 250 ml, 3-necked, round bottom flask. A drop of methyl iodide was added to initiate the reaction. After complete formation, the ether was replaced with anhydrous benzene until the boiling point was 70°. To this hot solution was added rapidly 10 .·4·g (0.0415 mole) of 2-bromobenzyl bromide in 50 ml of anhydrous benzene. The solution was heated to reflux for 8-1/2 hrs •. Upon cooling with an ice bath, the complex was decomposed slowly with 75 ml of 10% hydrochloric acid. The benzene layer was separated, dried over magnesium sulfate, concentrated, and vacuum distilled. The product was collected as_ a colorless oil which boiled at 170-177° (0.03 mm); yield 3.3 g (24%). The oil was crystallized from ethanol as white needles; mp 92.0-92.5°. Anal. Calcd. for C17H12BrCl: C, 61.56; H, J.65; Br, 24.10; Cl, 10069. Found: C, 61.66; H, J.74; Br, 24.12; Cl, 10.52. -97-

B. A Grignard reagent was prepared by adding 50 g (0.208 mole) of 1-bromo-J-chloronaphthalene in 250 ml of anhydrous ethyl ether to 5.1 g (0.208 g atom) of magnesium in a 2-1., 3-necked, round bottom flask. After the addition, the reagent was heated to reflux for 1 hr. To this was added dropwise 38.5 g (0.208 mole) of 2-bromobenzaldehyde in 100 ml of anhydrous ethyl ether. After the addition, the mixture was heated to·reflux for 4 hrs. The complex was decomposed with 50 ml of 20% ammonium chloride solution and 200 ml of 10% hydrochloric acid was added to dissolve magnesium salts. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The resulting oil was shown to be 2-bromophenyl-1- (3-chloronaphthyl)carbinol, which decomposed during distillation into a mixture of 2-(3-chloro-l- naphthylmethyl)bromobenzene and 2-bromophenyl 3-chloro-1-naphthyl ketone (see section A.2., Discussion of Results). In order to avoid this, the resulting oil was not distilled, but was reduced without further purification as described below. To 31.6 g (0.832 mole) of lithium aluminum hydride in a 2-1., 3-necked, round bottom flask with a -98-

mechanical stirrer, dropping funnel, and condenser, was added 200 ml of anhydrous ethyl ether. The system was maintained under nitrogen gas atmosphere. To this stirred slurry was added a solution of 177 g (1.664 moles) of aluminum chloride in 450 ml of anhydrous ether. An additional 250 ml of anhydrous ether was added. To this mixture was slowly added a solution of the above oil in 500 ml of anhydrous ether. The mixture was heated to gentle reflux for 5-1/2 hrs, and the excess lithium aluminum hydride was decomposed by adding 700 ml of ethyl acetate dropwise. The mixture was hydrolyzed by pouring it into cold 15% sulfuric acid and allowing it to remain overnight. The ether layer was separated, washed,once with 5% sodium hydroxide and twice with water. The solution was dried over magnesium sulfate, concentrated and distilled under reduced pressure. The product was collected as a colorless oil at 204-210° (0.15 mm); yield 4J.6 g (6J.2% from the aldehyde). The oil crystallized from hexane; mp 91-92°.

3-Bromophenyl 3-chloro-1-naphthyl ketone (47). . - A Grignard reagent was prepared by adding a solution of 25 g (0.104 mole) of 1-bromo-J- chloronaphthalene in 125 ml of anhydrous ethyl -99-

ether to 2.53 g (0.104 g atom) of magnesium. After the addition was complete, the mixture was heated to reflux for 1 hr, after which, 9.54 g (0.052 mole) of anhydrous cadmium chloride was added rapidly in the solid state. This was heated to reflux for 1-1/4 hrs, and the ether was replaced with )00 ml of anhydrous toluene. To this boiling solution was slowly added 22.8 g (0.104 mole) of 2-bromobenzoyl chloride in 220 ml of anhydrous toluene. The mixture was heated to reflux for 16 hrs. The complex was decomposed by the slow addition of 250 ml of 20% sulfuric acid to the cold solution, after which, it was heated to reflux for 1 hr. The organic layer was separated, washed with saturated sodium bicarbonate solution and twice with water, dried over magnesium sulfate, concentrated, and distilled under reduced pressure. The product was collected as a pale yellow oil at 212-217° (0.4 rrnn); yield 27.9 g (77.8%)a The oil was crystallized from ethanol as white crystals; mp 94-95°. Anal. Calcd. for c17H10BrC10: C, 59.07; H, 2.92; Br, 23.12; Cl, 10.26. Found: C, 59e00; H, 2.87; Br, 2J.J7; Cl, 10.11. -100-

/' 2-Bromophenyl-1-(J-chloronaphthyl)carbinol (lt.2,).

To a solution of 10 g (0.0289 mole) of 2-bromo- phenyl J-chloro-1-naphthyl ketone in 50 ml of pyridine in a 250 ml, )-necked, round bottom flask fitted with a mechanical stirrer, dropping funnel and reflux condenser, was added 7 g (0.185 mole) of sodium boro- hydride in JO ml of water. The solution was heated to reflux for 48 hrs. The mixture was cooled to room temperature and poured into 450 ml of 10% hydrochloric acid. The organic material was extracted with ether. The extracts were combined, washed once with 100 ml of 10% sodium bicarbonate solution and once with water, dried over magnesium sulfate, and concentrated. The resulting glass was crystallized from methanol, and recrystallized from ethanol as white crystals melting at 133-134°; yield 8.2 g (82%). Anal. Calcd. for C17H12BrClO: C, 58.73; H, J.48; Br, 22.99; Cl, 10.20. Found: C, 58.88; H, J.46; Br, 2).28; Cl, 9.95.

2-(J-Chloro-l-naphthylmethyl)-2'-carboxybenzo- phenone (fl) .

To 1.84 g (0.0755 g atom) of magnesium in a 500 ml, 3-necked, round bottom flask, was added a -101-

solution of 25 g (0.0755 mole) of 2-(J-chloro-l- naphthylmethyl)bromobenzene in 150 ml of anhydrous ethyl ether. The reaction was initiated with a drop of methyl iodide, and the mixture was heated to reflux for 11 hrs. The resulting dark brown solution was quickly poured into a 500 ml dropping funnel set in a 1-1., 3-necked flask containing a boiling solution of 11.1 g (0.075 mole) of phthalic anhydride in 250 ml of anhydrous benzene. The Grignard reagent was slowly added to this solution, and the ether flashed off. The residual ether was replaced with anhydrous benzene, and the mixture was heated to reflux for 6 hrs at 75°. The reaction mixture was hydrolyzed by adding it to a mixture of 200 g of ice and 40 ml of concentrated sulfuric acid. The benzene layer was separated and extracted five times each with alternating solutions of 5% sodium hydroxide and water. The aqueous extracts were combined and acidified with concentrated sulfuric acid. The resulting brown solid was extracted with ether and the ether solution was washed twice with water, concentrated to dryness, and the resulting yellow solid was recrystallized from benzene to give 14.95 g (52%) of pale yellow crystals -102-

melting at 198-199°. Two further recrystallizations from benzene gave pale yellow crystals; mp 216.5-217°. Anal. Calcd. for C25H17Cl03: C, 74.90; H, 4.27; Cl, 8.85. Found: C, 74.38; H, 4.22; Cl, 8.86.

2-(3-Chloro-l-naphthylmethyl)-2'-carbomethoxybenzo- phenone (.4_2). To 1.0 g (0.0025 mole) of 2-(3-chloro-l-naphthyl- methyl)-2'-carboxybenzophenone in a 100 ml round bottom flask, was added a mixture of 50 ml of methanol and_lO drops of concentrated sulfuric acid. The solution was heated to reflux for 48 hrs. The volume was reduced slightly, and upon cooling, the product crystallized as white crystals melting at 103-107°; yield 0.88 g (85%). · One recrystallization from methanol raised the melting point to 113-113.5°. Anal. Calcd. for c26H19c103 : C, 75.27; H, 4.62; Cl, 8.55. Found: C, 75.47; H, 4.53; Cl, 8.61.

6-Chloro-7-(2-carboxyphenyl)benz[a]anthracene (.21t).

To 2.0 g (0.005 mole) of 2-(3-chloro-l-naphthyl- methyl)-2'-carboxybenzophenone in a 250 ml flask, was added a mixture of 115 ml of glacial acetic acid and 30 ml of 48% hydrobromic acid. The solution was heated -103-

to reflux for 2-1/2 hrs, and then was poured into 100 ml of hot water. Upon cooling, the product precipitated, which was separated, washed with water, and dried. The resulting pale yellow crystals weighed 1.85 g (97%), and after recrystallization from ethanol, melted at 247.5-248.5°. Anal. Calcd. for c25H15c102: C, 78.43; H, 3.95; Cl, 9.26. Found: C, 78.26; H, 3.85; Cl, 9.24.

6-Chloro-7-(2-carbomethoxyphenyl)benz[a]anthracene (.2,2).

To O.J g (0.0008 mole) of 6-chloro-7-(2-carboxy- phenyl)benz[a]anthracene in a 100 ml flask was added 50 ml of methanol and 10 drops of concentrated sulfuric acid. The solution was heated to reflux for 74 hrs, after which, it was concentrated slightly. Upon cooling, 0.27 g (86.8%) of ester crystallized. Recrystallization from methanol gave pale yellow plates, mp 153.5-154.5°. Anal. Calcd. for C26H17Cl02: C, 78.68; H, 4.32; Cl, 8.93. Found: C, 7$.60; H, 4.39; Cl, 8.87.

14-Chlorodibenzo[hi,l]chrysen-9-one (.21).

A. To lwO g (0.0025 mole) of 2-(3-chloro-l- naphthylmethyl)-2'-carboxybenzophenone in a 100 ml flask was added 20 ml of polyphosphoric acid, and this -104-

mixture was heated with stirring at 220° for 10 min. The contents of the flask were poured into 200 ml of water, and a red solid precipitated. This product was dissolved in methylene chloride, and the solution was washed twice with water and concentrated to dryness. The residue was dissolved in benzene and chromatographed on florisil, using benzene as the eluent. The red band was collected, the percolate concentrated to a small volume and upon the addition of ethanol, 0.5 g (55%) of feathery orange needles crystallized. An analytical sample was prepared by recrystallization from N,N-di- methylfonnamide-ethanol; mp 252-253°.

Anal. Calcd. for C25H13ClO: C, 82.30; H, 3.59; Cl, 9.72. Found: C, 82.17; H, 3.61; Cl, 9.50. B. To a solution of 1.0 g (0.0025 mole) of 2-(3-chloro-l-naphthylmethyl)-2'-carboxybenzophenone in 50 ml of benzene in a 200 ml polyethylene bottle, was added 50 ml of liquid hydrogen fluoride, and this was stirred for 24 hrs. The benzene solution was neutralized with 10% sodium carbonate, washed with water, concentrated, and the resulting red precipitate was extracted with boiling ammonium hydroxide and filtered. Acidification of the ammonium hydroxide -105-

extract gave 0.2 g of 6-chloro-7-(2-carboxyphenyl)- benz[a]anthracene. The red product was dissolved in benzene and chromatographed on neutral alumina. The percolate containing the red band was concentrated and 0.1 g (11%) of 14-chlorodibenzo[hi,l]chrysen- 9-one crystallized as orange needles; mp 243-247°. C. To 0.62 g (0.0016 mole) of 6-chloro-7-(2- carboxyphenyl)benz[a]anthracene in a 50 ml flask was added 15 ml of polyphosphoric acid. This was heated, with stirring, at 245-250° for 8 min, and was then poured into 150 ml of water. A red solid precipitated which was chromatographed on florisil as above. Recrystallization from benzene-ethanol gave 0.30 g • (51%) of orange needles melting at 248-250°.

14-Chloro-9H-dibenzo[hi,l]chrysene (...21).

Into a 100 ml, 3-necked, round bottom flask equipped with a stirrer, reflux condenser and dropping funnel was placed a slurry of 0.029 g (0.00075 mole) of lithium aluminum hydride in 2 ml of anhydrous ethyl ether. To this was rapidly added a solution of 0.181 g (0.00135 mole) of aluminum chloride in 4 ml of anhydrous ether. This was followed by the addition -106-

of a solution of 0.22 g (0.0006 mole) of 14-chlorodi- benzo[hi,l]chrysen-9-one in 40 ml of anhydrous benzene. The mixture was heated to reflux for 20 min, and then was hydrolyzed with 4 ml of water followed by 6 ml of 6 N sulfuric acid. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and concentrated. Upon the addition of ethanol, the product crystallized as fine orange crystals, mp 172-174°; yield 0.16 g (76%). Further recrystalliza- tion from ethanol produced highly compact, brown-red crystals which were yellow when crushed. The melting point was the samee

Anale Calcd. for C25H15c1: C, 85.58; H, 4.31; Cl, 10.11. Found: c; 85.37; H! 4.40; Cl, 10.32.

Attempted Dehalogenation of 14-Chlorodibenzo[hi,l]- chrysen-9-one (2.Z). To a solution of 0.5 g (0.00137 mole) of 14-chlorodibenzo[hi,l]chrysen-9-one in 75 ml of anhydrous benzene was added 0.1 g (0.0143 g atom) of freshly cut pieces of lithium metal. This was heated to reflux for 18 hrs under a nitrogen atmosphere. The mixture was hydrolyzed with 30 ml of 10% hydrochloric -107-

acid. The benzene layer was separated and chromato- graphed to give 0.46 g of starting material, melting at 243-245°. This material gave a positive Beilstein test for halogen.

Dibenzo[hi,l]chrysen-9-one (~).

A slurry of 0.2 g (0.0006 mole) of 14-chlorodi- benzo[hi,l]chrysen-9-one, 0.12 g of 10% palladium on charcoal, 3.0 ml of 85% hydrazine hydrate and JO ml of methyl Cellosolve was stirred and heated to reflux for JO min. The catalyst was removed by suction filtration, and the residue was washed with 50 ml of hot methyl Cellosolve and 50 ml of chloroform. The washings were added to the filtrate and the solution was concentrated to dryness. The resulting residue was dissolved in benzene and chromatographed on neutral alumina, using 2:1 benzene-chloroform as the eluent. The percolate containing the red band was concentrated and changed to ethanol. The product crystallized as red needles; yield 0.1 g (55v2%). Recrystallization from acetic acid-ethanol gave a melting point of 216-218°. A mixed melting point with the product -108-

obtained from the cyclization of 7-(2-carboxyphenyl)- benz[a]anthracene was 215.5-218° (see section B.J., Discussion of Results).

2-(J-Chloro-l-naphthylmethyl)benzophenone (.§.Q).

To 25 g (0.0755 mole) of 2-(J-chloro-l-naphthyl- methyl)bromobenzene in 125 ml of anhydrous ethyl ether was added 1.84 g (0.0755 g atom) of magnesium turnings. A drop of methyl iodide was added to initiate the reaction, and the mixture was heated to reflux for 10 hrs. The Grignard reagent was transferred to a dropping funnel set in a 1-1., )-necked, round bottom flask fitted with a reflux condenser and mechanical stirrer. The flask contained a boiling solution of 10.6 g (0.0755 mole) of benzoyl chloride in 400 ml of benzene, and to this, the Grignard reagent was slowly added. Excess ether was distilled off, and the mixture was heated under reflux at 75° for 6 hrse The reaction was hydrolyzed by pouring it into a mixture of 40 ml of concentrated sulfuric acid and JOO g of ice-water. The benzene layer was separated, washed with 5% sodium hydroxide and twice with water, dried over magnesium sulfate, concentrated, and distilled under reduced pressure. The product was collected as a yellow oil -109-

and boiled at 230-245° (0.2 mm); yield 14.1 g (52.2%). The oil was chromatographed on acid alumina using hexane as the eluent. A colorless middle fraction was concentrated, and this oil was crystallized from methanol. A further recrystallization from methanol gave white crystals; mp 99-100°. Anal. Calcd. for c24H17c10: C, 80.78; H, 4.80; Cl, 9.94. Found: C, 80.56; H, 4.95; Cl, 9.81.

6-Chloro-7-phenylbenz[a]anthracene (§1}. During preliminary attempts to crystallize 1.5 g of 2-(3-chloro-l-naphthylmethyl}benzophenone from ethanol, pale green crystals were noticed in the solution. These were filtered and weighed 0.25 g (16%). Recrystallization from benzene-ethanol gave the melting point as 179-180°. Infrared and ultra- violet spectra indicated this to be the cyclized product (see section C.l., Discussion of Results). Anal. Calcd. for C24H15Cl: C, 85.07; H, 4.46; Cl, 10.46. Found: C, 85.11; H, 4.86; Cl, 10.03.

Attempted Preparation of 6-Chloro-7-phenylbenz[a]- anthracene (61).

Various sets of reagents and conditions were employed in the attempted cyclization of -110-

2-(3-chloro-l-naphthylmethyl)benzophenone without success, and they are listed as follows: glacial acetic acid and 48% hydrobromic acid at 110° for 2 hrs (starting material recovered); liquid hydrogen fluoride-benzene (1:1) for 24 hrs (starting material recovered); 100% liquid hydrogen fluoride for 5 hrs (starting material recovered); glacial acetic acid and 48% hydrobromic acid in a sealed tube at 180° for 5-1/2 hrs and 10 hrs (starting material and cleavage products recovered); glacial acetic acid and 47% hydriodic acid in a sealed tube at 180° for 2 hrs (starting material recovered with decomposition products); concentrated sulfuric acid at 25° for 20 hrs (decomposition products).

Dibenzo[a,l]pyrene (.£§.).

When stronger conditions than above were employed in an attempt to prepare 6-chloro-7-phenylbenz[a]- anthracene via the cyclization of 2-(3-chloro-l- naphthylmethyl)benzophenone, dibenzo(a,l]pyrene was produced unexpectedly. A. Basic alumina (25 g) was h~ated at 300° under vacuum for l hr. This was cooled, and 1.0 g (0.0028 mole) of 2-(3-chloro-l-naphthylmethyl)benzophenone was -111-

stirred into the alumina until a homogeneous mixture was prepared. This mixture was heated at 250-260° under reduced pressure (0.03 mm) for 1 hr. Upon cooling, this mixture was poured onto a packed column of neutral alumina and was eluted with benzene. A yellow band moved down which was collected, concen- trated, and upon changing the solvent to methanol, O.J3 g (39%) of bright yellow needles crystallized; mp 227-229° (Lit. 74 226-227°). Recrystallization from ethanol gave the analytical sample melting at 229.5-230°. Anal. Calcd. for C24H14: C, 95.33; H, 4.67. Found: C,* 95.17; H,* 4.61. A concentration of the methanol mother liquor produced 0.08 g (8.4%) of unidentified white crystals melting at 164-174°. B. A typical reaction with polyphosphoric acid is as follows: A mixture of 0.5 g (0.0014 mole) of 2-(3-chloro-l-naphthylmethyl)benzophenone and 15 ml of polyphosphoric acid was heated with stirring at 240-250° for 50 min. The hot mixture was poured into water and this was extracted twice with methylene chlorideQ The combined organic extracts were washed -112-

with water, concentrated to dryness, dissolved in benzene, and chromatographed on basic alumina, eluting with hexane. A colorless, blue fluorescent band was collected which yielded 0.25 g (52.8%) of an unidenti- fied mixture of white crystals, melting at 149-174°. Continued elution of the column with benzene removed a yellow band which, when crystallized from ethanol, gave 0.12 g (28.4%) of yellow needles identified as dibenzo[a,l]pyrene, melting at 218-222°.

2-(2-Naphthylmethyl)benzophenone (£7).

A Grignard reagent was prepared by the addition of 0.57 g {0.0236 g atom) of magnesium to a solution of 7.0 g {0.0236 mole) of 2-(2-naphthylmethyl)bromobenzene in 75 ml of anhydrous ethyl ether, and this was heated to reflux for 18 hrs. The Grignard reagent was trans- ferred to a dropping funnel set in a 500 ml, 3-necked, round bottom flask containing a boiling solution of 3.32 g {0.0236 mole} of benzoyl chloride in 100 ml of anhydrous benzene. The Grignard reagent was added slowly and the ether flashed off. Benzene (100 ml) was added and solvent was distilled off until the boiling point reached 76°. The mixture was heated to reflux for 6 hrs. The reaction was hydrolyzed with -113-

50 ml of 10% hydrochloric acid. The organic layer was washed once with 5%sodium hydroxide and once with water, dried over magnesium sulfate, and concentrated. The resulting oil was chromatographed on acid alumina using petroleum ether (bp 30-60°} as the eluent. A colorless, blue fluorescent band was recovered which gave 0.3 g of 12-phenylbenz[a]anthracene, mp 152-154°. An additional 2.65 g of this hydrocarbon, which was contaminated by a yellow impurity, was recovered upon further elution with petroleum ether. Continued elution with benzene gave, after concentration of the percolate, 2-(2-naphthylmethyl)benzophenone as a viscous brown oil; yield 2.6 g (34.2%). This was distilled under reduced pressure, and the product was collected as a yellow oil boiling at 221-226° (0.4 mm), [Lit.9 8 236-238° (1.0 mm)].

Attempted Preparation of Dibenzo[a,l]pyrene (66). These procedures were attempted in order to establish a possible mechanism for the unusual reaction discussed in section C.l., Discussion of Results. A. A homogeneous mixture of 0.5 g (0.00155 mole) of 2-{2-naphthylmethyl)benzophenone and 30 g of basic alumina which had previously been dried at 310-320° -114-

for 1 hr under vacuum, was heated at 240-250° for 1-1/2 hrs under vacuum. Upon cooling, the mixture was poured onto a packed neutral alumina column and this was eluted with hexane. A colorless, blue fluorescent band was collected which gave 0.21 g of 12-phenylbenz[a]anthracene as white crystals; mp 152-154°. Continued elution gave an additional 0.12 g of this hydrocarbon melting at 150-153°, which con- tained a slight amount of a yellow impurity. The total yield of 12-phenylbenz[a]anthracene was 0.33 g (70%). Continued elution with benzene gave a small amount of a yellow oil which would not crystallize from ethanol. The ultraviolet spectrum of this material was not indicative of either benz[a]anthracene or dibenzo[a,l]pyrene. B. A homogeneous mixture of 0.1 g of 12-phenyl- benz[a]anthracene and 25 g of basic alumina which was previously dried at 310-320° for 1 hr under vacuum, was heated at 260-270° for 1 hr under a pressure of 0.03 mm. Upon cooling, the mixture was poured onto a packed neutral alumina column and this was eluted with benzene. A yellow band was collected which gave a small amount of yellow oil. This oil could not be -115-

crystallized from methanol, and its ultraviolet spectrum was not indicative of dibenzo(a,l]pyrene.

2-(3-Cyano-l-naphthylmethyl}benzophenone (62}.

A solution of 5.0 g (0.014 mole} of 2-(3-chloro- l-naphthylmethyl}benzophenone and 2.5 g (0.028 mole} of cuprous cyanide in JO ml of N-methylpyrrolidone was heated to reflux for 72 hrs. The mixture was poured into a solution of 60 g of ferric chloride, 15 ml of concentrated hydrochloric acid, and 90 ml of water, and this was heated at 70-80° for 30 min. A viscous black layer precipitated. The liquid above the layer was separated and extracted twice with chloroform. The viscous material was extracted with chloroform and a heavy black emulsion was removed by filtration. The combined chloroform solutions were concentrated to dryness, and the residue was dissolved in toluene. This solution was washed once with 15% hydrochloric acid and twice with water, dried over magnesium sulfate, and concentrated. The resulting dark oil was dissolved in benzene and chromatographed on acid alumina using 2:1 hexane-benzene as the eluent. Concentration of the percolate gave the product as a yellow oil; yield J.01 g (62%). A portion of the oil -116-

was rechromatographed on acid alumina, eluting with 2:1 hexane-benzene, and the resulting pale yellow oil crystallized after three months standing in ethanol solution. Two recrystallizations from ethanol gave the analytical sample as white needles, melting at •

Anal. Calcd. for C25H17NO: C, 86.4.3; H, 4.9.3; N, 4.0J. Found: C,* 86.59; H,* 4.66; N,* J.96.

6-Cyano-7-phenylbenz[a]anthracene (63).

During preliminary attempts to crystallize 2-(J-cyano-l-naphthylmethyl)benzophenone, yellow crystals were noticed in the benzene solution. These, after recrystallization from benzene, were recovered as fine yellow crystals melting at 259.5-260°; weight, 0.56 g (15.7%). Infrared and ultraviolet spectra indicated this to be the cyclized product (see section C.2., Discussion of Results). Anal. Calcd. for C25H15N: C, 91.16; H, 4-59; N, 4.25. Found: C, 91.JO; H, 4 • .38; N, 4.JO. -117-

Naphtho[J,2,l-fg]naphthacen-9-one (l}.

A. A mixture of 0.5 g (0.0014 mole} of 2-(3-cyano- l-naphthylmethyl}benzophenone and 15 ml of polyphos- phoric acid was heated with stirring at 245-255° for 35 min. The resulting black mixture was poured into water and the organic material was extracted with methylene chloride; this was taken to dryness. The residue was dissolved in benzene and chromatographed on acid alumina, using benzene as the eluent. The orange band was collected to give 0.15 g of fine orange crystals. An initial pale green band was rechromato- graphed on neutral alumina, and an additional 0.04 g of orange product was recovered; total yield 0.19 g (40%}. Recrystallization from ethanol gave the analytical sample as an orange powder; mp 215.5-217°. Anal. Calcd. for C25H140: C, 90.89; H, 4.27.

Foun:d C* , 9 1.20;0 H,* 4.27. B. A mixture of 0.4 g (0.0012 mole} of 6-cyano- 7-phenylbenz[a]anthracene, 60 ml of glacial acetic acid, and 15 ml of 48% hydrobromic acid, was heated at 180° in a sealed Carius tube for 8 hrs. The contents of the tube were poured into water, and this was extracted twice with methylene chloride. The combined extracts -118-

were washed with water ~nd concentrated to dryness. The residue was dissolved in benzene and was purified by column chromatography to give 0.09 g (22.4%) of orange powder; mp 215.5-216.5°.

Attempted Preparation of Phenalo[2,3,4,5-defg]naph- thacene-4,$-quinone (4). Into a 6 ml capacity bomb was placed 0.5 g (0.0015 mole) of 7-(2,6-dimethylphenyl)benz[a]anthracene,* 1.12 g (0.00375 mole) of sodium dichromate dihydrate (25% molar excess), and 2.12 g of water. This was heated at 250° for 1a·hrs. The contents of the bomb were extracted with methylene chloride. The extract was washed once with water, and was concentrated to dryness. The residue was dissolved in benzene and chromatographed on basic alumina. A blue fluorescent band was collected which gave O.J9 g of starting material; mp 132-135°. Continued elution gave a small amount of a red oil. The ultraviolet spectrum of this material was later found not to be indicative of the desired product.

*This compound was prepared in three steps from 2-(1-naphthylmethyl}benzonitrile according to the p~or.edure of Borkovec in references 86 and 87. -119-

I 6-Cyano-7-(2-carboxyphenyl)benz[a]anthracene (.2.2.).

A solution of 1.0 g (0.00261 mole) of 6-chloro- 7-(2-carboxyphenyl)benz[a]anthracene, 0.35 g (0.00391 mole) of cuprous cyanide, JO ml of N-methylpyrrolidone, and 3 ml of acetonitrile, was heated to reflux for 29-1/2 hrs. The mixture was poured into a solution of 15 g of ferric chloride, 35 ml of concentrated hydrochloric acid, and 140 ml of water, and was heated at 65-70° for 1 hr. This was extracted with toluene and the organic solution was washed twice with water, and was filtered to remove an insoluble emulsion. After concentration to dryness, the residue was recrystallized from ethanol. This gave 0.44 g (45.2%) of yellow crystals. Two recrystallizations from benzene gave the analytical sample as pale yellow crystals; mp 261-263°. Anal. Calcd. for C26H15N02: C, 83.63; H, 4.05;

N, J.75. Found: C* , ol.72;0 H,* 4.04; N,* 1. 6 4. See Section D., Discussion of results.

Phenalo[2,3,4,5-defg]naphthacene-4,8-quinone (~).

A mixture of 0.37 g (0.001 mole) of 6-cyano-7- (2-carboxyphenyl)benz[a]anthracene, JO ml of glacial acetic acid, and 15 ml of 48% hydrobromic acid was -120-

heated in a sealed Carius tube at 180° for 4 hrs. The contents of the tube were poured into water, and this and a red residue in the tube were extracted with hot benzene. When the combined benzene extracts cooled, 0.11 g of quinone crystallized as bright red crystals. The benzene extracts were concentrated and chromato- graped on neutral alumina. Impurities were removed by elution with benzene. The product, which remained on the column as a red band, was removed by elution with chloroform. Concentration of the percolate gave an additional 0.05 g of bright red quinone. The total yield was 0.16 g (45.3%). The analytical sample melted at 340-J66°*(dec~). Anal. Calcd. for c26H12o2 : C, 87.63; H, J.J9. Found: c; 87.45; H;3.JS.

2-(l-Naphthylmethyl)-2'-carboxybenzophenone (12.). A Grignard reagent was prepared by the addition of a solution of 40 g (0.1348 mole) of 2-(1-naphthyl- methyl)bromobenzene in 300 ml of anhydrous ethyl ether to 3.28 g (0.1348 g atom) of magnesium turnings. The mixture was heated to reflux overnight. The Grignard reagent was quickly transferred to a dropping funnel set in a 3-necked, 1-1., round bottom flask -121-

equipped with a stirrer and reflux condenser. The reagent was slowly added to a boiling solution of 18.95 g (0.1280 mole) of phthalic anhydride in 400 ml of anhydrous benzene, and the ether flashed off. After the addition was complete, 300 ml of anhydrous benzene was added, the remaining ether distilled off, and the solution was heated to reflux for 4 hrs at 72°. The complex was decomposed by pouring the contents of the flask into a beaker containing 500 g of ice, 300 ml of water, and 80 ml of concentrated sulfuric acid. This was stirred until the benzene layer became very thick with yellow material. The benzene layer was extracted five times with a 10% sodium carbonate solution. The extracts were combined and acidified with sulfuric acid. The resulting tan precipitate was separated and recrystallized from benzene-petroleum ether (bp 30-60°). This gave 25.9 g (55.3%) of white feathery product melting at 158-161° (Lit. 3 159-160°).

7-(2-Carboxyphenyl)benz[a]anthracene (1).

A mixture of 2.74 g (0.00748 mole) of 2-(l-naph- thylmethyl-21-carboxybenzophenone, 24 ml of 48% hydrobromic acid, 6 ml of water, and 90 ml of glacial -122-

acetic acid was heated under reflux for l hr. Upon cooling to room temperature, white crystals formed. The product was filtered, washed with water, and recrystallized from ethanol. This gave 2.37 g (91%) of short needles melting at 133-135°. This compound was shown to be the mono-alcoholate, and an elemental analysis was obtained. ~. Calcd. for C27H2203: C, 82.21; H, 5.62. Found: C, 81.87; H, 5.65.

Partial Resolution of 7-(2-Carboxyphenyl}benz[a]- anthracene (1).

Brucine, 9.52 g (0.0241 mole) was added to a boiling solution of 8.4 g (0.0241 mole) of 7-(2- carboxyphenyl)benz[a]anthracene in 250 ml of ethanol. The volume was reduced to 200 ml and, upon cooling to room temperature, 7.6 g of salt crystallized. The salt was recrystallized five times from ethanol to give crystals with a constant specific optical rotation of * -10.77° in benzene. An analytical sample was prepared which melted at 156-159°.

*optical measurements were made at 25° with a Rudolph Model No. 70 polarimeter using a 4-dm jacketed tube. -123-

~. Calcd. for C43H42N206: C, 77.61; H, 5.70; · N, J.77. Found: C, 77.39; H, 5.76; N, J.88. The brucine salt was decomposed with dilute hydro- chloric acid. The optically active acid was recovered and recrystallized from ethanol to give white needles, mp 227-228°, which had a specific optical rotation of +18.84° in benzene. A further recrystallization from ethanol gave the acid with a 0° rotation. This racemic product melted at 218-219°. See section F., Discussion of Results. -124-

S Ul','C-1ARY -125-

The preparation of 2-(3-chloro-l-naphthyl- methyl)bromobenzene (46) was achieved by two methods. The cross-condensation reaction between 3-chloro-1- naphthylmagnesium bromide (41) and 2-bromobenzyl bromide, as well as the reaction of 41 with 2-bromo- benzaldehyde, followed by reduction of the resulting carbinol J±.2.with lithium aluminum hydride and aluminum chloride produced the desired compound. The latter reaction gave a better yield of 46. It was found that 2-bromophenyl-1-(3-chloro- naphthyl)carbinol (45) thermally decomposed into 46 and 2-bromophenyl.3-chloro-1-naphthyl ketone (47). A study of the thermally induced reaction of the carbinol J:.2.was made, and the products were quantita- tively analyzed by means of gas chromatography. It was concluded that the anomalous products of the reaction of an aryl Grignard reagent with a benzalde- hyde derivative were actually produced by the thermal disproportionation of the resulting carbinols during the distillation step. -126-

The keto-acid, 2-(3-chloro-l-naphthylmethyl)-

2'-carboxybenzophenone (_2l) was prepared by the inverse-addition of the Grignard reagent of 2-(3-chloro-l-naphthylmethyl)bromobenzene to phthalic anhydride. Cyclization of the keto acid .2l with an acetic and hydrobromic acid mixture gave 6-chloro-7-(2-carboxyphenyl)benz[a]anthracene (2!t;). Methyl ester derivatives were made for both the keto-acid .2l and the acid 2!!:· The cyclodehydration of either 2-(J-chloro-l- naphthylmethyl)-2'-carboxybenzophenone (22.) or 6-chloro-7-(2-carboxyphenyl)benz[a]anthracene (2!t;) with polyphosphoric acid gave 14-chlorodibenzo[hi,l]- chrysen-9-one (.21) in 50%. A lower yield of this product was obtained when the precursor keto-acid was treated with liquid hydrogen fluoride. The reduction derivative, 14-chloro-9H-dibenzo- (hi,l]chrysene (~) was prepared by treatment of 21. with lithium aluminum hydride and aluminum chloride. The unequivocal synthesis of dibenzo[hi,l]- chrysen-9-one (2) was achieved by the successful dehalogenation of 14-chlorodibenzo[hi,l]chrysen-9-one with 10% palladium-charcoal catalyst and hydrazine. -127-

The ketone 2 was shown to be identical to the compound produced from the cyclodehydration of 7-(2-carboxyphenyl)benz[a]anthracene (1). The ketone, 2-(J-chloro-l-naphthylmethyl)benzo- phenone (60) was prepared by the inverse-addition of the Grignard reagent of 2-(J-chloro-l-naphthylmethyl)- bromobenzene to benzoyl chloride. It was, found that a small amount (16%) of 6-chloro-7-phenylbenz[a]- anthracene (61) was formed during this preparation. By means of gas chromatography, it was shown that 61 resulted during the distillation of the ketone 60. The cyclodehydration of the ketone 60 failed when various standard cyclizing media were employed, and the reason for this is discussed. Cyclization attempts with polyphosphoric acid or alumina gave dibenzo[a,l]pyrene (66) as the only identifiable product. This unusual reaction obviously involves a rearrangement. A study was made and a mechanism for this reaction was postulated which is consistent with the experimental observations. The ketone, 2-(J-cyano-l-naphthylmethyl)benzo- phenone (~) was prepared by the improved procedure of reacting the chloro ketone 60 with cuprous cyanide -128-

in N-methylpyrrolidone. 6-Cyano-7-phenylbenz[a]- anthracene (.2.2,) was also produced in small quantity in this reaction as a consequence of the presence of the corresponding chloro compound 61 in the ketone 60 prior to reaction. Naphtho[),2,l-fg]naphthacen-9-one (1) was prepared by the treatment of 6-cyano-7-phenylbenz[a]- anthracene (.Ql) with a hydrobromic and acetic acid mixture at 180°, and also by the treatment of the cyano-ketone 62 with polyphosphoric acid. The novel use of polyphosphoric acid in cyano group hydrolysis is discussed. Phenalo[2,J,4,5-defg]naphthacene-4,8-quinone (lf:) was prepared by the treatment of 6-cyano-7-(2-carboxy- phenyl)benz[a]anthracene (22)with a hydrobromic and acetic acid mixture at 180°. The nitrile 22 was obtained by the reaction of chloro compound~ with cuprous cyanide. An attempted procedure for the preparation of the quinone lf: involved the oxidation of 7-(2,6-di- methylphenyl)benz[a]anthracene (1Q) to the corres- ponding diacid 1!. with aqueous sodium dichromateo Unfortunately this new method of oxidation failed in this case. -129-

The partial resolution of 7-(2-carboxyphenyl)- benz[a]anthracene (1) was achieved with the use of brucine. Only one optically active isomer was obtained, and this was racemized by treatment with boiling ethanol. An empirical rule used to quantita- tively determine the resistance of optically active biphenyls to racemization was applied to the acid 1, and the experimental observations were supported. During the course of this investigation sixteen new compounds were prepared and were all properly characterized, except the cyano-acid .22, which did not give acceptable analytical data. Infrared spectral observations were made on the spectra of the newly prepared compounds 2, l, ~' and 21• The regions of out-of-plane carbon-hydrogen bending absorptions, as well as, the carbonyl absorption frequencies were examined. These data further substantiated the assigned structures, and also pennitted the differentiation of the isomeric compounds 2 and l• -130-

APPENDIX .. 131-

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LITERATURECITED -149-

LITERATURECITED

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The preparation of 2-(3-chloro-l-naphthyl- methyl)bromobenzene was achieved by the cross-conden- sation reaction of 3-chloro-l-naphthylmagnesium bromide and 2-bromobenzyl bromide, as well as by the reaction of this Grignard reagent with 2-bromobenzaldehyde, followed by reduction of the resulting carbinol with lithium aluminum hydride and aluminum chloride. It was found that 2-bromophenyl-1-(3-chloro- naphthyl)carbinol thermally decomposed into the corresponding methylene compound and ketone. A study of the thermally induced reaction of the carbinol was made, and the products were quantitatively analyzed by means of gas chromatography. It was concluded that the anomalous products of the reaction of an aryl Grignard reagent with a benzaldehyde were actually p~duced by the thennal disproportionation of the resulting carbinols during the distillation step. The keto-acid, 2-(3-chloro-l-naphthylmethyl)- 2•-carboxybenzophenone was prepared by the inverse- addition of the Grignard reagent of 2-(3-chloro-l- naphthylmethyl)bromobenzene to phthalic anhydridee Cyclization of this keto-acid with an acetic and hydrobromic acid mixture gave 6-chloro-7-(2-carboxy- phenyl)benz[a]anthracene. Methyl ester derivatives were prepared from both this acid and the precursor keto-acid. The cyclodehydration of either 2-(J-chloro-l- naphthylmethyl)-2'-carboxybenzophenone or 6-chloro- 7-(2-carboxyphenyl)benz[a]anthracene with polyphos- phoric acid gave 14-chlorodibenzo[hi,l]chrysen-9-one.· Treatment of this ketone with lithium aluminum hydride and aluminum chloride gave the reduction derivative, 14-chloro-9H-dibenzo[hi,l]chrysene. The unequivocal synthesis of dibenzo[hi,l]- chrysen-9-one was achieved by the dehalogenation of 14-chlorodibenzo[hi,l]chrysen-9-one with 10% palladium- charcoal catalyst and hydrazine. The dehalogenated product was shown to be identical to the compound produced from the cyclodehydration of 7-(2-carboxy- phenyl)benz[a]anthracene. The ketone, 2-(3-chloro-l-naphthylmethyl)benzo- phenone was prepared by the inverse-addition of the Grignard reagent of 2-(3-chloro-l-naphthylmethyl)- bromobenzene to benzoyl chloride. It was found that a small amount (16%) of 6-chloro-7-phenylbenz[a]- anthracene was formed during the distillation of the precursor ketone. The cyclodehydration of this ketone failed when various standard cyclizing media were employed, and the reason for this is discussed. Cyclization attempts with polyphosphoric acid or alumina gave dibenzo[a,l]pyrene as the only identifi- able product. This unusual reaction obviously involves a rearrangement. A study was made and a mechanism for this reaction was postulated which is consistent with the experimental observations. The ketone, 2-(J-cyano"-l-naphthylmethyl)benzo- phenone was prepared by the reaction of the corres- ponding chloro ketone with cuprous cyanide in N-methylpyrrolidone. 6-Cyano-7-phenylbenz[a]- anthracene was also produced in small quantity in this reaction as a consequence of the presence of the corresponding chloro compound in the ketone prior to reaction. Naphtho[J,2,l-fg]naphthacen-9-one was prepared by the treatment of 6-cyano-7-phenylbenz[a]anthracene with a hydrobromic and acetic acid mixture at 180°, and also by the treatment of the precursor cyano ketone with polyphosphoric acid. The novel use of polyphos- phoric acid in cyano group hydrolysis is discussed. Phenalo[2,3,4,5-defg]naphthacene-4,8-quinone was prepared by the treatment of 6-cyano-7-(2-carboxy- phenyl)benz[a]anthracene with a hydrobromic and acetic acid mixture at 180°. An attempted procedure for the. preparation of this quinone involved the oxidation of 7-(2,6-dimethylphenyl)benz[a]anthracene to the corresponding diacid with aqueous sodium dichromate. Unfortunately this new method of oxidation failed in this case. The partial resolution of 7-(2-carboxyphenyl)- benz[a]anthracene was achieved with the use of brucine. Only one optically active isomer was obtained, and this was racemized by treatment with boiling ethanol. An empirical rule used to quantita- tively determine the resistance of optically active biphenyls to racemization was applied to this acid, and the experimental observations were supported. During the course of this investigation, sixteen new compounds were prepared and were all properly characterized, except 6-cyano-7-(2-carboxyphenyl)- benz[a]anthracene, which did not give acceptable analytical data. The reason for this is discussed. Infrared and ultraviolet spectra of all new compounds were recorded. Infrared spectral observations were made which gave further support to ,the assigned structures of the isomeric compounds naphtho[J,2,l-fg]- naphthacen-9-one and dibenzo[hi,l]chrysen-9-one.