Evelyn.Halcrow, B.Sc. Thesis Presented

SOM.2, ATTEMPTS TO PREPARE NEW COMPfUNDS OF POSSIBLE

ANTIMALARIAL ACTIVITY.

Barbara- Evelyn.Halcrow, B.Sc.

Thesis presented for the Degree of Ph.D.,

University of Edinburgh.

LZay, 1N-4. -1-

Contents.

Page .

1. Introduction and General Survey of the Literature ...... 2

II. Attempts to synthesise hydroxy- and chloro- derivatives of o- phenanthroline from 8- amino- quinoline and its derivatives 28

III. Synthesis of 4- chloro -8- nitro- and 4- chloro- 37 8- amino -quinaldines with the object of synthesising o- phenanthrolines from the latter. A study of the nitration of 4- chloro- quinaldine, and the synthesis of 4:8- disubstituted quinaldines

IV. Synthesis of o- phenanthroline and its 53 conversion to a number of basically substituted derivatives

V. Synthesis of derivatives of 2:3, 4':3'- 65 pyridoquinoline

VI. Experimental ...... 74

VII. Summary 118 1. IT] RC-1DUCTION AND (..;....RAL SI:JRVII-;Y OF TH3

LITIiIRATURE. -3-

INTRODUCTI - BURVEY OF TnE LI`l'_;RrsTURL.

The value of cinchona bark in relieving fevers

was known for many centuries before pure quinine was

first extracted from it in 1820 and used in the

treatment of malaria. Important advances in the

control of malaria came with the discovery of the

plasmodia in 1880 _by Laveran, and the disclosure by Ross that the anopheline mosquito is the

transmitting agent for the. disease.

Chemotherapeutic research into the problem began about 1890, when Ehrlich and Guttmann showed

that methylene blue was antimalarially active but much less so than quinine. Rabe's announcement in

1908 of the now accepted structure of quinine

stimulated attempts to prepare some of the cinchona

alkaloids and their derivatives. In 1913 haúfmann

(3er., 46, 1823) synthesised a number of simple

quinoline derivatives whose structure resembled

that of quinine. he prepared dialkylaminomethyl-

6- ethoxy- 4- ouinolyl- carbinols (IX, R = C2H5), which

he reported as being of low toxicity to humans but

of high toxicity to infusoria and paramoecia.

These compounds were tested. later and found to be

inactive on avian malaria.

The synthesis of the two drugs plasmoquin and

etch rin/ -4-

atebrin which with :quinine are mainly used at

present as antimalarials, came as a result of

j researches by $chuleman and his colleagues who

I began by modifying the methylene blue molecule (I) .

The activity was found to be enhanced when one of the

methyl groups was replaced by a diethylaminoethyl

group (II) .

N3C / CH3 N Gi,.-GN,- N HS

II.

This/ -5-

This word led'to the introduction of similar groups into the quinoline nucleus and ultimately to the development of plasmocj .in or 8-(-methyl-- diethyl aminobutylaino) -6- methoxy- quinoline. (III)

N3C o

CFF -CH3 CH CH a CHz-

N (C,.Ns)a

A natural extension of this work was the trial of similar substituents in other ring systems.

This research led Mietsch and Mauss (Angew.

47, 633) to the synthesis of ate'prin or 2- chloro -5-

(a(- methyl -S- diethylaminobutylamino) - 7- methoxy- acridine (IV), which possesses an acridine nucleus and which has a considerably lower toxicity than plasmoquin. In general, all these drugs, quinine ate; rind and plasmoquin, act on both the schizonts and gametocytes of Plasmodium vivax (benign tertian

Malaria) and Plasmodium malariae (quartan Malaria).

On Plasmodium falciparum (malignant tertian malaria) however, quinine and atebrin are schizonticidal only, whereas plasmoquin acts on the gametocytes and not on the schizonts. A paper has been published by

Curd(Ann. of Trop. Med. and Parasit. Vol. 37 No 2

1943) in which are collected results available in the literature of the relative activities of various drugs on a large number of species of malaria parasite in their respective hosts.

The method used tó test synthesised compounds for their antimalarial activity was devised by

Roehl at Elberfield and published in 1926. The potential antimalarial is given by mouth to canaries infected with avian .malaria, and the time taken for parasites to appear in the blood is compared .ith that for a non -treated bird. One of the disadvantages/ -7-

disadvantages of this method is that the effect

of a compound on'the parasites of avian malaria

may be different from that on the parasites of

human malaria. For example, sulphanilamide

compounds which have so far been tested are most

active against monkey malaria and to a lesser

extent on húman malaria, but their activity on

avian malaria is almost wholly lacking. Again,

the action of a drug upon two species of parasite

within the same host may differ. Sulphanilamide,

in a mixed infection of P. knowlesi and P. inui

in monkeys, eliminates P. knowlesi but -is inactive

on P. inui. It is ::znownl too that arsenical drugs

have considerable action against P. vivax infections

but little or none against P.malariae and P.

falciparum. In recent years other birds, especially

chickens and ducks, are being used in the place

of canaries for large scale preliminary tests.

Since plasmoquin and atebrin were synthesised,

a great amount of work has been done on the problem

of the relationship between chemical structure and

antimalarial activity.

The existence of activity comparable with that

of quinine in compounds such as cinchonine (V,

R = H, R' ,= CH: C J) and dihydroguinine (V, R = OCH3,

R' = CE2. CH3) shows that the methoxy and vinyl

groups of quinine (V, R = OCH3, R' = CII: CIT3) can be Modified without loss of activity. On the other/ -8-

other hand, changes in the secondary alcohol

( -CEO I) group, e.g. chlorination (- CIC1 -),

acetylation (- CHOAc -), reduction (-G42-), oxidation

( -CO- ) etc., cause a disappearance of activity.

CH CH-Ri CH). CHx CI-40'1-CH I i+H } N N

Oxidation of quinine under certain conditions

yields the inactive acid quitenine (V, R = OCH3,

R' = -C00ìí) where the vinyl group is replaced by

a carboxyl group. Activity however is restored

on esterification, and it was found by Goodson

that the activity increases with the molecular

weight of the alcohol used for esterification,

until it reaches a maximum at the butyl or amyl

compound, after which there is a decrease in

activity.

A great many compounds closely related to

' plasmoquin and atebrin have been prepared and

tested, chiefly by I4agidson in Russia, Fourneau

in France and Robinson in Britain, and this work

has brought to light many interesting phenomena. -c_

A curious alternuition in the activity of ::embers

of a series of 6- methoxy- 8- dialkylarlinoalkyla:nino-

quinolines (VI) was noted by Mazidson

(Terapeutichesky árkhiv. 15, 65,3, 137)

143C o

N(CaH,)a

The chemotherapeutic'indices for different

values of "n" were found to be

n a 3 1+- 5 6 7 8 9 lo

,i.. ai as 33.3 40 s

/3 /3.3 i° ,(, 6 -

This type of alternation is not generally

found,. for Magidson and 8trukov in the same paper

reported that when the, side -chain in position 8

was kept constant at -NH (CIS )2 îT(Ca n5 )2 and the

group in position 6 varied. from -OH to -OCsii ,

there was a continuous but irre filar fall in the

chemotherapeutic indices: -

-0H -OCH3 -0C2 H3 -OCaH7 -004H9 -0051i 1

13.3 6 4 1 1 0

2:1though/ -10-

Although hydroxy and ethoxy compounds show

appreciable activity, the choice of the methoxy

group in compounds receiving medical trial is well

founded, for no other group has proven superior

in tests on birds, a superiority due in part to

the lesser toxicity of the methoxy group over the

other substituents tried.

Again we may consider a series of acridines.

Magidson and Grigorowski(Chemico -Pharm.Ind.(U.S.S.R)

No.., 1, 1933) foLind that in 2- chloro- 7- !nethoxy-

acridines substituted in position 5 by the chain

-NH(CHa)nN(C2H8)2 where n = 2 to 6,. the chemo-

therapeutic activity increased with n and then

decreased,showing a maximum at n = 4

In 193, Magidson and Rubtzow(J.Gen.Chem.

Russ., 1937 1896 -1908) described the preparation

of some 4-dialkylaminoalkylamiiio-6- methoxy-

quinolines (VII).

VII.

'- CH(CH3) CHx .CIi2 CH2 .N(C2Hs)2

R: -CH2.CHOH.CH2- N(C2H5)2 -(C )4N(C2H5)2

These were found to be active against bird malaria, but analogous compounds substituted in the 2- position instead of the 4- position were found by a the/ 1

same authors to -be completely inactive. This was confirmed by 8chonhofer (Zeit. f. Physiol. Chem.,

1942, 2742 1. ) , who showed that besides compounds of the plùsmoquin type, quinoline derivatives substituted in the 4- and 6- position by a dialkyl- aminoalkylanino side -chain were active, but inactive compounds were obtained if this side -chain were In any other position.

A number of compo-.nC.s having a structure resembling that of quinine has been synthesised by

King and his colleagues. Among these compounds were 4- (6- methoxy- quinoly1)-- ol- piperidyl- carbinol

(VIII) (Ainley and King, Proc.Roy. Soc., 1933, 125

3, 60) and d.ibutyl -, diamyl -, and dihexyl- amino- methyl-6- methoxy- 4- quinolyl- carbinols (IX, R = 0Ií3),

(King and Work, J.C.3., 1940, 1307).

CN-

C H CHa

I 'CHoH-eli Ha , NH R3c o

RI CHoN - CHx N R

IX. These/ asau, spLlnOdti'.c0 0,113 san::oTOoLj jo asoLj; pziJrdaJd cf uuru_3nn7 'otjm q.T sT °uT*sadc4uT o;

aOT;ou ' MrO JraU o; "uTJrdadd aLj; ;sJT,T a1LT;Or

OT;aL¿w1"s TrTJrT:mT;Ltr. saOUrorsqns

aLjI Tn;ssaOOns a.LTau.;raJ; JO rTJrTrt.. Lm.Tm

apwrTTUrvcTTns sunocTuloO srij uaact pa;.JodaJ tq

TrJaAas 'sJa,JOr; ;nq at{; sTTnsaJ air sr r aToLtm

oTprJ;TZOO ,t(LlO; aptt...rTTusucTTnç dTasq.T sJraG_dr O; aq jd OU anTrA JaUTTa uT .ururnLj Jo urTAr 'rTJrTru: nc 'spLj aTpJOOOL oq `'00 TTrtjsa ooJ7} oo,c, dxr

Tc'T- 'O28T '89 '(09L r aaT;rJnO pur 2uoJ;s

OT;OrTlNcTodd uoT;Or Lto soTElou:-a t uT sRalluoul

0T0zrT11;rLldTn2 (y,) pur auTZrTprtldTns ,`Ix) aJr Lj;oq

r ;O anT uo Td arJntjdo uT s.jOn,,) a!TTr) J pur upA 'a:Y:.RQ OO5 dxF 'TOTE 'palëi -'0 pUr"(099

TTrusaT2o0 ,p) JatïF' pay:T .00ssv ' 'LTT (LLOT srtj

LuLnous ;sLta. auTzrtprLjdTns sT aAT;Oajza 1-suTGar Tin

sWJOJ Jo utiunLj rTJrTrtï; auTzrTprLjdTnO pur auios

jo sq.T sa1LT;rnTJáp sa auTzrJau..rudTn.s (IIY) aArU

urbous OT;opTiNaToJd uoT;Or ;nq aLq; anTrA Jo asaLlq.

uT uru;nq rTJrTru sadTnbaJ JaLIa.Jnj T;saAuT uoT;r

- N H r.oS 7N

1 MaN SO N

XII.

Importance. attaches to the discovery of a new compound, undecane 1:11 diamidine (XIII) ,

which is activa in avian and rionkey malaria and

which has been shown by Glyn-Hughes, Lourie and

Yorke (Ann. Trop. :íed. and Parasit. 32, 103, 1938)

to have a definite action in induced P.vivax

infections in neuro- syphilis. gis undecane 1:11

diamidine has a chemical structure different from

that of any known anti,,lalarial compound, the

existence of its activity nay open up new fields

of research.

HN GNI CN Ç -(C Ha )iI - N a N

XIII.

As the object of the present research is the

synthesis of derivatives of o- phenanthroline (XIJ)

with basic side- chains in one of the pyridine

rings, it is desirable to give a review of work

in this field on phenanthroline derivatives in

general, together with their biological effects

as far as they have been reported.

4 -15-

Phenanthrolines are frequently regarded as pyridoauinolines, the cuinoline nucleus (XV) being regarded as the basic one. In this case, o- phenanthroline becomes 7:8, 3':2'- pyridoquinoline mn- phenanthroline becomes either 5:6, .:':3'- pyridoquinoline or 7:8, 2':3'- pyridoquinoline, and p- phenanthroline becomes 5:6, 3':2'- pyridoquinoline.

XV.

phenanthrolines are so.aetimes called diaza- phenanthrenes and are distinguished by the positions the nitrogen atoms take up in the phenanthrene nucleus (XVI), the numbering naturally being that used for .the phenanthrene ring system. Thus, instead of o -, m-, and p- phenanthrolines, we have 4:5 -, 1:5- and 1:8 diaza phenanthrenes respectively.

Compounds described here will be termed o -, m- or p- phenanthrolines as this is considered the least cumbersome nomenclature, but frequently compounds/ -16--

compounds will be referred to in brackets as they

were originally named in the literature.

The present research is an extension of

recent work done by Kermack and reatherhead

(J.C.S., 1940, 1164) on derivatives of p-

phenanthroline and by ner:1ack and Webster (J.C.S.,

194 §, 213) on derivatives of m- phenanthroline.

The compounds prepared by these authors were

Obtained by condensing the chloro -m- or p-

phenanthroline with the appropriate bases, the

former being produced by the replacement of the

hydroxyl group by chlorine in the corresponding

hydroxy- phenanthrolines.

Two series of p- phenanthrolines were obtained,

in which the basic side- chains were in positions

2 and 4. The hydroxy -compounds required as

intermediates were synthesised by use of the

methods of Conrad and Limpach (Ber. 1931, 64, .970)

who showed that aniline andacetoacetic ester

react. together in two different ways according to

the conditions employed. 2- methyl -4- hydroxy-

and 2- hydroxy-4- methyl- euinolines were obtained

which on nitration followed by reduction yielded

the 6- amino -derivatives. The products of Skraup

syntheses on these amino- co..zpounds were 2- methyl-

4- hydroxy- and 2- hyd.roxy -4- methyl -p- phenanthrolines.

The hydroxy-m- phenanthrolines were prepared in two ways, the first by preparing a 5- or 7- amino- quinoline/ -17-

amino -quinoline containing a, hydroxyl group in position 2 or 4 and subjecting it to a Skraup synthesis., the second by condensing 5- or 7- amino- quinolines with acetoacetic ester using

Conrad and Limpach's method. -

These hydroxy-m- and p-= phenanthrolines were readily converted to the chloro- phenanthrolines, which were subsequently condensed with dialkylamino- alkylamines Examples of compounds obtained are

2 -d.ie thylaminopropyl amino -4- methyl -p -phe nanthrol ine

(XVII) , 4-diethylaminoethylamino-2- methyl -p- phenanthroline (XVIII) , and 6- (d -methyl -S- d.ie thylaminobutylamino) -8- methyl- m- phenanthrol ine

[or 2-(0(- Methyl- b- diethylaminobutylamino) -4- methyl -7 :8, 2' :3'- pyridoquinol ine] (XIX) . A compound found to have a possible slight antimalarial activity on P.relictum was -(d- me thyl -S -die thylaminobutylamino) -2- methyl -m- phenanthroline [or 4- (ol- methyl- S- diethylaminobutylamino)-2- methyl -5: 6, 2 :3'- pyridoquinoline1 (XX)

NN- (cHa)3- N (Ca Ha),

XVI I . -ls-

- N (Ca H5 a

X.7Ii II

C N3

(C NH C`a,"'lIN

. ,.P. 481874 describes among other compounds two p- phenanthrolines. One of these. was also prepared by Kermack and :eatherhead

( XVIII) . The other, 3-diethylaminoethylariino- p-phenanthroline (XXI) was prepared by condensing diethylaminoethylamine with 3- bromo- p- phenanthroline which was obtained by submitting 3-bromo -6- amino- quinoline to the

Skraup synthesis. `It was prepared also by condensing diethylaminoethyl chloride with

3- amino- p- phenanthroline and by condensing die thylaminoethylamine with 3- hydroxy -p- phenanthroline.

NH- CCNa)- N (CaHs)a

In addition to these publications describing phenanthrolines substituted in one of the pyridine rin7s, several patents have been published describing phenanthrolines substituted in the benzene ring. These are

mainly , -phenanthrolines, and to avoid some confusion/ -20-

confusion which exists in the literature the

nomenclature already used here will be used to .

describe these. Assuming that the two nitrogen

atoms are in positions 1 and 5, the positions

in the benzene ring will be 9 and 10.

The 9- and 10- amino- m- phenanthrolines

which are condensed with dialkylaminoalkyl

chlorides to obtain the desired 'products may

be synthesised in several ways, by the reduction

of the earresporiding nitro -phenanthroline, by

the action of ammonia on the halogenated

compound or by the conversion of the carboxylic

acid amide according to the Hoftann reaction.

The nitro- and halogenated derivatives are

prepared by subjecting the appropriate nitro -

or halogenated phenylene diamines to the Skraup

reaction.

Korczynski and 3rydówna (Bull. Soc. Chem.

de France (4) 37, 1483 (1925) ) prepared 9-

nitro-m- phenanthroline by the Skraup synthesis

on 1- nitro -3:5- phenylene diamine:-

N4,

ON The preparations of 10- chloro- and 10- bromo-m-phenanthrolines are described in

E.P. 454526. These are made from 1- chloro-

and 1- bromo- 2:4- phenylene diaminesby use of the

Skraup synthesis. Other halogenated compounds

also synthesised in this patent are 9- bromo -o-

and p- phenanthrolines.

In another patent 3öeseken and Bijlsma

(E.P. 454525) prepared £- amino -m- phenanthroline by reducing the nitro compound with tin and hydrochloric acid, and 10- amino-m- phenanthroline by the action of ammonia on the 10- bromo-

comp'ound. These two amino- derivatives are

stàted to be activo, the former against

üaemoproteus orizivorae and the latter against

P.relictum. In the same patent, these authors describe the preparation of 10-d.ialkylamino- alkylamino -m- phenanthrolines. Among these,

10- diethylaminopropylamino -m- phenanthroline is said to be active against P.relictum.

These 10- phenanthrolines may substituted '1- be obtained in a slightly different way, according to 13áeseken and BiAsma (E.P. 450624), by submitting 1- diethylanaino- and 1- diethylamino -- ethylamino -2:4- phenylene- diamine hydrochlorides to the Skraup reaction.

Two other compounds of interest have been prepared (G.P. 668968) which do not appear to have/ have been tested for _.:anti :larL.l activity, viz. 10- (i- methyl -S -die thylaminobu ty1amino) -m-

and. p -ph nanthr of ine s .

Very little work appears to have been done on o- phenanthroline derivatives, and no trace oc could be found/basically substituted o- phenanthrolines having been prepared similar to those m- and p- phenanthrolines already described. In p.p. 322252 nitro -o- phenanthroline was described as being obtainable by the nitration of o- phenanthroline but no experimental details are given. Hazelwood, Hughes and Lyons

(Journ. and. Proc. Roy. Soc. ïT. .: ales, 71, _462) have synthesised 2-°nethyl-4- hydroxy-o- phenanthroline by the condensation of S- anino- quinoline with acetoacetic ester at 100° and subsequent cyclisation in paraffin oil at 270 °.

The _zethod of synthesis shows the proauct to be

2- methyl -4- hydroxy- o- phenanthroline and not the isoneric 2- hydroxy -4- methyl- o- phenanthroline.

' It will be seen from the above review that some of these phenanthrolines according to the literature show considerable pro,nise as antinala.rials, and it was thought desirable to extend the work done on m- and p- phenanthrolines to o- phenanthroline.

mother group of pyridoquinolines is theoretically possible, viz. that in which the extra/ extra pyridine ri::1; is fused to the oyricine

ring of the nuinoline nucleus instead of to the

benzene ring as in the case of the phenanthrolines

ritte.ipts were made by Reissert and by ;ose and

8en to prepare /.hydroxy-2:3, 2' :3'-pyrido-

áuinoline (XLII) .

Reissert (Ber. 1895, 28, 119) decarboxylated

the condensation product of d'- chloro- nibotinic with anthranilic acid, acid /and interpreted the course of the reaction

as follows:-

400C H ooC N ooc\

Co CO HooC

N N1-1 \ N / NN -24-

Bose _rid Sen (J.C.S. 1931, 2840) obtained

the 3r. ie compound by condensing o- chloro- pyridine

with La- nthranilic ¿ cid:-

Co /N N ooC

1414 NH

Seide (nanalen, 192/1, 311) by

interaction of o- chloro -benzoic acid snd a- amino-

pyridine isolated a compound identical with the

product obtained by Reissert and by Bose and Sen:

Hooc -i- /-NEIx N CQ

However, Seide showed from its properties

that the compound obtained was not 4- hydroxy-

2:3, 2':3'- pyridoquinoline, but 2:3-dihydrobenz-

quinazolone -4 ( XXIII), and that cyclisation to

the nitrogen of the pyridine nucleus takes place

according to the scheme blow:- -ú5-

H HaoG

N N H Nooc ./ -co

XXIII.

Kermack and A'e3therhead condensed c(- chloro-

nicotinic acid with aniline in an effort to

obtain hydroxy -2:3, 2':3'- pyridoruinoline but

were in

of the anilino- nicotinic acid:

./--..eCooH

N N NN

------,Coo rk

'''. N ''''''IrH

In the course of the present research it

was observed that ethyl- 2:6- dimethyl- 4- chloro-

nicotinate (XXIV) is readily obtained according

to/ -26-

to the literature from acetoacetic ester and ammonia, according to the following series of reactions:-

CHa-eaoí:}- H3-GO- CH.).- Cook CH-C- NH

oH c oot Hi,Coofr Goo4 CH CH

II III I c -1-- C` N3C \Nlia }N \GH3 H3 cH3

CQ. OH coo q4-

r+3c \N/'cr3

XXIV.

This compound proved useful as starting material in preparation of pyridoquinolines of this class, viz. derivatives of 2:3, 4':3'- pyridoquinolines.

The work to be described below may be conveniently divided into four sections: -

Attempts to obtain suitable hydroxy- and chloro -derivatives of o- phenanthroline from 8- amino- quinoline and its derivatives by methods such as that of Conrad and Limpach,

Synthesis/ -27-

Synthesis of 4- chloro -8- nitro- and 4- chloro-

8- amino -quinaldines with the object of synthesising o- phenanthroline derivatives from the latter through the Skraup synthesis, this section including a study of the nitration of

4- chloro - quinaldine and the synthesis of a number of 4:8- disubstituted quinaldines,

An improved method for the synthesis of o-phenanthroline by the Skraup reaction from o- phenylene diamine, its conversion to 2- chloro -o- phenanthroline, and the synthesis from the latter compound of a number of basically substituted o- phenanthroline compounds, and

The synthesis of derivatives of 2:3, 4':3'- pyridoquinoline. -28 a

II. ATTEMPTS TO SYNTHESISE HYDROXY- AND CHLORO-

DERIV1 TIVES OF 07PHENANTHROLINE FROM 8-

AMINO-gUINOLINE AND ITS DERIVATIVES. -29-

By the use of similar methods to those used

in the synthesis of m- and p- phenanthrolines as

discussed above, it was proposed to synthesise

analogous o- phenanthrolines. 8- amino -quinoline

and 6- methoxy -8- amino- quinoline suggested

themselves as suitable starting materials. If

these are subjected to the Skraup synthesis or

condensed with acetoacetic ester, o- phenanthroline

derivatives are theoretically obtainable

. according to the schemes formulated below:J-

Skr4up rea+,o j

Ctt3 Gocrfi coo$F I -30-

3 o

N V NNy

GH3' co. ctliceo4Y - H.o

N3G o Po

Lk NO mac/ Lrt6 cH3 8- amino -quinoline was readily obtained by

submitting o- nitraniline to the Skraup synthesis

and reducing the 8- nitro -quinoline so obtained

with iron and hydrochloric acid. The Skraup

reaction on 8- amino -quinoline, which was carried

out with the object of preparing o- phenanthroline

(I), resulted in considerable tarring.

Purification by crystallisation from water or by

extraction with benzene was difficult, but a small

amount of a product melting indefinitely at 97°-

110° was obtained. According to the literature,

the melting point of o- phenanthroline is 117°.

With one molecule of water it melts at 102 °.

The condensation of 8- amino -quinoline with

acetoacetic ester in the presence of hydrochloric

acid as catalyst was carried out at 100° as

described by Hazelwood, Hughes and Lyons (Journ.

and Proc. Roy. Soc. N.S.Wales, 71, 462). The

oily product which was isolated and which was presumably/ -31-

presumably ethyl -4- (8- quinolyl- amino) -crotonate

(II) was added to paraffin oil at 270° and a solid

product was isolated from the reaction. This

however melted at 218° and not at 196° as stated by the above authors. Many experiments were

carried out but in none of them was a product

melting at 196° obtained. A number of variations

were introduced in some of these experiments, e.g.

one was carried out in the presence of iodine as

catalyst, butthe same compound melting at 218°

was isolated. Analysis figures for this compound

agreed with the theoretical figures for 2- methyl-

4- hydroxy -o- phenanthroline (III) and one molecule

of water.

This compound was refluxed at 140° with

phosphorus oxychloride and pentachioride for 3

hours in an attempt to replace the hydroxyl group

by chlorine. Excess phosphorus oxychloride was

distilled off under reduced pressure, the residue

dissolved in water and made alkaline with ammonia.

The light brown precipitate was crystallised and

found to melt at 144 -5 °. Although the compound

/gave no inorganic residue on heating and gave a

positive test for chlorine, the analysis figures

did not agree with those expected for 2- chloro -o-

phenanthroline or for the hydrated form of this

compound, the hydrogen figure being definitely too/ -32-

too low.

when 6- methoxy-8- amino -quinoline was submitted to the Skraup synthesis a large amount of tar was formed and purification was difficult.

The black acid reaction product was made alkaline and extracted with benzene to give a yellow solution with a green fluorescence, but on recovery of the benzene only an impure tarry material was obtainable. In another attempt to obtain the desired 5- methoxy -o- phenanthroline (IV), the iron complex method of extraction described for o- phenanthroline by Tartarini and Samaja

(Annali di Chimica Applicata 23, 351) was used.

A saturated solution of ferrous sulphate was added to the acid product and made alkaline with an aqueous suspension of calcium hydroxide. The precipitated calcium salts were filtered off and a saturated solution of mercuric chloride added to the filtrate. The precipitate at this stage, which is presumably the mercuric chloride salt of the iron complex, was filtered off and treated with concentrated sodium hydroxide, warmed, and excess calcium hydroxide added to the mixture.

The residue on taking down to dryness at 120° was extracted with petroleum ether and also with benzene. On taking doon the extracts to dryness the residues were negligible so that none of the desired compound, viz. 5- methoxy -o- phenanthroline, was/ -33-

was obtained in this experiment.

In the case of o- phenylene diamine submitted to the Skraup reaction which is described below

(D. 55 ) , small amounts of o-phenanthroline were successfully isolated by the use of this method.

Attempts were made to apply the modified

Skráup synthesis described in E.P. 394416 to

6- methoxy-8- amino -quinoline. In this method, to which further reference will be made below

(pp. 56,q6 ) , concentrated sulphuric acid is replaced by sulphuric acid of 69% strength.

Although this method has been found to be of great advantage in many cases, it did not succeed with 6- methoxy-8- amino -quinoline, only unsatisfactory impure products being obtained from benzene and alcohol extracts.

Repeated attempts to prepare 2- methyl -4- hydroxy-5- methoxy -o- phenanthroline (V) by condensation of 6- methoxy-8- amino -quinoline with acetoacetic ester in presence of HC1 were unsuccessful. The reactants were heated for

ten hours at .100° , the product taken up in ether and washed with sodium bicarbonate and water.

After drying, the ether was distilled off and the residual oil poured into paraffin oil at

270°. The tarry material deposited on cooling was washed with ligroin and treated with 5N hydrochloric acid. The yellow solid so obtained/ -34-

Obtained was soluble in water, gave a diazo reaction similar to that given by 6- methoxy -8- amino- quinoline and was evidently the hydrochloride of the original compound. The filtrate from the yellow solid was made alkaline with ammonia, and the precipitate on crystallisation from alcohol melted at 121°. It was found by analysis to be 6-methoxy-8-acetoacetylamino-quinoline (VI) .

Hic o

Hc-co cA-12./ n o

VI.

The amide may have been formed to some extent during the heating at 100 °, or alternatively it may have been formed, on pouring into paraffin at 270 °, from the amine and acetoacetic ester which had failed to condense to the quinolyl- crotonic ester. That the second alternative was the probable one was shown by refluxing 6- methoxy -8- amino- quinoline with four times its weight of ester for two to three hours.

The liquid product solidified when treated with petroleum ether and on crystallisation from alcohol the solid melted at 121°. It did not depress/ -35-

depress the melting point of the product

obtained previously and gave the same brown-green

colour with dilute ferric chloride solution.

Several attempts were made to cyclise

6- methoxy -8- acetoacetylamino -quinoline to give

2- hydroxy -4- methyl -5- methoxy- o- phenanthroline (VII)

as follows:-

143 3 \/ _ } o N

i off o VII.

Treatment with sulphuric acid by standing

overnight and heating at 100° for an hour

yielded yellow hair -like crystals which

recrystallised from water to melt at 160 -170° and

which gave a positive diazo reaction. It was

thought to be the sulphate of 6- methoxy -8- amino-

quinoline, and treatment of this compound with

20% sulphuric acid gave long yellow crystals

which recrystallised from hot water and melted

at 158 -170 °. A mixed melting point with the

compound obtained before was not depressed.

When 6- methoxy -8- acetoacetylamino -quinoline was/ -36-

was refluxed with phosphorus oxychloride for two i to three hours tarring took place and no pure

product could be isolated. -37-

III. SYNTHESIS OF 4- CHLOR0- 8- NITRO- AND

4- CHLOR0- 8- AMINO- QUINALDINES WITH THE

OBJECT OF SYNTHESISING O-PHENANTHROLINES

FROM THE LATTER. A STUDY OF THE

NITRATION OF 4- CHLORO- UINALDII, AND THE

SYTTTHLSIS OF 4:8- DISUBSTITUTED QUINALDIIS. -38-

then it was found that attempts to synthesise o- phenanthroline derivatives from 8- amino- quinoline and 6- methoxy-8- amino- quinoline were yielding no satisfactory results, another scheme was drawn up using aniline and aôetoacetic ester as starting materials, as shown below:-

o1-{

crib. co - Chia- Coo

NHa

Poce3 t\i pCCs N c-413

CHa

N oa

and

Nmke( Ii Ranej 113 3

CN3 NH -39-

Although no derivatives of o- phenanthroline were obtained, several derivatives of 8- amino- and

8- nitro- quinaldines were synthesised.

The condensation of aniline and acetoacetic ester to form 4- hydroxy -quinaldine and the conversion of this compound to 4- chloro- quinaldine were carried out by well known methods, but as far as can be found in the literature the nitration of 4- chloro - quinaldine has not been reported.

Quinoline itself nitrates in the 5- and 8- positions. (Kaufmann and Hüssy, 3er., 1908, 41

1735) . It was shown by Balaban (J.C.o. 1930,

2349) that the nitration of 2- hydroxy -lepidine yields solely 6-nitro-2-hydroxy-lepidine. When the isomeric 4- hydroxy -quinaldine was nitrated by

Kermack and Afveatherhead (J.C.S. 1939, 563) the

6- nitro -derivative was again the sole product.

In the case of lepidine itself as shown by

Johnston and Hamilton (J. Amer. Chem. Soc. 63,

2864, (1941) ) tpe nitro group enters the 8- position, and it was shown by Johnston and

Hamilton (loc. cit) and by Krahler and Burger

(J. Amer. Chem. Soc. 64, 2417 (1942) ) that the major product in the nitration of 2- chloro -lepidine

was 8- nitro -2- chloro -lepidine, while a small, amount

of the 6- nitro - isomer was also formed. In the light of these facts it was thought probable that

4- chloro - quinaldine would yield 4- chloro -8- nitro- quinal dine/ -40-

on nitration.

The nitration of 4- chloro- quinaldine with the object of preparing 4-chloro-8-nitro- quinaldine presented considerable difficulty.

Early experiments were carried out using fuming nitric acid and concentrated sulphuric acid, the

4- chloro -quinaldine being added to a mixture of the acids in the cold. This method is the one usually used in the nitration of quinoline itself and it was also used by Krahler and Burger to nitrate 2- chloro -lepidine. The nitration product after standing overnight at room temperature was made alkaline by degrees, three successive batches of precipitated material being obtained.

From the first two batches, by crystallisation from a mixture of benzene and petroleum ether or from 50% acetic acid, were separated and purified small amounts of a nitro -compound melting at

111 -3°. Analysis showed that it was a mono- nitro-

4- chloro -quinaldine, and the first indication that it wàs probably the 8- nitro -compound was given by the observation that the compound had a low basicity. It is well known that quinoline derivatives substituted by the nitro group in the

8- position are less basic than derivatives substituted in other positions in the benzene ring.

This is apparently due to the proximity of the nitro group to the pyridine nitrogen. The compound/ -41-

compound obtained here was found to be insoluble in U or 2N hydrochloric acid in the cold, acid of

5 or 4N strength being required to dissolve it.

That this compound was in fact 4- chloro -8- nitro- quinaldine was shown by the following series of experiments.

The nitro -4- chloro- quinaldine was reduced by gaseous hydrogen in the presence of Raney Nickel as catalyst according to the method of Albert and

Ritchie (J. Proc. Roy. Soc. N.S. Vales, 74, 74,

1940). This method avoids the risk of removing the chlorine, which might be run if other methods of reduction were employed.

The amino -4- chloro -kui naldine so formed was converted by the Sandmeyer reaction to the dichloro - quinaldine which was found to melt at 81 -2 °. o- chloro -aniline was condensed with acetoacetic ester forming the crotonic ester, which was then cyclised to give 4- hydroxy -8- chloro -quinaldine.

By treatment with phosphorus oxychloride and phosphorus pentachloride this compound gave 4:8- dichloro- quinaldine melting at 84 -5 °, which was found (mixed melting point) to be identical with the dichloro -quinaldine obtained before. 4:8- dichloro- quinaldine was prepared by Krahler and

3urger(J. :mer. Chem. Soc. 64, 2417) who reported a melting point of 87-8°.

As good yields of 4- chloro -8- nitro -quinaldine could/ -42-

could not be isolated by the methods described above due to loss during purification, it was necessary to improve the method of separation.

This was done as described later by making use of the varying solubilities of 4- chloro -8- nitro- quinaldine in hydrochloric acid of different normalities.

The third batch of material, obtained on making completely alkaline the filtrate from the previous batch, was crystallised from normal nitric acid, as 5- and 8- nitro- auinolines had been separated by Dufton (J.C.S. 61, 783) by making use of the insolubility of the nitrate of 5-nitro- quinoline in dilute nitric acid. It was hoped that this treatment would separate any 5- nitro -4- chloro- quinal dine from 8- nitro -4- chloro- quinaldine.

An orange precipitate was deposited on cooling.

It was washed and dried and found to melt at

126 -7 °. Its solution in water was neutralised with sodium hydroxide, when a white crystalline solid was obtained which on crystallisation from alcohol melted at 111 -3 °. The mixed melting point with 8- nitro -a- chloro -quinaldine which melts at

this temperature was found to be 82 -105 ° The , mixed melting point with 6- nitro -4- chloro- quinaldine, which melts at 142° as shown by Kermack and Weatherhead (J.C.S. 1939, 563) who prepared it by the action of phosphorus oxychloride and phosphorus/ -43-

phosphorus pentachloride on 6- nitro -4- hydroxy- quinaldine, was 90 -105 °. This showed that the compound melting at 111 -3° was probably 5- nitro-

4-chloro- quinaldine .

A similar batch was crystallised twice from normal nitric acid and the filtrate from the second crystallisation deposited more crystals on standing.

These proved to be 4-chloro-6-nitro-quinaldine.

Its melting point was 140 -2 °, and the mixed melting point with a sample prepared by Kermack and

Weatherhead (loc. cit) was 141 -3 °.

From these results it will. be seen that the chief product of the nitration was 4- chloro -8- nitro- quinaldine, but that small amounts of 4- chloro - 6- nitro- and probably 4- chloro -5- nitro -quinaldines were also formed. However, the overall yield was poor.

The method of nitration was later greatly improved by using potassium nitrate and 100% sulphuric acid as anything less concentrated (96 or 98 %) resulted in considerable quantities of compound remaining unattacked. The nitration product was made completely alkaline in one step instead of carrying this out in stages, and the

4- chloro -8- nitro -quinaldine was isolated from the product by dissolving it in hot 2N hydrochloric acid. After any insoluble impurity had been removed by filtration, the solution was diluted wi th/ -44-

with its own volume of Water, thus precipitating the 4- chloro -8- nitro- auinalñine which is insoluble in cold N hydrochloric acid. It was crystallised from alcohol as yellow needles.

Attempts were made to separate by chromatographic analysis ( " Principles and

Practice of Chromatography " by Zechmeister and

Cholnoky) those products left in the N hydrochloric acid after precipitation of the 4- chloro -8- nitro- quinaldine. The filtrate was made neutral with sodium hydroxide and the yellow solid so obtained was filtered off, wished and dried. It was then dissolved in benzene.

The glass adsorption tube used. was approximately 1.5 cm. in diameter with a narrowed end fitted with a porcelain disc and a pad of cotton wool. Karrer and Nielson, quoted in

" Principles and Practice of Chromatography ", p. 203, separated the three nitranilines and also the three nitrophenols using a column of slaked lime. Slaked lime was therefore considered a suitable adsorber for the separation of these nitro -compounds. It was prepared by sprinkling calcium oxide with water, crushing well, and sifting. It was then packed firmly but not too

tightly into the adsorption tube which was then

fitted by an adapter to a íilter.flask. A little benzene was passed through the adsorber with a slight/ -45-

slight lowering of pressure, followed by the benzene solution of the solids to be separated.

Two bands of colour were formed, a narrow orange band, and a broad yellow band in the lower part

of the tube. The separation of the two bands

was developed by petroleum ether. The benzene

solution which passed through the column

unadsorbed was pale pink in colour, and on

evaporation, the solid which remained smelt of

4- chloro - quinaldine and evidently consisted

largely of material which had escaped nitration.

The column of adsorber was extruded by shaking

and knocking, keeping the column intact as far

as possible. The coloured bands were cut out, boiled several times in benzene and filtered.

The benzene was then distilled off but pure

products were not obtained.

A second sample of the yellow material

obtained by making neutral the N hydrochloric

acid solution was crystallised twice from

benzene and found to melt at 234 -5 °. Analysis

showed that it was presumably a mono- nitro -4-

hydroxy -quinaldine. This compound which was

chlorine -free was insoluble in cold water, but

Soluble in hot water and soluble in dilute

sodium hydroxide. A mixed melting point with

4- hydroxy- quinaldine which melts at 230 -2° was

found to be 214-225°. The melting point of

6 -/ -46-

6- nitro -4- hydroxy -quinaldine is over 400° (Kermack and leatherhead, J.C.S. 1939, 563) .

8- nitro -4- hydroxy- quinaldine which melts at 224-

9° had been prepared as described later by

hydrolysis of 8- nitro -4- methoxy uinaldine.

mixed melting point of a sample of this and the

compound obtained here showed no depression. The

compound, which gave satisfactory analysis figures,

was therefore a purer sample of 4- hydroxy -8- nitro-

quinaldine than that obtained from 4- methoxy -8- nitro- quinaldine. Hydrolysis of 4- chloro -8- nitro-

quinaldine to the 4- hydroxy -8- nitro - quinaldine

isolated here evidently took place after nitration

and not before, for in the latter case the 4-

hydroxy-6- nitro- nuinaldine would have been isolated

at this point. It is probable that the hydrolysis

occurred during the process of separation, and so

the treatment with 2N hydrochloric acid was made

as brief as possible.

The combined filtrates from the benzene

mother liquors after separation of the 4- hydroxy-

8- nitro- quinaldine were submitted to

chromatographic analysis by passing through the

calcium hydroxide column, and developed as before

with petroleum ether. Similar results to those

of previous analyses were obtained, two bands

separating and a pale pink benzene solution

passing through, but again no pure compounds were

isolated/ -47-

isolated.

A third sample of the yellow material

obtained by neutralising the N hydrochloric acid

filtrate was boiled in N sodium hydroxide and

filtered hot. The small amount of insoluble material was found to be 4- chloro- 8- nitro-

quinaldine . Its melting point was 110 -4° and a mixed melting point 109-112°. The filtrate which was red in colour was made neutral with hydrochloric acid and the yellow material precipitated was found to be 4- hydroxy-8- nitro- quinaldine. Its melting point, 218 -227 °, showed it to be slightly impure but a mixed melting point with a sample (melting at 224-9 °) obtained by hydrolysis of the methoxy compound was not depressed (223 -30 °) . Chlorine was saovm to be absent from this compound.

It was thus shown that the nitration of 4- chloro- quinaldine yields mainly 4- chloro -8- nitro- quinaldine but that small amounts of 4- chloro -6- nitro- and probably 4- chloro -5 -nitro- quinaldines are also formed. It was also shown that in the working up of the product, a fraction of the __A- chloro-8-nitro-quinaldine is converteá/L 4- hydroxy-

8- nitro- quinaldine . There is an indication too that some of the 4- chloro -quinaldine escapes nitration.

These results are in agreement with those obtained/ -48-

obtained by Burger in the nitration of 2 -c l,ro- lepidine, but in sharp contrast to t....: dbt aftn I

in the nitration of the correspori : 7;; compounds, in which case the &-nitro derivat iTe were the sole products.

4- chloro -8- nitro- quinaldine was successfully reduced in alcoholic solution to 4- chllcro -B- no- quinaldine by gaseous hydrogen in presence of

Raney Nickel as catalyst, as described. abri and Ritchie (J. Proc. Roy. Soc. 1.3. W=Oes, 74,

74, 1940) . The amino- quinaldi e melting at we-

110° was obtained as yellow cri sta ltne plates in

55 yields.

The availability of _- chlorc -8- itro- end

4- chloro -8- amino- quinaldines it d firstly to atteargte

to prepare 2-methy1-4-chicro.-c _ __enthrolfuzne submitting 4- chloro -8 -amin -quinali diimrs tel Et Skr .`.. uHr,f synthesis, with the idea of tainüug* rnïl tü;. ft1LT, a series of o- phananthrolines substituted in position 4 by basic side -ca ^'n,, and second to

the preparation of quinaldines substituted in tt e

4- and 8- positions.

The Skraup reaction on 4-cb oro -83- mdma,

quinaldine, which was carried out us

concentrated sulphuric acid before the -e Tantlles

of the modified method described In ÿ -P' - a 4 A6

were realised, yielded no satisfactory product..

An impure solid was isolated wtose point

220-250°/ -49-

220-250°, was widely divergent from that (144-5°) given by the product obtained by the action of phosphorus oxychloride and phosphorus pentachloride on the compound assumed to be 2- methyl -4- hydroxy -o- phananthroline, as described in the previous section, but, as has been pointed out, this chloro- compound gave unsatisfactory analysis figures.

When 4- chloro -8- nitro -quinaldine was treated with sodium and methyl alcohol, a satisfactory yield of 4- methoxy -8- nitro -quinaldine, melting at

129-130°, was obtained.

4- methoxy-8- nitro -quinaldine was refluxed with

5N hydrochloric acid to hydrolyse it to the 4- hydroxy- compound. On taking down almost to dryness and adding water an orange solid melting at 231 -2° was isolated, but on recrystallisation with ethyl alcohol the melting point was lowered to 229°. mentioned above, a mixed melting point with the a subs ce obtained in the purification of 4- chloro-

8- nitro -quinaldine showed no depression, both compounds being 4- hydroxy -8- nitro- quinaldine.

When 4- methoxy -8- nitro -quinaldine was reduced by hydrogen in the presence of Raney Nickel as catalyst by the method of Albert and Ritchie, 4- methoxy-8- amino - quinaldine melting at 114-6° was isolated in satisfactory amounts. For analysis it was converted by treatment with acetic anhydride to 4- methoxy- 8- acetylamino- quinaldine, which/ - 50-

which was a well- defined compound melting at 144-6°.

Attempts were made to condense 4- methoxy -8- amino- quinaldine with diethylaminoethyl chloride hydrochloride, as the plasmoquin analogue which would be formed in this way would have considerable chemotherapeutic interest. The method followed was that used in the synthesis of 8- diethylaminoethylamino- quinoline by Magidson and 8trukov

(Archiv. der Pharmazie 1933, 271, 359), and again in the synthesis of 6-methoxy-8-diethylaminoethylamino-quinoline by the same authors (Archiv. der

Pharmazie 1934, 272, 74) . Equimolecular weights of 4- methoxy -8- amino -quinaldine and diethylaminoethyl chloride hydrochloride were heated together at 120 -140° for eight hours, when the diazo test gave a negative result. From the clear red brittle product a base was isolated in the form of a yellow oil which could not be induced to crystallise. A picrate was formed which did not crystallise Well and which gave an indefinite melting point. The yellow oil was also treated with salicylic acid in ethereal solution. A yellow oil was deposited which solidified on scratching and prolonged standing. The solid was crystallised from alcohol and found to meltat

212 -3° but gave very unsatisfactory analysis; figures and was evidently not the desired salicylate 4 -/ -51-

4- chloro -8- nitro -quinaldine was heated at

140 -150° with diethylaminoethylamine for four to

five hours under reflux. The oily product was

treated with N hydrochloric acid which dissolved most of the oil but which left behind a small

amount of a light brown solid melting at 104-6°.

From the acid solution on addition of ammonia a

dark brown solid separated which was extracted

with ligroin. On recovery of the ligroin a

reddish -brown oil was obtained which, by

treatment with picric acid in alcoholic solution,

yielded an impure orange solid of indefinite melting point. It was not improved by

crystallisation from alcohol. A second experiment carried out in the presence of a trace

of copper yielded similar results.

An attempt was made to isolate the desired basically substituted quinaldine by use of the

3 :5- dinitro-benzoic acid salt, as this was found

to be successful in purifying the o- phenanthroline

derivatives (p.1040. The reactants were heated

together as before, and after excess base had' been removed in vacuo the black tarry residue was

dissolved in 50jß, acetic acid, made alkaline with

ammonia and extracted with ether. The brown oil

which remained on removal of the ether was treated

with 3:5- dinitro- benzoic acid in alcohol. The z

sticky orange precipitate was crystallised twice from/ -52-

from alcohol but each time a brown solid was obtained which became sticky on standing in the air.

4- chloro -B- nitro- quinaldine was heated at

140 -150° with an equimolecular amount of d- methyl-

S- diethylaminobuty1amine for 2 -3 hours. The sticky black product was dissolved in dilute hydrochloric acid, leaving behind a little brown solid melting at 109 -111 °. The filtrate was made alkaline with ammonia and extracted with ether.

On recovery of the ether, only a black tarry material remained. An attempt was made to effect the condensation in the presence of dry phenol as solvent. The mixture was heated at 100° for

3 -4 hours and the product poured into 2N sodium hydroxide. The tarry material formed was extracted with N hydrochloric acid and the acid extract made alkaline with ammonia. A dark brown solid was precipitated which was found to be soluble in alcohol and benzene, but which did not crystallise successfully. -53-

IV. SYNTIESIS OF 0- PHENANTHROLINE AND ITS

CONVERSION TO A NUMBER OF BAASICALLY

SUBSTITUTED DERIVATIVES. - 54-

As efforts to obtain o- phenanthroline

derivatives by these methods did not appear to be

yielding satisfactory results, attention was

directed to obtaining o- phenanthroline in good

yields from o- phenylene diamine by means of the

Skraup synthesis, so that o- phenanthroline could

be used as a starting,material to obtain its

derivatives.

o- phenanthroline was prepared first by Blau

(Monatsh. 10, 66 (1898) ) by the Skraup synthesis,

from o- phenylene diamine as well as from 8-amino-

quinoline, but he does not however describe the

.experimental conditions. C.R.Smith (J. Amer. Chem.

Soc. 52 , 402 (1930) ) studying the application of

a modified Skraup synthesis to the three phenylene

diamines, prepared in good yield m- and p-

phenanthrolines from m- and p- phenylene diamines

respectively, but states that he did not succeed

in obtaining o- phenanthroline from o- phenylene

diamine under the same conditions. The

preparation of o- phenanthroline from o- phenylene

diamine by the Skraup synthesis was carried out by

a yield Hieber (Ber. 61, 2150 (1926) ) who obtained

of 30%. Instead of using an organic solvent to

extract/ -55-

extract the base, Hieter used a dilute solution of sulphuric acid from which the base was precipitated by the addition of a concentrated solution of mercuric chloride. There is little doubt that o- phenanthroline is formed in the Skraup reaction but owing to the large amount of tar it is difficult to separate it. This is confirmed by

Tartarini and Samaja (Annali di Chimica Applicata,

23, 351) who obtained o- phenanthroline in good yields by using a more complicated method of isolation. These authors precipitated the iron complex of the base with sodium perchlorate, or, preferably, with mercuric chloride. The resultant crystalline salt was then decomposed with alkali and the base extracted with petroleum ether.

In the present work, some experiments were first carried out on the application of the ordinary

Skraup synthesis to o- phenylene diamine. Much tarring occurred, but by making the diluted acid product al saline with sodium hydroxide and extracting with ether small amounts of a white solid melting at 98 -110° were obtained. In an experiment following Tartarini and Samaja's iron complex method of extraction a small amount of material melting at 115 -7° was obtained, but the yield was very poor compared with that claimed by these authors, and the method was found to be laborious and time- consuming.

o- phenanthroline/ -56-

o- phenanthroline was eventually obtained with relative ease in good yield by the use of

the modified Skraup synthesis (cf. .P. 394416) .

The general idea of the modification is to introduce a certain amount of water to ensure milder conditions and so reduce tarring. o- phenylene diamine was refluxed with 69% sulphuric acid, 80% arsenic acid and 90% glycerine for two hours. The absence of a diazo reaction could not be used to test for the end of the reaction as o- phenylene diamine reacts with nitrous acid to give benz -triazole (I) :-

NH;. Ho\\I, + -- NIa O

It was found, however, that the end of the reaction was marked by frothing of the black acid liquid. when the reaction product was diluted with water and made alkaline with ammonia, a black tar was deposited and filtered off. The tar and filtrate were extracted separately with benzene and thé extracts combined to give a red- orange solution. When. the benzene was removed bÿ distillation a light brown solid melting at

99 -105 ° / -57-

990 -1050 was obtained in 50iß yield.

It will be seen that the successful application of the modified Skraup synthesis to o- phenylene diamine with the greatly increased yields ofo- phenanthroline constitutes a considerable improvement over previous methods.

The scheme formulated below, which involves a well -known series of reactions, shows how a number of o- phenanthrolines substituted by basic side- chains in position 2 was obtained:-

CM I in ni1'ro ben zen c

II.

IV. -58-

o- phenanthroline methiodide (II) was

obtained by refluxing a solution of o- phenanthroline

in benzene with methyl iodide for an hour, when the yellow methiodide was deposited in 50 -60% yields. Better yields were obtained however by dissolving the o- phenanthroline in nitro -benzene and allowing to stand overnight in contact with methyl iodide at 37 °. The yellow crystals which were deposited were washed with benzene till free from nitrobenzene and crystallised from alcohol.

By allowing the nitro benzenes filtrate to stand

in contact with more methyl iodide, more of the

desired compound was deposited, bringing the yield to 80 -90% of the theoretical. The compound, which

fhe. was found by analysis to be /mono -methiodide, melted at 210 -213 °. hs the 2 nitrogen atoms in o- phenanthroline are identical, there is no possibility of two isomeric mono -methiodides being formed as in the case of m-phenanthroline.

Oxidation of o- phenanthroline methiodide to

1- methyl- 2- o- phenanthrolone (III)was carried out using/ -59-

using alkaline potassium ferricyanide solution.

Saturated solutions of sodium hydroxide and o- phenanthroline methiodide were added alternately to a saturated solution of potassium ferricyanide in the cold. Some difficulties in obtaining a satisfactory product, encountered in early experiments, were overcome by ensuring the presence of a large excess of sodium hydroxide.

The yellow precipitate which was deposited was filtered off and extracted with benzene. ns 1- methyl -2 -o- phenanthrolone was found to be somewhat soluble even in strongly alakaline solution, the filtrate was taken down to dryness and also extracted with benzene. On recovery of the benzene from-the combined extracts, 75j yields of 1- methyl -2 -o- phenanthrolone were

obtained. The compound was crystallised. from benzene and found to melt at 123-4°.

To prepare 2- chloro- o- phenanthroline (IV),

1- methyl -2 -o- phenanthrolone was refluxed at 160''

with phosphorus oxychloride and phosphorus pentachioride for 8 hours, at the end of which

time all solid material was in solution. ixcess phosphorus oxychiorid_e was distilled off under reduced pressure, and ice and water were added

to dissolve the solid residue. Neutralisation

with ammonia gave a light brown precipitate which

was crystallised from water. The compound, and which was obtained in 706 yields, /melted at 126°,

depressed/ /l - 60-

depressed the melting point of the 1- methyl -2 -o- phenanthrolone and gave a satisfactory analysis

figure for chlorine.

The final stage in the synthesis was the

condensation of 2- chloro -o- phenanthroline with

various bases. It was heated with piperidine

for two hours at 100° and after removal of excess

piperidine under reduced pressure the product was

dissolved in 4N acetic acid, made alaline with

ammonia and extracted with ether. On recovery

of the ether, an orange oil was isolated which

was treated with picric acid in alcoholic solution.

The orange solid deposited was crystallised from

alcohol, to melt at 213 -7° and was shown by

analysis to be the mono -picrate of 2- piperidino -o-

phenanthroline with one molecule of water.

The condensation with aniline was also

carried out at 100° and after 2 hours heating the

product showed the presence of chlorine ions.

Water and sodium hydroxide were added and excess

aniline removed by steam distillation. The solid

which was left was filtered off and crystallised

from alcohol as pale yellow rods, melting at

231 -2 °. Analysis figures agreed with the

theoretical ones for 2- anilino- o- phenanthroline,

but the compound gave a faintly positive copper wire

test for chlorine.

2- chloro- o- phenanthroline and diethylamino-

ethylamine were heated at 140 -150° for 6 -7 hours. After/ after excess base had been removed, the oily product, which gave a positive test for ionised

chlorine, was dissolved in 2N acetic acid and made

alkaline with ammonia. It was then extracted with ether to give a yellow solution with a green fluorescence and on removal of the ether the base was obtained as a yellow oil. The oil did not give a hydrobromide with alcoholic hydrogen bromide, but with alcoholic hydrogen chloride a pale yellow precipitate was deposited which, however, was deliquescent in the air. With picric acid in alcoholic solution, a yellow solid was obtained whose melting poiait 177 -187° was not improved by crystallisation. The salicylate was deposited as an oil by salicylic acid in ethereal solution, but it failed to solidify on scratching and standing. The hydrochloride was dissolved_ in dilute hydrochloric acid, and on adding a saturated aqueous solution of -mercuric chloride a salt was precipitated wWhich, on crystallisation from N hydrochloric acid, melted with softening at 200'. Its analysis fir greed with the theoretical figares _ 1.cu1e of the base with three molecules - . yaroch: uric acid, one molecule cf molecule of water. The put-fi, if- amínoe thyl a nino- o-gh_enan throlir e was Tre_ ,,I.y improved by the use of its ._, _ salt with 3:5/ -62-

3:5- dinitro- benzoic acid. It was formed from alcoholic solution and crystallised from alcohol as long yellow rectangular plates melting at

190 -2 °. Analysis showed it to contain one molecule of 2- diethylaminoethylamino -o- phenanthroline and two molecules of 3:5- dinitro- benzoic acid.

The condensation of 2- chloro -o- phenanthroline with diethylaminopropylamine was carried out by heating the two compounds at 170 -180° for five hours. The oily pros .uct after removal of excess base in'vacuo was treated with alcoholic hydrogen bromide. The orange precipitate which was formed on addition of acetone was crystallised from alcohol and found to melt at 274 -284 °.

Its analysis figures were very unsatisfactory.

The figures for carbon, hydrogen and bromine agreed with the theoretical ones for the dihydrob romide of diethylaminopropylamine but the nitrogen figure was 1% low. Later, the working up of the product was carried out as for the 2- diethylaminoethylamino -o- phenanthroline.

After excess base had been removed; the product was taken up in 2N acetic acid, made alkaline with ammonia and extracted with ether. On removal of the ether, the base was obtained as a yellow oil. As in the case of 2- diethylaminoethylamino-o- phenanthroline, several attempts were/ - 63-

were made to convert the base into a suitable

salt for analysis. The hydrob romide and

hydrochloride which were both formed as yellow

solids were found to be deliquescent in the air.

The picrate did not crystallise well, whilst

me rcuricchloride gave a crystalline salt melting

at 200 -210° which did not give a satisfactory

analysis. As before, the 3:5- dinitro- benzoate

was found to be the most satisfactory salt for

purifying the base. It crystallised from alcohol

as long yellow rectangular prisms melting at

150 -2° and was found by analysis to consist of one molecule of 2- diethylaminopropylamino -o- phenanthroline and two molecules of 3 :5- dinitro- benzoic acid.

2- chloro- o- phenanthroline and O( -methyl- _

die thylaminobutylamine were condensed together

and the product worked up in the same way as beforé, the base being obtained as an orange brown

oil. An impure picrate was formed melting at

130 -155° with darkening at 115°, but it would not

crystallise well. The mercuric chloride salt was

formed with difficulty and found to melt at 170-

180° . Its analysis figures for carbon, hydrogen

and nitrogen agreed fairly well with the

theoretical ones for one molecule of 2- (a- methyl-

8- diethylaminobutylamino) -o -phe nanthroline with

two molecules of hydrochloric acid and one of mercuric/ - 64-

Í mercuric chloride. Ultimately, the base was

isolated successfully as the 3:5- dinitro -benzoate,,

It was formed as an Oil when alcoholic solutions

of the two substances were mixed. It solidified,

however, on standing and was crystallised from

alcohol as small yellow needles melting at 157 -8 °.1

It was found by analysis to consist of one

molecule of 2 -(0(- methyl- S-- diethylaminobutylamino)-

o- phenanthroline with two molecules of 3:5- dinitro- benzoic acid and one molecule of water.

The last three compounds are compounds of

the type it was desired to synthesise, i.e. o-

phenanthroline compounds carrying a basic side -

chain. The chief difficulty met with in the

synthesis was that of obtaining a salt suitable

for the purification of the base.and for its

characterisation and analysis. For all three

compounds the 3:5- dinitro- benzoate was superior

to any of the other salts investigated, and it

would seem that 3:5- dinitro- benzoic acid may prove

to be a reagent especially useful in isolating

and purifying bases similar to those described

ab Ove . - 65-

V. SYNTEESIS OF DERIVATIV,61S OF 2:3, 4's3'-

PYRIDOQUINOLIIT,±3S. - 67-

. thylAQ- amino- crotonate (I) . was prepared by

Precht (3., 11, 1194) who saturated with gaseous

:ammonia an ethereal solution of ethyl acetoacetate

cooled in ice. This method was tried and a small

amount of solid which was deposited was filtered

off. It melted in a very short time to a yellow

liquid. The ethereal solution was again

saturated with ammonia and on recovery of the

ether mòre yellow' liquid was obtained which

distilled at 131 -2° at 50mms. pressure. Setter yields of ethyl ,B- amino- crotonate were obtained however by the method described by Duisberg

(A. 213, 71). The ethyl acetoacetate was shaken up well with aqueous ammonia and the yellow oily layer which separated distilled at 100 -110° at 20 mms. pressure.

The condensation of ethyl /4- amino- crotonate to form ethyl 2:6- dimethyl -4 -chloro- nicotinate (II) was carried out as described by Michaelis and

Hanisch (s., 35, 3156) by the action of phosphorus oxychloride in dry benzene. Satisfactory yields were obtained of a yellow oil which had a smell slightly suggestive of that of mice and which distilled at 130- 150° at 14 mms. as described in the literature.

Ethyl 2 :6- dimethyl -4- chloro- nicotinate was refluxed with 5N hydrochlor'ic acid to hydrolyse it to 2:6- dimethyl -4- chloro- nicotinic acid. On evaporating/ -68-

evaporating to dryness a brown oil was obtained which could not be crystallised but which was presumably the hydrochloride of the acid. It was treated directly with p- anisidine in amyl alcohol in the presence of potassium carbonate and a trace of copper bronze. On working up the product, a colourless compound was obtained which was chlorine -free and which melted at 275°. Its analysis figures agreed with the theoretical figures for 2:6- dimethyl -4 -(p- anisidine)- nicotinic acid (III).

Ethyl 2 :6- dimethyl -4- chloro -nicotinate itself was treated with p- anisidine at 140 -150° in the presence of copper bronze, and the solid piloduct which was formed with frothing was crystallised as colourless leaflets and found to be identical with the 2:6- dimethyl -4-(p- anisidino)- nicotinic acid isolated before, and no trace of the expected ester could be found. The de- ethylation of the ester is presumably caused by the action of hydrogen chloride formed in the course of the reaction.

An experiment was carried out in which ethyl

2 :6- dimethyl -4- chloro- nicotinate and p- anisidine were heated together at 100°, the lower temperature being used for the heating with the object of isolating the ester before it could be hydrolysed by hydrogen chloride. The product was/ -69-

was diluted with water, made alkaline with sodium

carbonate and steam distilled to remove excess

p- anisidine. The residue was filtered hot and

on cooling a greyish material was deposited.

After crystallisation from aqueous alcohol it melted at 88 -90 °, and analysis showed it to be

the desired ethyl 2: 6- dimethyl -4- (p- anisidino)- nicotinate. On taking down the aqueous filtrate,

2:6-dimethyl- 4- (p- anisidino)- nicotinic acid was deposited.

When 2:6-dimethyl- 4- (p- anisidino)- nicotinic acid was dissolved in phosphorus oxychloride and refluxed for two hours a greenish yellow material was deposited in the course of the reaction.

After excess phosphorus oxychloride had been distilled off in vacuo, the green residue which remained was made alkaline by a solution of sodium carbonate in the presence of ice and ether, and extracted with ether. The extract was deep red in colour with a purple fluorescence. The ether was distilled off, leaving a yellow solid which, after crystallisation from alcohol, melted at 293-5°. .It was found by analysis to be 4-

hydroxy-6- methoxy-2' : 6'- dimethyl -2:3, 4':3'- pyridoquinoline (IV) instead of the desired

4- chloro- 6- methoxy -2' : 6'- dimethyl -2 : 3, 4/:31- that pyridoquinoline . It seems therefore cyclisation had taken place but that the hydroxy- compound/ -70-

compound had not been converted to the expected

chloro- derivative. Experiments were therefore

carried out in which the acid was heated with a

mixture of phosphorus oxychloride and phosphorus

pentachloride, and great care was taken in working

up the product to avoid conditions which might

cause hydrolysis of the chlorine atom, but the

product isolated was always the same, viz. 4-

hydroxy-6- methoxy -2' : 6'- dimethyl -2:3,

pyridoquinoliné. It appeared therefore that the

chloro- compound could not be obtained, and so it

was not necessary to have ether present when

treating with sodium carbonate, the object of the

ether being to remove as quickly as possible any

chloro - compound which might be formed, from the

presence of water which might hydrolyse it. The

hydroxy- compound was conveniently isolated by

filtering off directly the light brown precipitate

deposited on making alkaline with sodium carbonate

and crystallising it from alcohol.

The possibility arises that cyclisation with

loss of water may occur with the formation of a

lactam structure, as follows:-

3c N H

cN3 Ct13 -71-

The resulting structure, being without any actual or potential hydroxy- group, could not form a chloro -derivative, and so its failure to react with phosphorus oxychloride and phosphorus

pentachloride would be accounted for. . However, this compound, containing as it does a four- membered lactam ring, would. be expected to be susceptible to hydrolysis with the formation of the original ac±d.

When the compound was heated at 100° with 4N hydrochloric acid only slight solution took place, and the residue which melted at 300 -310° with darkening contained chlorine. When treated with sodium hydroxide the original compound was recovered.

The chlorine- containing material was evidently a hydrochlorideinsoluble in excess hydrochloric acid.

When the compound was heated at 100° with 4N sodium hydroxide it slowly dissolved. On cooling, a crystalline compound was deposited,, melting at

283-290°, and was shown by mixed melting point

(285 -292 °) to be the unchanged compound.

These experiemnts show that this compound has considerable stability to both acid and alkali, and this makes the lactam structure improbable. It would seem therefore that the compound pos:essez the structure IV, and is in fact 4- hydroxy- 6- :methoxy-

2': 6'- dimethyl -2:3, 4':3'- pyridoquinoline.

A further attempt was made to obtain 4- chloro-

6- methoxy- 2':6'- dimethyl -2:3, 4':3'- pyridoquinoline, this time by heating 4- hydroxy- 6- methoxy- 2' :6'- dimethyl/ - 72-

dimethyl -2:3, 4':3'- pyridoquinoline with a mixture of phosphorus oxychloride and phosphorus pentachloride.ixcess oxychloride was removed in vacuo and the residue made alkaline with sodium carbonate in the presence of ice and ether.

After shaking, the ether was removed, and further extraction with ether gave an orange solution with no fluorescence. On distilling off the ether, a sticky orange material was obtained which could not be purified by boiling either in ligroim or alcohol. The intractable product, although it may have contained some of the desired chloro- compound was obviously impure and it looked as if conditions of treatment had been too drastic.

This suggested the use of a diluting solvent, and so an experiment was carried out in which the pyridoquinoline, phosphorus oxychloride and phosphorus pentachloride were dissolved in dry redistilled nitrobenzene and the mixture refluxed for four hours. A dark yellow solid was deposited

during the reaction, and on cooling it was filtered

off and washed with benzene. It :pelted at 305- and depressed the melting 315° , contained chlorine, in point of the original compound. Treatment the

cold with N sodium hydroxide for 45 minutes

yielded the original 4- hydroxy- pyridoquinoline The (m.p. 275-285°. Iviixed m.p. 285 -295 °) .

product was evidently the hydrochloride of the

original/ -73-

original 4- hydroxy -pyridoquinoline, the melting point agreeing with that (300 -310 °) given by the product obtained as described above by the direct action of hydrochloric acid on 4- hydroxy -6- methoxy

2' : 6'-dimethyl-2:3, 4' :3'-pyridoquinoline :

It is thus shown that 2: 6- dimethyl -4- (p- anisidino) -nicotinic acid was 'successfully cyclised to yield 4- hydroxy-6- methoxy -2' : 6'- dimethyl -2:3, 4':3'-pyridoquinoline, but so far it has been found impossible to obtain the 4- chloro-pyridoquinoline and therefore impossible

to condense it with suitable bases. - 74-

VI . E R NTAL -75-

8-nit ro -quinoline.

o- nitraniline (22 gm.) , glycerine (48 gm.) , concentrated sulphuric acid (44 gm.) and arsenic acid (23 gm.) were mixed together and boiled for

2 -3 hours, after which time the d.iazo test gave a negative result. The product was diluted with its own volume of water and made alkaline with sodium hydroxide. The dark brown precipitate was filtered off and recrystallised from alcohol. m.p.

87-8°. Yield 16 gm. (50 -60% theory) .

8- amino -quinoline.

Powdered iron (30 gm.), concentrated hydrochloric acid (2 c.c.) and water (20 c.c.) were heated to 100° under air condenser. 8- nitro- quinoline (29 gm.) was then added gradually with vigorous shaking and continued heating over the space of 2 -3 hours. After standing overnight, the product was made alkaline with sodium hydroxide and steam distilled. The solid deposited in the distillate was filtered off, and more was obtained by extraction with ether. from the filtrate m'p' .

theory) . 66 -7° . Yield 18.6 gm. (78% -76-

o -johenanthroline from 8- amino- quinoline.

8- amino -quinoline (10.5 gm.) and glycerine

(15 gm.) were mixed together. . A mixture of concentrated sulphuric acid (7.5 c.c.) and arsenic acid solution (7.5 c.c. Sp.Gr. 1.8) was slowly added with shaking. Heat was applied to produce gentle boiling, steam being allowed to escape.

After half an hour, an air condenser was attached and boiling continued for 3 -4 hours, the condenser being removed from time to time to allow the escape of steam. The product, which gave a negative diazo test, was diluted with water, made alkaline with ammonia and extracted with benzene while still warm. On removal of the benzene a brown oil remained which', on boiling with petroleum' ether, solidified to a brown solid. m.p. 97-110°.

Yield 1.8 gm. The considerable amount of tar which remained after extraction with benzene was boiled in benzene to give a further 0.7 gm. of solid.

Condensation of 8- amino -quinoline with ethyl acetoacetate.

(Hazelwood, Hughes and Lyons. J. and Proc. Roy.

Soc. N.S. Wales 71, 462) .

acetoacetate 8- amino -quinoline (10 gm.) , ethyl

acid (3 drops) were ( 8 gm.) and 5N hydrochloric 10 hours. heated at 100° under air condenser for The/ -77-

The oily product was ta_;en up' in ether, washed with sodium bicarbonate and mater, and the ether extracts dried over anhydrous sodium sulphate.

The ether was removed by distillation, and the excess ester removed under reduced pressure. The residual oil was poured slowly into 6 times its volume of paraffin oil kept at 270 °. The tarry solid deposited on cooling was separated from the paraffin and washed with Petroleum ether. It was recrystallised from alcohol and then from benzene as small white rods. m.p. 218 -9 °. Yield 1.85 gm.

(Found: C, 69.0; H, 5.0; N, 12.3. C1 3H1 0 7N2 .

H20 reouires C, 68.4; H, 5.3; N, 12.3%) .

The compound is soluble in alcohol and dilute hydrochloric acid.. It is slightly soluble in acetone and insoluble in water, ether, benzene and dilute sodium hydroxide.

2- methyl -4- chloro- o- phenanthroline ?.

The product from the previous experiment phosphorus ( 1 gm.) was refluxed at 140° with pentachloride oxychloride ( 6 c.c.) and phosphorus

(1 gm.) for 3 hours. Excess oxychloride was distilled off under reduced pressure and the residue treated with water. after a little black impurity had been filtered off, the clear brown solution was made alcaline with ammonia. The pale/ -78-

pale brown precipitate was filtered off and recrystallised twice from aqueous alcohol. The light brown amorphous material melted at 144-5°.

(Found: C, 64.6; H, 3.3. CL 3H9N2 Cl requires

C, 68.2; H, 3.9. Ci 3H9N2 Cl.H2 0 requires C, 63.2;

H, 4.4%).

The. compound is soluble in alcohol, benzene, acetone and N hydrochloric acid. It is insoluble in water, and in N sodium hydroxide. It gave no inorganic residue on heating and gave a positive copper wire test for chlorine.

Skraup reaction on 6- methoxy -8- amino -quinoline.

1. 6 -me thoxy- 8- amino- quinoline (15 gm.) , glycerine (24 gm.), concentrated sulphuric acid

(22 gm.) and arsenic acid (12 gm.) were boiled under reflux for 2 -3 hours, when the diazo test gave a negative result. The black acid liquid was poured into its own volume' of water and after filtering off a little tarry impurity it was made alkaline with sodium hydroxide. A black tarry material was deposited and filtered off. The tar and filtrate were extracted separately with ether, but on recovery of the 'ether an impure brown oil was obtained which could not be crystallised satisfactorily. Extraction with benzene yielded similar results. -79-

2. In this experiment , . the working up of the product was modified, the method used for the separation of o- phenanthroline by Tartarini and

Samaja (Annali di Chimica Applicata 23, 351) being adopted. To the black acid reaction product, from the materials as described above,. was added a saturated solution of ferrous sulphate

(containing 46 gm.), and a suspension of calcium hydroxide added until alkaline. The precipitated salts were filtered off, and to the filtrate was added a saturated solution of mercuric chloride.

The precipitate was filtered off, treated with. excess sodium hydroxide, warmed, and excess solid calcium hydroxide added. The mixture was then thoroughly dried at 120° and extracted with petroleum ether and with benzene. On recovery of these sólvents, only a little oily residue was obtained.

3. (cf. L.P. 394416)

6- methoxy -8- amino- quinoline (10 gm.), glycerine (18 c.c.), arsenic acid (27.2 gm.),

69% sulphuric acid (73 c.c.) and water (10 c.c.) were refluxed together for 3 -4 hours, after which

time the diazo reaction was negative. The

reaction product was diluted with water and made

alkaline with ammonia. The tar which was

deposited/ -80-

deposited was filtered off and the tar and the

filtrate extracted separately with benzene to give a yellow solution with a green fluorescence.

The extracts were shaken with charcoal-but-on

recovery of the benzene a little brown solid was

obtained which could not be crystallised

successfully. The tar was also extracted with

alcohol. The dark red solution obtained was boiled with charcoal, and on distilling off the

alcohol a red tarry material was obtained which,

however, again did not crystallise well.

Condensation of 6- methox -8- amino -quinoline with

ethyl acetoacetate.

6- methoxy -8- amino- quinoline (12 gm.) , ethyl

acetoacetate (8 gm.) and 5N hydrochloric acid

(3 drops) were heated together at 100° for 10

hours. The product was taken up in ether and

washed with sodium bicarbonate and water. lifter

drying, the ether was distilled off and the

residual oil was poured into paraffin oil (150-

200 c.c.) at 270°. The tarry solid which was

deposited on cooling was separated from the

paraffin and washed with ligroin. It was treated

with 5N hydrochloric acid, and a little insoluble

yellow solid, which was soluble in water and

which gave a positive diazo test, was filtered

off. It was evidently the hydrochloride of

6 -% - 81-

6- methoxy-8- amino -quinoline. The filtrate was made alkaline with ammonia and the tarry solid which was deposited was crystallised from alcohol. m.p. 121°.

(Found: C, 65.3; H, 5.1. Cl 4Hi 403N2 requires

C, 65.1; H, 5.4%) .

The, compound is slightly soluble in cold

dilute sodium hydroxide, soluble in ,the hot. It gives a brown -green colour with ferric chloride solution. That this compound was in fact 6- methoxÿ-8- acetoacetylamino - quinoline was shown in

the following way.

6- methoxy -8- amino -quinoline (6 gm.) and ethyl acetoacetate (30 c.c.) were refluxed under

air condenser for 2 -3 hours. The liquid product was treated with petroleum ether. On standing

it solidified and was crystallised from alcohol. m.p. 120 -1 °. Mixed m.p. with previous product

120-1°. This compound gives the same brown -green

colour with ferric chloride.

Attempts to cyclise 6- methoxy -8- acetoacetylamino - guinoline

1. 6-methoxy-8-acetoacetylamino- quinoline

(2 gm.) was dissolved in 100% sulphuric acid

(2 c.c.) and the solution left to stand overnight

at room temperature. It was then heated at 100°

for/ -82

for an hour, and on dilution with water yellow hair -like crystals were deposited. These were recrystallised from water. m.p. 160-170°. The diazo test gave a positive result. That the

compound was the sulphate of 6- methoxy -8- amino-

quinoline was shown by treating this latter

compound with 20% sulphuric acid, when a compound which, when recrystallised from waters melted at

158 -170° was obtained, Mixed m.p. with previous product 159-169°.

The mother liquor from the sulphate deposited

a tarry material on addition of ammonia. It gave

a positive diazo reaction but no crystalline

'material could be obtained..

2. 6-imethoxy-8-acetoacetylamino-qúinoline

(1 gm.) was refluxed with phosphorus oxychloride

(5 c.c.) for 2 hours at 130 -140 °. After cooling,

excess phosphorus oxychloride was distilled off

in vacuo and the residue was diluted with water.

A small amount of tar was filtered off and the

filtrate made alkaline with ammonia. A brown

tarry solid was deposited which was not improved

by crystallisation from alcohol. No pure compound

could be isolated. -83-

4- hydroxy- quinaldine.

(Limpach. Ser. 1931, 64, 969) .

riniline (47 gm.), ethyl acetoacetate (65 gm.) and concentrate, hydrochloric acid (0.1 c.c.) were kept at 37° for 24 hours, and afterwards in a vacuum desiccator over sulphuric acid for a further

24 hours in order to remove water formed. The mixture was added slowly to paraffin at 270 °, which temperature was maintained till addition was complete. On cooling, the.dark brown oily deposit solidified to a hard brown mass. The paraffin was poured off and the solid washed thoroughly with petroleum ether. Yield of crude material, 80 gm. m.p. 210-225°. This was boiled in water and on cooling a white powdery material was deposited, m.p. 230 -232 °.

4- chl o ro- quinal dine .

4-hydroxy-quinaldine (73 gm.) was heated with a mixture of phosphorus pentachloride (95 gm.) and phosphorus oxychloride (250 c.c.) under air condenser on the oil bath at 110 -130° for 4 hours.

The excess oxychloride was distilled off under reduced pressure. The purplish residue was diluted with water, made alkaline with sodium hydroxide and steam distilled. The white solid obtained in the distillate was filtered and dried.

It/ -84--

It has a characteristic smell. m.p. 35 -9° (m.p. in the literature 42 °) . Yield 56 gm. (632 theory)

Nitration of 4- chloro -quinaldine.

4- chloro -quinaldine (45 gm.) was dissolved in 100% sulphuric acid (298 gm.), made by mixing oleum (202 gm., containing 10% free sulphur trioxide) and concentrated sulphuric acid (96 gm.), the solution being kept cold in a freezing mixture of ice and salt with mechanical stirring. Finely divided potassium nitrate (35 gm.) was added in small portions over a period of 2 hours. After standing overnight at room temperature, the reaction mixture was poured on to crushed ice and made alkaline with sodium hydroxide, the temperature being kept below zero by the simultaneous addition of more ice. The yellow precipitate was washed well and dried. It was then treated with 2N hydrochloric acid (200 c.c.), brought to boiling and immediately filtered from a small amount of insoluble material. The solution was diluted to twice its volume, and 4- chloro -8- nitro -quinaldine, which is soluble in hot 2N but insoluble in cold .

N hydrochloric acid was deposited as a yellow solid and recrystallised from alcohol. m.p. 111 -113 °.

Yield 12.5 gm.

(Found: C, 53.9; H, 2.9. Ci oH,O2N2Cl requires c, 53.9;/ -85-

C, 53.9; H, 3.1%).

4-chloro-8-nitBo-quinaldine recrystallises as yellow needles from alcohol, 50%acetic acid, and a mixture of benzene and petroleum ether. It is insoluble in cold water, slightly soluble in the hot. It is insoluble in sodium hydroxide, and insoluble in N/10 and N hydrochloric acid. It is partly soluble in 2 and 3N acid and completely soluble in 4 -10 N hydrochloric acid.

The N hydrochloric acid solution left behind after the 4- chloro -8- nitro- quinaldine had been filtered off contained various other products as described in Section III. It is not necessary to describe in detail again the isolation of these, which include 4- chloro -5- nitro- and 4- chloro - 6- nitro- quinaldines and also 4- hydroxy -8- nitro- quinaldine. This latter compound was isolated by making neutral with sodium hydroxide the N hydrochloric acid solution and crystallisation of the precipitate with benzene. It was deposited as yellow needles, which were chlorine -free. m.p.

234 -5 °. A mixed melting point with a sample of

4- hydroxy -8- nitro -quinaldine (m.p. 224 -9 °) obtained as described below by the hydrolysis of 4- methoxy-

8- nitro -quinaldine was found to be 226-233°.

(Found: C, 58.3; H, 4.3. Cl o Hs 0sN6t requires

C, 58.8; H, 3.9%).

4- hydroxy -8- nitro- quienaldine is soluble in hot water/ -86-

l water and is deposited on cooling. It is soluble in alcohol, dilute hydrochloric acid and dilute sodium hydroxide. -87-

4-h rd_ro-8-chloro-quinaldine

o- chloro -aniline (64.5 gm.), ethyl

acetoacetate (65 gm.) and concentrated hydrochloric

acid (0.1 c.c.) were kept at 37° for several lays

in a vacuum desiccator over concentrated sulphuric acid. The liquid was then poured into paraffin kept at 270 °. On cooling, the crystalline solid

formed was filtered, washed with petroleum ether and recrystallised from alcohol. m.p. 226-230°.

4:8- dichloro- Quinaldine.

4-hydroxy- 8- chl oro- quinal L-ine - phosphorus pentachloride (6.5 gm.) and p-inorus

oxychloride (25 c.c.) were heated on the oil path

at 160° for 2 hours, after which time excess

phosphorus 'oxychioride was distilled off in vacuum.

The residue was diluted with eater, made alkaline

with sodium hydroxide and steam distilled. The

white solid obtained in the distillate was filtered

off, and crystallise as colourless needles from

petroleum ether. me-D.

(Found: J, 56'.8; __, ./ :i ._ -k re 5.ií rels

C, 56.6; H, 3.3A).

The 4:8- dichloro -quin .ldine `h, -..:pared was

used to prove the formula of L_ ,r'a- -ntro-

quina.ldine, as discussed in the theoretical section. -88-

4- chloro -8- amino- quinaldine.

4- chloro -8- nitro- quinaldine (3 gm.) was dissolved with heating in alcohol (45 c.c.) in a stout bottle suitable for shaking and evacuation, and about 3 -4 c.c. of Raney Nickel catalyst sludge, as prepared by Albert and Ritchie (J. and Proc. Roy

Soc. N.S. Wales 74, 74, 1940) was added. The bottle was evacuated and filled with hydrogen from a Kipp apparatus. The bottle was then placed in an electric shaker, and with vigorous shaking taking place, hydrogen was led in from a container previously filled from the Kipp apparatus. The pressure behind the hydrogen was provided by water flowing in from a reservoir directly above the container, and the level of this water, as shown in an external capillary tube, provided a convenien method of measuring the volume of hydrogen used up.

The rate of absorption of hydrogen was regulated by controlling the rate of passage of bubbles through a short length of water contained i. a U- tube -between the container and the bottle. When absorption slowed down, the bottle was reheated and evacuated until no more hydrogen was absorbed. This was done three times, the time taken to obtain complete absorption being about 45 minutes, and the volume of hydrogen absorbed being 1.1 litres.

(Theoretical volume, 1 litre). On filtering off the catalyst, the solution was fóund to have been change d/ -80-

changed from a reddish orange to a dark greenish

.yellow. The alcohol was evaporated down to a

small volume and the grey crystals which separated

were crystallised as yellow plates from alcohol.

m.p. 108-110°. Yield 1.5 gm. (60; Theory) .

(Found: C, 62.0; H, 4.9. C1oHs aC1 requires

C, 62.3; H, 4.7A) .

The crystals of 4- chloro -8- :.mine- quinoline

crystals became tinged with red,, /.peeping. This

was thought to be due to internal condensation.

The copper wire test for chlorine gave a positive

result, as also did the diazo reaction.

4- chloro -8- amino= quinaldine is insoluble in

cold water, and slightly soluble in the hot. It is

slightly soluble in cold N hydrochloric acid,

soluble in the hot, and soluble in cold 10îi

hydrochloric acid. It is soluble in benzene,

acetone, ether and ligroin.

4:8-dichloro-ouinaldine from 4-chloro--am.ino-

quinaldine.

4-chloro-8-amino-quinaldine (0.5 gm. , wat er

(2.5 c.c.) , and concentrated" hydrochloric acid

(1 c.c.) were cooled in an ice and salt freezing

mixture, and a solution of sodium nitrite (0.25 ga'

in water (2 c.c.) was added slowly with stirring.

Nitrous acid was shown to be in excess by testing

with/ with potassium iodide- starch paper.

Cuprous chloride was meanwhile prepared by

boiling a mixture ofcupric chloride (0.15 g~i.) , water (0.15 c.c.), concentrated hydrochloric acid

(0.5 c.c.) anc. copper (0.07 gm.) until the copper went into solution. The white cuprous chloride was precipitated on cooling.

To the suspension of cuprous chloride so obtained the diazotised solution was added slowly with stirring in the cold. Nitrogen was given off with frothing. The mixture was allowed to regain normal temperature and heated gently on the steam bath to about 30°. When all frothing had ceased, the solution was made alkaline and steam distilled. The white solid obtained was filtered off and recrystallised several times from petroleum ether, m.p. 81-2°. Mixed m.p. with

4:8- dichloro -quinaldine (m.p. 84 -5 °), prepared from o- chloro -aniline as described before, was

83-4°.

Repeated crystallisations of the compound from petroleum ether failed to raise the melting point to 84 °, although the mixed melting point showed that it was, apart from a small amount of impurity, essentially the desired compound.

Skrau reaction on 4- chloro -8- amino -quinaldine.

4- chloro-8- amino- quinaldine (1.4- gm.) , glycerine/ -91-

glycerine (1.9 gm.), arsenic acid (0.9 gm.) and concentrated sulphuric acid (1.8 gm.) were boiled on the sand bath for 2 -3 hours. The diazo reaction gave a negative result. On dilution with water a considerable amount of a black tarry material was filtered off, and the filtrate made alkaline with sodium hydroxide. The brown precipitate formed was filtered off, and found to melt at 220 -250 °. The melting point was widely divergent from that (144-5 °) given by the chloro -compound prepared as described before (p.77) .

The compound obtained here could not be improved by crystallisation and no pure product was isolated.

4-methoxy-8-nitro7Iguinaldine .

Sodium (2 gm.) was dissolved in methyl alcohol

(100 c.c.) . 4- chloro -8- nitro -quinaldine (10 gm.) was added and the mixture refluxed on the steam bath for 1 -2 hours. Most of the methyl alcohol was evaporated off and the residue diluted with water. The solid precipitated was recrystallised as long colourless plates from alcohol, which gave a negative copper wire test for chlorine m.p.

129-130°. Yield 6.75 gm.

(Found: C, 60.7; H, 4.9. C,. i Hi 0 03Ii2 requires

C, 60.5; H, 4.6A).

4- methoxy -8- nitro -quinaldine is insoluble in

cold water and slightly soluble in the hot. It

is/ -CO

is soluble in N hydrochloric acid, insoluble in

N and lON sodium hydroxide. It is soluble in benzene, acetone-, and ether, insoluble in ligroin, c ól d and hot.

4 -hy_dr oxy- 8- nitro - quinal diné .

4- methoxy -8- nitro - quinaldine (0.5 gm.) and

5N hydrochloric acid (5 c.c.) were refluxed for about an hour. The solution was evaporated down almost to dryness and diluted with water. insoluble orange solid was obtained. m.p. 231-2°.

On recrystallisation from alcohol, however, the melting point of the yellow feathery solid obtained was lowered to 224-9°. The mixed melting point with a sample of the 4- hydroxy -8- nitr -a- quinaldine f(m.p. 234 -5 °) isolated in the nitration of 4- chloro- quinaldine was 226-233°.

When ammonia was added to the filtrate from the orange solid, a yellow solid was deposited. m.p. 122-6°. Mixed m.p. with 4- methoxy -8- nitro- quinaldine was 124-130 °, showing that some of the material was unchanged.

4- methoxy-8- amino- quinaldine. -93-

4- methoxy -8- amino -ouinaldine.

4- methoxy -8- nitro - quinal dine (6 gm.) was dissolved in alcohol (90 c.c.) in a suitable bottle, as described before in the reduction of 4- chloro -8- nitro -quinaldine, and Raney Nickel catalyst sludge in alcohol (8 -10 c.c.) was added. The bottle was warmed in the water bath to about 50°, evacuated, and twattached as before to the hydrogen supply.

When absorption fell, the bottle was reheated.

1.9 litres of hydrogen were required to complete absorption. Theoretical volume, 2 litres. The catalyst was filtered off and washed with alcohol.

The alcohol was evaporated down to small volume and the grey crystals which were deposited were recrystallised as pale brown prisms, from alcohol. m.p. 115-6°. Yield 3 gm. (60% Thoery) .

(Found: C, 68.9; H, 5.8. Cli Hi 2ON requires

C, 70.2; H, 6.4%).

4- methoxy -8- amino - quinal dine, which gives a positive diazo reaction is insoluble in cold water, slightly soluble in the hot. It is insoluble in N and lON sodium hydroxide, slightly soluble in hot N sodium hydroxide. It is slightly soluble in cold N hydrochloric acid and soluble in hot N and cold 10N hydrochloric acid.

It is soluble in benzene, acetone and ether, slightly soluble in cold ligroin, soluble in the hot. -94-

4-methoxy-8-acetylamino-quinaldine.

4 -me thoxy- 3- amino -quinaldine (0.3 gm.) was warmed with acetic anhydride (3 c.c.) in the water bath for a few minutes. On cooling, white crystalline needles were deposited, filtered off and washed with water. The filtrate was diluted with water to decompose acetic anhydride, made alkaline with ammonia, when more white solid was obtained. m.p. 144-6°. Yield 0.35 gm.

(Found: C, 67.2; H, 5.8. Ci 3 HL 40;4 Na requires

C, 67.8; H, 6.1%).

4- methoxy -8- acetylamino - quinaldine is insoluble in cold water, slightly soluble in the hot. It is insoluble in cold and hot N sodium hydroxide.

It is soluble in N hydrochloric acid, alcohol and benzene, slightly soluble in cold and soluble in hot ligroin.

Attempt to condense 4- methoxyy-8- amino -quinaldine with diethylaminoethyl chloride.

4- methoxy -8- amino - quinaldine (2 gm.) and diethylaminoethyl chloride hydrochloride (2 gm.) were heated at 120 -140° for 8 hours. The diazo test gave a negative result. The red brittle product was dissolved. in water, made alkaline with ammonia and extracted with ether. On distilling AT the ether. a yellow oil was obtained/ -95-

obtained. A yellow picrate was formed melting

indefinitely at 190 -210° with blackening.

Treatment of the oil with salicylic acid in ethereal solution yielded an oil which solidified

on prolonged standing. It was crystallised from alcohol as a canary yellow amorphous material. m.p. 213-3°, but the analysis figures were very unsatisfactory.

(round: C, 62.6; H, 4.7. C17H250N2. C7H603 requires C, 67.8; H, 7.3. C17H 50N3. 2C7H603 requires C, 66.1; H, 6.6. C1 7Hâ 50N3 3C7H603 requires C, 65.1; H, 6.1%).

Attempt to condense 4- chloro -8- nitro -quinaldine with diethylaminoethylamine.

4- chloro -8- nitro -quinaldine (1.2 gm.) and diethylaminoethylamine (0.64 gm.) were heated at 140 -150° for 5 hours, when the product gave a positive silver nitrate test for ionised chlorine.

Excess amine was removed by distillation in vacuo and the black tarry residue dissolved in 50 ¡L acetic acid. The dark brown solution was made

.alkaline with ammonia, when a black precipitate was formed. Extraction with ether gave a red- orange solution. The ether was distilled off leaving a brown oil, which on treatment with

3:5-dir tro- benzoic acid en alcoholic solution yielded/ -96-

yielded a sticky orange precipitate.

Crystallisation from alcohol gave a brown

precipitate which became sticky on exposure to

the air. All. attempts to obtain a crystalline

solid suitable for analysis failed.

o-phenanthroline.

(cf. E.P. 394416)

o- phenylene diamine (40 m.) was mixed with

69J sulphuric. acid (880 c.c.) and water (24 c.c.).

Glycerine (216 gm.) and 80ía arsenic acid (200 c.c.)

were added in that order and the mixture boiled under reflux for 2 -3 hours. After this time,

the appearance of frothing seemed to indicate

the completion of the reaction. As explained

'in Section IV the absence of the diazo reaction

could not be used to test for the end of the

reaction. The acid product, which had become black during heating, was diluted with its own volume of water and made alakline with ammonia.

On standing overnight the thin tarry deposit hardened slightly. It was separated by filtration and the filtrate extracted with benzene, to give a solution pale orange in colour. The tar' also was boiled with benzene several times under reflux until the extracts were colourless. This extract was deep red. The/ -97-

The two extracts were combined and shaken with charcoal, dried over anhydrous sodium sulphate, filtered and most of the benzene was distilled off. A pale brown solid separated, and after filtration more solid was obtained by distilling off more benzene. m.p. 99 -105 °. Yield 30 gm.

(50% Theory) . On recrystallisation from benzene and drying in the pistol the m.p. rose to 108-

112°. m.p. of o- phenanthroline, 117 °. m.p. of the monohydrate of o- phenanthroline, 102°.

o- phenanthroline is insoluble in cold water, soluble in the hot. It is soluble in N hydrochloric acid, and insoluble in N sodium hydroxide. It dissolves in cold ferrous sulphate solution to give a deep red colour due to the formation of the iron complex of the base. o- phenanthroline is soluble in alcohol, benzene and acetone in the cold. It is insoluble in cold ether and ligroin, difficultly soluble in the hot.

o-phenanthroline methiodide.

o- phenanthroline (6 gm.) was dissolved with slight warming in nitrobenzene (approx. 150 c.c.) and methyl iodide (5 c.c.) was added. The mixture was kept at 37° for 24 hours. The long yellow crystalline plates which separated were filtered/ -98-

filtered, and washed with benzene until free from nitrobenzene. More crystals were obtained by

treating the nitrobenzene solution with more methyl iodide (2 -3 c.c.) and standing again at

37° for 24 hours. The yellow compound was

crystallised from alcohol. m.p. 210 -3 °. Yield 8.5 gm. (94% Theory).

(Found: C, 48.8; H, 3.8; I, 40.2. C1QH3NN .

CH3I requires C, 48.4; H, 3.4; I, 39.4%).

o- phenanthroline mono -methiodide is soluble in water. It is almost completely soluble in cold

N hydrochloric acid, soluble in the hot and in cold

10N hydrochloric acid. It is insoluble in N and

1ON sodium hydroxide. It gives a white precipitate with silver nitrate in dilute nitric acid. It .gives no colour with ferrous sulphate solution. It is insoluble in benzene, cold and hot, slightly soluble in cold and warm acetone.

It is insoluble in ether and. ligroin, cold and hot.

1-methl-2-o-phenanthrolone

To a saturated solution of potassium ferricyanide

(7.3 gm.) in water were added alternately a.little at a time saturated solutions in water of sodium hydroxide and o- phenanthroline methiodide. (3 gm.) in the cold. Excess/ Excess sodium hydroxide was added till no further precipitation took place. The yellow precipitate which was deposited was filtered off, dried. and extracted with benzene by boiling under reflux until the extract was colourless. The extracts were coloured red with a green fluorescence. The filtrate from the yellow precipitate was evaporated to small volume on the steam bath and the pale pink residual solid was also extracted with benzene. The combined extracts were shaken with charcoal, filtered and dried over anhydrous sodium sulphate. On recovery of the benzene, a brown material was obtained. It was recrystallised from both water and benzene as rectangular plates, but it was found

difficult to rid the compound of the solvents, as

the analyses of .the samples obtained from the

respective crystallisations show.m.p. 123 -4 °.

Yield 1.5 gm.

(Crystallisation from water. Found: C, 72.6;

H, 5.4. CL 3Hi oON2 requires C, 74.3; H, 4.8.

CL 3 Hi o 0Na . µHa 0 requires C, 72.9; H, 4.92 Crystallisation from benzene. Found: C, 75.5;

H, 5.1. GL 3H4.001 requires C, 74.3; H, 4.8.

H, 5.0%) . Cl 3HL o ONa . Ñ-C6H6 requires C, 75.8;

1- methyl- 2- o- phenanthrolone is irisoluble

in N and lON sodium hydroxide. It is fairly

soluble in cold N hydrochloric acid and soluble

in/ -100-

in hot N and cold 1ON hydrochloric acid. It gives no colour with ferrous sulphate solution.

It is soluble in acetone, insoluble in cold and soluble in hot alcohol.

2-chloro-o-phenanthroline.

1- methyl -2 -o- phenanthrolone (6 gm.) was added to a mixture of phosphorus pentachloride (7.2 gm.) and phosphorus oxychloride (54 c.c.) and refluxed under air condenser on the oil bath for approximately 8 hours. After this time the solid material had gone into so] ii on. Excess phosphorus oxychloride was distilled off under reduced. pressure. Water in the presence of crushed ice was added to dissolve the residue and ammonia was added until alkaline. The pale brown prècirpitate which separated was filtered, washed well and crystallised from water as colourless needles. m.p. 129 -130 °. Mixed melting point with 1- methyl- 2- o- phenanthrolone 90 -105 °.

Yield 5 gm. (80% Theory) . The compound gave a positive test for chlorine.

(Found: N, 17.1. C sil7N2 Cl requires N, 16.6%) .

2- chloro -o- phenanthroline is soluble in N hydrochloric acid, insoluble in N sodium hydroxide. It is insoluble in cold water but dissolves in ferrous sulphate solution to give a deep yellow solution. It is soluble in alcohol/ -101 -

alcohol, benzene and ether.

2- piperidino-o- phenanthroline.

2- chloro -o- phenanthroline (1 gm.) and piperidine (0.5 ó .) were heated at 100° for

2 -3 hours, when the silver nitrate test for ionised chlorine gave a positive result. excess piperidine was distilled off in vacuo and the product dissolved in 4N acetic acid, made alkaline with ammonia and extracted with ether. The ether solution was then extracted wuth 4N acetic acid. The acid layer was separated off, made alkaline with ammonia and extracted again with ether. On recovery of the ether, an orange oil was obtained which was dissolved in alcohol and treated with an alcoholic solution of picric acid.

An orange solid was precipitated and crystallised three times from.alcohol as yellow rods. m.p.

213 -7 °.

(Found: C, 54.4; H, 4.2. CnHj 7N3 . C6H307N3.

HQ0 requires C, 54.1; H, 4.3) .

The picrate is insoluble in cold ',rater, slightly soluble in the hot. It is soluble'in benzene and acetone.

2-anilino-o-phenanthroline. -102-

2-anilino-o-phenanthroline.

2- chloro -o- phenanthroline (0.5 gm.) and aniline (0.5 c.c.) were heated at 100° for 2 hours, when the silver nitrate test for ionised

chlorine gave a positive result. The orange

oily product was diluted with water, made alkaline with sodium hydroxide and steam distilled to remove excess aniline. The pale brown solid which was left was filtered off. It gave a positive copper wire test for chlorine, which was persistent after three crystallisations from alcohol, but on

crystallising twice more from benzene this almost

disappeared. It was formed as colourless rods. m.p. 231 -3 °.

(Found: C, 79.4; H, 4.4. CL BHi sN3 requires

C, 79.7; H, 4.8%) .

2- anilino -o- phenanthroline is insoluble in cold and hot water. It is slightly soluble in cold N hydrochloric acid, but is soluble in the hot and in cold 5N hydrochloric acid. It is

insoluble in cold and hot Ind sodium hydroxide.

It is soluble in acetone. It is insoluble in cold ferrous sulphate solution, but on boiling the colour of the compound was changed from pale yellow to orange and it was partly soluble giving an orange solution.

2-dieth,ylaminoethylamino-o-phenanthroline . -103-

2- diethylaminoethylamino-o-phenanthroline.

2- chloro -o- phenanthroline (3 g:n.) and diethylaminoethylamine (2.5 gm.) were heated together at 140 -150° for 4 hours. Chlor re ions were shown to be present. Excess amine was removed in vacuo and the thick residual oil was dissolved in 2N acetic acid in which it formed a red solution with Veen fluorescence. After drying the ether extracts, the ether was distilled off and the base obtained as a thick orange oil. Alcoholic hydrogen bromide did not give any precipitate. A yellow picrate was formed from alcoholic solution. m.p. 177 -187 °.

When examined microscopically it appeared amorphous and could not be improved by crystallisation. The oily salicylate did not solidify on scratching and prolonged. standing.

The hydrochloride was formed as a pale yellow solid soluble in alcohol. It was washed with acetone, dried and found to melt at 230 -250° with softening at 60° and darkening at 170 °.

It was deliquescent on standing in the air. It was dissolved in N hydrochloric acid and a saturated aqueous solution of mercuric chloride added until no further precipitate was deposited.

This precipitate was recrystallised from N hydrochloric acid as bright yellow'leaflets. m.p. 225 -230° with softening at 2000.

(Found/ -104-

(Found: C, 31.4; H, 3.4; N, 8.0. c H22N4.

3HC1. HgC12. H2O requires C, 31.0; H, 3.9;

N, 8.1%).

The oily base was treated. in alcoholic solution with 3:5-dinitro-benzoic acid. The sält was formed as an orange oil which on scratching solidified almost immediately. It was recrysatllised twice from alcohol as long yellow rectangular plates. m.p. 190-192°. Yield from 3 gm. 2- chloro -o- phenanthroline, 5 gm.

(Found: C, 53.7; H, 4.4. Cl 8Ha2 N4. 2C7H406N2 requires C, 53.5; H, 4.2 %).

The 3:5- dinitro -benzoate is insoluble in cold water, difficultly soluble in the hot. It is sparingly soluble in cold and hot benzene, insoluble in cold acetone, slightly soluble in the hot. It is insoluble in cold and hot ether.

2- die th_yl aminopropylamino- o_phenanthrol ine .

2- chloro -o- phenanthroline (3 gm.) and diethylaminopropylamine (2.5 gm.) were heated at 150-160° for 3 -4 hours, at the end of which time the silver nitrate test for chloride ions gave a positive result. :excess amine was distilled off in vacuo, and the hard oily residue dissolved in 2N acetic acid to give a red solution. On making alkaline with ammonia a pale brown oily solid was deposited and extracted/ --105-

extracted with ether. The ether extracts were 0 yellow in colour with a green fluorescence.

After drying, the ether was removed by

distillation leaving a thick orange- brown oil.

The hydrobromide was formed as an oil by

treatment with alcoholic hydrogen bromide. It

solidified on scratching but the yellow solid

formed which was soluble in water was deliquescent

in the air.

A yellow picrate was formed which on

crystallisation twice from methyl ethyl retofe

melted at 198-203°.

(Found: C, 49.6; ii, 4.0. Cl9HQ4N4. 206E307 t3

requires C, 48.6; H, 3.9A). As tie analysis

figures for the picrate were not very

satisfactory attempts were made to obtain a more

suitable salt for purification.

Treatment of the oily base obtained from the

ether with alcoholic hydrogen chloride gave a

sticky material which formed a pale yellow solid

on scratching. This compound which was

presumably the hydrochloride was filtered off and

washed with acetone, but it deliquesced in the air.

' It was dissolved in N hydrochloric acid and a

saturated solution of mercuric chloride added. 4 The yellow solid deposited was crystallised twice

from N hydrochloric acid as yellow needles, m.p.

200 -210° , b'ut it did not give a satisfactory analysis./ -106-

analysis.

(Found: C, 27.8; H, 3.3; N, 8.3. 01 9H2 4 N4

2HgC12 requires C, 26.8; H, 2.2; N, 6.6jß.

Ci 9 H 41` 4 . HgC12 . Hg(OH)2. NH3 requires C, 27.5;

H, 3.5; N, 8.4%) .

The 3:5- dinitro- benzoate was formed from alcoholic solution as an orange oil which solidified on scratching and prolonged standing.

The solid was crystallised three times from alcohol. It formed long yellow rectangular prisms. m.p. 150 -2 °. From an experiment using

3 gm. 2- chloro -o- phenanthroline in which all the product was converted into this salt, the yield was 4 gm.

(Found: C, 53.8; H, 4.4. 019H2.0.4. 2C7H406N2 requires C, 54.0; H, 4.4%).

The 3:5- dinitro- benzoate is slightly soluble in cold water, soluble in the hot. It is insoluble in cold benzene, slightly soluble in the hot and insoluble in cold and warm ethér. It is slightly soluble in acetone in the cold, and soluble in the hot.

- (0C- methyl -t- diethylaminobutyla ino -ó- phenanthroline .

2-chloro-o-phenanthroline (3 gm.) and 04- methy1- 8- diethylaminobutylamine (3.4 gm.) were heated at 160 -170° for 5 -6 hours, when chloride ions/ -107-

ions were shown to be present. excess amine was removed by distillation in vacuo and the reddish -brown hard residual oil was dissolved in

2N acetic acid. The red solution which had a green fluorescence was made alkaline with ammonia and extracted with ether, to give' a dark orange solution with green fluorescence. On removal of the ether by distillation, the base was obtained as a red -brown oil.

A'yellow amorphous picrate was formed whose melting point, 130 -=155° with darkening at 115°, was not improved by crystallisation from alcohol.

The oil did not give a hydrob romide with alcoholic hydrogen bromide. On treatment with alcoholic hydrogen chloride a reddish -brown solution was obtained which yielded no deposit on addition of acetone. The alcoholic solution was evaporated

down to small volume in vacuo and the residue

diluted with N hydrochloric acid. On the addition

of a saturated solution of mercuric chloride a

sticky material was formed which solidified on standing for several days. The yellow -brown

solid was crystallised twice from 2N hydrochloric acid. It formed a pale yellow amorphous solid. m.p. 170-180°.

(Found: C, 36.6; H, 3.9; N, 7.7. Cai H4,8N4

2HC1. HgCl2 requires C, 37.1; H, 4.4; N, 8.2%).

The 3:5- dinitro- benzoate was deposited as an

oil/ -1o8-

oil which solidified on standing. It was

crystallised from alcohol, forming small yellow

needles. m.p. 157 -8 °. Yield from 3 gm. 2- chloro-

o- phenanthrol ine , 5 gin.

(Found: C, 54.1; H, 4.9. 021 H2 a '\T . 2C7 H40 6Na

H20 requires C, 54.0; H, ß-.9; } .

The 3:5- dinitro- benzoate is slightly soluble

in cold water, soluble in the hot. It is slightly

soluble in cold and hot benzene, slightly soluble

in cold and soluble in hot acetone. It is

insoluble in cold and warm ether.

Of the three yellow 3:5- dinitro- benzoates

prepared as described above, the 2-diethylamino-

ethylamino-o-phenanthroltne salt formed the largest

crystals, the other two bIling in a more finely

divided form. Their properties are similar, all

three salts being sparingly soluble in water and

in organic solvents. It is interesting to nótice

also that in each experiment the base gave a green

fluorescence in both ether and acetic acid.

4-amino ethyl crotonate.

(Duisberg A. 213, 171)

Ethyl acetoacetate (100 c.c.) and aqueous

ammonia (S.G. 0.88. 100c.c.) were shaken up

thoroughly together in a separating funnel. A

white emulsion separated out which later coagulated

to/ -102-

to form a pale yellow oil. This oil, which

formed the bottom layer, was run off, washed with water and dried in a vacuum desiccator over

sulphuric acid. It was then distilled, that fraction distilling between 100 -1100/20 mm. being collected. Yield 45 gm.

,thyl 2 : 6- dimethyl -4- chloro -nicotinate .

(Michaelis, Hanisch. B. 35, 3156) .

?.-amino ethyl crotonate (40 gm.) was

dissolved in dry benzene (110 c.c.) and phosphorus

oxychloride (46 c.c.) added. The mixture became turbid and on warming hydrogen chloride was given

off. The yellow mixture was refluxed on the oil bath for 45 minutes, during which time it became reddish -brown in colour and a fine yellow precipitate separated. After standing overnight, the mixture was poured on to crushed ice. On shaking well, to allow all the phosphorus oxychloride to react with water, heat was generated and the bottom aqueous layer was run off from the top benzene layer in a separating funnel and treated with a saturated aqueous -solution of sodium carbonate until alkaline to litmus. Steam distillation yielded an oily product which was extracted with ether. After drying, the ether was distilled off and the residue distilled, that fraction/ -110-

fraction distilling at 130 -150 ° /14 mm. being

retained. Yield 12.9 gm. The oil had a smell

resembling that of mice,' as described in the literature.

Hydrolysis of Ethyl 2: 6- dimethyl -4- chloro- nicotinate and condensation of the roduct with

2manisidine.

Ethyl 2 :6- dimethyl -4- chloro -nicotinate (2 gm.)

water (14 c.c.) and concentrated hydrochloric acid

(6 c.c.) were refluxed on the oil bath for 2 hours,

the colour of the solution changing from pale

yellow to orange. On evaporating to dryness, a brown viscous oil was obtained which was soluble

in water. It was deposited from aqueous solution by sodium acetate, and also by ammonia, in an

excess of which it was soluble, being deposited

again by acetic acid. The oil was left overnight

in a vacuum desiccator over sulphuric acid in the presence of potassium hydroxide 'As this oil,

which is presumably the hydrochloride of 2:6-

dimethyl-4- chloro- nicotinic acid, could not be

obtained in a crystalline form it was treated with

p- anisidine as follows: -

Potassium carbonate (2.6 gm.) , p- anisidine

(1.1 gm.), amyl alcohol (10 c.c.) and a trace of

copper bronze were added to the oil, and the mixture/ mixture refluxed under air condenser for 4 -5 hours

Steam distillation removzd excess amyl alcohol and

the purple residual solution was made slightly aci

with acetic acid. A dark grey material was

deposited and recrystallised from hot water as

colourless chlorine -free leaflets. m.p. 275 -7 °.

(Found: C, 66.1; H, 5.6. Ci 5Hi 603112 requires

C, 66.2; H, 5.9%(.

Condensation of :methyl 2:6-dimethfyl-4- chloro- nicotinate directl with .- anisidine.

1. Ethyl 2 : 6- dime thyl -4- chl or o -ni c of ina to

(3 gm.) , p- anisidine (1.6 gm.) and a trace of

copper bronze were warmed up slowly on the oil bath to 146 =150° and kept at this temperature for an hour, after which time the silver nitrate test for

ionised chlorine was positive. The solid product, which was formed with frothing after about half an hour, was boiled in water several times until solution was complete, and filtered hot. On cooling, a white material was deposited and recrystallised from alcohol. On evaporating down the aqueous filtrate to small volume, more material was obtained and also crystallised from alcohol.

It formed colourless leaflets. m.p. 273 -5 °.

Mixed m.p. with 2:6-dimethyl-4-(p-anisidino)- nicotinic acid (m.p. 275 °) obtained in previous experiment/ -112-

experiment, 274-5°. Yield 1.5 gm. (407 Theory) .

No trace of the expected ester could be found.

2:6- dimethyl- 4- (p- anisidino)- nicotinic acid is insoluble in cold water, soluble in the hot.

It is soluble in dilute and concentrated sodium carbonate solution. It is soluble in dilute sodium hydroxide but insoluble in concentrated sodium hydroxide and is precipitated from dilute sodium hydroxide by making neutral with acetic acid. It is slightly soluble in cold 50¡ glacial acetic acid, soluble on warming. It is insoluble in cold benzene and acetone, slightly soluble in the hot.

2. Ethyl 2:6- dimethyl -4- chloro- nicotinate

(1 gm.), p- anisidine (0.6 gm.) and a trace of copper bronze were heated at 100° for 5 hours.

The product, which gave a positive test for chloride ions, was diluted with water, made alkaline with sodium carbonate and steam distilled.

The residue was filtered hot, and on cooling a grey material was precipitated. It was recrystallised twice from alcohol as colourless needles. m.p. 88 -90 °.

(Found: C, 67.3; H, 6.6. C1 7 H2 o 03 N2 requires

C, 68.0; H, 6.6%).

The aqueous mother liquor from the grey material was evaporated down to small volume and the/ -113-

the solid deposited was crystallised from alcohol. m.p.272-4°. Mixed m.p. with 2:6- dimethyl -4-

(p- anisidino)- nicotinic acid, 273 -5 °.

Ethyl 2:6-dimethyl -4 -(p- anisidino) -nicotinate is insoluble in water, soluble on heating. It is soluble in dilute hydrochloric acid, insoluble in cold and hot sodium hydroxide. It is soluble in alcohol and benzene.

Cyclisation of 2:6-dimeth,yl-4-(p- anisidino)- nicotinic acid.

1. 2:6- dimethy1- 4- (p- anisidino)- nicotinic acid

(1 gm.) was ,distiolved in redistilled phosphorus oxychloride (8 c.c.) and refluxed for 2 hours. A greenish yellow material Was deposited. Excess phosphorus oxychioríde was distilled off in vacuo, and to the green residue were added ether, finely ground ice and a saturated solution of sodium carbonate until alkaline. On shaking well, the ether became dark red in colour and showed a purple fluorescence. Extraction was continued until the ether was colourless. After drying, the ether was takem off and the yellow residual solid recrystallised from alcohol as yellow triangular plates. m.p. 293 -7° The compound contained no chlorine. It was anáhysed and the figures were found to agree with the theoretical figures for

4- hydroxy -6- methoxy-2' : 6'- dimethyl -2:3, 41:3'- pyridoquinoline / T -114-

pyridoquinoline, instead of the 4- chloro -derivtive

(Found: C, 70.2; H1.5.2. C1 5Hy 402ND requires

C, 70.8; H, 5.5%) .

In an attempt to obtain the chloro -derivative,

a similar experiment was carried out with the

addition of phosphorus pentachloride (0.8 gm.) to

the above proportions of reactants. After

refluxing for 2 hours, the excess oxychloride was

removed in vacuo and the dark yellow residue

worked up in the same way as before, by making

alkaline with sodium carbonate in the presence of

ice and extracting with ether. The ether solution

which again showed an orange red colour with purple

fluorescence yielded, on distilling off the ether,

a yellow solid which on crystallisation from

alcohol, melted at 293 -5 °. Mixed m.p. with

previous .product 292-4°.

When it was realised that the chloro- compound

could not be obtained, the working up of the

product was carried out without the ether

extraction. The light brown precipitate deposited

on making alkaline with sodium carbonate was

filtered off and recrystallised from alcohol.

4- hydroxy- 6- methoxy- 2':6'- dimethyl -2:3,

pyridoquinoline is insoluble in cold water, but

soluble in hot wáter, giving a greenish- yellow

solution with a blue fluorescence. Its solutions

in hydrochloric acid and in sodium hydroxide show a/ -115-

a strong green fluorescence, more marked in the alkali than in the acid. An ammoniacal solution shows a faint green fluorescence. The compound is soluble in 10;ó glacial acetic acid giving a yellow solution with green fluorescence. The alcoholic and ethereal solutions are red in colour with a purple fluorescence.

Digestion of the compound with 41ß hydrochloric acid at 100° gave the hydrochloride insoluble in excess acid, m.p. 300 -310° with darkening, which by treating with sodium hydroxide yielded the original compound. m.p. 290-295 °.

Mixed m.p. 290-2950.

Digestion of the compound with 4W sodium hydroxide at 100° yielded the original compound on cooling. m.p. 283-290°. Mixed m.p. 285-292°.

4- hydroxy-6- methoxy -2' :6'- dimethyl -2 :3, 4':3?- pyridoquinoline is insoluble in cold and hot benzene, and soluble in hot nitrobenzene. It is insoluble in cold and hot sodium carbonate solution.

2. 4-hydroxy-6-methoxy-2' : 6'-dimethyl-2:3,

4':3'- pyridoquinoline (0.4 gm.), phosphorus oxychloride (2,5 c.c.) and phosphorus pentachloride il gm.) were heated at 100 -1109 for 4 hours on the oil bath, As the compound did not. go into solution, the mixture was heated at 130 -140° for

10/ 116-

10 hours, after which time the solution formed was dark brown with a little black deposit.

Excess oxychloride was distilled off in vacuo, and to the residue were added ether, ice and sodium carbonate solution. After shaking well, th4 ether was separated off and extraction continued until the ether, which showed no fluorescence, was no longer coloured orange. On distilling off the ether, an orange sticky material was obtained which was insoluble in hot water and in hot dilute hydrochloric acid. It would not crystallise well from alcohol or ligroin, and no pure compound could be' isolated.

3. ' 4-hydroxy-6-methoxy-2':6'-dimethyl-2:3,

4':3'-pyridoquinoline (1 gm.) was dissolved in dry redistilled nitrobenzene ..25 c.c.) and phosphorus oxychloride (6 c.c.) and phosphorus pentachloride (2 gm.) were added. The mixture was refluxed gently on the oil bath at 140 -150° for 4 hours.. The dark yellow solid which was deposited was filtered off and washed with benzene. m.p. 305 -315 °. Yield 0.75 gm. Mixed m.p. with

original compound (m.p. 293 °) , 260-290°. The copper wire test for chlorine was positive. This compound (0.25 gm.) was treated with N sodium hydroxide (2.5 c.c.) in the cold for 45. minutes.

The insoluble solid was filtered, washed and dried. m.p./ -117-

m.p. 275-285°. Mixed m.p. with 4-hydroxy-6-methoxy1-

2'; 6'- diinethyl -2:3, 4':3'- pyridoquiholine, 285-295°.

The copper wire test for chlorine was negative.

It Giculd seem that the compound melting at 305-

315° which separated was the hydrochloride of the original compound. The hydrochloride prepared by the direct action of hydrochloric acid on the 4- hydroxy- pyridoquinoline, as described above, melts at this temperature.

r -118-

VII . S UMMJlti.RY -119-

SUMMARY.

1. A survey is given of the literature dealing with antimalarial compounds, With some aspects of the relationship between activity and chemical structure. Special reference is made to work done on phenanthroline derivatives.

II. Various attempts have been made to synthesise hydroxy- and chloro- derivatives of o- phenanthroline from 8- amino- quinoline and its derivatives, but these did not yield very satisfactory results.

III The nitration of 4-chloro-quinaldine has been accomplished and a study of the various products of the reaction is given. The 8- nitro- derivative is the main product, but 4- chloro -6- nitro- quinaldine has also been isolated, and a further compound, m.p. 111 -113 °, probably 4- chloro-

5- nitro -quinaldine. 4- chloro -8-nitro -quinaldine has been successfully reduced to 4- chloro -8- amino- quinaldine, but no o- phenanthroline derivative

' s could be obtained when this compound was submitted to the Skraup reaction. Several 4:8- disubstituted quinaldines are described.

IV. -120-

IV. o- phenanthroline has been prepared in relatively good yields and with greater ease by use of a modified Skraup reaction on o- phenylene diamine. From it 2- chloro -o- phenanthroline has been synthesised, and by condensation of this compound with suitable bases a series of o- phenanthroline derivatives substituted in position

2 by basic side -chains has been obtained. These are best isolated as their salts with 3:5- dinitro- benzoic acid, which has been found to possess marked advantages over picric acid for this purpose.

V. - 4- hydroxy- C- methoxy- 2':6'- dimethyl -2 :3, 4':3' pyridoquinoline has been synthesised, but all attempts to prepare the 4- chloro- derivative have igt4§71 Unsuccessful.' Derivatives of 2:3, 4':3'- pyridoquinoline substituted by basic aide- chains in position 4 were therefore not obtained.